Risk reduction of cognitive decline and dementia: WHO guidelines

RISK REDUCTION OF COGNITIVE DECLINE AND DEMENTIA WHO GUIDELINES

iRISK REDUCTION OF COGNITIVE DECLINE AND DEMENTIA WHO GUIDELINES ii Risk reduction of cognitive decline and dementia: WHO guidelines Risk reduction of cognitive decline and dementia: WHO guidelines ISBN 978-92-4-155054-3 © World Health Organization 2019 Some rights reserved. This work is available under the Creative Commons Attribution-NonCommercial-ShareAlike 3.0 IGO licence (CC BY-NC-SA 3.0 IGO; https://creativecommons.org/licenses/by-nc-sa/3.0/igo). Under the terms of this licence, you may copy, redistribute and adapt the work for non-commercial purposes, provided the work is appropriately cited, as indicated below. In any use of this work, there should be no suggestion that WHO endorses any specific organization, products or services. The use of the WHO logo is not permitted. If you adapt the work, then you must license your work under the same or equivalent Creative Commons licence. 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The mention of specific companies or of certain manufacturers’ products does not imply that they are endorsed or recommended by WHO in preference to others of a similar nature that are not mentioned. Errors and omissions excepted, the names of proprietary products are distinguished by initial capital letters. All reasonable precautions have been taken by WHO to verify the information contained in this publication. However, the published material is being distributed without warranty of any kind, either expressed or implied. The responsibility for the interpretation and use of the material lies with the reader. In no event shall WHO be liable for damages arising from its use. Design and layout: Erica Lefstad Printed in France iii FOREWORD ........................................................... v ACKNOWLEDGEMENTS ................................... vi ACRONYMS .......................................................... viii EXECUTIVE SUMMARY .................................... x 1. INTRODUCTION ........................................ xiv 1.1 Background and rationale for these guidelines ..... 1 1.2 Related WHO guidelines and tools ......................... 3 1.3 Target audience .................................................... 4 1.4 Goals and objectives ............................................ 4 1.5 Guiding principles ................................................ 5 2. GUIDELINE DEVELOPMENT PROCESS ........................................................ 6 2.1 Guideline development group ............................... 7 2.2 Declarations of interest by the GDG members and external reviewers ......................................... 7 2.3 Collaboration with external partners ..................... 8 2.4 Identifying, appraising and synthesizing available evidence ................................................ 8 2.5 Decision-making during the GDG meeting .............. 10 2.6 Document preparation and peer review ................ 11 3. EVIDENCE AND RECOMMENDATIONS ............................. 12 3.1 Physical activity interventions ............................. 13 3.2 Tobacco cessation interventions .......................... 16 3.3 Nutritional interventions ..................................... 18 3.4 Interventions for alcohol use disorder .................. 22 3.5 Cognitive interventions ....................................... 25 3.6 Social activity ...................................................... 27 3.7 Weight management ........................................... 29 3.8 Management of hypertension .............................. 32 3.9 Management of diabetes ...................................... 35 3.10 Management of dyslipidaemia ............................. 38 3.11 Management of depression ................................. 40 3.12 Management of hearing loss ................................ 43 4. IMPLEMENTATION CONSIDER ATIONS ................................... 46 5. PUBLICATION, DISSEMINATION AND EVALUATION ................................... 48 5.1 Publication and dissemination ............................... 49 5.2 Monitoring and evaluation ..................................... 50 5.3 Implications for further research ............................ 50 5.4 Future review and update ...................................... 51 REFERENCES ...................................................... 52 ANNEX 1: GUIDELINE DEVELOPMENT GROUP MEMBERS ........................................... 60 ANNEX 2: ASSESSMENT OF CONFLICT OF INTEREST ....................................................... 62 ANNEX 3: SCOPING QUESTIONS ............... 67 ANNEX 4: EVIDENCE REVIEW METHODOLOGY ................................................ 72 WEB ANNEX: EVIDENCE PROFILES (WHO/MSD/MER/19.1); https://www.who.int/mental_health/neurology/dementia/ guidelines_risk_ reduction/en/index.html GLOSSARY ............................................................ 77 CONTE NTS iv Risk reduction of cognitive decline and dementia: WHO guidelines vFOREWORD Dementia is a rapidly growing public health problem affecting around 50 million people around the world. There are nearly 10 million new cases every year and this figure is set to triple by 2030. Dementia is a major cause of disability and dependency among older people and can devastate the lives of affected individuals, their carers and families. Additionally, the disease inflicts a heavy economic burden on societies as a whole, with the costs of caring for people with dementia estimated to rise to US$ 2 trillion annually by 2030. While there is no curative treatment for dementia, the proactive management of modifiable risk factors can delay or slow onset or progression of the disease. In May 2017, the Seventieth World Health Assembly endorsed a Global Action Plan on the Public Health Response to Dementia 2017–2025, urging Member States to develop, as soon as feasible, ambitious national responses to address this challenge. Dementia risk reduction is one of the seven action areas in the global action plan. These new WHO guidelines provide the knowledge base for health care providers, governments, policy-makers and other stakeholders to reduce the risks of cognitive decline and dementia through a public health approach. As many of the risk factors for dementia are shared with those of non- communicable diseases, the key recommendations can be effectively integrated into programmes for tobacco cessation, cardiovascular disease risk reduction and nutrition. I urge all stakeholders to make the best use of these recommendations to improve the lives of people with dementia, their carers and their families. Dr Ren Minghui Assistant Director-General for Universal Health Coverage/Communicable and Noncommunicable Diseases, World Health Organization vi Risk reduction of cognitive decline and dementia: WHO guidelines GUIDELINE DEVELOPMENT GROUP Chair: Martin Prince, King’s College, London, United Kingdom. Members: Charles Alessi, Public Health England, London, United Kingdom; Kaarin J Anstey, University of New South Wales, Sydney, Australia; Kimberly Ashby-Mitchell, Caribbean Public Health Agency, Port of Spain, Trinidad and Tobago; Adelina Comas- Herrera, London School of Economics, London, United Kingdom; Amit Dias, Department of Preventive and Social Medicine, Goa Medical College Bambolim, Goa, India; Cleusa P Ferri, Federal University of São Paulo, São Paulo, Brazil; Riadh Gouider, Razi Hospital, Faculty of Medicine, Tunis, Tunisia; Shinya Ishii, Ministry of Health, Labour and Welfare, Tokyo, Japan; Yves Joanette, Canadian Institutes of Health Research, Government of Canada; Joseph Kibachio, Ministry of Health, Nairobi, Kenya; Miia Kivipelto, Karolinska Institutet, Stockholm, Sweden; Shanthi Mendis, Colombo, Sri Lanka; Ayesha Motala, University of KwaZulu-Natal, Durban, South Africa; Ronald C Petersen, Mayo Clinic, Rochester, United States of America; Dorairaj Prabhakaran, Public Health Foundation of India, New Delhi, India; Suzana Shahar, Universiti Kebangsaan Malaysia, Selangor, Malaysia; Ameenah Bibi Mia Sorefan, Ministry of Health and Quality of Life, Quatre-Bornes, Mauritius; Kusumadewi Suharya (Dy), Alzheimer’s Disease International, Jakarta, Indonesia; Huali Wang, Dementia Care & Research Center, Peking University Institute of Mental Health, Beijing, China. Grade methodologist: Corrado Barbui, University of Verona, Italy. EXTERNAL REVIEW GROUP Abdullah Al Khatami, Ministry of Health, Saudi Arabia; Emiliano Albanese, Università della Svizzera italiana, Switzerland; Alistair Burns, University of Manchester, United Kingdom; Linda Clare, University of Exeter, United Kingdom; Jacqueline Dominguez, Institute for Dementia Care Asia, Quezon City, Philippines; Hillary Doxford, 3 Nations Dementia Working Group, United Kingdom; Maelënn Guerchet, Global Observatory for Ageing and Dementia Care, King’s College London, United Kingdom; Mariella Guerra, Institute of Memory, Depression and Related Disorders, Lima, Peru; Luis Miguel F Gutiérrez Robledo, Instituto Nacional de Geriatría, Institutos Nacionales de Salud de México, Mexico City, Mexico; Vladimir Hachinski, University of Western Ontario in London, Ontario, Canada; Qurat-ul Ain Khan, Aga Khan University Hospital, Karachi, Pakistan; Sebastian Koehler, Maastricht University, The Netherlands; Jae-hong Lee, University of Ulsan College of Medicine, Seoul, Republic of Korea; Gill Livingstone, University College London, United Kingdom; Jean Claude Mbanya, Doctoral School of Life Sciences, Health and Environment, University of Yaoundé I, Cameroon; James McKillop, service user group representative, United Kingdom; Elaine Rashbrook, Public Health England, United Kingdom; Rajat Ray, National Drug Dependence Treatment Centre, All India Institute of Medical Sciences, New Delhi, India; Helen Rochford Brennan, European Working Group of People with Dementia, Ireland; Andrew Sommerlad, University College London, United Kingdom; Kate Swaffer, Dementia Alliance International, Australia; Weili Xu, Karolinska Institutet, Finland. WHO GUIDELINE STEERING GROUP Overall coordination: Tarun Dua, Programme Manager, Department of Mental Health and Substance Abuse; Neerja Chowdhary, Technical Officer, Department of Mental Health and Substance Abuse. WHO headquarters members: Katthyana Aparicio Reyes, Department of Service Delivery and Safety; Islene Araujo de Carvalho, Department of Ageing and Life Course; Lubna Bhatti, Department of Prevention of Noncommunicable Diseases; Fiona Bull, Department of Prevention of Noncommunicable Diseases; Shelly Chadha, Department of Management of Noncommunicable Diseases, Disability, Violence and Injury Prevention; Alarcos Cieza, Department of Management of Noncommunicable Diseases, Disability, Violence and Injury Prevention; Stéfanie Fréel, Department of Mental Health and Substance Abuse; Maria Garcia Casal, Department of Nutrition for Health and Development; Angela Luzia Herscheid, ACK NOWLE DG E M E NTS viiAcknowledgements Department of Mental Health and Substance Abuse; Michal Herz, Department of Mental Health and Substance Abuse; Dzmitry Krupchanka, Department of Mental Health and Substance Abuse; Artin Mahdanian, Department of Mental Health and Substance Abuse; Shanthi Pal, Department of Essential Medicines and Health Products; Anne Margriet Pot, Department of Ageing and Life Course; Gojka Roglic, Department of Management of Noncommunicable Diseases, Disability, Violence and Injury Prevention; Katrin Seeher, Department of Mental Health and Substance Abuse. WHO regional office advisors: Nazneen Anwar, WHO Regional Office for South-East Asia; Dan Chisholm, WHO Regional Office for Europe; Devora Kestel, WHO Regional Office for the Americas; Sebastiana Da Gama Nkomo, WHO Regional Office for Africa; Khalid Saeed, WHO Regional Office for the Eastern Mediterranean; Martin Vandendyck, WHO Regional Office for the Western Pacific. WHO evidence review and synthesis teams: Mariagnese Barbera, University of Eastern Finland, Kuopio, Finland; Nicole A Ee, University of New South Wales, Sydney, Australia; Jenni Kumlala, Karolinska Institutet, Stockholm, Sweden; Ruth Peters, University of New South Wales, Sydney, Australia; Lidan Zheng, University of New South Wales, Sydney, Australia. FUNDING SOURCE Funds received from Public Health England, United Kingdom; Centers for Disease Control and Prevention, United States of America; and the WHO Core Voluntary Contributions Account were used for the development of these guidelines. viii Risk reduction of cognitive decline and dementia: WHO guidelines ACE angiotensin converting enzyme AD Alzheimer disease ADAS-cog Alzheimer Disease Assessment Scale-Cog ADL activities of daily living AHRQ Agency for Healthcare Research and Quality (United States of America) ARB angiotensin receptor blocker BMI body mass index CCB calcium channel blocker CI confidence interval CVRF cardiovascular risk factors CVD cardiovascular disease DALYs disability-adjusted life years DASH dietary approaches to stop hypertension DoI declaration of interest EMBASE Excerpta Medica dataBASE ERG external review group GDG guideline development group (WHO) GDP gross domestic product GRADE Grading of Recommendations Assessment, Development and Evaluation HIV human immunodeficiency virus IADL instrumental activities of daily living ICOPE Integrated Care for Older People (WHO) LMIC low- and middle-income countries MCI mild cognitive impairment MDRS Mattis Dementia Rating Scale MeSH Medical Subject Headings mhGAP Mental Health Gap Action Programme (WHO) MMSE Mini Mental State Examination NCDs noncommunicable diseases NIA National Institute on Aging (United States of America) NICE National Institute of Health and Care Excellence (United Kingdom) OR odds ratio ACRONYMS ixAcronyms PEN Package of Essential Noncommunicable Disease Interventions (WHO) PICO population, intervention, comparison, outcome PUFA polyunsaturated fatty acids RCT randomized controlled trial RR relative risk SMD standardized mean difference x Risk reduction of cognitive decline and dementia: WHO guidelines E XECUTIVE SUMMARY INTRODUCTION Dementia is a rapidly growing global public health problem. Worldwide, around 50 million people have dementia, with approximately 60% living in low- and middle-income countries (LMIC). Every year, there are nearly 10 million new cases. The total number of people with dementia is projected to reach 82 million in 2030 and 152 million in 2050. Dementia leads to increased costs for governments, communities, families and individuals, and to loss in productivity for economies. In 2015, the total global societal cost of dementia was estimated to be US$ 818 billion, equiv- alent to 1.1% of global gross domestic product (GDP). Crucially, while age is the strongest known risk factor for cognitive decline, dementia is not a natural or inevi- table consequence of ageing. Several recent studies have shown a relationship between the development of cognitive impairment and dementia with lifestyle- related risk factors, such as physical inactivity, tobacco use, unhealthy diets and harmful use of alcohol. Certain medical conditions are associated with an increased risk of developing dementia, including hypertension, diabetes, hypercholesterolemia, obesity and depression. Other potentially modifiable risk factors include social isolation and cognitive inactivity. The existence of potentially modifiable risk factors means that prevention of dementia is possible through a public health approach, including the implementation of key interventions that delay or slow cognitive decline or dementia. In May 2017, the Seventieth World Health Assembly endorsed the Global action plan on the public health response to dementia 2017–2025 (WHO, 2017a). The action plan includes seven strategic action areas and xiExecutive Summary dementia risk reduction is one of them. The action plan calls upon the WHO Secretariat to strengthen, share and disseminate an evidence base to support policy interventions for reducing potentially modifiable risk factors for dementia. This involves providing a database of available evidence on the prevalence of those risk factors and the impact of reducing them; and supporting the formulation and implementation of evidence-based, multisectoral interventions for reducing the risk of dementia. The risk reduction guidelines for cognitive decline and dementia are aligned with WHO’s mandate to provide evidence-based guidance for a public health response to dementia. GUIDELINE DEVELOPMENT METHODS The process of development of these guidelines followed the WHO handbook for guideline development and involved: 1. recruitment of the guideline development group (GDG); 2. declaration of interest by GDG members and peer reviewers; 3. scoping review to formulate questions and select outcomes; 4. identification, appraisal and synthesis of available evidence; 5. formulation of recommendations with inputs from a wide range of stakeholders; and 6. preparation of documents and plans for dissemination. The GDG, an international group of experts, provided input into the scope of the guidelines and assisted the steering group in developing the key questions. A total of 12 PICO (population, intervention, comparison and outcome) questions were developed. To address the PICO questions, a series of searches for systematic reviews was conducted and Grading of Recommendations Assessment, Development and Evaluation (GRADE) evidence profiles prepared. During a meeting at WHO headquarters in Geneva, 2–3 July 2018, the GDG discussed the evidence, sought clarifications and interpreted the findings in order to develop recommendations. The GDG considered the balance of benefit and harm of each intervention; values and preferences; costs and resource use; and other relevant practical issues for providers in LMIC. When making a strong recommendation, the GDG was confident that the desirable effects of the inter- vention outweigh any undesirable effects. When the GDG was uncertain about the balance between the desirable and undesirable effects, the GDG issued a conditional recommendation. Strong recommenda- tions imply that most individuals would want the intervention and should receive it, while conditional recommendations imply that different choices may be appropriate for individual patients and they may require assistance at arriving at management decisions. The GDG members reached a unanimous agreement on all the recommendations and ratings. xii Risk reduction of cognitive decline and dementia: WHO guidelines SUMMARY OF RECOMMENDATIONS Physical activity interventions Physical activity should be recommended to adults with normal cognition to reduce the risk of cognitive decline. Quality of evidence: moderate Strength of the recommendation: strong Physical activity may be recommended to adults with mild cognitive impairment to reduce the risk of cognitive decline. Quality of evidence: low Strength of the recommendation: conditional Tobacco cessation interventions Interventions for tobacco cessation should be offered to adults who use tobacco since they may reduce the risk of cognitive decline and dementia in addition to other health benefits. Quality of evidence: low Strength of the recommendation: strong Nutritional interventions The Mediterranean-like diet may be recommended to adults with normal cognition and mild cognitive impairment to reduce the risk of cognitive decline and/or dementia. Quality of evidence: moderate Strength of the recommendation: conditional A healthy, balanced diet should be recommended to all adults based on WHO recommendations on healthy diet. Quality of evidence: low to high (for different dietary components) Strength of the recommendation: conditional Vitamins B and E, polyunsaturated fatty acids and multi-complex supplementation should not be recommended to reduce the risk of cognitive decline and/or dementia. Quality of evidence: moderate Strength of the recommendation: strong Interventions for alcohol use disorder Interventions aimed at reducing or ceasing hazardous and harmful drinking should be offered to adults with normal cognition and mild cognitive impairment to reduce the risk of cognitive decline and/or dementia in addition to other health benefits. Quality of evidence: moderate (for observational evidence) Strength of the recommendation: conditional Cognitive interventions Cognitive training may be offered to older adults with normal cognition and with mild cognitive impairment to reduce the risk of cognitive decline and/or dementia. Quality of evidence: very low to low Strength of the recommendation: conditional Social activity There is insufficient evidence for social activity and reduction of risk of cognitive decline/dementia. Social participation and social support are strongly connected to good health and well- being throughout life and social inclusion should be supported over the life-course. xiiiExecutive Summary Weight management Interventions for mid-life overweight and/or obesity may be offered to reduce the risk of cognitive decline and/or dementia. Quality of evidence: low to moderate Strength of the recommendation: conditional Management of hypertension Management of hypertension should be offered to adults with hypertension according to existing WHO guidelines. Quality of evidence: low to high (for different interventions) Strength of the recommendation: strong Management of hypertension may be offered to adults with hypertension to reduce the risk of cognitive decline and/or dementia. Quality of evidence: very low (in relation to dementia outcomes) Strength of the recommendation: conditional Management of diabetes mellitus The management of diabetes in the form of medications and/or lifestyle interventions should be offered to adults with diabetes according to existing WHO guidelines. Quality of evidence: very low to moderate (for different interventions) Strength of the recommendation: strong The management of diabetes may be offered to adults with diabetes to reduce the risk of cognitive decline and/or dementia. Quality of evidence: very low Strength of the recommendation: conditional Management of dyslipidaemia Management of dyslipidaemia at mid-life may be offered to reduce the risk of cognitive decline and dementia. Quality of evidence: low Strength of the recommendation: conditional Management of depression There is currently insufficient evidence to recommend the use of antidepressant medicines for reducing the risk of cognitive decline and/or dementia. The management of depression in the form of antidepressants and/or psychological interventions should be provided to adults with depression according to existing WHO mhGAP guidelines. Management of hearing loss There is insufficient evidence to recommend use of hearing aids to reduce the risk of cognitive decline and/or dementia. Screening followed by provision of hearing aids should be offered to older people for timely identification and management of hearing loss as recommended in the WHO ICOPE guidelines. xiv Risk reduction of cognitive decline and dementia: WHO guidelines 1 INTRODUC TION 1Introduction 1.1 BACKGROUND AND RATIONALE FOR THESE GUIDELINES Dementia, a group of disorders characterized by a decline from a previously attained cognitive level that affects activities of daily living (ADL) and social functioning, poses one of the greatest global challenges for health and social care in the 21st century. In 2015, dementia affected 50 million people worldwide (or roughly 5% of the world’s elderly population, i.e. those above the age of 60 years). The number of people with dementia is expected to increase to 82 million in 2030 and 152 million by 2050 with the estimated proportion of the population aged 60 and over with dementia at a given time between 5 to 8% 1 because dementia rises exponentially during old age and the world’s population is ageing. These projections assume constant age- and sex-specific prevalence of dementia over time, and, accordingly, the steepest rises are expected especially in low- and middle- income countries (LMIC), where the demographic changes will be more marked. Dementia is a major cause of disability and dependency among older people worldwide, and it has a significant impact not only on individuals but also on carers, families, communities and societies. Dementia accounts for 11.9% of the years lived with disability due to a noncommunicable disease (NCD) worldwide. Dementia leads to increased costs for governments, communities, families and individuals, and to loss in productivity for economies. The annual global cost of dementia is estimated to be US$ 818 billion (OECD, 2015; WHO, 2017b). Nearly 85% of costs are related to family and social, rather than medical, care (GBD 2015 Neurological Disorders Collaborator Group, 2017). Most health systems are ill-equipped and under-resourced to respond to the current needs associated with dementia. Thus, societal ageing and the associated increases in dementia prevalence will likely have major health-service implications for the care of people with dementia and support for affected families. There are many different causes and types of demen- tia. Primary dementias include: dementia due to Alzheimer disease (AD), vascular dementia, dementia with Lewy bodies and frontotemporal dementia (in which the decline in cognitive abilities itself is mostly due to an underlying neurodegenera-tive process and not directly caused by other etiologies). Alzheimer disease is the most common, followed by vascular dementia and dementia with Lewy bodies. Mixed dementia with features of more than one type is also common, especially in older adults, while frontotemporal dementia is a less common form but relatively more frequent before old age. Secondary dementias are those caused by, or closely related to, some other recognizable disease, such as HIV, head injury, multiple sclerosis, thyroid disorders or vitamin B12 deficiency. In these secondary dementias, cognitive impairment is typically accompanied by symptoms and signs in other organ systems and the treatment focuses on management of the underlying disease. For the scope of these guidelines we refer to primary dementias. Though early treatment of some diseases may have the potential to prevent the onset of secondary dementias, we are not including these 1 WHO & King’s College London (2017). Global prevalence of dementia – updated figures 2017. Available at: https://www.who.int/news-room/fact-sheets/detail/dementia 2 Risk reduction of cognitive decline and dementia: WHO guidelines secondary dementias in the scope of these guidelines since there are prevention or appropriate management and treatment strategies for most of these specific diseases and conditions, which effectively reduce dementia-related signs and symptoms. However, late-onset dementia is a heterogeneous and multifactorial condition and some factors (i.e. head trauma, B12 deficiency earlier in life) may also contribute to the development of dementia later in life (not only secondary dementia). RISK FACTORS FOR DEMENTIA Non-modifiable risk factors for dementia include gene polymorphisms, age, gender, race/ethnicity and family history. Crucially, while age is the strongest known risk factor for cognitive decline, dementia is not a natural or inevitable consequence of ageing. During the last two decades, several studies have shown a relationship between the development of cognitive impairment and dementia with educational attainment, and lifestyle-related risk factors, such as physical inactivity, tobacco use, unhealthy diets and harmful use of alcohol. Further, certain medical conditions are associated with an increased risk of developing dementia, including hypertension, diabetes, hypercholesterolemia, obesity and depression. Other potentially modifiable risk factors may include social isolation and cognitive inactivity. The risk factors included in the scope of these guidelines were chosen based on recent systematic reviews and guidelines, i.e. National Institute of Health and Care Excellence (United Kingdom) (NICE, 2015); the United States of America Agency for Healthcare Research and Quality (AHRQ) systematic review (Kane et al., 2017); the World Alzheimer report 2014 (Prince, et al., 2014) and the report by the Lancet Commission on Dementia Prevention, Intervention, and Care (Livingston et al., 2017). The current focus on modifiable risk factors is justified by their potential to be targeted for prevention of dementia, and/or the delay of the progression of cognitive decline. NEED FOR THESE GUIDELINES The existence of potentially modifiable risk factors means that prevention of dementia is possible through a public health approach, including the implementation of key interventions that delay or slow cognitive decline or dementia. In May 2017, the Seventieth World Health Assembly endorsed the Global action plan on the public health response to dementia 2017–2025 (WHO, 2017a). The vision of the action plan is a world in which dementia is prevented and people with dementia and their carers live well and receive the care and support they need to fulfil their potential with dignity, respect, autonomy and equality. The goal of the action plan is to improve the lives of people with dementia, their carers and families, while decreasing the impact of dementia on them as well as on communities and countries. The action plan includes seven strategic action areas, and dementia risk reduction is one of them. The action plan calls upon the WHO Secretariat to strengthen, share and disseminate an evidence base to support policy interventions for reducing potentially modifiable risk factors for dementia. This involves providing a database of available evidence on the prevalence of those risk factors and the impact of reducing them; and supporting the formulation and implementation of evidence-based, multi-sectoral interventions for reducing the risk of dementia. These current guidelines represent the first steps to support countries as they develop approaches to delay or prevent the onset of dementia. 3Introduction The risk reduction guidelines for cognitive decline and dementia are aligned with WHO’s mandate to provide evidence-based guidance for a public health response to dementia. By supporting health and social care professionals, particularly by improving their capacity to provide evidence-based, multisectoral, gender and culturally appropriate interventions to the general population, including modifiable dementia risk factors that are shared with other NCDs, the risk of developing dementia can be potentially reduced, or its progression delayed. Thus, the guidelines align with WHO’s work in the area of prevention and management of NCDs, which aims to support countries to reduce the incidence, morbidity and mortality of NCDs. WHO has collaborated with a range of stakeholders, including international and national public health agencies working in the area of prevention of NCDs and dementia. The guidelines are in close conceptual and strategic synergy with other WHO action plans and strategies, i.e. the Comprehensive mental health action plan 2013– 2020,2 the Global action plan for the prevention and control of noncommunicable diseases 2013–2020,3 the Global strategy and action plan on ageing and health 2016–2020,4 the Global strategy to reduce harmful use of alcohol5 and the Global strategy on diet, physical activity and health.6 Furthermore, this work is aligned with the WHO move towards making health services more people-centred. Finally, the work will contribute to the attainment of Sustainable Development Goal 3, target 3.8, i.e. achieve universal health coverage, including financial risk protection, access to quality essential healthcare services and access to safe, effective, quality and affordable essential medicines and vaccines for all (UN, 2019). 1.2 RELATED WHO GUIDELINES AND TOOLS Several existing WHO guidelines and tools designed for the general population are relevant for addressing health conditions that may increase the risk of cognitive decline or dementia in individuals with normal cognition or mild cognitive impairment (MCI). The following WHO guidelines and tools were consulted when developing the current guidelines: • mhGAP Intervention guide – Version 2.0 for mental, neurological and substance use disorders in non- specialized health settings. Geneva: WHO, 2016. http://www.who.int/mental_health/mhgap/mhGAP_ intervention_guide_02/en/ • Prevention and control of noncommunicable diseases: guidelines for primary health care in low- resource settings. Geneva: WHO, 2012. http://apps. who.int/iris/bitstream/10665/76173/1/9789241548397_ eng.pdf • Package of essential noncommunicable (PEN) disease interventions for primary health care in low-resource settings. Geneva: WHO, 2010. http:// www.who.int/cardiovascular_diseases/publications/ pen2010/en/ • Global recommendations on physical activity for health. Geneva: WHO, 2010. http://www.who.int/ dietphysicalactivity/publications/9789241599979/en/ • Integrated care for older people (ICOPE): Recommendations on interventions to improve physical and mental capacities of older people at community level. Geneva: WHO, 2016. 2 Available at http://www.who.int/mental_health/action_plan_2013/en/ 3 Available at http://www.who.int/nmh/publications/ncd-action-plan/en/ 4 Available at http://who.int/ageing/global-strategy/en/ 5 Available at http://www.who.int/substance_abuse/activities/gsrhua/en/ 6 Available at http://www.who.int/dietphysicalactivity/Indicators%20English.pdf 4 Risk reduction of cognitive decline and dementia: WHO guidelines • HEARTS Technical package for cardiovascular disease management in primary health care: evidence-based treatment protocols. http://www. who.int/cardiovascular_diseases/hearts/en/ • Global age-friendly cities: a guide. Geneva: WHO, 2007. http://www.who.int/ageing/publications/Global_ age_friendly_cities_Guide_English.pdf • Recommendations on healthy diet. Geneva: WHO, 2019. http://www.who.int/en/news- room/fact-sheets/detail/healthy-diet • Strengthening health systems for treating tobacco dependence in primary care. Geneva: WHO, 2013. http://www.who.int/tobacco/publications/building_ capacity/training_package/treatingtobaccodependence/en/ • Framework on integrated people-centred health services. Geneva: WHO, 2016. http://apps.who.int/ gb/ebwha/pdf_files/WHA69/A69_39-en.pdf?ua=1 These existing WHO guidelines and tools address some of the interventions that are included in the scope of the current guidelines, but they do not include cognitive decline or dementia as outcomes. Where the current guidelines overlap with the other guidelines, e.g. ICOPE guidelines, which provide recommendations on cognitive interventions in people with MCI, we have referred to these existing recommendations, rather than developing new ones. The current guidelines, therefore, complement, but do not duplicate, existing work. 1.3 TARGET AUDIENCE The guidelines are primarily targeted at health care providers working at a first or second level facility or at district level, including basic outpatient and inpatient services. The health care providers could be doctors, nurses or other cadres of health workers. Quality improvement teams at all levels of the system will benefit from the work. In addition, the guidelines and their derivative products have implications for policy-makers, health care planners and programme managers at national and international level, as well as the general population. 1.4 GOALS AND OBJECTIVES • To provide evidence-based recommendations on lifestyle behaviours and interventions to delay or prevent cognitive decline and dementia in the general population. • To provide evidence-based recommendations on management of specific physical and mental health conditions to delay or prevent cognitive decline and dementia. 5Introduction These guidelines provide up-to-date WHO evidence- based recommendations to facilitate implementing the Global action plan on the public health response to dementia 2017–2025, the Comprehensive mental health action plan 2013–2020 and WHO’s Mental Health Gap Action Programme (mhGAP),7 the Global action plan for the prevention and control of noncommunicable diseases 2013–2020,8 the Global strategy and action plan on ageing and health 2016–2020,9 the Global strategy to reduce harmful use of alcohol,10 and the Global strategy on diet, physical activity and health.11 1.5 GUIDING PRINCIPLES The following principles have informed the development of these guidelines and should guide their implementation: • The guidelines should expedite the achievement of the goals outlined in the Global action plan on the public health response to dementia 2017–2025, as well as target 3.4 of the Sustainable Development Goals, which focuses on reducing the premature mortality from NCDs and the promotion of mental health and well-being (UN, 2019). • The process of developing these guidelines, and their subsequent implementation, should concretely foster the right to equal levels of health for people at risk of cognitive decline and dementia and promote their active involvement. • The recommendations should be implemented with accompanying efforts to safeguard the human rights of persons living with cognitive decline and dementia, including reduction of stigma and discrimination, reducing barriers to seek health and social care services, and ensuring informed decision-making in treatment choices. Implementation of the recommendations should be tailored to the local context, including the availability of financial and human resources. However, the inequities addressed in these guidelines are common across all countries, and should be made a priority in health services. 7 Available at http://www.who.int/mental_health/action_plan_2013/en/ 8 Available at http://www.who.int/nmh/publications/ncd-action-plan/en/ 9 Available at http://who.int/ageing/global-strategy/en/ 10 Available at http://www.who.int/substance_abuse/activities/gsrhua/en/ 11 Available at http://www.who.int/dietphysicalactivity/Indicators%20English.pdf 6 Risk reduction of cognitive decline and dementia: WHO guidelines GUIDE LINE DEVE LOPME NT PROCESS 2 7Guideline development process The process of developing these guidelines followed the WHO Handbook for guideline development (2nd edition, http://apps.who.int/ medicinedocs/en/m/abstract/Js22083en/). It consisted of the following steps. 2.1 GUIDELINE DEVELOPMENT GROUP A WHO guideline steering group, led by the Department of Mental Health and Substance Abuse, was established with representatives from WHO regional offices and relevant WHO departments and programmes. The guideline steering group provided overall support to the guideline development process. Two additional groups were established: a guideline development group (GDG) and an external review group (ERG). The GDG included a panel of academicians and clinicians with multidisciplinary expertise on the conditions covered by the guidelines. Consideration was given to geographic diversity and gender balance (see Annex 1). As a respected researcher in the field, the Chairperson was selected for their extensive experience of guideline development methodology, and their participation in other guideline development groups. Each potential GDG member was asked to complete the WHO declaration of interest (DoI) form. These were reviewed by the steering group. 2.2 DECLARATIONS OF INTEREST BY THE GDG MEMBERS AND EXTERNAL REVIEWERS All GDG members, peer reviewers and systematic review team members were requested to complete the DoI prior to the evidence review process for guideline development. Invitations to participate in the GDG meeting were sent only after the DoI had been reviewed and approved. The GDG members were also required to complete a confidentiality undertaking. Once received, the WHO Secretariat reviewed the DoIs, as well as additional information (internet and bibliographic database search), and evaluated if there were any conflicts of interest and if so, whether these required a management plan. The group composition was finalized after this process. The names and brief biographies of the members being considered for participation in the GDG were disclosed for public notice and comment prior to the meeting. At the beginning of the GDG meeting, the DoI of each GDG member were presented and GDG members, as well as external partners, were asked to update their DoI with relevant changes by notifying the WHO Secretariat. Declarations of interest were reassessed for potential conflict before the face-to-face meeting in Geneva. None of the members had major conflicts of interest. All decisions were documented (see Annex 2). 8 Risk reduction of cognitive decline and dementia: WHO guidelines 2.3 COLLABORATION WITH EXTERNAL PARTNERS The Center for Alzheimer Research at the Karolinska Institutet, Stockholm, Sweden, and the School of Psychology at the University of New South Wales and Neuroscience Research, Australia, supported the development of the guidelines by conducting the evidence review and synthesis. 2.4 IDENTIFYING, APPRAISING AND SYNTHESIZING AVAILABLE EVIDENCE The procedure of the scoping review to identify the draft population, intervention, comparison, outcome (PICO) questions consisted of the identification of potentially modifiable risk factors and interventions for cognitive decline or dementia. These interventions are summarized in existing WHO guidelines listed earlier, such as the Prevention and control of noncommunicable diseases; Package of essential noncommunicable (PEN) disease interventions for primary health care in low-resource settings; and Integrated care for older people (ICOPE) guidelines. These guidelines, however, do not include cognitive decline or dementia as outcomes. Among recent summary reports, the Lancet Commission on Dementia Prevention, Intervention, and Care report summarizes the emerging knowledge on dementia risk factors and interventions (Livingston et al., 2017). The risk factors and interventions reported in this set of systematic reviews included education, exercise, maintaining social engagement, reducing smoking, and management of hearing loss, depression, hypertension, diabetes and obesity. Another systematic review requested and supported by the National Institute on Aging (NIA) at the National Institutes of Health, United States of America, also identified risk factors and evidence for interventions, specifically cognitive training, blood pressure management and exercise (Kane et al., 2017). The interventions reported in these reviews have formed the basis of the interventions included in the PICO questions. The population in these guidelines considered adults with normal cognition as well as those with MCI. We use the term MCI to refer to a disorder characterized by impairment of memory, learning difficulties and reduced ability to concentrate on a task for more than brief periods, beyond what is expected in normal ageing. There is often a marked feeling of mental fatigue when mental tasks are attempted, and new learning is found to be subjectively difficult even when objectively successful. None of these symptoms is so severe that a diagnosis of dementia can be made. Individuals diagnosed with MCI, however, are at greater risk of developing dementia; the inclusion of adults with MCI in these guidelines will enable the use of interventions to slow the progression of cognitive decline, i.e. the transition from MCI to dementia itself. 9The scope of these guidelines is prevention/risk reduction of cognitive decline or dementia (main outcomes of interest). Cognitive decline is defined as a noticeable and measurable loss or abnormality in attention functions, memory functions or higher level cognitive functions (including attention, language and reasoning). Dementia is a syndrome that includes cognitive decline and other symptoms and can be diagnosed based on ICD-10 criteria. It involves a decline in memory with impairment of at least one other cognitive function, such as skilled movements (limb apraxia), language (aphasia) or executive function (e.g. planning, attention and abstract reasoning). This decline should represent a change from previous behaviour, and impair social and/or occupational functioning. As stated in the background section, when we use the word dementia in this document, we are referring to the primary or neurodegenerative dementias. The GDG provided input into the scope of the guidelines and assisted the steering group in developing the key questions. Twelve PICO-structured questions were developed (Annex 3). Outcomes were rated by GDG members according to their importance, as “critical”, “important” or “unimportant”. Those outcomes rated as critical and important were selected for inclusion into the PICO. Regular communication and discussions with the GDG were held by email and teleconferences, respectively. The systematic review team developed protocols to review the evidence that existed for the inter- ventions to reduce the risk of cognitive decline and/ or dementia (as outlined in the PICO questions) for adults with normal cognition or MCI (Annex 4). Existing relevant systematic reviews were identified for each of the PICO questions. The steering group assessed the quality of existing reviews using the assessment of multiple systematic reviews (AMSTAR) checklist. Systematic reviews found to be of high quality were also assessed for timeliness to ensure that the most current evidence was used. The Grading of Recommendations Assessment, Development and Evaluation (GRADE) methodology (Guyatt et al., 2011), as well as the WHO Handbook for guideline development, were used to develop the evidence profiles. The quality assessment of the evidence was performed according to GRADE considering study design – randomized controlled trials (RCT) or observational studies, risk of bias, inconsistency, indirectness, imprecision and risk of reporting bias. Evidence was characterized as either high, moderate, low or very low. Guideline development process 10 Risk reduction of cognitive decline and dementia: WHO guidelines 2.5 DECISION-MAKING DURING THE GDG MEETING The GDG met at the WHO headquarters in Geneva, 2–3 July 2018. The evidence review was sent out in advance and it was summarized in a presentation during the meeting. The GDG members discussed the evidence, clarified points and interpreted the findings in order to develop recommendations based on the draft prepared by the WHO Secretariat. The GDG considered the relevance of the recommendations for adults with normal cognition or MCI based on the GRADE Evidence-to-Decision (EtD) framework (Alonso-Coello et al., 2016), considering the balance of benefit and harm of each intervention; values and preferences of the individuals involved; costs and resource use; acceptability of the intervention to health care providers in LMIC; feasibility of implementation; and impact on equity and human rights. No surveys or formal cost-effectiveness studies to determine resource constraints were conducted but discussions of these domains were informed by the combined expertise and experience of the GDG members. Equity and human rights were considered by specifically searching databases that include studies from LMIC, examining data for disaggregation for specific subgroups. Potential differential effects of the interventions on different subgroups of people related to economic status, employment or occupation, education, place of residence, gender or ethnicity were considered by the GDG. Taking into account these considerations, when making a strong recommendation, the GDG was confident that the desirable effects of the intervention outweigh any undesirable effects. When the GDG was uncertain about the balance between the desirable and undesirable effects, the GDG issued a conditional recommendation. Strong recommendations imply that most individuals would want the intervention and should receive it, while conditional recommendations imply that different choices may be appropriate for individual patients and they may require assistance at arriving at management decisions. In some instances, even when the quality of evidence was low or very low, it was agreed that if the recommendation would be of general benefit, and this was seen to outweigh the harms, it may still be rated as strong. In the event of a disagreement, the Chair and the Methodologist would ascertain whether the dispute was related to the interpretation of the data or to the way that the recommendation was formulated. If a consensus agreement was not reached, the GDG members agreed to a majority vote of 70%, to determine a decision. WHO staff members present at the meeting, as well as other external technical experts involved in the collection and review of the evidence, were excluded from voting. The GDG members reached a consensus agreement on all recommendations and ratings and voting was not needed. 11 2.6 DOCUMENT PREPARATION AND PEER REVIEW The draft guideline and evidence profiles prepared by WHO staff and the GDG were circulated to the ERG and the steering group. The role of the ERG was to identify any errors or missing data and to comment on clarity, setting-specific issues and implications for implementation rather than changing the recommen- dations. All inputs and remarks were discussed and agreed with the GDG by email. 12 Risk reduction of cognitive decline and dementia: WHO guidelines This section provides an overview of each PICO question described under the following headings: background; recommendations and additional considerations; supporting evidence for the recommendations and the rationale for the recommendations based on the evidence synthesized as well as criteria listed in the EtD tables. Complete evidence profiles for each PICO question including the GRADE tables and the EtD tables are included in the Web Annex. EVIDE NCE AND RECOMME NDATIONS 3 13Evidence and recommendations Population: Adults (age above 18 years) with normal cognition or MCI Intervention: Physical activity interventions (aerobic, resistance training or multicomponent physical activity) Comparison: Care as usual or no intervention Outcomes: • Critical – Cognitive function – Incident MCI – Dementia • Important – Quality of life – Functional level (ADL, IADL) – Adverse events – Drop-out rates For adults with normal cognition or MCI, are physical activity interventions more effective than usual care or no intervention in reducing the risk of cognitive decline and/or dementia? 3.1 PHYSICAL ACTIVITY INTERVENTIONS BACKGROUND A physically active lifestyle is linked to brain health. In large observational studies with follow-up periods extending decades, physically active people seem less likely to develop cognitive decline, all-cause dementia, vascular dementia and Alzheimer disease when compared with inactive people (Gallaway et al., 2017; Hamer & Chida, 2009; Sofi et al., 2011; Stephen et al., 2017). Especially, the highest levels of physical exercise seem to be most protective (Hamer & Chida, 2009; Sofi et al., 2011). Physical activity seems to have beneficial effects on brain structures, which may underlie this association (Rovio et al., 2010). Other potential mechanisms underlying the association are most likely indirect, such as the positive effects of physical exercise on other modifiable cardiovascular risk factors (CVRFs), including hypertension, insulin resistance and high cholesterol levels as well as other biological mechanisms, including but not limited to enhancing the immune system function, anti-inflammatory properties, and increasing neurotrophic factors. Physical activity interventions are described in WHO’s Global recommendations on physical activity for health (2010). RECOMMENDATIONS AND CONSIDERATIONS RECOMMENDATION 1: Physical activity should be recommended to adults with normal cognition to reduce the risk of cognitive decline. Quality of evidence: moderate Strength of the recommendation: strong 14 Risk reduction of cognitive decline and dementia: WHO guidelines RECOMMENDATION 2: Physical activity may be recommended to adults with MCI to reduce the risk of cognitive decline. Quality of evidence: low Strength of the recommendation: conditional WHO’s Global recommendations on physical activity for health (2010) (http://www.who.int/dietphysicalactivity/publications/9789241599979/en/) Below is an extract from these recommendations for adults 65 years and above: For adults 65 years and above, physical activity includes recreational or leisure-time physical activity, transportation (e.g. walking or cycling), occupational (if the person is still engaged in work), household chores, play, games, sports or planned exercise, in the context of daily, family, and community activities. In order to improve cardiorespiratory and muscular fitness, bone and functional health, and reduce the risk of NCDs, depression and cognitive decline, the following are recommended: 1. Adults aged 65 years and above should do at least 150 minutes of moderate-intensity aerobic physical activity throughout the week, or do at least 75 minutes of vigorous-intensity aerobic physical activity throughout the week, or an equivalent combination of moderate- and vigorous-intensity activity. 2. Aerobic activity should be performed in bouts of at least 10 minutes’ duration. 3. For additional health benefits, adults aged 65 years and above should increase their moderate- intensity aerobic physical activity to 300 minutes per week, or engage in 150 minutes of vigorous-intensity aerobic physical activity per week, or an equivalent combination of moderate- and vigorous-intensity activity. 4. Adults of this age group with poor mobility should perform physical activity to enhance balance and prevent falls on 3 or more days per week. 5. Muscle-strengthening activities should be done involving major muscle groups, on 2 or more days per week. 6. When adults of this age group cannot do the recommended amounts of physical activity due to health conditions, they should be as physically active as their abilities and conditions allow. Overall, across all the age groups, the benefits of implementing the above recommendations, and of being physically active, outweigh the harms. At the recommended level of 150 minutes per week of moderate-intensity activity, musculoskeletal injury rates appear to be uncommon. In a population- based approach, in order to decrease the risks of musculoskeletal injuries, it would be appropriate to encourage a moderate start with gradual progress to higher levels of physical activity. 15Evidence and recommendations Additional considerations include: • Physical activity is easily available for everybody and has a large range of beneficial effects. • Aerobic activity plays a key role in the beneficial effect of physical activity. SUPPORTING EVIDENCE AND RATIONALE For physical activity interventions (e.g. aerobic, resistance training or multicomponent physical activity) compared with usual care or no intervention, four systematic reviews were identified for six different physical activity interventions (Barha et al., 2017; Barreto et al., 2017; Northey et al., 2018; Song et al., 2018). These were: 1. Aerobic exercise intervention versus usual care or no intervention in adults with normal cognition. 2. Training exercise intervention versus usual care or no intervention in adults with normal cognition. 3. Multimodal exercise intervention versus usual care or no intervention in adults with normal cognition. 4. Aerobic exercise intervention versus usual care or no intervention in adults with MCI. 5. Training exercise intervention versus usual care or no intervention in adults with MCI. 6. Multimodal exercise intervention versus usual care or no intervention in adults with MCI. For cognitive outcomes in healthy adults, there is moderate quality evidence which indicates that physical activity interventions have a positive effect on cognition. There is low to moderate quality evidence that suggests that physical activity does not affect risk of MCI and dementia. For cognitive outcomes in adults with MCI, there is low quality evidence that indicates that physical activity interventions have a positive effect on cognition. However, these benefits are not consistent across all cognitive domains. The evidence shows that the effect size is larger for aerobic training versus resistance training and there is stronger evidence for adults with normal cognition (especially aerobic training) than in adults with MCI. The GDG concluded that the desirable effects of physical activity outweighed the undesirable effects. Overall, low to moderate quality evidence has shown that physical activity has a small but beneficial effect on cognition. Even in MCI populations, low quality evidence suggests cognitive benefits of physical exercise. The effect of these interventions seems to be mostly due to aerobic exercise. Based on the quality of evidence, a strong recommendation was made for healthy adults and a conditional one for adults with MCI. 16 Risk reduction of cognitive decline and dementia: WHO guidelines Population: Adults with normal cognition or MCI who use tobacco Intervention: Interventions for tobacco cessation (behavioural interventions and pharmacological interventions including nicotine replacement therapy, bupropion, varenicline) Comparison: Care as usual or no intervention Outcomes: • Critical – Cognitive function – Incident MCI – Dementia • Important – Quality of life – Functional level (ADL, IADL) – Adverse events – Drop-out rates For adults with normal cognition or MCI who use tobacco, are interventions for tobacco cessation more effective than usual care or no intervention in reducing the risk of cognitive decline and/or dementia? 3.2 TOBACCO CESSATION INTERVENTIONS BACKGROUND Tobacco dependence is the leading cause of preventable death globally, causing an estimated 5 million deaths per year (WHO, 2011) and worldwide medical costs ranging in billions of US dollars (Lightwood et al., 2000). Tobacco is the major risk factor for a number of conditions, including many types of cancers, cardiovascular diseases (CVDs) and risk factors, and respiratory disorders (US Department of Health Human Services, 2004), and tobacco cessation has been demonstrated to significantly reduce these health risks (Pirie et al., 2013). Tobacco cessation has also been associated with reduced depression, anxiety and stress, and improved mood and quality of life compared with continuing to smoke (Taylor et al., 2014). Tobacco dependence is also associated with other disorders and age-related conditions, such as frailty and work ability in older people (Amorim et al., 2014; Kojima et al., 2015), as well as dementia and cognitive decline (Durazzo et al., 2014). Interventions to treat tobacco dependence can be very diverse, based on either or both behavioural/ psychological strategies and various pharmacological treatments. Non-pharmacological interventions can have mixed results (Niaura, 2008). Counselling is the most frequently used approach, but others have also been explored, such as mindfulness-based approaches, cognitive behavioural therapy, behavioural activation therapy, motivational interviewing, contingency manage- ment, and exposure and/or aversion to smoking. Among the pharmacological therapies for tobacco cessation, nicotine replacement therapy, bupropion and varenicline are the most common, but low overall treatment efficacy and adverse effects are key limitations (Gómez-Coronado et al., 2018). Combinations of non-pharmacological and pharmacological approaches seem to be the most effective in supporting tobacco cessation (Gómez- Coronado et al., 2018). 17Evidence and recommendations Additional considerations include: • In keeping with interventions described in the WHO training package for tobacco dependence, people who make use of tobacco should be advised to quit and the appropriate programmes aimed at preventing tobacco use uptake, promoting tobacco cessation, as well as diagnosing and treating tobacco dependence, should be established (http://www.who.int/ tobacco/publications/building_capacity/training_ package/treatingtobaccodependence/en/). The interventions include behavioural interventions, as well as pharmacological ones (i.e. nicotine replacement therapy, bupropion, varenicline). • Individual level interventions should be provided in the context of population level tobacco cessation programmes. SUPPORTING EVIDENCE AND RATIONALE No systematic reviews comparing tobacco cessation interventions with no intervention were identified. A large body of observational evidence is available on tobacco smoking as a risk factor for cognitive impairment and dementia. These studies show an association between tobacco smoking (including in mid-life) and dementia, or cognitive decline, in later life (Beydoun et al., 2014; Di Marco et al., 2014; Lafortune et al., 2016; North et al., 2015; Xu et al., 2015; Zhong et al., 2015). Only limited adverse events have been reported and only for pharmacological interventions (Motooka et al., 2018). Therefore, any type of intervention aimed at tobacco cessation is likely to be more beneficial than detrimental. The GDG made a strong recommendation although evidence from experimental intervention trials is not available, since tobacco use has substantial established harm and the epidemiological/ observational evidence on tobacco use and increased risk of dementia fulfils most of the Bradford-Hill’s criteria for causation (Lafortune et al., 2016). The evidence is strong, the population attributable risk is high, reproducible in different settings and with different study designs, specific, and indicates a dose- response effect. In addition, criteria such as temporality (mid-life smoking is correlated to a higher risk of late life dementia) (Lafortune et al., 2016), coherence (experimental laboratory results are in keeping with the observational evidence) (Durazzo et al., 2014) and mecha- nistic evidence suggest that smoking causes brain damage, underpinning subsequent cognitive decline. RECOMMENDATIONS AND CONSIDERATIONS RECOMMENDATION: Interventions for tobacco cessation should be offered to adults who use tobacco since they may reduce the risk of cognitive decline and dementia in addition to other health benefits. Quality of evidence: low Strength of recommendation: strong 18 Risk reduction of cognitive decline and dementia: WHO guidelines 3.3 NUTRITIONAL INTERVENTIONS Population: Adults with normal cognition or MCI Intervention: Dietary supplements (e.g. B vitamins, antioxidants, omega-3 and ginkgo) Comparison: Care as usual/placebo or one treatment versus another Outcomes: • Critical – Cognitive function – Incident MCI – Dementia • Important – Quality of life – Functional level (ADL, IADL) – Adverse events – Drop-out rates 3.3a For adults with normal cognition or MCI, are nutritional interventions including dietary supplements more effective than usual care or no intervention in reducing the risk/progression of cognitive decline and/or dementia? 3.3b For adults with normal cognition or MCI, are nutritional interventions such as healthy dietary patterns (e.g. the Mediterranean diet) more effective than usual care or no intervention in reducing the risk/progression of cognitive decline and/or dementia? Population: Adults with normal cognition or MCI Intervention: Healthy dietary pattern (e.g. the Mediterranean diet) Comparison: Care as usual or no intervention Outcomes: • Critical – Cognitive function – Incident MCI – Dementia • Important – Quality of life – Functional level (ADL, IADL) – Adverse events – Drop-out rates BACKGROUND A healthy diet throughout the life course plays a crucial role in optimal development, and in maintaining health and preventing NCDs. Previous dietary intervention studies have shown that dietary changes are involved in prevention of many conditions that increase the risk of dementia, such as diabetes (Diabetes Prevention Program Research Group, 2002; Tuomilehto et al., 2001) and CVD (Rees et al., 2013). Mechanistic and animal models have 19Evidence and recommendations suggested a variety of pathways that link dietary factors to neuropathological changes in the development of dementia (Swaminathan & Jicha, 2014). Therefore, dietary factors may be involved in the development of dementia, both directly and through their role on other risk factors, and a healthy diet may have a great preventive potential for cognitive impairment. The Mediterranean diet is the most extensively studied dietary approach, in general as well as in relation to cognitive function. Several systematic reviews of observational studies have concluded that high adherence to the Mediterranean diet is associated with decreased risk of MCI and AD, but modest adherence is not (Singh et al., 2014; Wu & Sun, 2017). Moreover, among participants with normal cognition, higher adherence is associated with better episodic memory and global cognition (Loughrey et al., 2017). Other promising dietary approaches associated with better cognitive function include: dietary approaches to stop hypertension (DASH) (Berendsen et al., 2017; Morris et al., 2015a; 2015b; Wengreen et al., 2013); and the brain health-specific Mediterranean-DASH Intervention for Neurodegenerative Delay (MIND) diet. Concerning individual foods and nutrients, consumption of fruit and vegetables (Jiang et al., 2017; Wu et al., 2017) and fish (Bakre et al., 2018; Zhang et al., 2016) are most consistently associated with decreased risk of dementia. Higher fish consumption has been linked to lower memory decline among healthy participants in many studies (Samieri et al., 2018), as well as intake of polyunsaturated fatty acids (PUFA) (fish-derived) (Zhang et al., 2016). Other foods and nutrients that have been associated with reduced risk of dementia or cognitive impairment are nuts, olive oil and coffee (Solfrizzi et al., 2017). Evidence has also been reported concerning folate, vitamin E, carotenes, vitamin C and vitamin D (Balion et al., 2012; Dangour et al., 2010; Rafnsson et al., 2013; Travica et al., 2017), but findings are inconsistent. RECOMMENDATIONS AND CONSIDERATIONS RECOMMENDATION 1: The Mediterranean-like diet may be recommended to adults with normal cognition and MCI to reduce the risk of cognitive decline and/or dementia. Quality of evidence: moderate Strength of the recommendation: conditional RECOMMENDATION 2: Healthy, balanced diet should be recommended to all adults based on WHO recommendations on healthy diet. Quality of evidence: low to high (for different dietary components) Strength of the recommendation: strong RECOMMENDATION 3: Vitamins B and E, PUFA and multi-complex supplementation should not be recommended to reduce the risk of cognitive decline and/or dementia. Quality of evidence: moderate Strength of the recommendation: strong 20 Risk reduction of cognitive decline and dementia: WHO guidelines Additional considerations include: • The evidence and recommendations provided assume that the nutritional status and potential micronutrients deficiencies in both mid-life and old age have been assessed and treated. • A balanced and varied diet represents a natural source of polyphenols and protein. • The recommendation about vitamins B and E, PUFA and multi-complex supplementation applies to people without nutrient deficiency. SUPPORTING EVIDENCE AND RATIONALE Observational studies have consistently reported that a healthy diet is associated with better cognitive performance (Berendsen et al., 2017; Frith et al., 2018; Loughrey et al., 2017; Morris et al., 2015; Wengreen et al., 2013), but the evidence from clinical trials is more inconsistent (D’Cunha et al., 2018; Fitzpatrick-Lewis et al., 2015a; 2015b; Forbes et al., 2015; Radd-Vagenas et al., 2018; Solfrizzi et al., 2018). It is important to acknowledge that interventions with dietary modifications that improve several aspects of dietary intake at once are more likely to promote better cognition compared with supplementation with only some nutrients. Dietary factors may have synergistic effects that are only evident in combinations of foods ( Jacobs Jr et al., 2009). WHO recommendations on a healthy diet (http://www.who.int/en/news-room/fact-sheets/detail/healthy-diet) For adults, the WHO guidelines recommend the following. A healthy diet contains: • Fruits, vegetables, legumes (e.g. lentils, beans), nuts and whole grains (e.g. unprocessed maize, millet, oats, wheat, brown rice). • At least 400 g (five portions) of fruits and vegetables a day. Potatoes, sweet potatoes, cassava and other starchy roots are not classified as fruits or vegetables. • Less than 10% of total energy intake from free sugars which is equivalent to 50 g (or around 12 level teaspoons) for a person of healthy body weight consuming approximately 2000 calories per day, but ideally less than 5% of total energy intake for additional health benefits. Most free sugars are added to foods or drinks by the manufacturer, cook or consumer, and can also be found in sugars naturally present in honey, syrups, fruit juices and fruit juice concentrates. • Less than 30% of total energy intake from fats. Unsaturated fats (found in fish, avocado, nuts, sunflower, canola and olive oils) are preferable to saturated fats (found in fatty meat, butter, palm and coconut oil, cream, cheese, ghee and lard) and trans-fats of all kinds, including both industrially produced trans-fats (found in processed food, fast food, snack food, fried food, frozen pizza, pies, cookies, biscuits, wafers, margarines and spreads) and ruminant trans-fats (found in meat and dairy foods from ruminant animals, such as cows, sheep, goats, camels and others). It is suggested to reduce the intake of saturated fats to less than 10% of total energy intake and trans-fats to less than 1% of total energy intake. In particular, industrially produced trans-fats are not part of a healthy diet and should be avoided. • Less than 5 g of salt (equivalent to approximately 1 teaspoon) per day and use iodized salt. 21Evidence and recommendations Regarding nutritional interventions, such as dietary supplements or healthy dietary patterns (e.g. the Mediterranean diet) compared with usual care or no intervention, six systematic reviews were identified for nine different nutritional interventions. These interventions were: 1. Multi-supplement complexes versus placebo in adults with normal cognition (D’Cunha et al., 2018). 2. Multi-supplement complexes versus placebo in adults with MCI (Fitzpatrick-Lewis et al., 2015). 3. PUFA versus placebo (Forbes et al., 2015). 4. Vitamin B versus placebo (Forbes et al., 2015). 5. Vitamin E versus placebo (Forbes et al., 2015). 6. Polyphenols versus placebo (Solfrizzi et al., 2018). 7. Protein supplementation versus placebo (Solfrizzi et al., 2018). 8. Chicken essence versus placebo (Teoh et al., 2016). 9. Mediterranean diet versus alternate or usual diet (Radd-Vagenas et al., 2018). The outcomes of incident MCI and dementia were only reported for interventions involving multi- supplement complexes in adults with normal cognition and the Mediterranean diet (D’Cunha et al., 2018; Radd-Vagenas et al., 2018). However, neither of these interventions showed a direct effect in reducing the incidence of dementia and/or MCI. All of the interventions/comparisons reported cognitive outcomes. There was moderate quality evidence that the Mediterranean diet can improve verbal and visual memory (Radd-Vagenas et al., 2018). A meta-analysis showed results that approached significance for global cognition and consistently positive, but non-significant, results were reported for all other cognitive outcomes (attention, working memory, processing speed, language and executive function) (Radd-Vagenas et al., 2018). A consistent positive effect of polyphenols on cognitive performance was also found, however, the quality of the evidence was low (Solfrizzi et al., 2018). Similarly, protein supplementations were found to have a beneficial effect on cognition in older adults, but the results were inconsistent and the quality of the evidence was low (Solfrizzi et al., 2018). Overall, no effects were found for multi-complex (D’Cunha et al., 2018; Fitzpatrick-Lewis et al., 2015), vitamins B and E (Forbes et al., 2015), and PUFA supplementation (Forbes et al., 2015). Low-quality evidence was reported for protein and polyphenols supplementation (Solfrizzi et al., 2018), and moderate evidence of a beneficial effect of the Mediterranean diet was found (Radd-Vagenas et al., 2018). Three multi-supplement complex interventions: docosahexaenoic acid (DHA) + eicosapentaenoic acid (EPA) + vitamin E + soy phospholipids + tryptophan + melatonin; vitamin E + multivitamin; lyophilized royal jelly + gingko biloba + Panax ginseng; were examined and none showed an increased risk of any serious adverse event during the follow-up period (moderate quality evidence, Fitzpatrick-Lewis et al., 2015). The GDG concluded that the benefits of a Mediterranean diet and a balanced diet outweighed the harms and provided conditional and strong recommendations respectively. The GDG noted that vitamin E and protein supplementation at high doses have been associated with undesirable non- anticipated effects that outweigh the benefits and recommended against their use. 22 Risk reduction of cognitive decline and dementia: WHO guidelines Population: Adults with normal cognition or MCI and excessive use of alcohol Intervention: • Behavioural and psychological interventions to treat alcohol use disorder (e.g. motivational interviewing) • Pharmacological interventions to treat alcohol use disorder Comparison: Care as usual or no intervention Outcomes: • Critical – Cognitive function – Incident MCI – Dementia • Important – Quality of life – Functional level (ADL, IADL) – Adverse events – Drop-out rates For adults with normal cognition or MCI and alcohol use disorder, are behavioural and psychological interventions to treat alcohol use disorder more effective than usual care or no intervention in reducing the risk of cognitive decline and/or dementia? 3.4 INTERVENTIONS FOR ALCOHOL USE DISORDER BACKGROUND Excessive alcohol consumption is common in many countries (Gell et al., 2015). In 2012, 5.9% of all deaths worldwide (about 3.3 million) were directly attributable to harmful use of alcohol (WHO, 2014). Furthermore, excessive consumption of alcohol is one of the leading causes of general disability globally (WHO, 2014), being a direct cause in more than 200 diseases including risk factors for dementia and injury conditions (WHO, 1992; WHO 2019a). There is extensive evidence on excessive alcohol as a risk factor for dementia and cognitive decline (Langballe et al., 2015; Sachdeva et al., 2016; Zhou et al., 2014). Several approaches have been applied in interventions aimed at hazardous and harmful use of alcohol. Pharmacological therapies with different types of drugs (e.g. opioid antagonists, ALDH2 inhibitors) have shown various degrees of efficacy for adults with alcohol use disorders, although none of them showed to be superior in comparison trials. Behaviour and psychological interventions have shown to be effective in alcohol use disorders, and especially among those with hazardous and harmful drinking. Screening and brief intervention in primary care is one of the most cost-effective means of reducing alcohol-attributable morbidity and deaths (Kaner, 2018). Interventions for alcohol use disorder have been described in the mhGAP Intervention guide - Version 2.0 for mental, neurological and substance use disorders in non-specialized health settings (http://www.who.int/mental_health/mhgap/mhGAP_ intervention_guide_02/en/). 23Evidence and recommendations RECOMMENDATIONS AND CONSIDERATIONS RECOMMENDATION Interventions aimed at reducing or ceasing hazardous and harmful drinking should be offered to adults with normal cognition and MCI to reduce the risk of cognitive decline and/or dementia in addition to other health benefits. Quality of evidence: moderate (for observational evidence) Strength of the recommendation: conditional WHO mhGAP Intervention guide - Version 2 for mental, neurological and substance use disorders in non-specialized health settings (http://www.who.int/mental_health/mhgap/mhGAP_intervention_guide_02/en/) The WHO mhGAP Intervention guide recommends the following: Harmful use of alcohol • Provide psychoeducation and emphasize that the level/pattern of alcohol use is causing harm to health. • Explore the person’s motivations for alcohol use. Conduct motivational interviewing. • Advise stopping alcohol completely or consuming at a non-harmful level (if a non-harmful level exists) and indicate your intention in supporting the person in doing so. Ask the person if they are ready to try to make this change. • Explore strategies for reducing or stopping use and strategies for reducing harm. • Address food, housing and employment needs. • Offer regular follow-up. Alcohol dependence • Thiamine during alcohol use. • Diazepam during alcohol detoxification to treat withdrawal symptoms. • Naltrexone, acamprosate or disulfiram to prevent relapse after detoxification. • Psychosocial interventions if available, e.g. cognitive behaviour therapy, motivational enhancement therapy, contingency management therapy, family counselling or therapy, problem-solving counselling or therapy; self-help groups. 24 Risk reduction of cognitive decline and dementia: WHO guidelines Additional considerations include: • Interventions can be based on lifestyle/ behavioural changes or pharmacological treatments in accordance with the WHO mhGAP guidelines. Lifestyle behavioural interventions are likely to be more acceptable and have fewer adverse events. • A U-shaped relationship between alcohol consumption and cognitive function has been reported. However, due to methodological limitations in most studies that describe this effect, it is not possible to assume that a light to moderate consumption of alcohol is, in fact, protective toward dementia and/or cognitive decline. This, in addition to other health risks and the social and economic burden associated with alcohol, do not favour a general recommendation of its use. • Individual level interventions should be provided in the context of WHO Global strategy to reduce harmful use of alcohol (WHO 2010) and population level interventions, through strengthening restrictions on alcohol availability, enforcing drink driving countermeasures, facilitating access to screening, brief interventions, and treatment, enforcing bans or comprehensive restrictions on alcohol advertising, sponsorship, and promotion, raising prices on alcohol through excise taxes and pricing policies. SUPPORTING EVIDENCE AND RATIONALE No systematic reviews were identified for interventions for hazardous and harmful alcohol consumption (behavioural, psychological and pharmacological interventions) and reduced the risk of cognitive decline and/or dementia. However, a large body of observational evidence is available on alcohol as a risk factor for cognitive decline and dementia (Beydoun et al., 2014; Hersi et al., 2017; Ilomaki et al., 2015; Lafortune et al., 2016; Piazza-Gardner et al., 2013; Xu et al., 2017). Generally, single studies did not always show similar results (mostly due to differences in study design) but the most consistent pattern is that of a U-shaped relationship between alcohol consumption and dementia and/or cognitive impairment, which clearly links excessive alcohol consumption to a significantly increased risk (Xu et al., 2017). A range of adverse events has also been reported for pharmacological interventions aimed at reducing excessive alcohol consumption while lifestyle interventions are mostly based on behavioural interventions and no evidence of adverse events (apart from those related to withdrawal syndrome) have been identified (NICE, 2011). Overall, the GDG concluded that the benefits outweighed the harms and, based on the strong observational evidence, made a conditional recommendation for interventions to reduce or cease hazardous and harmful alcohol use. 25Evidence and recommendations Population: Adults with normal cognition or MCI Intervention: • Cognitive stimulation • Cognitive training Comparison: Care as usual or no intervention Outcomes: • Critical – Cognitive function – Incident MCI – Dementia • Important – Quality of life – Functional level (ADL, IADL) – Adverse events – Drop-out rates For adults with normal cognition or MCI is cognitive stimulation or cognitive training more effective than usual care or no intervention in reducing the risk of cognitive decline and/or dementia? 3.5 COGNITIVE INTERVENTIONS BACKGROUND Dementia is preceded by cognitive decline. However, not everyone who is exposed to dementia risk factors will go on to develop cognitive impairment. The concept of cognitive reserve has been proposed as a protective factor that may reduce the risk of clinical onset of dementia and cognitive decline (Stern, 2012). Cognitive reserve refers to the brain’s ability to cope with or compensate for neuropathology or damage (Stern, 2012). Studies have shown that increased cognitive activity may stimulate (or increase) cognitive reserve and have a buffering effect against rapid cognitive decline (Stern & Munn, 2010) as well as a significant reduction in the risk of MCI or AD diagnosis in those who reported high compared with low levels of cognitive activities (combined OR = 0.38, 95% CI: 0.15–0.99) (Sattler, 2012). Increased cognitive activity can be achieved through cognitive stimulation therapy and/or cognitive training. Cognitive stimulation therapy refers to “participation in a range of activities aimed at improving cognitive and social functioning” (Clare & Woods, 2004), while cognitive training refers to “guided practice of specific standardized tasks designed to enhance particular cognitive functions” (Clare & Woods, 2004). The NIA (United States of America) identified cognitive training as an intervention aimed at preventing or delaying the onset of age-related cognitive decline, MCI, or clinical Alzheimer’s-type dementia (Kane et al., 2017). Additionally, the WHO ICOPE guidelines (http://www. who.int/ageing/publications/guidelines-icope/en/) recommend cognitive stimulation for older adults with cognitive impairment. These interventions were assessed against outcomes that were judged as critical and important for this population. 26 Risk reduction of cognitive decline and dementia: WHO guidelines SUPPORTING EVIDENCE AND RATIONALE For cognitive stimulation versus usual care or no intervention in healthy older adults, evidence was extracted from one systematic review (Strout et al., 2016). No evidence for adults with MCI was available. The review reported that half of the interventions evaluated proved to be effective in improving cognitive outcomes in at least one cognitive domain – executive function, attention, memory, language and/or processing speed (Strout et al., 2016). The quality of the evidence was low. The results were reported in narrative form and no meta-analysis was conducted. No evidence for incident MCI or dementia was available. For cognitive training versus usual care or no intervention in healthy older adults, evidence was extracted from one systematic review (Chiu et al., 2017). The review conducted a meta-analysis which showed that cognitive training in healthy older adults has a moderate positive effect on overall cognitive functioning. The quality of evidence was low. No evidence for incident MCI or dementia was available. For cognitive training versus usual care or no intervention in adults with MCI, evidence was extracted from two systematic reviews (Chandler et al., 2016; Sherman et al., 2017). With regards to cognitive function outcome, the quality of evidence is low showing that cognitive training in adults with MCI has a small positive effect on cognition. With regards to incident dementia outcome, the quality of evidence is very low as the results were narratively reported. It was reported that one study found that half of the control group, but none of the intervention group, developed dementia at the 8-month follow-up, while another found that more of the intervention group reported incident dementia at the 2-year follow-up (Chandler et al., 2016). With regards to quality of life and functional level, the quality of evidence is low showing that cognitive training in adults with MCI has a small positive effect on ADL but not quality of life. The evidence for cognitive interventions is mainly in studies with older adults. The GDG concluded that in this population the desirable effects of the intervention outweighed the undesirable effects and provided a conditional recommendation for cognitive training. The evidence for cognitive stimulation in reducing the risk of dementia was insufficient and no recommendation was made by the GDG. RECOMMENDATIONS AND CONSIDERATIONS RECOMMENDATION: Cognitive training may be offered to older adults with normal cognition and with MCI to reduce the risk of cognitive decline and/or dementia. Quality of evidence: very low to low Strength of the recommendation: conditional 27Evidence and recommendations Population: Adults with normal cognition or MCI Intervention: Comparison: Care as usual or no intervention Outcomes: • Critical – Cognitive function – Incident MCI – Dementia • Important – Quality of life – Functional level (ADL, IADL) – Adverse events – Drop-out rates For adults with normal cognition or MCI is preserving and promoting a high level of social activity more effective than usual care or no intervention in reducing the risk of cognitive decline and/or dementia? 3.6 SOCIAL ACTIVITY BACKGROUND Social engagement is an important predictor of well- being throughout life (Cherry et al., 2011). Social disengagement conversely, has been shown to place older individuals at increased risk of cognitive impairment and dementia (Fratiglioni et al., 2004). A systematic review and meta-analysis of longitudinal cohort studies showed that lower social participation, less frequent social contact and loneliness were associated with higher rates of incident dementia (Kuiper et al., 2015). The Lancet Commission on Dementia Prevention, Intervention, and Care identified social engagement as an intervention that could be used to prevent dementia (Livingston et al., 2017). RECOMMENDATIONS AND CONSIDERATIONS There is insufficient evidence for social activity and reduction of risk of cognitive decline/dementia. Social participation and social support are strongly connected to good health and well-being throughout life and social inclusion should be supported over the life-course. (Global age-friendly cities: a guide, http://www.who.int/ageing/publications/Global_age_friendly_ cities_Guide_English.pdf) 28 Risk reduction of cognitive decline and dementia: WHO guidelines SUPPORTING EVIDENCE AND RATIONALE For preservation and promotion of social activity including community and family engagement versus care as usual or no intervention, evidence was extracted from one systematic review examining adults with normal cognition (Kelly et al., 2017). No evidence for adults with MCI was available. For cognitive function outcomes, the quality of the evidence is very low. Three RCTs, which assessed the association between cognitive function and social activity, were deemed eligible. The review findings were reported narratively (Kelly et al., 2017). Overall cognition was measured by varied composite measures of global cognition, including the ADAS-cog, MMSE and MDRS. One of the three RCTs found social activity intervention to be significantly associated with improvements in cognitive function (Pitkala et al., 2011). No data were available for incident MCI or dementia, quality of life, functional level (ADL, IADL), adverse events or drop-outs. The GDG concluded that the evidence is limited and inconclusive, so no recommendation was made for social activity and risk of cognitive decline/dementia. Furthermore, there is a risk of bias arising from reverse causality whereby low social engagement prior to diagnosis of cognitive decline or dementia may be at least in part due to the disease process. The GDG did not make a recommendation against social activity as they concluded that social activity has a wide range of other benefits to health and well-being. 29Evidence and recommendations Population: Adults with normal cognition or MCI who are overweight or obese Intervention: Weight management • Non-pharmacological interventions, e.g. cognitive behavioural intervention strategies, lifestyle interventions • Pharmacological interventions, e.g. weight loss medication (e.g. orlistat) Comparison: Care as usual or no intervention Outcomes: • Critical – Cognitive function – Incident MCI – Dementia • Important – Quality of life – Functional level (ADL, IADL) – Adverse events – Drop-out rates For adults with normal cognition or MCI who are overweight or obese, are interventions for weight reduction (or control of obesity) more effective than usual care or no intervention in reducing the risk of cognitive decline and/or dementia? 3.7 WEIGHT MANAGEMENT BACKGROUND Overweight and obesity are some of the best characterized and established risks for a variety of NCDs, responsible for at least 2.8 million deaths each year worldwide, and of an estimated 35.8 million (2.3%) of global disability-adjusted life years (DALYs) (WHO, 2019b). In 2008, 35% of adults aged 20+ were overweight (BMI ≥ 25 kg/m2) (34% men and 35% of women), with significantly variable prevalence among world areas, with the United States of America, Europe and the Eastern Mediterranean regions with the highest concentration of people with overweight/ obesity (WHO, 2019b). Overweight and obesity, in particular, have been linked to a number of medical complications such as Type 2 diabetes (Chan et al., 1994), cancer (Renehan et al., 2015), premature mortality (Fontana & Hu, 2014), and CVD (Eckel, 1997), both as direct risk factors as well as risks for other cardiovascular risk factors, such as high cholesterol and hypertension. Obesity has been steadily rising, particularly among older adults in the last few decades (Nguyen & El-Serag, 2010) and although an increasing body of evidence suggests that overweight (25 < BMI < 30) in older adults could be more protective than normal weight in terms of overall mortality (Flicker et al., 2010), a link has also been established between excess of fat body mass and cognitive impairment (Xu et al., 2011). A recent systematic review and meta-analysis of observational studies conducted on a total of about 600 000 individuals showed that obesity (but not overweight) at mid-life increases the risk of dementia (RR = 1.33; 95% CI: 1.08–1.63) (Albanese et al., 2017). It has been suggested that weight loss could indirectly reduce the risk of dementia by improving a variety of metabolic factors linked with the pathogenesis of cognitive impairment and dementia (i.e. glucose 30 Risk reduction of cognitive decline and dementia: WHO guidelines tolerance, insulin sensitivity, blood pressure, oxidative stress, and inflammation) (Bennett et al., 2009). However, a direct beneficial effect of weight reduction intervention is also plausible. Although, so far, evidence of potential cognitive benefits of weight loss seem to be strongly associated with increased physical activity (Colcombe et al., 2006; Erickson et al., 2010), in 2011 a systematic review concluded that intentional weight loss can improve performance in some cognitive domains, at least in people with obesity (Siervo et al., 2011). Additional considerations include: • Lifestyle interventions that included both diet and physical activity components seemed to show the best results. • In addition to interventions at individual level, lifestyle interventions at the population level, such as activity parks, green spaces and infrastructure to support active commuting, need to be considered. • Being underweight in both late-mid-life and old age might be associated with a higher risk of dementia. However, it is likely that this association is explained, at least in part, by reverse causality, whereby brain pathology may cause weight loss before the clinical onset of dementia. • Unintentional weight loss and malnutrition are associated with poor health outcomes and should be investigated and treated at all ages. However, it is unlikely that interventions that favour weight gain in people who are underweight in either mid- or late life can reduce the risk of dementia or cognitive impairment. RECOMMENDATION: Interventions for mid-life overweight and/or obesity may be offered to reduce the risk of cognitive decline and/or dementia. Quality of evidence: low to moderate Strength of the recommendation: conditional WHO guidance on overweight and obesity outlined in Prevention and control of noncommunicable diseases: guidelines for primary health care in low-resource settings (2012) (http://www.who.int/nmh/publications/phc2012/en/) WHO guidance on overweight and obesity should be followed. • Advise overweight patients to reduce weight by following a balanced diet. • Advise patients to give preference to low glycaemic-index foods (beans, lentils, oats and unsweetened fruit) as the source of carbohydrates in their diet. • Advise patients to reduce sedentary behaviour and practise regular daily physical activity appropriate for their physical capabilities (e.g. walking). RECOMMENDATIONS AND CONSIDERATIONS 31Evidence and recommendations SUPPORTING EVIDENCE AND RATIONALE For weight reduction with behavioural and/or lifestyle interventions (or control of obesity) compared with usual care or no intervention, evidence was extracted from one systematic review examining adults with normal cognition who are overweight or obese (Veronese et al., 2017). No evidence for adults with MCI was available. There was low to moderate evidence that lifestyle interventions aimed at weight reduction could improve cognitive function in the attention, memory and language domains. Interventions were very short (ranging from 8 to 48 weeks). No data were found in relation to incident MCI and dementia outcomes. No evidence of adverse events was identified. For pharmacological interventions for weight reduction (or control of obesity) compared with usual care or no intervention, no systematic reviews were found. The GDG concluded that the benefits of the interventions outweighed the harms and provided a conditional recommendation. Since the observational evidence of a correlation between overweight/obesity and increased risk of dementia is stronger and more consistent in mid-life than in late life (Hersi et al., 2017; Lafortune et al., 2016; Pedditzi et al., 2016; Prickett et al., 2015; Xu et al., 2015), the GDG made a conditional recommendation for this population. 32 Risk reduction of cognitive decline and dementia: WHO guidelines Population: Adults with normal cognition or MCI with hypertension Intervention: Antihypertensive medication, lifestyle interventions Comparison: Placebo/no intervention Outcomes: • Critical – Cognitive function – Incident MCI – Dementia • Important – Quality of life – Functional level (ADL, IADL) – Adverse events – Drop-out rates For adults with normal cognition or MCI and hypertension, is treatment of hypertension more effective than placebo/no intervention in reducing the risk of cognitive decline/dementia? 3.8 MANAGEMENT OF HYPERTENSION BACKGROUND Hypertension in mid-life has been associated with an increased risk of late life dementia (Kivipelto et al., 2001). In particular, a pattern of increased blood pressure during mid-life followed by a rapid decrease in blood pressure later in life has been found in individuals who go on to develop dementia (Kivipelto et al., 2001; Launer et al., 2000; Stewart et al., 2009). There is mixed evidence relating to the reduction of blood pressure in late mid- or late life and subsequent cognitive decline or dementia, however, there is evidence to show that the reduction of hypertension can have substantial benefits in reducing cardiovascular morbidity and mortality and thus improving overall health of the ageing population (Musini et al., 2009). Hypertension can be prevented through a range of lifestyle factors, including eating a healthy diet, maintaining a healthy weight and participating in an adequate amount of physical activity. It can also be controlled through antihypertensive medication. However, the evidence for the effectiveness of blood pressure lowering treatments in reducing the risk of cognitive decline and dementia risk is mixed. RECOMMENDATION 1: Management of hypertension should be offered to adults with hypertension according to existing WHO guidelines. Quality of evidence: low to high (for different interventions) Strength of the recommendation: strong RECOMMENDATIONS AND CONSIDERATIONS 33Evidence and recommendations HEARTS Technical package for cardiovascular disease management in primary health care: evidence-based treatment protocols (http://apps.who.int/iris/bitstream/handle/10665/260421/WHO-NMH-NVI-18.2-eng.pdf?sequence=1) Medications used to treat hypertension • There are four main classes of antihypertensive medications: angiotensin converting enzyme (ACE) inhibitors; angiotensin receptor blockers (ARB); calcium channel blockers (CCB); and thiazide and thiazide-like diuretics. Any of these four classes of antihypertensive medication may be used unless there are specific contraindications. Proper treatment of hypertension usually requires a combination of hypertension medications. Notes on specific hypertension medications • Pregnant women and women of childbearing age not on effective contraception should not be given ACE inhibitors, ARBs or thiazide/thiazide-like diuretics; CCBs should be used. If not controlled with intensification dose of medication, refer to specialist. • Beta blockers are not recommended as first-line therapy. If a heart attack has been diagnosed within the previous three years, or there is atrial fibrillation or heart failure, then a beta blocker should be added to the starting dose of antihypertensive medication. Patients with angina may also benefit from treatment with a beta blocker. Other treatment considerations • If there is a prior heart attack or stroke, or the person is otherwise at high risk of CVD, start a statin at the same time as starting antihypertensive medication. (Statins should not be used in women who are or who may become pregnant.) • If there is a prior heart attack or ischemic stroke, start low-dose aspirin. • The hypertension protocols included in this module serve well for initiation and maintenance of successful treatment. If there are serious adverse events, lack of control of blood pressure, or if a major medical event intervenes, then referral to a specialist will be needed. • If the patient is already on another medication regimen, blood pressure is controlled to the target level, and the medications the patient is taking are accessible and affordable, there is no reason to change the regimen. • If the patient feels faint on standing, check blood pressure while standing. If the systolic blood pressure is consistently less than 110 mm Hg in a patient on medical treatment, consider reducing the dosage or number of medications used. RECOMMENDATION 2: Management of hypertension may be offered to adults with hypertension to reduce the risk of cognitive decline and/or dementia. Quality of evidence: very low (in relation to dementia outcomes) Strength of the recommendation: conditional 34 Risk reduction of cognitive decline and dementia: WHO guidelines SUPPORTING EVIDENCE AND RATIONALE For treatment of hypertension in the form of antihypertensive medication versus placebo or no intervention, evidence was extracted from two systematic reviews examining adults with normal cognition and hypertension (Parsons et al., 2016; Weiss et al., 2016). No evidence for adults with MCI was available. With regard to cognitive function and incident dementia outcomes, the quality of the evidence was low, which showed that antihypertensive therapy has no effect on cognitive decline or incidence of dementia. With regard to quality of life and functional level outcomes, the quality of evidence is very low, showing that antihypertensive therapy does not decrease quality of life or functional level. With regard to adverse events, the quality of evidence was very low, showing mixed findings with regard to antihypertensive use. There were no data on incident MCI and overall drop- out rates. Initial results from the SPRINT-MIND trial, a substudy of the Systolic Blood Pressure Intervention Trial (SPRINT) that aims to evaluate the effect of intensive blood pressure control on risk of dementia, support the possibility of a dose-response relationship between blood pressure and risk of cognitive decline or dementia (SPRINT-MIND 2019). Observational evidence suggests a strong association between hypertension and incident cognitive decline/dementia. For treatment of hypertension in the form of lifestyle interventions versus placebo or no intervention, no systematic reviews were found. The GDG made a strong recommendation for management of hypertension for its established health benefits and a conditional recommendation for hypertension management for reducing the risk of cognitive decline/dementia. The GDG concluded that though there is limited clinical trial evidence that treatment of hypertension reduces the risk of cognitive decline or dementia, the benefits outweighed the harms since the evidence suggests that intervention does not lower quality of life or functional level and there are mixed results regarding adverse effects which may depend on the drug used. Additionally, robust evidence for a causal relationship is available. 35Evidence and recommendations Population: Adults with normal cognition or MCI with diabetes mellitus Intervention: • Medications for glycaemic control • Diet and lifestyle interventions Comparison: Placebo/no intervention Outcomes: • Critical – Cognitive function – Incident MCI – Dementia • Important – Quality of life – Functional level (ADL, IADL) – Adverse events – Drop-out rates For adults with normal cognition or MCI and diabetes mellitus, is treatment of diabetes more effective than placebo/no intervention in reducing the risk of cognitive decline and/or dementia? 3.9 MANAGEMENT OF DIABETES BACKGROUND The presence of late life diabetes has been linked to an increased risk of dementia (Luchsinger, 2010; Prince et al., 2014; Profenno et al., 2010). However, the mechanism by which this occurs is unclear. Poor glucose control has been associated with lower cognitive functioning and greater cognitive decline (Yaffe et al., 2012). In addition, the complications associated with diabetes, such as nephropathy (kidney damage), retinopathy (eye damage), hearing impair- ment and CVD, have all been found to increase the risk of dementia (Bruce et al., 2014; Exalto et al., 2013). The literature examining interventions that aim to improve glycaemic control shows mixed findings with regard to cognitive outcomes (Launer et al., 2011; Luchsinger et al., 2011). In addition, the evidence on the effectiveness of medication for diabetes in reducing dementia risk is inconsistent (Cheng et al., 2014; Moore et al., 2013; Parikh et al., 2011). There is some evidence to suggest that treating the cardiovascular comor- bidities associated with diabetes, such as high choles- terol and hypertension, may mediate the risk for dementia (Johnson et al., 2012; Parikh et al., 2011). 36 Risk reduction of cognitive decline and dementia: WHO guidelines RECOMMENDATION 1: Management of diabetes in the form of medications and/or lifestyle interventions should be offered to adults with diabetes according to existing WHO guidelines. Quality of evidence: very low to moderate (for different interventions) Strength of the recommendation: strong RECOMMENDATION 2: Management of diabetes may be offered to adults with diabetes to reduce the risk of cognitive decline and/or dementia. Quality of evidence: very low Strength of the recommendation: conditional Package of essential noncommunicable (PEN) disease interventions for primary health care in low-resource settings (https://www.who.int/cardiovascular_diseases/publications/pen2010/en/). For individuals with diabetes, the WHO guidelines recommend the following treatments: Type 1 diabetes • Daily insulin injections (Level 1). Type 2 diabetes • Oral hypoglycaemic agents for Type 2 diabetes, if glycaemic targets are not achieved with modification of diet, maintenance of a healthy body weight and regular physical activity (Level 1). • Metformin as initial drug in overweight patients (Level 1) and non-overweight (Level 4). • Other classes of antihyperglycaemic agents, added to metformin if glycaemic targets are not met (Level 3). • Reduction of cardiovascular risk for those with diabetes and 10-year cardiovascular risk > 20% with aspirin, angiotensin converting enzyme inhibitor and statins (Level 1). RECOMMENDATIONS AND CONSIDERATIONS 37Evidence and recommendations SUPPORTING EVIDENCE AND RATIONALE For treatment of diabetes in the form of medications for glycaemic control versus placebo or no intervention, evidence was extracted from one systematic review examining adults with normal cognition and Type 2 diabetes (Areosa Sastre et al., 2017). No evidence for adults with MCI was available. The quality of the evidence was moderate for cognitive function outcomes and very low for incident dementia outcomes, which showed intensive as opposed to standard glycaemic control has an unclear effect on cognitive function and no effect on incident dementia. The evidence reviewed included data from a large study set across 215 collaborating centres in 20 countries in Asia, Australasia, Europe and North America. The quality of evidence for adverse events was very low, showing intensive glycaemic control increases the risk of hypoglycaemic events. No data on incident MCI, quality of life, functional outcomes or drop-out rates were available. Overall, in adults with normal cognition, the evidence may favour standard glycaemic control because intense glycaemic control has no effect on cognitive function but may result in increased episodes of hypoglycaemia. For treatment of diabetes in the form of diet and life- style interventions versus placebo or no intervention, evidence was extracted from one systematic review examining adults with normal cognition and Type 2 diabetes (Podolski et al., 2017). No evidence for adults with MCI was available. The quality of evidence was very low and the findings were mixed. No meta- analysis was conducted and there were no robust data on clinical significance. The GDG made a strong recommendation for management of diabetes for its established health benefits and a conditional recommendation for diabetes management for reducing the risk of cognitive decline/dementia. The GDG concluded that though there is limited clinical trial evidence on the management of diabetes to reduce the risk of cognitive decline or dementia, the benefits outweighed the harms and there is robust observational evidence to suggest diabetes increases the risk of cognitive decline and dementia. 38 Risk reduction of cognitive decline and dementia: WHO guidelines Population: Adults with normal cognition or MCI with dyslipidaemia Intervention: • Statins (e.g. simvastatin and pravastatin) • Lifestyle interventions Comparison: Placebo or no intervention Outcomes: • Critical – Cognitive function – Incident MCI – Dementia • Important – Quality of life – Functional level (ADL, IADL) – Adverse events – Drop-out rates For adults with normal cognition or mild cognitive impairment and dyslipidaemia, is treatment of dyslipidaemia more effective than placebo or no intervention in reducing the risk of cognitive decline and/or dementia? 3.10 MANAGEMENT OF DYSLIPIDAEMIA BACKGROUND Elevated serum cholesterol is one of the key modifiable cardiovascular risk factors. A third of ischaemic heart disease worldwide is attributable to dyslipidaemia and it is estimated to be the cause of 2.6 million deaths (4.5% of total) per year, as well as a considerable proportion of disability (WHO, 2019b). The prevalence of raised total cholesterol among countries seems to correlate with wealth: in high-income countries, more than 50% of adults have elevated total cholesterol level, more than double the rate in low-income countries (WHO, 2019c). The idea that raised level of blood cholesterol could be related to an increased risk of dementia was already introduced in the mid-1970s (Richardson et al., 2000). Since then, a number of epidemiological studies have demonstrated a close relationship between high serum cholesterol levels and the onset of AD/dementia (Kivipelto et al., 2002; Solomon et al., 2007; Whitmer et al., 2005), but results have been inconsistent, with other studies showing no or negative correlation (Mainous et al., 2005; Mielke et al., 2005). Based on the severity of the dyslipidaemia and CVD overall risk, lifestyle or pharmacological approaches can be undertaken to reduce blood cholesterol. Weight reduction and decreasing saturated fats in the diet (decreasing the consumption of food of animal origin) are the most common and effective lifestyle recommen- dations (Perk et al., 2012). However, dyslipidaemia is often controlled and managed pharmacologically, with statins being the drugs of first choice. Several observational studies have investigated the possible beneficial effect of statins therapy in preventing dementia, but bias and heterogeneity hampered the overall quality of the evidence (Song et al., 2013; Swiger et al., 2013; Wong et al., 2013). Recently, a re-analysis of statin use in AD patients from failed clinical trials suggested that the use of simvastatin may slow the progression of cognitive decline in some people (Geifman et al., 2017). 39Evidence and recommendations RECOMMENDATIONS AND CONSIDERATIONS RECOMMENDATION: Management of dyslipidaemia at mid-life may be offered to reduce the risk of cognitive decline and dementia. Quality of evidence: low Strength of the recommendation: conditional Additional considerations include: • Statin treatment in older adults should not be specifically initiated for preventing cognitive decline and/or dementia but may be used for other health benefits according to WHO’s Prevention and control of noncommunicable diseases: guidelines for primary health care in low-resource settings (http://www.who.int/nmh/publications/phc2012/en/). SUPPORTING EVIDENCE AND RATIONALE For control of dyslipidaemia through treatment with statins compared with placebo, evidence was extracted from one systematic review examining adults with normal cognition and dyslipidaemia (McGuinness et al., 2016). No evidence for adults with MCI was available. The quality of the evidence was moderate for cognitive function outcomes and low for incident dementia outcomes, showing that treatment with statins has no effect on either incident dementia and/or cognitive decline. There is moderate quality evidence that the treatment with statins does not increase the incidence of serious adverse events. A large body of observational evidence has linked dyslipidaemia to an increased risk of dementia and/or cognitive decline and found an association between control of dyslipidaemia and reduction of dementia and/or cognitive decline risk (Geifman et al., 2017; Hersi et al., 2017; Reitz, 2013; Song et al., 2013). Overall, indirect evidence suggests that managing dyslipidaemia in mid-life can help reduce the risk of cognitive decline and/or dementia. No studies were identified that specifically aimed at controlling dyslipidaemia through lifestyle interventions and included outcomes related to dementia and/or cognitive impairment. The GDG concluded that the desirable effects of dyslipidaemia treatment outweigh the undesirable effects and made a conditional recommendation. The observational evidence reported a stronger correlation between high cholesterol and dementia in mid-life rather than late life (Hersi et al., 2017; Reitz, 2013). The systematic review evidence that focused on clinical trials in older adults (65+) showed that statin treatment has no effect on cognition or dementia outcomes (McGuinness et al., 2016). Therefore, the GDG concluded that there were no grounds to recommend the use of statin and the control of cholesterol in late life but only in mid-life. 40 Risk reduction of cognitive decline and dementia: WHO guidelines Population: Adults with normal cognition or MCI with moderate to severe depressive disorder Intervention: • Pharmacological interventions to treat depression (antidepressant medication) • Psychological interventions to treat depression (e.g. cognitive behavioural therapy, problem-solving therapy, interpersonal therapy, behavioural activation) Comparison: Care as usual or placebo or no intervention Outcomes: • Critical – Cognitive function – Incident MCI – Dementia • Important – Quality of life – Functional level (ADL, IADL) – Adverse events – Drop-out rates For adults with normal cognition or mild cognitive impairment and depressive disorder, is treatment of depression more effective than usual care, placebo or no intervention in reducing the risk of cognitive decline and/or dementia? 3.11 MANAGEMENT OF DEPRESSION BACKGROUND There is a substantial body of evidence linking depression to cognitive decline and dementia. A review carried out as part of the World Alzheimer Report in 2014 combined 32 studies into a meta-analysis which looked at the effect of depression on the risk of incident dementia. This involved 62,568 participants with a median follow-up of 5 years (range 2 to 17). The review reported that the presence of depression nearly doubled the risk of dementia (pooled effect size = 1.97, 95% CI: 1.67–2.32) (Prince et al., 2014). The authors also carried out a meta-regression looking at follow-up time. They reported a trend toward smaller effect sizes in studies with longer follow-up suggesting that depression may have a prodromal role in dementia. It is noteworthy to mention that cognitive impairment may be the main symptom of depression in the elderly; a phenomenon that used to be called pseudodementia. There are several potential explanations for the link between depression and cognitive impairment or dementia. Some of these include associations between depression, noradrenergic changes and white matter lesions, depression which stems from insight into impairment at early stages of decline, depression highlighting underlying deficits, i.e. by reducing motivation and bringing its own cognitive deficits (Camus et al., 2004; Jorm, 2001; Kales et al., 2005; Schweitzer et al., 2002). 41Evidence and recommendations RECOMMENDATIONS AND CONSIDERATIONS There is currently insufficient evidence to recommend the use of antidepressant medicines for reducing the risk of cognitive decline and/or dementia. The management of depression, in the form of antidepressants and/or psychological interventions, should be provided to adults with depression according to existing WHO mhGAP guidelines. WHO mhGAP Intervention guide - Version 2 for mental, neurological and substance use disorders in non-specialized health settings (https://www.who.int/mental_health/mhgap/mhGAP_intervention_guide_02/en/) For adults with moderate to severe depressive disorder, the WHO guidelines recommend the following treatments: Psychosocial/non-pharmacological treatment and advice • Psychoeducation (for the person and his or her family, as appropriate). • Addressing current psychosocial stressors. • Reactivate social networks. • Brief psychological treatments, if available. • Offer regular follow-up. Antidepressant medication • Select an antidepressant from the National or WHO Formulary. Selective serotonin reuptake inhibitors (fluoxetine) and tricyclic antidepressants (amitriptyline) are antidepressants mentioned in the WHO Formulary and are on the WHO model list of essential medicines. • In selecting an antidepressant, consider the symptom pattern of the person, the side-effect profile of the medication, and the efficacy of previous antidepressant treatments, if any. • For co-morbid medical conditions, before prescribing antidepressants, consider potential for drug-disease or drug-drug interaction. Consult the National or the WHO Formulary. • Combining antidepressants with other psychotropic medication requires supervision by, or consultation with a specialist. 42 Risk reduction of cognitive decline and dementia: WHO guidelines SUPPORTING EVIDENCE AND RATIONALE For pharmacological interventions to treat depression (antidepressant medication) compared with usual care or placebo, evidence was extracted from one systematic review examining adults with normal cognition and major depressive disorder (Baune et al., 2018). No evidence for adults with MCI was available. The review conducted a network meta-analysis and reported standardized mean differences in the Digit Symbol Substitution Test as a measure of cognition function. The review reported that vortioxetine (versus placebo) improved cognitive functioning while duloxetine, sertraline, citalopram, escitalopram, phenelzine and nortriptyline showed no effect (Baune et al., 2018). The quality of the evidence was very low and no data were reported for incident MCI or dementia outcomes, quality of life, adverse events, functional level or drop-out rates. Overall, the true balance of effects is difficult to ascertain. The evidence favours the use of vortioxetine (but not other pharmacological interventions) to treat depression for reducing the risk of cognitive decline or dementia. However, no data on adverse effects were available, e.g. drug-related side-effects or interactions. For psychological interventions to treat depression compared with placebo or no intervention, no relevant systematic reviews were found. The GDG therefore concluded that there was insufficient evidence currently for depression manage- ment and reduction of risk of cognitive decline/ dementia. They also concluded that the management of depression is important for its other benefits and did not make a negative recommendation against this intervention. 43Evidence and recommendations Population: Adults with normal cognition or MCI with hearing loss Intervention: Interventions to treat hearing loss (e.g. hearing aids) Comparison: Care as usual or no intervention Outcomes: • Critical – Cognitive function – Incident MCI – Dementia • Important – Quality of life – Functional level (ADL, IADL) – Adverse events – Drop-out rates For adults with normal cognition or MCI and hearing loss, is treatment of hearing loss more effective than usual care, or no intervention in reducing the risk of cognitive decline and/or dementia? 3.12 MANAGEMENT OF HEARING LOSS BACKGROUND Hearing loss is a prevalent age-related disorder. As the fourth leading cause of years lived with disability in the global population (WHO, 2012), it is estimated to affect one in three adults aged 65 and older, with this statistic growing annually (Wilson et al., 2017). The implications of hearing loss, however, are often underestimated both at the individual and population level (Blustein et al., 2018). Hearing impairment has debilitating consequences on functional ability and social and emotional well-being. Deteriorations in hearing impact on individuals’ ability to communicate with others, which in turn can result in feelings of frustration, isolation, loneliness (Ciorba et al., 2012). Older adult populations who already experience the isolating effects of age-related factors, such as diminished mobility, driving cessation, death of partners or living alone, are particularly vulnerable to these psychosocial impacts. Hearing loss is also associated with increased risk of cognitive decline or dementia (Lin et al., 2013). A recent meta-analysis of prospective cohort studies showed that the relative risk of hearing impairment on incident Alzheimer’s and MCI was 2.82 (95% CI: 1.47–5.42). (Zheng et al., 2017). Additionally, a meta-analysis published by the Lancet Commission showed that hearing loss can almost double the risk of incident dementia (RR = 1.94, 95% CI: 1.38–2.73) (Livingston et al., 2017). Hearing loss and cognitive impairment or dementia, individually, and in combination, predict functional ability and burden of care. Hearing loss interventions, therefore, have the potential to substantially improve outcomes for older people on multiple domains. 44 Risk reduction of cognitive decline and dementia: WHO guidelines WHO Guidelines on integrated care for older people (ICOPE) (http://www.who.int/ageing/publications/guidelines-icope/en/) For older adults, WHO recommends the following: Screening followed by provision of hearing aids should be offered to older people for timely identification and management of hearing loss. Considerations for recommendation: • Community awareness about hearing loss and the positive benefits of audiological rehabilitation in older people, through community case finding and outreach activities, should be promoted. • Health care professionals should be encouraged to screen older adults for hearing loss by periodically questioning them about their hearing. Audiological examination, otoscopic examination and the whispered voice test are also recommended. • Hearing aids are the treatment of choice for older people with hearing loss, because they minimize reduction in hearing and improve daily functioning. • Medications should be reviewed for potential ototoxicity. • People with chronic otitis media or sudden hearing loss, or who fail any screening tests, should be referred to an otolaryngologist. There is insufficient evidence to recommend use of hearing aids to reduce the risk of cognitive decline and/or dementia. Screening followed by provision of hearing aids should be offered to older people for timely identification and management of hearing loss as recommended in the WHO ICOPE guidelines. RECOMMENDATIONS AND CONSIDERATIONS 45Evidence and recommendations SUPPORTING EVIDENCE AND RATIONALE For interventions to treat hearing loss (e.g. hearing aids) versus care as usual or no intervention, evidence was extracted from one systematic review examining adults with normal cognition and hearing loss (Cherko et al., 2016). No evidence for adults with MCI was available. For cognitive function and quality of life, the quality of evidence is very low. No meta-analyses were performed and results were reported narratively with no numerical data to support conclusions (Cherko et al., 2016). Based on two studies including measures of cognitive function, the review concluded that while hearing aids use was found to be associated with improvements in cognitive function, these benefits may be limited in that cognitive improvements have been shown to revert to baseline at 1 year follow-up. They also concluded that use of hearing aids in older people was associated with improvements in quality of life outcomes based on two studies. Overall, the evidence does not favour either the intervention or the comparison. Hearing aids may improve quality of life but the amount of evidence available is limited. No data are available for incident MCI or dementia, functional level (ADL, IADL), adverse events or drop-outs. The GDG concluded that there is currently insufficient evidence to recommend the use of hearing aids to reduce the risk of cognitive decline/dementia. The GDG also concluded that the use of hearing aids is important to correct hearing loss in older adults for their other benefits and recommend following the ICOPE guidelines in this regard. 46 Risk reduction of cognitive decline and dementia: WHO guidelines IMPLEME NTATION CONSIDE R ATIONS 4 47 Implementation considerations Countries will be supported to implement the guidelines through training of health care personnel and using centres of excellence on improved quality of care. The implementation will also be supported locally through the adoption of the Global action plan on the public health response to dementia 2017– 2025; the Comprehensive mental health action plan 2013–2020; and the Global action plan for the prevention and control of noncommunicable diseases 2013–2020 at country level. The national capacity building process will also be supported through WHO collaboration with international organizations and associations. Given that many of the interventions included in these guidelines are strongly related to the management of risk factors for CVD and diabetes, the implementation of these recommendations should be combined, whenever possible and in the relevant target population, with the ongoing prevention programmes to reduce the risk of these conditions. The optimal preventive effect may be obtained by addressing several risk factors at the same time. Collaboration among different stake- holders and multidisciplinary approaches will also be needed. The recommendations contained in these guidelines should be adapted into a locally appropriate document that can meet the needs of each country and its health services. WHO headquarters will work closely with the regional and country offices, as well as implementing partners and public health agencies at the national level, to ensure communication and country-specific adaptations of the guidelines, through regional and national meetings. As countries consider how to implement these guidelines, the budgetary and human resource requirements, and other health systems implications should be analysed to identify which inputs and systems are currently available, and which areas require additional investment. These may include training of health workers, supply of medicines and adaptations of health information systems to collect data on service utilization. To support country implementation, WHO will produce a series of subsidiary tools that will address clinical and service delivery aspects of the imple- mentation of the recommendations included in these guidelines. 48 Risk reduction of cognitive decline and dementia: WHO guidelines PUBLIC ATION, DISSEMINATION AND EVALUATION 5 49Publication, dissemination and evaluation 5.1 PUBLICATION AND DISSEMINATION The guidelines will be disseminated as a print publication and electronically on a dedicated internet space on the WHO website. The guidelines will be disseminated through both the mental health and NCD dissemination activities of the Global action plan on the public health response to dementia 2017–2025 (such as the Global Dementia Observatory knowledge exchange platform), the Comprehensive mental health action plan 2013–2020 and the Global action plan for the prevention and control of noncommunicable diseases 2013–2020. These guidelines will be appended to the mhGAP guidelines and disseminated through the mhGAP evidence resource centre and other mhGAP derivative products, including the mhGAP Intervention guide. Since these guidelines are linked to other WHO guidelines such as NCD and ICOPE guidelines and other resources on ageing, dissemination will occur along with these guidelines. The guidelines and products are developed in English, and will be translated into other WHO official languages for wider dissemination and in collaboration with WHO regional offices. Local adaptation is necessary to ensure that the guidelines are appropriate for the local conditions that affect the care of people with cognitive decline and dementia in health facilities and the community. Adaptation will include language translation and ensuring that the interventions are acceptable in the specific socio-cultural context and suitable for the local health system. The ADAPTE manual for guideline adaptation outlines the approach to be used.12 The acceptability and applicability of the recommendations will be examined in the specific cultural context, including the availability of health services, expertise and resources, and the organization of health services, as well as population characteristics, cultural beliefs and value judgments. Relevant departments in ministries of health will be notified of the guidelines through WHO regional and country offices. A briefing package will be prepared for technical officers outside of WHO headquarters that will include an executive summary and Q&A related to policy and programme implications. Dissemination will also be encouraged through WHO collaboration with international organizations and associations. In coordination with WHO Communications, the media will be notified of the new guidelines. Countries will be supported to implement the guidelines through the training of health care personnel on improved quality of care and using centres of excellence. Capacity-building activities will be undertaken through web-based platforms and regional workshops. Dissemination will be supported by the publication of selected systematic reviews and evidence in peer review journals, and presentations and workshops at key conferences and events. 12 http://www.g-i-n.net/document-store/working-groups-documents/adaptation/adapte-resource-toolkit-guideline-adaptation-2-0.pdf 50 Risk reduction of cognitive decline and dementia: WHO guidelines 5.2 MONITORING AND EVALUATION Following publication of these guidelines, WHO will continue to collect regular feedback from implemen- tation activities in order to evaluate their usefulness and impact. Information will be used to evaluate the quality of the guidelines and to identify areas where improvement is required. WHO’s Global Dementia Observatory, an online data and knowledge exchange platform for dementia, provides the framework for monitoring implementation of these guidelines13. 5.3 IMPLICATIONS FOR FURTHER RESEARCH The majority of the recommendations align with current guidelines for the treatment of pre-existing health conditions and dependencies. However, more evidence is needed to determine what the impact of these interventions are on the outcomes of incident MCI or dementia. No recommendations could be made for social activity and hearing loss due to insufficient evidence. Some trials are currently being conducted for hearing loss interventions. These guidelines may need to be updated once these results are released. However, currently there is little research being conducted that examines the impact of social activity on cognitive decline and dementia. Part of the difficulty in conducting this type of research is that social activity is difficult to define and quantify, and it is also difficult to differentiate it from the physical or mental activities which are often a component of this type of intervention. The development of standardized protocols for social activity interventions may therefore need to precede the running of clinical trials. Some of the evidence presented here is based on RCTs with relatively short follow-up periods (e.g. interventions for cognitive training, depression, social activity). This limits our ability to judge the potential impact of the interventions on the development of cognitive decline and dementia as they have long prodromal periods. More evidence needs to be gathered with longer term follow-up periods in order to more accurately estimate the impact of these interventions in reducing the risk of cognitive decline/ dementia in the long run. In addition, more research needs to be conducted to understand how timing affects the impact of these interventions on cognitive decline and dementia (e.g. mid-life versus late life physical activity). The prevalence of dementia is increasing in LMIC. However, the majority of clinical trials have been conducted in high-income countries, so there is very little evidence on the effectiveness of these interventions for LMIC. More attention needs to be given to understanding how best to reduce the risk of cognitive decline and dementia in LMIC. 13 Available at: https://www.who.int/mental_health/neurology/dementia/Global_Observatory/en/ 51 The PICO questions applied to gather evidence for the preparation of these guidelines included interventions on single risk factors. However, given the multifactor etiology of dementia, and the interaction of risk factors across the lifestyle of each individual, multidomain approaches have been increasingly researched and show potential to be more effective than single-factor strategies. Recently, three large multidomain RCTs – the Finnish Geriatric Intervention Study to Prevent Cognitive Impairment and Disability (FINGER); Effect of long-term omega-3 PUFA supplementation with or without multidomain intervention on cognitive function in elderly adults with memory complaints (MAPT); and Prevention of dementia by intensive vascular care (preDIVA) – have been completed (Ngandu et al., 2015; Andrieu et al., 2017; Moll von Charante et al., 2016). Although only the multidomain lifestyle intervention tested in FINGER reported significant results in the primary analysis, the overall findings from the three trials suggested that targeting individuals at increased risk could be the most effective strategy. In particular, other interventions showed significant results in participants with an elevated dementia risk score, in MAPT (as in FINGER), and individuals with untreated hypertension at baseline, in preDIVA, respectively. In the context of multidomain interventions, new technologies and e-health solutions could also provide useful tools for risk reduction, by broadening the reach of such interventions (Barbera et al., 2018). Given the heterogeneity of risk profiles among older populations, global initiatives, such as the World Wide FINGERS Network (www.wwfingers.com), have been launched recently with the specific purpose of testing similar interventions, which have been adapted in diverse geographical and cultural settings (Kivipelto et al., 2017). Further research on the efficacy of multidomain interventions that are adjusted to specific geographical and cultural contexts, in populations at increased risk, and by making use of novel e-health tools (if possible) is, therefore, needed. 5.4 FUTURE REVIEW AND UPDATE It is expected that the guidelines will be reviewed again in five years. New evidence in these areas is regularly monitored by the WHO Secretariat, in consultation with GDG members and technical experts identified for the evidence review process, WHO collaborating centres and academic institutions. With the increasing evidence from multidomain intervention trials expected to be reported in the coming years, the addition of a PICO question addressing such interventions should be considered in future revisions. Publication, dissemination and evaluation 52 Risk reduction of cognitive decline and dementia: WHO guidelines Albanese E, Launer LJ, Egger M, Prince MJ, Giannakopoulos P, Wolters, FJ et al. (2017). 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Corrado Barbui M European University of Verona, Italy Mental health research and training, public health, health systems strengthening 5. Adelina Comas-Herrera F European London School of Economics, United Kingdom Health economist, dementia research 6. Amit Dias M South-East Asia Department of Preventive and Social Medicine, Goa Medical College, India Dementia, public health in LMIC 7. Cleusa P Ferri F Americas Federal University of São Paulo, Brazil Research in dementia and 10/66 group, dementia risk factors in LMIC 8. Riadh Gouider M Eastern Alzheimer’s Centre, Razi Hospital, Tunis; Tunisian Society of Neurology, Tunisia Dementia research in areas of epidemiology, neuropsychological assessment and risk factors 9. Shinya Ishii M Western Pacific Health and Welfare Bureau for the Elderly; Ministry of Health, Labour and Welfare, Tokyo, Japan Health policy, neurology of Alzheimer’s disease and dementia 10. Yves Joanette M Americas Canadian Institutes of Health Research, Government of Canada Dementia research 11. Joseph Kibachio M African Ministry of Health, Nairobi, Kenya Public health, health policy, NCDs 12. Miia Kivipelto F European Karolinska Institutet, Stockholm University, Stockholm, Sweden Dementia research in the field of early diagnosis and prevention 13. Shanthi Mendis F South-East Asia Independent consultant in global health, Sri Lanka NCDs and cardiology, health policy development, capacity strengthening, implementation research particularly in LMIC 61Annex 1: Guideline development group members Name Gender WHO region Affiliation Area of expertise 14. Ayesha Motala F African University of KwaZulu-Natal, South Africa Epidemiology and genetics of diabetes mellitus 15. Ronald Petersen M Americas Mayo Clinic, United States of America Memory disorders, aging and Alzheimer's disease 16. Dorairaj Prabhakaran M South-East Asia Centre for Chronic Conditions and Injuries & Public Health Foundation of India Cardiovascular disease prevention, epidemiology, developmental origin, and biomarkers of cardiovascular diseases and diabetes 17. Martin Prince M European Health Foundation of India Public health aspects of ageing and chronic disease in LMIC, dementia, guideline development 18. Suzana Shahar F Western Pacific Universiti Kebangsaan, Malaysia Nutrition, micronutrients, dietary interventions 19. Ameenah Bibi Mia Sorefan F African Alzheimer’s Association of Mauritius; Ministry of Health & Quality of Life, Mauritius Ageing, dementia and Alzheimer’s disease 20. Kusumadewi Suharya (Dy) F Western Pacific Alzheimer’s Disease International, Indonesia Dementia and public health 21. Huali Wang F Western Pacific Dementia Care & Research Center, Peking University Institute of Mental Health, China Dementia research and education 62 Risk reduction of cognitive decline and dementia: WHO guidelines ANNEX 2: ASSESSMENT OF CONFLICT OF INTEREST INDIVIDUALS INVOLVED IN ASSESSMENT OF CONFLICT OF INTEREST: Tarun Dua, Programme Manager, Department of Mental Health and Substance Abuse, WHO headquarters. Neerja Chowdhary, Technical Officer, Department of Mental Health and Substance Abuse, WHO headquarters. To comply with WHO’s Conflict of Interest Policy, the Secretariat followed the revised Guidelines for Declaration of Interests (WHO Experts).14 Declarations of interest (DoI) were requested from: (a) all GDG members; (b) all external partners involved in the evidence review process; (c) all experts invited to review the evidence profiles. A letter requesting completion of a DoI form and submission of a curriculum vitae as well as was sent to all GDG members, the external review group and external partners. They were asked to agree to the publication of a summary of declarations in the guide- line. The GDG members were also required to complete a confidentiality undertaking. Once received, the WHO Secretariat reviewed the DoIs as well as additional information (internet and bibliographic database search) and evaluated if there are any conflicts of interest and if so, whether these require a management plan. In order to enhance its management of conflicts of interest as well as strengthen public trust and transparency in connection with WHO meetings and activities involving the provision of technical/normative advice, the names and brief biographies members being considered for participation in the GDG were disclosed for public notice and comment prior to the meeting. At the beginning of the GDG meeting, the DoI of each GDG member were presented and GDG members and external partners were asked to update their DoI with relevant changes by notifying the responsible technical officer. The follow up and suggested actions agreed upon to manage the conflicts of interest declared are summarized below: • If members declare interests that are relevant to the meeting, the WHO Secretariat will note any potential conflict of interest and summarize these and then decide whether and to what extent they can participate in the guideline development. • If the conflict is deemed to be significant, the WHO Secretariat will decide if the conflict necessitates exclusion of that person from participating in the guideline process or if their participation should be limited. • These decisions are made on a case-by-case basis. Below is a summary of the Declared conflicts of interest and how these were managed. A. GDG MEMBERS GDG Members with no relevant interests declared on the DOI form and no relevant interests found in the CV 1. Kaarin J Anstey, University of New South Wales, Sydney, Australia; 2. Kimberly Ashby-Mitchell, Caribbean Public Health Agency, Port of Spain, Trinidad and Tobago; 3. Corrado Barbui, University of Verona, Verona, Italy. 4. Amit Dias, Department of Preventive and Social Medicine, Goa Medical College Bambolim, Goa, India; 5. Suharya Dy (Kusumadewi), Alzheimer’s Disease International, Jakarta, Indonesia; 6. Cleusa P. Ferri, Federal University of Sao Paulo, Sao Paulo, Brazil. 7. Riadh Gouider, Razi Hospital, Faculty of Medicine, Tunis, Tunisia; 8. Shinya Ishii, Ministry of Health, Labour and Welfare, Tokyo, Japan; 14 WHO Office of Compliance, Risk Management and Ethics (CRE) http://intranet.who.int/homes/cre/ethics/doiexperts/ 63 9. Yves Joanette, Canadian Institute of Health Research, Government of Canada. 10. Joseph Kibachio, Ministry of health, Nairobi, Kenya; 11. Shanthi Mendis, Colombo, Sri Lanka; 12. Dorairaj Prabhakaran, Public Health Foundation of India, New Delhi, India; 13. Ameenah Bibi Mia Sorefan, Ministry of Health and Quality of Life, Quatre-Bornes, Mauritius GDG members who have declared an interest on the DOI form or where a potentially relevant interest has been noted from the CV Charles Alessi, Public Health England, London, United-Kingdom Dr Alessi declared that the travel costs for the GDG meeting were covered by his organization. Action: This interest was deemed insignificant or minimal and unlikely to affect, or be reasonably perceived to affect, Dr Alessi’s judgement in the development of the present guidelines. He is deemed to be participating in the guideline development process in an individual capacity and not representing any organization. No further action was necessary Adelina Comas-Herrera, London School of Economics, London, United-Kingdom Dr Comas-Herrera declared in her DoI from that she had received research support routed via her University on various research projects on dementia in 2015 and 2016. These amounts were used to pay her salary by the University. She also declared receiving a payment of US$1000 in 2017 to advise a pharmaceutical company, Axovant Sciences GmbH. The topic was on the availability of data on dementia costs for a medicine that has since been withdrawn due to lack of effectiveness. Action: It was felt that this interest is insignificant or minimal and unlikely to affect, or be reasonably perceived to affect, Dr Comas-Herera’s judgement in the development of the present guidelines. No further action was necessary. Miia Kivipelto, Karolinska Institutet, Stockholm, Sweden Dr Kivipelto declared in her DoI form that she currently serves on the Advisory Board of a Finnish company that focuses on early diagnosis and e-health solutions for which she received €2500. She is also on the Governance committee of AARP, a non-profit organization for healthy ageing for which she received €800. She also declared that she has received research grants related to risk factors for dementia and is a founding member of World-Wide Fingers, an interdisciplinary network to share experiences, harmonize data and plan joint international initiatives for the risk reduction of cognitive decline and dementia. Action: This interest was deemed insignificant or minimal and unlikely to affect, or be reasonably perceived to affect, Dr Kivipelto’s judgement in the development of the present guidelines. She is deemed to be participating in the guideline development process in an individual capacity and not representing any organization. No further action was necessary Ayesha Motala, University of KwaZulu-Natal, Durban, South Africa. Dr Motala declared that as a public servant working in a government institute, she seeks sponsorships to meetings from various organizations, especially when her scientific abstracts are accepted for presentations. The sponsorships are merely for attending the meetings, with no obligation to the sponsoring companies. Annex 2: Assessment of conflict of interest 64 Risk reduction of cognitive decline and dementia: WHO guidelines Details of such sponsorship for which she received a total amount of US$26 000: 4–8 December 2017: International Diabetes Federation (IDF) Congress, Abu Dhabi: Sanofi Aventis sponsorship for travel and accommodation; 11–15 September 2017: European Association for the Study of Diabetes (EASD) Congress, Lisbon: Pfizer sponsorship for travel and accommodation; 8–13 June 2018: American Diabetes Association (ADA), San Diego: Boehringer Ingelheim sponsorship for travel and accommodation: a member of her collaborating scientific team presented a paper. Action: It was felt that this interest is insignificant or minimal and unlikely to affect, or be reasonably perceived to affect, Dr Motala’s contribution as an external reviewer for these guidelines. No further action was necessary. Ronald C. Petersen, Mayo Clinic, Rochester, USA Dr Petersen declared that he is a clinical trials consultant for five pharmaceutical companies: from four of these (Roche Inc, Merck Inc, Genetech Inc and GE Healthcare) he receives less than US$ 10 000 and from one (Biogen Inc) he receives less that US$ 15 000 as consultancy fees. Action: It was felt that this interest is unlikely to affect, or be reasonably perceived to affect, Dr Petersen’s contribution as an external reviewer for these guidelines since these grants are not related to the topic of interest. No further action was necessary. Martin Prince, King’s College London, London, United Kingdom Professor Prince declared in his DOI form that he currently receives research support through a grant from the National Institute of Health Research (NIHR, UK) amounting to £7 million over four years. Professor Prince is the PI and 20% of his salary costs are charged to the grant. The work focuses on health systems strengthening in sub Saharan Africa and one theme relates to the topic of these guidelines i.e. integrated primary healthcare for multimorbid conditions. Action: It was felt that this interest is insignificant or minimal and unlikely to affect, or be reasonably perceived to affect, Professor Prince’s judgement in the development of the present guidelines. No further action was necessary Suzana Shahar, Universiti Kebangsaan Malaysia, Selangor, Malaysia Dr Sahar has declared in her DoI form that she has a clinical trial agreement through her University with Biotropics, a company that develops bio-resources into superior natural health product. The research involves evaluating the efficacy of Asian traditional herbs in improving cognition and mood. The funding amount is US$ 100 000 between 2014 and 2018. Action: It was felt that this interest is insignificant or minimal and unlikely to affect, or be reasonably perceived to affect, Dr Sahar’s contribution as an external reviewer for these guidelines. No further action was necessary Huali Wang, Dementia Care & Research Center, Peking University Institute of Mental Health, Beijing, China. Dr Wang declared in her DoI form that prior to 2016, she had worked as a consultant with Neowave Inc. to develop a tablet-based cognitive training program. She also declared that she had received support for travelling to meetings form Eisai China amounting to US$ 7000 prior to 2017. The meeting were all Alzheimer’s Disease International (ADI) conferences. 65 Action: It was felt that this interest is insignificant or minimal and unlikely to affect, or be reasonably perceived to affect, Dr Wang’s contribution as an external reviewer for these guidelines. No further action was necessary B. EXTERNAL REVIEW GROUP Members of the external review group with no relevant interests declared on the DOI form and no relevant interests found in the CV 1. Abdullah Al Khatami, Ministry of Health, Saudi Arabia 2. Alistair Burns, University of Manchester, UK 3. Linda Clare, University of Exeter, UK 4. Jacqueline Dominguez, Institute for dementia care Asia, Quezon city, Philippines 5. Maelënn Guerchet, The Global Observatory for Ageing and Dementia Care, King's College London, UK 6. Mariella Guerra, Institute of Memory, Depression and Related Disorders – IMEDER, Lima, Peru 7. Luis Miguel F. Gutiérrez Robledo, Instituto Nacional de Geriatría, Institutos Nacionales de Salud de México, Mexico City, Mexico 8. Vladimir Hachinski, University of Western Ontario in London, Ontario, Canada 9. Qurat ul Ain Khan, Aga Khan University Hospital, Karachi, Pakistan. 10. Sebastian Koehler, Maastricht University, The Netherlands 11. Jae-hong Lee, University of Ulsan College of Medicine, Seoul, Korea 12. Gill Livingstone, University college London, UK 13. Jean Claude Mbanya, Doctoral School of Life Sciences, Health and Environment, University of Yaoundé I, Cameroon. 14. James McKillop, Service user group representative, UK 15. Rajat Ray, National Drug Dependence Treatment Centre, All India Institute of Medical Sciences, New Delhi, India 16. Helen Rochford Brennan, European Working Group of people with dementia, Ireland 17. Kate Swaffer, Dementia Alliance International, Australia 18. Weili Xu, Karolinska Institute, Finland Members of the external review group who have declared an interest on the DOI form or where a potentially relevant interest has been noted from the CV Emiliano Albanese, Universita della Svizzera italiana, Switzerland Dr Albanese declared in his DoI form that he receives research support from the Economic and Research Council UK as part of the STRIDE (Strengthening responses to dementia in developing countries) research consortium which focuses on dementia research in low and middle income countries. The amount of US$ 50 000 is provided to the institution to which he is affiliated. Action: It was felt that this interest is insignificant or minimal and unlikely to affect, or be reasonably perceived to affect, Dr Albanese’s contribution as an external reviewer for these guidelines. No further action was necessary. Hillary Doxford, 3 Nations Dementia Working Group, UK Ms Doxford declared in her DoI form that she has served on a grant review panel assessing and prioritizing grant applications for funding dementia research projects for the National Institute for Health Research, UK. The income she received for this was £450. She is also a voluntary member of the Dementia Programme Board in the UK Department of Health and Social Care as a person with lived experience. Action: It was felt that this interest is insignificant or minimal and unlikely to affect, or be reasonably perceived to affect, Ms Doxford’s contribution as an external reviewer for these guidelines. No further action was necessary. Annex 2: Assessment of conflict of interest 66 Risk reduction of cognitive decline and dementia: WHO guidelines Elaine Rashbrook, Public Health England, UK Dr Rashbrook declared in her DoI form that she is employed by Public Health England (PHE), a government agency, as Consultant Specialist Life Course since 2015. PHE supports work on dementia risk reduction in line with the government strategy. There is no identified financial value for the work. Action: It was felt that this interest is insignificant or minimal and unlikely to affect, or be reasonably perceived to affect, Dr Rashbrook’s contribution as an external reviewer for these guidelines. She is deemed to be providing her review in an individual capacity and not representing any organization. No further action was necessary. Andrew Sommerlad, University College London, UK Dr Sommerlad declared in his DoI form that he receives research support from the Wellcome Trust in the form of a personal research fellowship to examiner whether social isolation is a risk factor for dementia The amount of funding is £201 311 from 2016 to 2019. Action: It was felt that this interest is insignificant or minimal and unlikely to affect, or be reasonably perceived to affect, Dr Sommerlad’s contribution as an external reviewer for these guidelines. No further action was necessary B. EXTERNAL PARTNERS External partners with no relevant interests declared on the DOI form and no relevant interests found in the CV 1. Mariagnese Barbera, University of Eastern Finland, Kuopio, Finland; 2. Nicole A. Ee, University of New South Wales, Sydney, Australia; 3. Jenni Kumlala, Karolinska Institutet, Stockholm, Sweden; 4. Ruth Peters, University of New South Wales, Sydney, Australia; 5. Lidan Zheng, University of New South Wales, Sydney, Australia. None of the external partners declared relevant interests on the DOI forms nor were relevant interests found in the CV.   67 ANNEX 3: SCOPING QUESTIONS INTERVENTIONS ADDRESSING LIFESTYLE AND BEHAVIOUR RISK FACTORS 1. Physical activity interventions For adults with normal cognition or mild cognitive impairment, are physical activity interventions more effective than usual care or no intervention in reducing the risk of cognitive decline and/or dementia? P: Adults (age above 18 years) with normal cognition or MCI I: Physical activity interventions (aerobic, resistance training or multicomponent physical activity) C: Care as usual or no intervention O: • Critical – Cognitive function – Incident MCI – Dementia 2. Tobacco cessation interventions For adults with normal cognition or mild cognitive impairment who use tobacco, are interventions for tobacco cessation more effective than usual care or no intervention in reducing the risk of cognitive decline and/or dementia? P: Adults with normal cognition or MCI who use tobacco I: Interventions for tobacco cessation (behavioural interventions and pharmacological interventions including nicotine replacement therapy, bupropion, varenicline) C: Care as usual or no intervention O: • Critical – Cognitive function – Incident MCI – Dementia 3. Nutritional interventions 3a. For adults with normal cognition or mild cognitive impairment, are nutritional interventions such as dietary supplements more effective than usual care or no intervention in reducing the risk of cognitive decline and/or dementia? P: Adults with normal cognition or MCI I: Dietary supplements (e.g. B vitamins, antioxidants, omega-3 and ginkgo); C: Care as usual or no intervention O: • Critical – Cognitive function – Incident MCI – Dementia • Important – Quality of life – Functional level (ADL, IADL) – Adverse events – Drop-out rates • Important – Quality of life – Functional level (ADL, IADL) – Adverse events – Drop-out rates • Important – Quality of life – Functional level (ADL, IADL) – Adverse events – Drop-out rates Annex 3: Scoping questions 68 Risk reduction of cognitive decline and dementia: WHO guidelines 3b. For adults with normal cognition or mild cognitive impairment, are nutritional interventions such as healthy dietary patterns (e.g. Mediterranean diet) more effective than usual care or no intervention in reducing the risk of cognitive decline and/or dementia? P: Adults with normal cognition or MCI I: Healthy dietary pattern (e.g. Mediterranean diet) C: Care as usual or no intervention O: • Critical – Cognitive function – Incident MCI – Dementia 4. Interventions for alcohol use disorder For adults with normal cognition or mild cognitive impairment and alcohol use disorder, are behavioural and psychological interventions to treat alcohol use disorder more effective than usual care or no intervention in reducing the risk of cognitive decline and/or dementia? P: Adults with normal cognition or MCI and excessive use of alcohol I: • Behavioural and psychological interventions to treat alcohol use disorder (e.g. motivational interviewing) • Pharmacological interventions to treat alcohol use disorder C: Care as usual or no intervention O: • Critical – Cognitive function – Incident MCI – Dementia • Important – Quality of life – Functional level (ADL, IADL) – Adverse events – Drop-out rates • Important – Quality of life – Functional level (ADL, IADL) – Adverse events – Drop-out rates 69 SPECIFIC INTERVENTIONS 5. Cognitive interventions For adults with normal cognition or mild cognitive impairment is cognitive stimulation or cognitive training more effective than usual care or no intervention in reducing the risk of cognitive decline and/ or dementia? P: Adults with normal cognition or MCI I: • Cognitive stimulation • Cognitive training C: Care as usual or no intervention O: • Critical – Cognitive function – Incident MCI – Dementia 6. Social activity For adults with normal cognition or mild cognitive impairment is preserving and promoting a high level of social activity more effective than usual care or no intervention in reducing the risk of cognitive decline and/or dementia? P: Adults with normal cognition or MCI I: Preservation and promotion of social activity including community and family engagement C: Care as usual or no intervention O: • Critical – Cognitive function – Incident MCI – Dementia • Important – Quality of life – Functional level (ADL, IADL) – Adverse events – Drop-out rates • Important – Quality of life – Functional level (ADL, IADL) – Adverse events – Drop-out rates Annex 3: Scoping questions 70 Risk reduction of cognitive decline and dementia: WHO guidelines INTERVENTIONS FOR HEALTH CONDITIONS 7. Weight management For adults with normal cognition or mild cognitive impairment who are overweight or obese, are interventions for weight reduction (or control of obesity) more effective than usual care or no intervention in reducing the risk of cognitive decline and/or dementia? P: Adults with normal cognition or MCI who are overweight or obese I: Weight management • Non-pharmacological interventions, e.g. cognitive-behavioural intervention strategies, lifestyle interventions • Pharmacological interventions, e.g. weight-loss medication (e.g. orlistat) C: Care as usual or no intervention O: • Critical – Cognitive function – Incident MCI – Dementia 8. Management of hypertension For adults with normal cognition or mild cognitive impairment and hypertension, is treatment of hypertension more effective than placebo/no intervention in reducing the risk of cognitive decline/dementia? P: Adults with normal cognition or MCI with hypertension I: Antihypertensive medication, lifestyle interventions C: Placebo/no intervention O: • Critical – Cognitive function – Incident MCI – Dementia 9. Management of diabetes mellitus For adults with normal cognition or mild cognitive impairment and diabetes mellitus, is treatment of diabetes more effective than placebo/no intervention in reducing the risk of cognitive decline and/or dementia? P: Adults with normal cognition or MCI with diabetes mellitus I: • Medications for glycaemic control • Diet and lifestyle interventions C: Placebo/no intervention O: • Critical – Cognitive function – Incident MCI – Dementia • Important – Quality of life – Functional level (ADL, IADL) – Adverse events – Drop-out rates • Important – Quality of life – Functional level (ADL, IADL) – Adverse events – Drop-out rates • Important – Quality of life – Functional level (ADL, IADL) – Adverse events – Drop-out rates 71Annex 3: Scoping questions 10. Management of dyslipidaemia For adults with normal cognition or mild cognitive impairment and dyslipidaemia, is treatment of dyslipidaemia more effective than placebo or no intervention in reducing the risk of cognitive decline and/or dementia? P: Adults with normal cognition or MCI with dyslipidaemia I: • Statins (e.g. simvastatin and pravastatin) • Lifestyle interventions C: Placebo or no intervention O: • Critical – Cognitive function – Incident MCI – Dementia 11. Management of depression For adults with normal cognition or mild cognitive impairment and depressive disorder, is treatment of depression more effective than usual care, placebo or no intervention in reducing the risk of cognitive decline and/or dementia? P: Adults with normal cognition or MCI with moderate to severe depressive disorder I: • Pharmacological interventions to treat depression (antidepressant medication) • Psychological interventions to treat depression (e.g. cognitive behavioural therapy, problem-solving therapy, interpersonal therapy, behavioural activation) C: Care as usual or placebo or no intervention O: • Critical – Cognitive function – Incident MCI – Dementia 12. Management of hearing loss For adults with normal cognition or mild cognitive impairment and hearing loss, is treatment of hearing loss more effective than usual care, or no intervention in reducing the risk of cognitive decline and/or dementia? P: Adults with normal cognition or MCI with hearing loss I: Interventions to treat hearing loss (e.g. hearing aids) C: Care as usual or no intervention O: • Critical – Cognitive function – Incident MCI – Dementia • Important – Quality of life – Functional level (ADL, IADL) – Adverse events – Drop-out rates • Important – Quality of life – Functional level (ADL, IADL) – Adverse events – Drop-out rates • Important – Quality of life – Functional level (ADL, IADL) – Adverse events – Drop-out rates 72 Risk reduction of cognitive decline and dementia: WHO guidelines ANNEX 4: EVIDENCE REVIEW METHODOLOGY Comprehensive searches of major bibliographic databases were conducted to identify one systematic review that matched each of the outcomes for each of the PICO questions. The aim was to identify systematic reviews that were timely, of high quality and relevant to each of the PICO questions. The search strategies differed slightly between the two teams (based in the Karolinska Institutet, Sweden and University of New South Wales, Australia. However, in general, the following process was employed: 1. Search for systematic reviews (including meta- analyses) that were published in the last 2 years for each of the PICO questions. The searches were run from April to June 2018. 2. If no relevant high-quality systematic reviews were identified from the 2 years for any of the PICO questions, the search was expanded to include systematic reviews from the last 5 years for that PICO question. For the relevant PICO questions, the 2016 AHRQ systematic review was also consulted. The aim of the AHRQ review was to examine interventions to prevent cognitive decline and dementia. The review systematically searched records between January 2009 and September 2016. 3. For the hearing loss question, there was very limited evidence available, therefore searches were expanded to include all systematic reviews ever published. 4. Based on the GDG’s feedback during the GDG meeting in July 2018, the searches were expanded to further include systematic reviews of obser- vational studies. The searches were re-run July to August 2018. The following bibliographic databases were searched: • Bibliographic • Medline • Cochrane • PsycInfo • Embase • NICE. Relevant to LMIC • Global Index Medicus/Global Health Library • WHO regional database • WHOLIS • Database of impact evaluations • AJOL • KoreaMed • IndMED • HrCak • ArabPsycNet • HERDIN NeON • EurasiaHealth. After the searches were run using the search strategies listed below, titles and abstracts of all results were screened in Endnote; subsequently the full texts of those papers were reviewed that could not be excluded based on the title/abstract review. GRADE EVIDENCE TABLES For each outcome of each PICO question, one or more systematic reviews were then selected to be used within the GRADE evidence tables. The following criteria were used when selecting which systematic review to use within the GRADE evidence tables: • Published in the last 5 years, ideally 2 years (timeliness). • High quality (i.e. measured using AMSTAR 215 criteria). 15 Shea BJ, Grimshaw JM, Wells GA, Boers M, Andersson N, Hamel C et al (2007). Development of AMSTAR: a measurement tool to assess the methodological quality of systematic reviews. BMC Medical Research Methodology. 7:10. 73Annex 3: Scoping questions • Closely relevant to the PICO question. • Comprehensive systematic reviews given preference, where possible. • Cochrane reviews or other meta-analyses given preference, where possible/appropriate. The GRADE methodology involves rating the quality of the studies included in the systematic review according to study design, risk of bias, inconsistency, indirectness, imprecision, and publication bias. Together with the effect sizes of studies, an overall “certainty of evidence” is provided of either very low, low, moderate or high. GRADE evidence tables were completed using the GRADEpro online tool.16 The same criteria were used as for the mhGAP Intervention guide when completing the GRADE evidence tables in terms of the assessment of the quality of studies (for risk of bias, inconsistency, indirectness, imprecision, and publication bias).17 SEARCH STRATEGIES Separate searches were performed for each of the 12 PICO questions. Where PICO questions included both pharmacological and non-pharmacological interventions, searches were run separately for these. Filters were used in the bibliographic databases where possible to restrict the searches to systematic reviews and meta-analyses, as well as to humans. No further restrictions were employed, for example in terms of language (apart from the publication date, as mentioned above). The “advanced search” option was selected in bibliographic databases, where possible. PICO 1 For adults with normal cognition or mild cognitive impairment, are physical activity interventions more effective than usual care or no intervention in reducing the risk of cognitive decline and/or dementia? Search strategy (dementia OR cognit* OR “mild cognitive impairment” OR “Alzheimer disease” OR “dementia vascular” OR “dementia multi-infarct” OR MCI OR “cognitive dysfunction” OR neuropsychologi* OR “Health-Related Quality” Of Life OR “life quality” OR “Activities Daily Living” OR “Chronic Limitation of Activity” OR “Limitation of Activity, Chronic” OR ADL OR “activities of daily living” OR “Drug-Related Side Effects and Adverse Reactions” OR “Adverse Drug Event” OR “Adverse Drug Reaction” OR “Long Term Adverse Effects” OR “Adverse Effects, Long Term Disease-Free Survival” OR “Event-Free Survival” OR “Adverse effects”) AND (Exercise OR “exercise therapy” OR “Acute Exercise” OR “Aerobic Exercise” OR “Exercise Training” OR “Exercise, Aerobic” OR “Exercise, Isometric” OR “Exercise, Physical” OR “Isometric Exercise OR Physical Activity” OR “resistance training”) PICO 2 For adults with normal cognition or mild cognitive impairment who use tobacco, are interventions for tobacco cessation more effective than usual care or no intervention in reducing the risk of cognitive decline and/or dementia? Search strategy (dementia OR cognit* OR mild cognitive impairment OR Alzheimer disease OR dementia vascular OR dementia multi-infarct OR MCI OR cognitive dysfunction OR neuropsychologi* OR Health-Related Quality Of Life OR life quality OR Activities, Daily Living OR Chronic Limitation of Activity OR Limitation 16 https://gradepro.org/ 17 See http://www.who.int/mental_health/mhgap/evidence/mhgap_ guideline_process_2009.pdf 74 Risk reduction of cognitive decline and dementia: WHO guidelines of Activity, Chronic OR ADL OR activities of daily living OR Drug-Related Side Effects and Adverse Reactions OR Adverse Drug Event OR Adverse Drug Reaction OR Long Term Adverse Effects OR Adverse Effects, Long Term Disease-Free Survival OR Event-Free Survival OR Adverse effects) AND (Tobacco OR smoking OR Tobacco use cessation OR giving up smoking OR quitting smoking OR stopping smoking OR smoking cessation OR smoking reduction OR tobacco use cessation products OR varenicline OR nicotinic agonists OR Nicotine Inhalant OR Nicotine Lozenge OR Nicotine Lozenges OR Nicotine Nasal Spray OR Nicotine Patch OR Nicotine Polacrilex OR Nicotine Replacement Products OR Nicotine Transdermal Patch OR Smoking Cessation Products) AND (Behavior OR behaviour OR drug therapy OR pharmacologic therapy OR pharmacotherapy OR Cognitive behavioural therapy OR Cognitive behavioural therapy OR Drug therapy OR cognitive therapy OR online therapy OR treatment) PICO 3 3a. For adults with normal cognition or mild cognitive impairment, are nutritional interventions such as dietary supplements more effective than usual care or no intervention in reducing the risk/ progression of cognitive decline and/or dementia? 3b. For adults with normal cognition or mild cognitive impairment, are nutritional interventions such as healthy dietary patterns (e.g. Mediterranean diet) more effective than usual care or no intervention in reducing the risk/progression of cognitive decline and/or dementia? Search strategy (dementia OR cognit* OR “mild cognitive impairment” OR “Alzheimer disease” OR Alzheimer* OR “dementia vascular” OR “dementia multi-infarct” OR MCI OR “cognitive dysfunction” OR neuropsychologi* OR “Health-Related Quality Of Life” OR “life quality” OR “quality of life” OR “Activities of Daily Living” OR “Chronic Limitation of Activity” OR “Limitation of Activity, Chronic” OR ADL OR “activities of daily living” OR “Drug-Related Side Effects and Adverse Reactions” OR “Adverse Drug Event” OR “Adverse Drug Reaction” OR “Long Term Adverse Effects” OR “Adverse Effects, Long Term” OR “Disease-Free Survival” OR “Event-Free Survival” OR “Adverse effects”) AND (“Dietary supple- ments” OR “Dietary Supplementations” OR “Food Supplementations” OR “Food Supplements” OR “Herbal Supplements” OR Neutraceuticals OR Nutraceuticals OR Nutriceuticals OR diet or vitamin or food) PICO 4 For adults with normal cognition or mild cognitive impairment and alcohol use disorder, are behavioural and psychological interventions to treat alcohol use disorder more effective than usual care or no intervention in reducing the risk of cognitive decline and/or dementia? Search strategy (dementia OR cognit* OR mild cognitive impairment OR Alzheimer disease OR dementia vascular OR dementia multi-infarct OR MCI OR cognitive dysfunction OR neuropsychologi* OR Health-Related Quality Of Life OR life quality OR Activities, Daily Living OR Chronic Limitation of Activity OR Limitation of Activity, Chronic OR ADL OR activities of daily living OR Drug-Related Side Effects and Adverse Reactions OR Adverse Drug Event OR Adverse Drug Reaction OR Long Term Adverse Effects OR Adverse Effects, Long Term Disease-Free Survival OR Event-Free Survival OR Adverse effects) AND (Alcohol drinking OR Binge drinking OR Drunkenness OR alcohol intoxication OR alcoholism OR alcohol withdrawal) AND (Add in Behavior OR behaviour OR drug therapy OR pharmacologic therapy OR pharmacotherapy OR Cognitive behavioural therapy OR Cognitive behavioural therapy OR Drug therapy OR cognitive therapy OR online therapy OR treatment) 75Annex 3: Scoping questions PICO 5 For adults with normal cognition or mild cognitive impairment is cognitive stimulation or cognitive training more effective than usual care or no intervention in reducing the risk of cognitive decline and/or dementia? Search strategy (systemati* or meta analys*) and (dementia or cognit* or MCI or neuropsycholog* or Alzheimer*) and ("Brain training" OR "cognitive training" OR "Brain fitness" OR Games OR "Memory training" OR (Stimulation AND cognit*) PICO 6 For adults with normal cognition or mild cognitive impairment is preserving and promoting a high level of social activity more effective than usual care or no intervention in reducing the risk of cognitive decline and/or dementia? Search strategy ("social interaction" or "social Networks" or "social processes" or "social behaviour" or "social behavior" or "community networks" or "social media" or family) and (dementia or cognit* or "mild cognitive impairment" or MCI or "cognitive dysfunction" or neuropsycholog* or Alzheime*) and (systemati* or meta-analys*) PICO 7 For adults with normal cognition or mild cognitive impairment who are overweight or obese, are interventions for weight reduction (or control of obesity) more effective than usual care or no intervention in reducing the risk of cognitive decline and/or dementia? Search strategy (dementia OR cognit* OR mild cognitive impairment OR Alzheimer disease OR dementia vascular OR dementia multi-infarct OR MCI OR cognitive dysfunction OR neuropsychologi* OR Health-Related Quality Of Life OR life quality OR Activities, Daily Living OR Chronic Limitation of Activity OR Limitation of Activity, Chronic OR ADL OR activities of daily living OR Drug-Related Side Effects and Adverse Reactions OR Adverse Drug Event OR Adverse Drug Reaction OR Long Term Adverse Effects OR Adverse Effects, Long Term Disease-Free Survival OR Event-Free Survival OR Adverse effects) AND (Overweight OR Body weight or Body mass index OR weight loss OR Body weight changes) AND (Behavior OR behaviour OR drug therapy OR pharmacologic therapy OR pharmacotherapy OR Cognitive behavioural therapy OR Cognitive behavioural therapy OR Drug therapy OR cognitive therapy OR online therapy OR treatment OR Appetite depressants) PICO 8 For adults with normal cognition or mild cognitive impairment and hypertension, is treatment of hypertension more effective than placebo/no intervention in reducing reduce the risk of cognitive decline/dementia? Search strategy (systemati* or meta-analys*) and (dementia or cognit* or "mild cognitive impairment" or MCI or "cognitive dysfunction" or neuropsycholog* or Alzheimer's or Alzheimer) and (behaviour or behavior or "drug therapy" or "pharmacologic therapy" or pharmacotherapy or "cognitive behavioural therapy" or "cognitive behavioral therapy" or "cognitive therapy" or "online therapy" or "anti-hypertensive" or antihypertensive or treatment) and (hypertension or "blood pressure" or systolic or diastolic or prehypertension) 76 Risk reduction of cognitive decline and dementia: WHO guidelines PICO 9 For adults with normal cognition or mild cognitive impairment and diabetes mellitus, is treatment of diabetes more effective than placebo/no intervention in reducing the risk of cognitive decline and/or dementia? Search strategy (systemati* or meta-analys*) and (dementia or cognit* or "mild cognitive impairment" or MCI or "cognitive dysfunction" or neuropsycholog* or Alzheime*) .ab. and diabetes.af. and ("hypoglycemic agents" or treatment or therapy or pharmacotherapy or behaviour or behavior) PICO 10 For adults with normal cognition or mild cognitive impairment and dyslipidaemia, is treatment of dyslipidaemia more effective than placebo or no intervention in reducing reduce the risk of cognitive decline and/or dementia? Search strategy (dementia OR cognit* OR mild cognitive impairment OR Alzheimer disease OR dementia vascular OR dementia multi-infarct OR MCI OR cognitive dysfunction OR neuropsychologi* OR Health-Related Quality Of Life OR life quality OR Activities, Daily Living OR Chronic Limitation of Activity OR Limitation of Activity, Chronic OR ADL OR activities of daily living OR Drug-Related Side Effects and Adverse Reactions OR Adverse Drug Event OR Adverse Drug Reaction OR Long Term Adverse Effects OR Adverse Effects, Long Term Disease-Free Survival OR Event-Free Survival OR Adverse effects) AND (Cholesterol OR Hypercholes-terolemia OR lipo- proteins OR HDL cholesterol OR LDL cholesterol OR triglycerides) AND (Behavior OR behaviour OR drug therapy OR pharmalogic therapy OR pharmacotherapy OR Cognitive behavioural therapy OR Cognitive behavioural therapy OR Drug therapy OR cognitive therapy OR online therapy OR treatment OR statins OR Hydroxymethylglutaryl-CoA Reductase Inhibitors OR Anticholesteremic agents) PICO 11 For adults with normal cognition or mild cognitive impairment and depressive disorder, is treatment of depression more effective than usual care, placebo or no intervention in reducing the risk of cognitive decline and/or dementia? Search strategy (depression or depressive) and (systemati* or meta- analys*) and (dementia or cognit* or "mild cognitive impairment" or MCI or "cognitive dysfunction" or neuropsycholog* or Alzheimer's or Alzheimer*) and (treatment or therapy or pharmacotherapy or antidepressan* or antidepressiv*) PICO 12 For adults with normal cognition or mild cognitive impairment and hearing loss, is treatment of hearing loss more effective than usual care, or no intervention in reducing the risk of cognitive decline and/or dementia? Search strategy (hearing aids OR Cochlear implants Or hearing implants) AND (hearing loss OR deafness OR hearing impairment OR hypoacusis OR intervention OR treatment) AND (dementia OR cognit* OR mild cognitive impairment OR Alzheimer's disease OR dementia vascular OR dementia multi-infarct OR MCI OR cognitive dysfunction OR neuropsycholog*) 77Glossary Adverse event Any untoward medical occurrence in a patient or clinical investigation subject caused by health care management. Aerobic exercise A type of physical exercise that requires free oxygen to adequately meet energy demands via the aerobic metabolism. During aerobic exercise, oxygen is used to “burn” fats and glucose in order to produce adenosine triphosphate, the basic energy carrier for all cells. This type of exercise improves physical fitness by promoting the circulation of oxygen through the blood, is associated with an increased rate of breathing, and includes any type of exercise that, when performed at levels of intensity sufficiently supported by the aerobic metabolism, can be performed for extended periods of time. Behavioural activation A behavioural treatment for depression in which the person with depression is guided to increase the number of rewarding activities in his or her life. Body mass index An objective measurement calculated as body mass (or weight in kg) divided by the square of the body height (in metres), universally expressed in units of kg/m2. BMI is used as approximate indicator of the amount of tissue mass (muscle, bone, and fat) in an individual. Based on the correlation between BMI and the degree of risk for certain disease, such as diabetes or atherosclerosis, BMI values are categorized as underweight, normal weight, overweight, or obese; obesity can also be subcategorized in moderate severe and morbid. Cognitive behavioural intervention/therapy A type of psychological therapy that involves identifying and correcting distorted maladaptive beliefs, while using thought exercises and real experiences to facilitate symptom reduction and improved functioning. Cognitive decline The physiological decay of brain functions such as memory, attention or learning ability, for example, which is associated with the normal ageing process. It differs from cognitive impairment in that anyone who ages develops some kind of cognitive decline, although at different degrees. Cognitive impairment, instead, is normally the result of a pathological event: injury, disease, or increased levels of cognitive decline. Cognitive function Cerebral activities, i.e. reasoning, memory, attention, and language that lead to the attainment of information and knowledge. Cognitive stimulation Participation in a range of activities designed to improve cognitive and social functioning. Cognitive training Guided practice of specific standardized tasks designed to enhance particular cognitive functions. Dementia Dementia, a group of disorders characterized by a decline from a previously attained cognitive level that affects activities of daily living or social functioning. Dietary supplements Dietary supplements include vitamins, minerals, fibre, fatty acids, or amino acids, among other substances. They are either intended to provide nutrients in order to increase their consumption, or to provide non-nutrient chemicals which are claimed to have a biologically beneficial effect. Health-related quality of life An individual’s or a group’s perceived physical and mental health over time. As a multidimensional concept, it includes domains related to physical, mental, emotional and social functioning, and it is a way to assess the impact of health status on quality of life. Mediterranean diet A diet which consists of a high intake of cereals, fruits, fish, legumes, and vegetables and low intake of meat and dairy. G LOSSARY 78 Risk reduction of cognitive decline and dementia: WHO guidelines Mild cognitive impairment A disorder characterized by impairment of memory, learning difficulties and reduced ability to concentrate on a task for more than brief periods. There is often a marked feeling of mental fatigue when mental tasks are attempted, and new learning is found to be subjectively difficult even when objectively successful. None of these symptoms are so severe that a diagnosis of either dementia or delirium can be made. Motivational interviewing An established evidence-based practice in the treatment of individuals with substance use disorders that focuses on exploring and resolving ambivalence and centres on motivational processes within the individual that facilitate change. Multidomain intervention Intervention normally aimed to prevent/address a certain disease or condition by acting simultaneously on a range of risk factors, which may be either correlated or independent from each other. Nicotine replacement therapy A type of treatment that makes use of special products which provide small, steady doses of nicotine to help stop cravings and relieve withdrawal symptoms when an individual is trying to stop using tobacco. These products include nicotine gum, nicotine inhaler, nicotine nasal spray, nicotine lozenges, and nicotine patch. They do not contain any of the other chemicals found in tobacco products. Physical activity Any bodily movement produced by skeletal muscles that requires energy expenditure – including activities undertaken while working, playing, carrying out household chores, travelling, and engaging in recreational pursuits Physical exercise: subcategory of physical activity that is planned, structured, repetitive, and aims to improve or maintain one or more components of physical fitness. Problem-solving therapy A type of psychological therapy where the patient systematically identifies his or her problems; generates alternative solutions for each problem; selects the best solution; develops and conducts a plan; and evaluates whether this has solved the problem. Quality of life An individual’s perception of their position in life in the context of the culture and value systems in which they live and in relation to their goals, expectations, standards and concerns. Resistance training A form of physical exercise that, by the moving of the limbs against high loads or fixed resistances, causes skeletal muscles contraction, building their strength, anaerobic endurance, and size. The external resistance can be represented by dumbbells, rubber exercise tubing, the own body weight, bricks, bottles of water, machine specifically designed to this purpose, or any other object that causes the muscles to contract. The forces involved must be such that relatively few repetitions are possible without a substantial rest period. Resistance or strength training is primarily an anaerobic activity, although some proponents have adapted it to provide the benefits of aerobic exercise through circuit training. Social activity Social activities are varied and difficult to define, however they may include meeting friends, attending events or functions, volunteering or participating in occupational duties or group recreational activities.

For further information, please contact: Department of Mental Health and Substance Abuse, World Health Organization Avenue Appia 20 CH-1211 Geneva 27 Switzerland Email: whodementia@who.int Website: www.who.int/mental_health/ neurology/dementia/en ISBN 978-92-4-155054-3

RISK REDUCTION OF COGNITIVE DECLINE AND DEMENTIA WHO GUIDELINES

iRISK REDUCTION OF COGNITIVE DECLINE AND DEMENTIA WHO GUIDELINES ii Risk reduction of cognitive decline and dementia: WHO guidelines Risk reduction of cognitive decline and dementia: WHO guidelines ISBN 978-92-4-155054-3 © World Health Organization 2019 Some rights reserved. This work is available under the Creative Commons Attribution-NonCommercial-ShareAlike 3.0 IGO licence (CC BY-NC-SA 3.0 IGO; https://creativecommons.org/licenses/by-nc-sa/3.0/igo). Under the terms of this licence, you may copy, redistribute and adapt the work for non-commercial purposes, provided the work is appropriately cited, as indicated below. In any use of this work, there should be no suggestion that WHO endorses any specific organization, products or services. The use of the WHO logo is not permitted. If you adapt the work, then you must license your work under the same or equivalent Creative Commons licence. 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If you wish to reuse material from this work that is attributed to a third party, such as tables, figures or images, it is your responsibility to determine whether permission is needed for that reuse and to obtain permission from the copyright holder. The risk of claims resulting from infringement of any third-party-owned component in the work rests solely with the user. General disclaimers. The designations employed and the presentation of the material in this publication do not imply the expression of any opinion whatsoever on the part of WHO concerning the legal status of any country, territory, city or area or of its authorities, or concerning the delimitation of its frontiers or boundaries. Dotted and dashed lines on maps represent approximate border lines for which there may not yet be full agreement. The mention of specific companies or of certain manufacturers’ products does not imply that they are endorsed or recommended by WHO in preference to others of a similar nature that are not mentioned. Errors and omissions excepted, the names of proprietary products are distinguished by initial capital letters. All reasonable precautions have been taken by WHO to verify the information contained in this publication. However, the published material is being distributed without warranty of any kind, either expressed or implied. The responsibility for the interpretation and use of the material lies with the reader. In no event shall WHO be liable for damages arising from its use. Design and layout: Erica Lefstad Printed in France iii FOREWORD ........................................................... v ACKNOWLEDGEMENTS ................................... vi ACRONYMS .......................................................... viii EXECUTIVE SUMMARY .................................... x 1. INTRODUCTION ........................................ xiv 1.1 Background and rationale for these guidelines ..... 1 1.2 Related WHO guidelines and tools ......................... 3 1.3 Target audience .................................................... 4 1.4 Goals and objectives ............................................ 4 1.5 Guiding principles ................................................ 5 2. GUIDELINE DEVELOPMENT PROCESS ........................................................ 6 2.1 Guideline development group ............................... 7 2.2 Declarations of interest by the GDG members and external reviewers ......................................... 7 2.3 Collaboration with external partners ..................... 8 2.4 Identifying, appraising and synthesizing available evidence ................................................ 8 2.5 Decision-making during the GDG meeting .............. 10 2.6 Document preparation and peer review ................ 11 3. EVIDENCE AND RECOMMENDATIONS ............................. 12 3.1 Physical activity interventions ............................. 13 3.2 Tobacco cessation interventions .......................... 16 3.3 Nutritional interventions ..................................... 18 3.4 Interventions for alcohol use disorders ................. 22 3.5 Cognitive interventions ....................................... 25 3.6 Social activity ...................................................... 27 3.7 Weight management ........................................... 29 3.8 Management of hypertension .............................. 32 3.9 Management of diabetes ...................................... 35 3.10 Management of dyslipidaemia ............................. 38 3.11 Management of depression ................................. 40 3.12 Management of hearing loss ................................ 43 4. IMPLEMENTATION CONSIDER ATIONS ................................... 46 5. PUBLICATION, DISSEMINATION AND EVALUATION ................................... 48 5.1 Publication and dissemination ............................... 49 5.2 Monitoring and evaluation ..................................... 50 5.3 Implications for further research ............................ 50 5.4 Future review and update ...................................... 51 REFERENCES ...................................................... 52 ANNEX 1: GUIDELINE DEVELOPMENT GROUP MEMBERS ........................................... 60 ANNEX 2: ASSESSMENT OF CONFLICT OF INTEREST ....................................................... 62 ANNEX 3: SCOPING QUESTIONS ............... 67 ANNEX 4: EVIDENCE REVIEW METHODOLOGY ................................................ 72 WEB ANNEX: EVIDENCE PROFILES (WHO/MSD/MER/19.1); https://www.who.int/mental_health/neurology/dementia/ guidelines_risk_ reduction/en/index.html GLOSSARY ............................................................ 77 CONTE NTS iv Risk reduction of cognitive decline and dementia: WHO guidelines vFOREWORD Dementia is a rapidly growing public health problem affecting around 50 million people around the world. There are nearly 10 million new cases every year and this figure is set to triple by 2050. Dementia is a major cause of disability and dependency among older people and can devastate the lives of affected individuals, their carers and families. Additionally, the disease inflicts a heavy economic burden on societies as a whole, with the costs of caring for people with dementia estimated to rise to US$ 2 trillion annually by 2030. While there is no curative treatment for dementia, the proactive management of modifiable risk factors can delay or slow onset or progression of the disease. In May 2017, the Seventieth World Health Assembly endorsed a Global Action Plan on the Public Health Response to Dementia 2017–2025, urging Member States to develop, as soon as feasible, ambitious national responses to address this challenge. Dementia risk reduction is one of the seven action areas in the global action plan. These new WHO guidelines provide the knowledge base for health care providers, governments, policy-makers and other stakeholders to reduce the risks of cognitive decline and dementia through a public health approach. As many of the risk factors for dementia are shared with those of non- communicable diseases, the key recommendations can be effectively integrated into programmes for tobacco cessation, cardiovascular disease risk reduction and nutrition. I urge all stakeholders to make the best use of these recommendations to improve the lives of people with dementia, their carers and their families. Dr Ren Minghui Assistant Director-General for Universal Health Coverage/Communicable and Noncommunicable Diseases, World Health Organization vi Risk reduction of cognitive decline and dementia: WHO guidelines GUIDELINE DEVELOPMENT GROUP Chair: Martin Prince, King’s College, London, United Kingdom. Members: Charles Alessi, Public Health England, London, United Kingdom; Kaarin J Anstey, University of New South Wales, Sydney, Australia; Kimberly Ashby-Mitchell, Caribbean Public Health Agency, Port of Spain, Trinidad and Tobago; Adelina Comas- Herrera, London School of Economics, London, United Kingdom; Amit Dias, Department of Preventive and Social Medicine, Goa Medical College Bambolim, Goa, India; Cleusa P Ferri, Federal University of São Paulo, São Paulo, Brazil; Riadh Gouider, Razi Hospital, Faculty of Medicine, Tunis, Tunisia; Shinya Ishii, Ministry of Health, Labour and Welfare, Tokyo, Japan; Yves Joanette, Canadian Institutes of Health Research, Government of Canada; Joseph Kibachio, Ministry of Health, Nairobi, Kenya; Miia Kivipelto, Karolinska Institutet, Stockholm, Sweden; Shanthi Mendis, Colombo, Sri Lanka; Ayesha Motala, University of KwaZulu-Natal, Durban, South Africa; Ronald C Petersen, Mayo Clinic, Rochester, United States of America; Dorairaj Prabhakaran, Public Health Foundation of India, New Delhi, India; Suzana Shahar, Universiti Kebangsaan Malaysia, Selangor, Malaysia; Ameenah Bibi Mia Sorefan, Ministry of Health and Quality of Life, Quatre-Bornes, Mauritius; Kusumadewi Suharya (Dy), Alzheimer’s Disease International, Jakarta, Indonesia; Huali Wang, Dementia Care & Research Center, Peking University Institute of Mental Health, Beijing, China. Grade methodologist: Corrado Barbui, University of Verona, Italy. EXTERNAL REVIEW GROUP Abdullah Al Khatami, Ministry of Health, Saudi Arabia; Emiliano Albanese, Università della Svizzera italiana, Switzerland; Alistair Burns, University of Manchester, United Kingdom; Linda Clare, University of Exeter, United Kingdom; Jacqueline Dominguez, Institute for Dementia Care Asia, Quezon City, Philippines; Hillary Doxford, 3 Nations Dementia Working Group, United Kingdom; Maelënn Guerchet, Global Observatory for Ageing and Dementia Care, King’s College London, United Kingdom; Mariella Guerra, Institute of Memory, Depression and Related Disorders, Lima, Peru; Luis Miguel F Gutiérrez Robledo, Instituto Nacional de Geriatría, Institutos Nacionales de Salud de México, Mexico City, Mexico; Vladimir Hachinski, University of Western Ontario in London, Ontario, Canada; Qurat-ul Ain Khan, Aga Khan University Hospital, Karachi, Pakistan; Sebastian Koehler, Maastricht University, The Netherlands; Jae-hong Lee, University of Ulsan College of Medicine, Seoul, Republic of Korea; Gill Livingstone, University College London, United Kingdom; Jean Claude Mbanya, Doctoral School of Life Sciences, Health and Environment, University of Yaoundé I, Cameroon; James McKillop, service user group representative, United Kingdom; Elaine Rashbrook, Public Health England, United Kingdom; Rajat Ray, National Drug Dependence Treatment Centre, All India Institute of Medical Sciences, New Delhi, India; Helen Rochford Brennan, European Working Group of People with Dementia, Ireland; Andrew Sommerlad, University College London, United Kingdom; Kate Swaffer, Dementia Alliance International, Australia; Weili Xu, Karolinska Institutet, Finland. WHO GUIDELINE STEERING GROUP Overall coordination: Tarun Dua, Programme Manager, Department of Mental Health and Substance Abuse; Neerja Chowdhary, Technical Officer, Department of Mental Health and Substance Abuse. WHO headquarters members: Katthyana Aparicio Reyes, Department of Service Delivery and Safety; Islene Araujo de Carvalho, Department of Ageing and Life Course; Lubna Bhatti, Department of Prevention of Noncommunicable Diseases; Fiona Bull, Department of Prevention of Noncommunicable Diseases; Shelly Chadha, Department of Management of Noncommunicable Diseases, Disability, Violence and Injury Prevention; Alarcos Cieza, Department of Management of Noncommunicable Diseases, Disability, Violence and Injury Prevention; Stéfanie Fréel, Department of Mental Health and Substance Abuse; Maria Garcia Casal, Department of Nutrition for Health and Development; Angela Luzia Herscheid, ACK NOWLE DG E M E NTS viiAcknowledgements Department of Mental Health and Substance Abuse; Michal Herz, Department of Mental Health and Substance Abuse; Dzmitry Krupchanka, Department of Mental Health and Substance Abuse; Artin Mahdanian, Department of Mental Health and Substance Abuse; Shanthi Pal, Department of Essential Medicines and Health Products; Anne Margriet Pot, Department of Ageing and Life Course; Gojka Roglic, Department of Management of Noncommunicable Diseases, Disability, Violence and Injury Prevention; Katrin Seeher, Department of Mental Health and Substance Abuse. WHO regional office advisors: Nazneen Anwar, WHO Regional Office for South-East Asia; Dan Chisholm, WHO Regional Office for Europe; Devora Kestel, WHO Regional Office for the Americas; Sebastiana Da Gama Nkomo, WHO Regional Office for Africa; Khalid Saeed, WHO Regional Office for the Eastern Mediterranean; Martin Vandendyck, WHO Regional Office for the Western Pacific. WHO evidence review and synthesis teams: Mariagnese Barbera, University of Eastern Finland, Kuopio, Finland; Nicole A Ee, University of New South Wales, Sydney, Australia; Jenni Kumlala, Karolinska Institutet, Stockholm, Sweden; Ruth Peters, University of New South Wales, Sydney, Australia; Lidan Zheng, University of New South Wales, Sydney, Australia. FUNDING SOURCE Funds received from Public Health England, United Kingdom; Centers for Disease Control and Prevention, United States of America; and the WHO Core Voluntary Contributions Account were used for the development of these guidelines. viii Risk reduction of cognitive decline and dementia: WHO guidelines ACE angiotensin converting enzyme AD Alzheimer disease ADAS-cog Alzheimer Disease Assessment Scale-Cog ADL activities of daily living AHRQ Agency for Healthcare Research and Quality (United States of America) ARB angiotensin receptor blocker BMI body mass index CCB calcium channel blocker CI confidence interval CVRF cardiovascular risk factors CVD cardiovascular disease DALYs disability-adjusted life years DASH dietary approaches to stop hypertension DoI declaration of interest EMBASE Excerpta Medica dataBASE ERG external review group GDG guideline development group (WHO) GDP gross domestic product GRADE Grading of Recommendations Assessment, Development and Evaluation HIV human immunodeficiency virus IADL instrumental activities of daily living ICOPE Integrated Care for Older People (WHO) LMIC low- and middle-income countries MCI mild cognitive impairment MDRS Mattis Dementia Rating Scale MeSH Medical Subject Headings mhGAP Mental Health Gap Action Programme (WHO) MMSE Mini Mental State Examination NCDs noncommunicable diseases NIA National Institute on Aging (United States of America) NICE National Institute of Health and Care Excellence (United Kingdom) OR odds ratio ACRONYMS ixAcronyms PEN Package of Essential Noncommunicable Disease Interventions (WHO) PICO population, intervention, comparison, outcome PUFA polyunsaturated fatty acids RCT randomized controlled trial RR relative risk SMD standardized mean difference x Risk reduction of cognitive decline and dementia: WHO guidelines E XECUTIVE SUMMARY INTRODUCTION Dementia is a rapidly growing global public health problem. Worldwide, around 50 million people have dementia, with approximately 60% living in low- and middle-income countries (LMIC). Every year, there are nearly 10 million new cases. The total number of people with dementia is projected to reach 82 million in 2030 and 152 million in 2050. Dementia leads to increased costs for governments, communities, families and individuals, and to loss in productivity for economies. In 2015, the total global societal cost of dementia was estimated to be US$ 818 billion, equiv- alent to 1.1% of global gross domestic product (GDP). Crucially, while age is the strongest known risk factor for cognitive decline, dementia is not a natural or inevi- table consequence of ageing. Several recent studies have shown a relationship between the development of cognitive impairment and dementia with lifestyle- related risk factors, such as physical inactivity, tobacco use, unhealthy diets and harmful use of alcohol. Certain medical conditions are associated with an increased risk of developing dementia, including hypertension, diabetes, hypercholesterolemia, obesity and depression. Other potentially modifiable risk factors include social isolation and cognitive inactivity. The existence of potentially modifiable risk factors means that prevention of dementia is possible through a public health approach, including the implementation of key interventions that delay or slow cognitive decline or dementia. In May 2017, the Seventieth World Health Assembly endorsed the Global action plan on the public health response to dementia 2017–2025 (WHO, 2017a). The action plan includes seven strategic action areas and xiExecutive Summary dementia risk reduction is one of them. The action plan calls upon the WHO Secretariat to strengthen, share and disseminate an evidence base to support policy interventions for reducing potentially modifiable risk factors for dementia. This involves providing a database of available evidence on the prevalence of those risk factors and the impact of reducing them; and supporting the formulation and implementation of evidence-based, multisectoral interventions for reducing the risk of dementia. The risk reduction guidelines for cognitive decline and dementia are aligned with WHO’s mandate to provide evidence-based guidance for a public health response to dementia. GUIDELINE DEVELOPMENT METHODS The process of development of these guidelines followed the WHO handbook for guideline development and involved: 1. recruitment of the guideline development group (GDG); 2. declaration of interest by GDG members and peer reviewers; 3. scoping review to formulate questions and select outcomes; 4. identification, appraisal and synthesis of available evidence; 5. formulation of recommendations with inputs from a wide range of stakeholders; and 6. preparation of documents and plans for dissemination. The GDG, an international group of experts, provided input into the scope of the guidelines and assisted the steering group in developing the key questions. A total of 12 PICO (population, intervention, comparison and outcome) questions were developed. To address the PICO questions, a series of searches for systematic reviews was conducted and Grading of Recommendations Assessment, Development and Evaluation (GRADE) evidence profiles prepared. During a meeting at WHO headquarters in Geneva, 2–3 July 2018, the GDG discussed the evidence, sought clarifications and interpreted the findings in order to develop recommendations. The GDG considered the balance of benefit and harm of each intervention; values and preferences; costs and resource use; and other relevant practical issues for providers in LMIC. When making a strong recommendation, the GDG was confident that the desirable effects of the inter- vention outweigh any undesirable effects. When the GDG was uncertain about the balance between the desirable and undesirable effects, the GDG issued a conditional recommendation. Strong recommenda- tions imply that most individuals would want the intervention and should receive it, while conditional recommendations imply that different choices may be appropriate for individual patients and they may require assistance at arriving at management decisions. The GDG members reached a unanimous agreement on all the recommendations and ratings. xii Risk reduction of cognitive decline and dementia: WHO guidelines SUMMARY OF RECOMMENDATIONS Physical activity interventions Physical activity should be recommended to adults with normal cognition to reduce the risk of cognitive decline. Quality of evidence: moderate Strength of the recommendation: strong Physical activity may be recommended to adults with mild cognitive impairment to reduce the risk of cognitive decline. Quality of evidence: low Strength of the recommendation: conditional Tobacco cessation interventions Interventions for tobacco cessation should be offered to adults who use tobacco since they may reduce the risk of cognitive decline and dementia in addition to other health benefits. Quality of evidence: low Strength of the recommendation: strong Nutritional interventions The Mediterranean-like diet may be recommended to adults with normal cognition and mild cognitive impairment to reduce the risk of cognitive decline and/or dementia. Quality of evidence: moderate Strength of the recommendation: conditional A healthy, balanced diet should be recommended to all adults based on WHO recommendations on healthy diet. Quality of evidence: low to high (for different dietary components) Strength of the recommendation: conditional Vitamins B and E, polyunsaturated fatty acids and multi-complex supplementation should not be recommended to reduce the risk of cognitive decline and/or dementia. Quality of evidence: moderate Strength of the recommendation: strong Interventions for alcohol use disorders Interventions aimed at reducing or ceasing hazardous and harmful drinking should be offered to adults with normal cognition and mild cognitive impairment to reduce the risk of cognitive decline and/or dementia in addition to other health benefits. Quality of evidence: moderate (for observational evidence) Strength of the recommendation: conditional Cognitive interventions Cognitive training may be offered to older adults with normal cognition and with mild cognitive impairment to reduce the risk of cognitive decline and/or dementia. Quality of evidence: very low to low Strength of the recommendation: conditional Social activity There is insufficient evidence for social activity and reduction of risk of cognitive decline/dementia. Social participation and social support are strongly connected to good health and well- being throughout life and social inclusion should be supported over the life-course. xiiiExecutive Summary Weight management Interventions for mid-life overweight and/or obesity may be offered to reduce the risk of cognitive decline and/or dementia. Quality of evidence: low to moderate Strength of the recommendation: conditional Management of hypertension Management of hypertension should be offered to adults with hypertension according to existing WHO guidelines. Quality of evidence: low to high (for different interventions) Strength of the recommendation: strong Management of hypertension may be offered to adults with hypertension to reduce the risk of cognitive decline and/or dementia. Quality of evidence: very low (in relation to dementia outcomes) Strength of the recommendation: conditional Management of diabetes mellitus The management of diabetes in the form of medications and/or lifestyle interventions should be offered to adults with diabetes according to existing WHO guidelines. Quality of evidence: very low to moderate (for different interventions) Strength of the recommendation: strong The management of diabetes may be offered to adults with diabetes to reduce the risk of cognitive decline and/or dementia. Quality of evidence: very low Strength of the recommendation: conditional Management of dyslipidaemia Management of dyslipidaemia at mid-life may be offered to reduce the risk of cognitive decline and dementia. Quality of evidence: low Strength of the recommendation: conditional Management of depression There is currently insufficient evidence to recommend the use of antidepressant medicines for reducing the risk of cognitive decline and/or dementia. The management of depression in the form of antidepressants and/or psychological interventions should be provided to adults with depression according to existing WHO mhGAP guidelines. Management of hearing loss There is insufficient evidence to recommend use of hearing aids to reduce the risk of cognitive decline and/or dementia. Screening followed by provision of hearing aids should be offered to older people for timely identification and management of hearing loss as recommended in the WHO ICOPE guidelines. xiv Risk reduction of cognitive decline and dementia: WHO guidelines 1 INTRODUC TION 1Introduction 1.1 BACKGROUND AND RATIONALE FOR THESE GUIDELINES Dementia, a group of disorders characterized by a decline from a previously attained cognitive level that affects activities of daily living (ADL) and social functioning, poses one of the greatest global challenges for health and social care in the 21st century. In 2015, dementia affected 50 million people worldwide (or roughly 5% of the world’s elderly population, i.e. those above the age of 60 years). The number of people with dementia is expected to increase to 82 million in 2030 and 152 million by 2050 with the estimated proportion of the population aged 60 and over with dementia at a given time between 5 to 8% 1 because dementia rises exponentially during old age and the world’s population is ageing. These projections assume constant age- and sex-specific prevalence of dementia over time, and, accordingly, the steepest rises are expected especially in low- and middle- income countries (LMIC), where the demographic changes will be more marked. Dementia is a major cause of disability and dependency among older people worldwide, and it has a significant impact not only on individuals but also on carers, families, communities and societies. Dementia accounts for 11.9% of the years lived with disability due to a noncommunicable disease (NCD) worldwide. Dementia leads to increased costs for governments, communities, families and individuals, and to loss in productivity for economies. The annual global cost of dementia is estimated to be US$ 818 billion (OECD, 2015; WHO, 2017b). Nearly 85% of costs are related to family and social, rather than medical, care (GBD 2015 Neurological Disorders Collaborator Group, 2017). Most health systems are ill-equipped and under-resourced to respond to the current needs associated with dementia. Thus, societal ageing and the associated increases in dementia prevalence will likely have major health-service implications for the care of people with dementia and support for affected families. There are many different causes and types of demen- tia. Primary dementias include: dementia due to Alzheimer disease (AD), vascular dementia, dementia with Lewy bodies and frontotemporal dementia (in which the decline in cognitive abilities itself is mostly due to an underlying neurodegenera-tive process and not directly caused by other etiologies). Alzheimer disease is the most common, followed by vascular dementia and dementia with Lewy bodies. Mixed dementia with features of more than one type is also common, especially in older adults, while frontotemporal dementia is a less common form but relatively more frequent before old age. Secondary dementias are those caused by, or closely related to, some other recognizable disease, such as HIV, head injury, multiple sclerosis, thyroid disorders or vitamin B12 deficiency. In these secondary dementias, cognitive impairment is typically accompanied by symptoms and signs in other organ systems and the treatment focuses on management of the underlying disease. For the scope of these guidelines we refer to primary dementias. Though early treatment of some diseases may have the potential to prevent the onset of secondary dementias, we are not including these 1 WHO & King’s College London (2017). Global prevalence of dementia – updated figures 2017. Available at: https://www.who.int/news-room/fact-sheets/detail/dementia 2 Risk reduction of cognitive decline and dementia: WHO guidelines secondary dementias in the scope of these guidelines since there are prevention or appropriate management and treatment strategies for most of these specific diseases and conditions, which effectively reduce dementia-related signs and symptoms. However, late-onset dementia is a heterogeneous and multifactorial condition and some factors (i.e. head trauma, B12 deficiency earlier in life) may also contribute to the development of dementia later in life (not only secondary dementia). RISK FACTORS FOR DEMENTIA Non-modifiable risk factors for dementia include gene polymorphisms, age, gender, race/ethnicity and family history. Crucially, while age is the strongest known risk factor for cognitive decline, dementia is not a natural or inevitable consequence of ageing. During the last two decades, several studies have shown a relationship between the development of cognitive impairment and dementia with educational attainment, and lifestyle-related risk factors, such as physical inactivity, tobacco use, unhealthy diets and harmful use of alcohol. Further, certain medical conditions are associated with an increased risk of developing dementia, including hypertension, diabetes, hypercholesterolemia, obesity and depression. Other potentially modifiable risk factors may include social isolation and cognitive inactivity. The risk factors included in the scope of these guidelines were chosen based on recent systematic reviews and guidelines, i.e. National Institute of Health and Care Excellence (United Kingdom) (NICE, 2015); the United States of America Agency for Healthcare Research and Quality (AHRQ) systematic review (Kane et al., 2017); the World Alzheimer report 2014 (Prince, et al., 2014) and the report by the Lancet Commission on Dementia Prevention, Intervention, and Care (Livingston et al., 2017). The current focus on modifiable risk factors is justified by their potential to be targeted for prevention of dementia, and/or the delay of the progression of cognitive decline. NEED FOR THESE GUIDELINES The existence of potentially modifiable risk factors means that prevention of dementia is possible through a public health approach, including the implementation of key interventions that delay or slow cognitive decline or dementia. In May 2017, the Seventieth World Health Assembly endorsed the Global action plan on the public health response to dementia 2017–2025 (WHO, 2017a). The vision of the action plan is a world in which dementia is prevented and people with dementia and their carers live well and receive the care and support they need to fulfil their potential with dignity, respect, autonomy and equality. The goal of the action plan is to improve the lives of people with dementia, their carers and families, while decreasing the impact of dementia on them as well as on communities and countries. The action plan includes seven strategic action areas, and dementia risk reduction is one of them. The action plan calls upon the WHO Secretariat to strengthen, share and disseminate an evidence base to support policy interventions for reducing potentially modifiable risk factors for dementia. This involves providing a database of available evidence on the prevalence of those risk factors and the impact of reducing them; and supporting the formulation and implementation of evidence-based, multi-sectoral interventions for reducing the risk of dementia. These current guidelines represent the first steps to support countries as they develop approaches to delay or prevent the onset of dementia. 3Introduction The risk reduction guidelines for cognitive decline and dementia are aligned with WHO’s mandate to provide evidence-based guidance for a public health response to dementia. By supporting health and social care professionals, particularly by improving their capacity to provide evidence-based, multisectoral, gender and culturally appropriate interventions to the general population, including modifiable dementia risk factors that are shared with other NCDs, the risk of developing dementia can be potentially reduced, or its progression delayed. Thus, the guidelines align with WHO’s work in the area of prevention and management of NCDs, which aims to support countries to reduce the incidence, morbidity and mortality of NCDs. WHO has collaborated with a range of stakeholders, including international and national public health agencies working in the area of prevention of NCDs and dementia. The guidelines are in close conceptual and strategic synergy with other WHO action plans and strategies, i.e. the Comprehensive mental health action plan 2013– 2020,2 the Global action plan for the prevention and control of noncommunicable diseases 2013–2020,3 the Global strategy and action plan on ageing and health 2016–2020,4 the Global strategy to reduce harmful use of alcohol5 and the Global strategy on diet, physical activity and health.6 Furthermore, this work is aligned with the WHO move towards making health services more people-centred. Finally, the work will contribute to the attainment of Sustainable Development Goal 3, target 3.8, i.e. achieve universal health coverage, including financial risk protection, access to quality essential healthcare services and access to safe, effective, quality and affordable essential medicines and vaccines for all (UN, 2019). 1.2 RELATED WHO GUIDELINES AND TOOLS Several existing WHO guidelines and tools designed for the general population are relevant for addressing health conditions that may increase the risk of cognitive decline or dementia in individuals with normal cognition or mild cognitive impairment (MCI). The following WHO guidelines and tools were consulted when developing the current guidelines: • mhGAP Intervention guide – Version 2.0 for mental, neurological and substance use disorders in non- specialized health settings. Geneva: WHO, 2016. http://www.who.int/mental_health/mhgap/mhGAP_ intervention_guide_02/en/ • Prevention and control of noncommunicable diseases: guidelines for primary health care in low- resource settings. Geneva: WHO, 2012. http://apps. who.int/iris/bitstream/10665/76173/1/9789241548397_ eng.pdf • Package of essential noncommunicable (PEN) disease interventions for primary health care in low-resource settings. Geneva: WHO, 2010. http:// www.who.int/cardiovascular_diseases/publications/ pen2010/en/ • Global recommendations on physical activity for health. Geneva: WHO, 2010. http://www.who.int/ dietphysicalactivity/publications/9789241599979/en/ • Integrated care for older people (ICOPE): Recommendations on interventions to improve physical and mental capacities of older people at community level. Geneva: WHO, 2016. 2 Available at http://www.who.int/mental_health/action_plan_2013/en/ 3 Available at http://www.who.int/nmh/publications/ncd-action-plan/en/ 4 Available at http://who.int/ageing/global-strategy/en/ 5 Available at http://www.who.int/substance_abuse/activities/gsrhua/en/ 6 Available at http://www.who.int/dietphysicalactivity/Indicators%20English.pdf 4 Risk reduction of cognitive decline and dementia: WHO guidelines • HEARTS Technical package for cardiovascular disease management in primary health care: evidence-based treatment protocols. http://www. who.int/cardiovascular_diseases/hearts/en/ • Global age-friendly cities: a guide. Geneva: WHO, 2007. http://www.who.int/ageing/publications/Global_ age_friendly_cities_Guide_English.pdf • Recommendations on healthy diet. Geneva: WHO, 2019. http://www.who.int/en/news- room/fact-sheets/detail/healthy-diet • Strengthening health systems for treating tobacco dependence in primary care. Geneva: WHO, 2013. http://www.who.int/tobacco/publications/building_ capacity/training_package/treatingtobaccodependence/en/ • Framework on integrated people-centred health services. Geneva: WHO, 2016. http://apps.who.int/ gb/ebwha/pdf_files/WHA69/A69_39-en.pdf?ua=1 These existing WHO guidelines and tools address some of the interventions that are included in the scope of the current guidelines, but they do not include cognitive decline or dementia as outcomes. Where the current guidelines overlap with the other guidelines, e.g. ICOPE guidelines, which provide recommendations on cognitive interventions in people with MCI, we have referred to these existing recommendations, rather than developing new ones. The current guidelines, therefore, complement, but do not duplicate, existing work. 1.3 TARGET AUDIENCE The guidelines are primarily targeted at health care providers working at a first or second level facility or at district level, including basic outpatient and inpatient services. The health care providers could be doctors, nurses or other cadres of health workers. Quality improvement teams at all levels of the system will benefit from the work. In addition, the guidelines and their derivative products have implications for policy-makers, health care planners and programme managers at national and international level, as well as the general population. 1.4 GOALS AND OBJECTIVES • To provide evidence-based recommendations on lifestyle behaviours and interventions to delay or prevent cognitive decline and dementia in the general population. • To provide evidence-based recommendations on management of specific physical and mental health conditions to delay or prevent cognitive decline and dementia. 5Introduction These guidelines provide up-to-date WHO evidence- based recommendations to facilitate implementing the Global action plan on the public health response to dementia 2017–2025, the Comprehensive mental health action plan 2013–2020 and WHO’s Mental Health Gap Action Programme (mhGAP),7 the Global action plan for the prevention and control of noncommunicable diseases 2013–2020,8 the Global strategy and action plan on ageing and health 2016–2020,9 the Global strategy to reduce harmful use of alcohol,10 and the Global strategy on diet, physical activity and health.11 1.5 GUIDING PRINCIPLES The following principles have informed the development of these guidelines and should guide their implementation: • The guidelines should expedite the achievement of the goals outlined in the Global action plan on the public health response to dementia 2017–2025, as well as target 3.4 of the Sustainable Development Goals, which focuses on reducing the premature mortality from NCDs and the promotion of mental health and well-being (UN, 2019). • The process of developing these guidelines, and their subsequent implementation, should concretely foster the right to equal levels of health for people at risk of cognitive decline and dementia and promote their active involvement. • The recommendations should be implemented with accompanying efforts to safeguard the human rights of persons living with cognitive decline and dementia, including reduction of stigma and discrimination, reducing barriers to seek health and social care services, and ensuring informed decision-making in treatment choices. Implementation of the recommendations should be tailored to the local context, including the availability of financial and human resources. However, the inequities addressed in these guidelines are common across all countries, and should be made a priority in health services. 7 Available at http://www.who.int/mental_health/action_plan_2013/en/ 8 Available at http://www.who.int/nmh/publications/ncd-action-plan/en/ 9 Available at http://who.int/ageing/global-strategy/en/ 10 Available at http://www.who.int/substance_abuse/activities/gsrhua/en/ 11 Available at http://www.who.int/dietphysicalactivity/Indicators%20English.pdf 6 Risk reduction of cognitive decline and dementia: WHO guidelines GUIDE LINE DEVE LOPME NT PROCESS 2 7Guideline development process The process of developing these guidelines followed the WHO Handbook for guideline development (2nd edition, http://apps.who.int/ medicinedocs/en/m/abstract/Js22083en/). It consisted of the following steps. 2.1 GUIDELINE DEVELOPMENT GROUP A WHO guideline steering group, led by the Department of Mental Health and Substance Abuse, was established with representatives from WHO regional offices and relevant WHO departments and programmes. The guideline steering group provided overall support to the guideline development process. Two additional groups were established: a guideline development group (GDG) and an external review group (ERG). The GDG included a panel of academicians and clinicians with multidisciplinary expertise on the conditions covered by the guidelines. Consideration was given to geographic diversity and gender balance (see Annex 1). As a respected researcher in the field, the Chairperson was selected for their extensive experience of guideline development methodology, and their participation in other guideline development groups. Each potential GDG member was asked to complete the WHO declaration of interest (DoI) form. These were reviewed by the steering group. 2.2 DECLARATIONS OF INTEREST BY THE GDG MEMBERS AND EXTERNAL REVIEWERS All GDG members, peer reviewers and systematic review team members were requested to complete the DoI prior to the evidence review process for guideline development. Invitations to participate in the GDG meeting were sent only after the DoI had been reviewed and approved. The GDG members were also required to complete a confidentiality undertaking. Once received, the WHO Secretariat reviewed the DoIs, as well as additional information (internet and bibliographic database search), and evaluated if there were any conflicts of interest and if so, whether these required a management plan. The group composition was finalized after this process. The names and brief biographies of the members being considered for participation in the GDG were disclosed for public notice and comment prior to the meeting. At the beginning of the GDG meeting, the DoI of each GDG member were presented and GDG members, as well as external partners, were asked to update their DoI with relevant changes by notifying the WHO Secretariat. Declarations of interest were reassessed for potential conflict before the face-to-face meeting in Geneva. None of the members had major conflicts of interest. All decisions were documented (see Annex 2). 8 Risk reduction of cognitive decline and dementia: WHO guidelines 2.3 COLLABORATION WITH EXTERNAL PARTNERS The Center for Alzheimer Research at the Karolinska Institutet, Stockholm, Sweden, and the School of Psychology at the University of New South Wales and Neuroscience Research, Australia, supported the development of the guidelines by conducting the evidence review and synthesis. 2.4 IDENTIFYING, APPRAISING AND SYNTHESIZING AVAILABLE EVIDENCE The procedure of the scoping review to identify the draft population, intervention, comparison, outcome (PICO) questions consisted of the identification of potentially modifiable risk factors and interventions for cognitive decline or dementia. These interventions are summarized in existing WHO guidelines listed earlier, such as the Prevention and control of noncommunicable diseases; Package of essential noncommunicable (PEN) disease interventions for primary health care in low-resource settings; and Integrated care for older people (ICOPE) guidelines. These guidelines, however, do not include cognitive decline or dementia as outcomes. Among recent summary reports, the Lancet Commission on Dementia Prevention, Intervention, and Care report summarizes the emerging knowledge on dementia risk factors and interventions (Livingston et al., 2017). The risk factors and interventions reported in this set of systematic reviews included education, exercise, maintaining social engagement, reducing smoking, and management of hearing loss, depression, hypertension, diabetes and obesity. Another systematic review requested and supported by the National Institute on Aging (NIA) at the National Institutes of Health, United States of America, also identified risk factors and evidence for interventions, specifically cognitive training, blood pressure management and exercise (Kane et al., 2017). The interventions reported in these reviews have formed the basis of the interventions included in the PICO questions. The population in these guidelines considered adults with normal cognition as well as those with MCI. We use the term MCI to refer to a disorder characterized by impairment of memory, learning difficulties and reduced ability to concentrate on a task for more than brief periods, beyond what is expected in normal ageing. There is often a marked feeling of mental fatigue when mental tasks are attempted, and new learning is found to be subjectively difficult even when objectively successful. None of these symptoms is so severe that a diagnosis of dementia can be made. Individuals diagnosed with MCI, however, are at greater risk of developing dementia; the inclusion of adults with MCI in these guidelines will enable the use of interventions to slow the progression of cognitive decline, i.e. the transition from MCI to dementia itself. 9The scope of these guidelines is prevention/risk reduction of cognitive decline or dementia (main outcomes of interest). Cognitive decline is defined as a noticeable and measurable loss or abnormality in attention functions, memory functions or higher level cognitive functions (including attention, language and reasoning). Dementia is a syndrome that includes cognitive decline and other symptoms and can be diagnosed based on ICD-10 criteria. It involves a decline in memory with impairment of at least one other cognitive function, such as skilled movements (limb apraxia), language (aphasia) or executive function (e.g. planning, attention and abstract reasoning). This decline should represent a change from previous behaviour, and impair social and/or occupational functioning. As stated in the background section, when we use the word dementia in this document, we are referring to the primary or neurodegenerative dementias. The GDG provided input into the scope of the guidelines and assisted the steering group in developing the key questions. Twelve PICO-structured questions were developed (Annex 3). Outcomes were rated by GDG members according to their importance, as “critical”, “important” or “unimportant”. Those outcomes rated as critical and important were selected for inclusion into the PICO. Regular communication and discussions with the GDG were held by email and teleconferences, respectively. The systematic review team developed protocols to review the evidence that existed for the inter- ventions to reduce the risk of cognitive decline and/ or dementia (as outlined in the PICO questions) for adults with normal cognition or MCI (Annex 4). Existing relevant systematic reviews were identified for each of the PICO questions. The steering group assessed the quality of existing reviews using the assessment of multiple systematic reviews (AMSTAR) checklist. Systematic reviews found to be of high quality were also assessed for timeliness to ensure that the most current evidence was used. The Grading of Recommendations Assessment, Development and Evaluation (GRADE) methodology (Guyatt et al., 2011), as well as the WHO Handbook for guideline development, were used to develop the evidence profiles. The quality assessment of the evidence was performed according to GRADE considering study design – randomized controlled trials (RCT) or observational studies, risk of bias, inconsistency, indirectness, imprecision and risk of reporting bias. Evidence was characterized as either high, moderate, low or very low. Guideline development process 10 Risk reduction of cognitive decline and dementia: WHO guidelines 2.5 DECISION-MAKING DURING THE GDG MEETING The GDG met at the WHO headquarters in Geneva, 2–3 July 2018. The evidence review was sent out in advance and it was summarized in a presentation during the meeting. The GDG members discussed the evidence, clarified points and interpreted the findings in order to develop recommendations based on the draft prepared by the WHO Secretariat. The GDG considered the relevance of the recommendations for adults with normal cognition or MCI based on the GRADE Evidence-to-Decision (EtD) framework (Alonso-Coello et al., 2016), considering the balance of benefit and harm of each intervention; values and preferences of the individuals involved; costs and resource use; acceptability of the intervention to health care providers in LMIC; feasibility of implementation; and impact on equity and human rights. No surveys or formal cost-effectiveness studies to determine resource constraints were conducted but discussions of these domains were informed by the combined expertise and experience of the GDG members. Equity and human rights were considered by specifically searching databases that include studies from LMIC, examining data for disaggregation for specific subgroups. Potential differential effects of the interventions on different subgroups of people related to economic status, employment or occupation, education, place of residence, gender or ethnicity were considered by the GDG. Taking into account these considerations, when making a strong recommendation, the GDG was confident that the desirable effects of the intervention outweigh any undesirable effects. When the GDG was uncertain about the balance between the desirable and undesirable effects, the GDG issued a conditional recommendation. Strong recommendations imply that most individuals would want the intervention and should receive it, while conditional recommendations imply that different choices may be appropriate for individual patients and they may require assistance at arriving at management decisions. In some instances, even when the quality of evidence was low or very low, it was agreed that if the recommendation would be of general benefit, and this was seen to outweigh the harms, it may still be rated as strong. In the event of a disagreement, the Chair and the Methodologist would ascertain whether the dispute was related to the interpretation of the data or to the way that the recommendation was formulated. If a consensus agreement was not reached, the GDG members agreed to a majority vote of 70%, to determine a decision. WHO staff members present at the meeting, as well as other external technical experts involved in the collection and review of the evidence, were excluded from voting. The GDG members reached a consensus agreement on all recommendations and ratings and voting was not needed. 11 2.6 DOCUMENT PREPARATION AND PEER REVIEW The draft guideline and evidence profiles prepared by WHO staff and the GDG were circulated to the ERG and the steering group. The role of the ERG was to identify any errors or missing data and to comment on clarity, setting-specific issues and implications for implementation rather than changing the recommen- dations. All inputs and remarks were discussed and agreed with the GDG by email. 12 Risk reduction of cognitive decline and dementia: WHO guidelines This section provides an overview of each PICO question described under the following headings: background; recommendations and additional considerations; supporting evidence for the recommendations and the rationale for the recommendations based on the evidence synthesized as well as criteria listed in the EtD tables. Complete evidence profiles for each PICO question including the GRADE tables and the EtD tables are included in the Web Annex. EVIDE NCE AND RECOMME NDATIONS 3 13Evidence and recommendations Population: Adults (age above 18 years) with normal cognition or MCI Intervention: Physical activity interventions (aerobic, resistance training or multicomponent physical activity) Comparison: Care as usual or no intervention Outcomes: • Critical – Cognitive function – Incident MCI – Dementia • Important – Quality of life – Functional level (ADL, IADL) – Adverse events – Drop-out rates For adults with normal cognition or MCI, are physical activity interventions more effective than usual care or no intervention in reducing the risk of cognitive decline and/or dementia? 3.1 PHYSICAL ACTIVITY INTERVENTIONS BACKGROUND A physically active lifestyle is linked to brain health. In large observational studies with follow-up periods extending decades, physically active people seem less likely to develop cognitive decline, all-cause dementia, vascular dementia and Alzheimer disease when compared with inactive people (Gallaway et al., 2017; Hamer & Chida, 2009; Sofi et al., 2011; Stephen et al., 2017). Especially, the highest levels of physical exercise seem to be most protective (Hamer & Chida, 2009; Sofi et al., 2011). Physical activity seems to have beneficial effects on brain structures, which may underlie this association (Rovio et al., 2010). Other potential mechanisms underlying the association are most likely indirect, such as the positive effects of physical exercise on other modifiable cardiovascular risk factors (CVRFs), including hypertension, insulin resistance and high cholesterol levels as well as other biological mechanisms, including but not limited to enhancing the immune system function, anti-inflammatory properties, and increasing neurotrophic factors. Physical activity interventions are described in WHO’s Global recommendations on physical activity for health (2010). RECOMMENDATIONS AND CONSIDERATIONS RECOMMENDATION 1: Physical activity should be recommended to adults with normal cognition to reduce the risk of cognitive decline. Quality of evidence: moderate Strength of the recommendation: strong 14 Risk reduction of cognitive decline and dementia: WHO guidelines RECOMMENDATION 2: Physical activity may be recommended to adults with MCI to reduce the risk of cognitive decline. Quality of evidence: low Strength of the recommendation: conditional WHO’s Global recommendations on physical activity for health (2010) (http://www.who.int/dietphysicalactivity/publications/9789241599979/en/) Below is an extract from these recommendations for adults 65 years and above: For adults 65 years and above, physical activity includes recreational or leisure-time physical activity, transportation (e.g. walking or cycling), occupational (if the person is still engaged in work), household chores, play, games, sports or planned exercise, in the context of daily, family, and community activities. In order to improve cardiorespiratory and muscular fitness, bone and functional health, and reduce the risk of NCDs, depression and cognitive decline, the following are recommended: 1. Adults aged 65 years and above should do at least 150 minutes of moderate-intensity aerobic physical activity throughout the week, or do at least 75 minutes of vigorous-intensity aerobic physical activity throughout the week, or an equivalent combination of moderate- and vigorous-intensity activity. 2. Aerobic activity should be performed in bouts of at least 10 minutes’ duration. 3. For additional health benefits, adults aged 65 years and above should increase their moderate- intensity aerobic physical activity to 300 minutes per week, or engage in 150 minutes of vigorous-intensity aerobic physical activity per week, or an equivalent combination of moderate- and vigorous-intensity activity. 4. Adults of this age group with poor mobility should perform physical activity to enhance balance and prevent falls on 3 or more days per week. 5. Muscle-strengthening activities should be done involving major muscle groups, on 2 or more days per week. 6. When adults of this age group cannot do the recommended amounts of physical activity due to health conditions, they should be as physically active as their abilities and conditions allow. Overall, across all the age groups, the benefits of implementing the above recommendations, and of being physically active, outweigh the harms. At the recommended level of 150 minutes per week of moderate-intensity activity, musculoskeletal injury rates appear to be uncommon. In a population- based approach, in order to decrease the risks of musculoskeletal injuries, it would be appropriate to encourage a moderate start with gradual progress to higher levels of physical activity. 15Evidence and recommendations Additional considerations include: • Physical activity is easily available for everybody and has a large range of beneficial effects. • Aerobic activity plays a key role in the beneficial effect of physical activity. SUPPORTING EVIDENCE AND RATIONALE For physical activity interventions (e.g. aerobic, resistance training or multicomponent physical activity) compared with usual care or no intervention, four systematic reviews were identified for six different physical activity interventions (Barha et al., 2017; Barreto et al., 2017; Northey et al., 2018; Song et al., 2018). These were: 1. Aerobic exercise intervention versus usual care or no intervention in adults with normal cognition. 2. Training exercise intervention versus usual care or no intervention in adults with normal cognition. 3. Multimodal exercise intervention versus usual care or no intervention in adults with normal cognition. 4. Aerobic exercise intervention versus usual care or no intervention in adults with MCI. 5. Training exercise intervention versus usual care or no intervention in adults with MCI. 6. Multimodal exercise intervention versus usual care or no intervention in adults with MCI. For cognitive outcomes in healthy adults, there is moderate quality evidence which indicates that physical activity interventions have a positive effect on cognition. There is low to moderate quality evidence that suggests that physical activity does not affect risk of MCI and dementia. For cognitive outcomes in adults with MCI, there is low quality evidence that indicates that physical activity interventions have a positive effect on cognition. However, these benefits are not consistent across all cognitive domains. The evidence shows that the effect size is larger for aerobic training versus resistance training and there is stronger evidence for adults with normal cognition (especially aerobic training) than in adults with MCI. The GDG concluded that the desirable effects of physical activity outweighed the undesirable effects. Overall, low to moderate quality evidence has shown that physical activity has a small but beneficial effect on cognition. Even in MCI populations, low quality evidence suggests cognitive benefits of physical exercise. The effect of these interventions seems to be mostly due to aerobic exercise. Based on the quality of evidence, a strong recommendation was made for healthy adults and a conditional one for adults with MCI. 16 Risk reduction of cognitive decline and dementia: WHO guidelines Population: Adults with normal cognition or MCI who use tobacco Intervention: Interventions for tobacco cessation (behavioural interventions and pharmacological interventions including nicotine replacement therapy, bupropion, varenicline) Comparison: Care as usual or no intervention Outcomes: • Critical – Cognitive function – Incident MCI – Dementia • Important – Quality of life – Functional level (ADL, IADL) – Adverse events – Drop-out rates For adults with normal cognition or MCI who use tobacco, are interventions for tobacco cessation more effective than usual care or no intervention in reducing the risk of cognitive decline and/or dementia? 3.2 TOBACCO CESSATION INTERVENTIONS BACKGROUND Tobacco dependence is the leading cause of preventable death globally, causing an estimated 5 million deaths per year (WHO, 2011) and worldwide medical costs ranging in billions of US dollars (Lightwood et al., 2000). Tobacco is the major risk factor for a number of conditions, including many types of cancers, cardiovascular diseases (CVDs) and risk factors, and respiratory disorders (US Department of Health Human Services, 2004), and tobacco cessation has been demonstrated to significantly reduce these health risks (Pirie et al., 2013). Tobacco cessation has also been associated with reduced depression, anxiety and stress, and improved mood and quality of life compared with continuing to smoke (Taylor et al., 2014). Tobacco dependence is also associated with other disorders and age-related conditions, such as frailty and work ability in older people (Amorim et al., 2014; Kojima et al., 2015), as well as dementia and cognitive decline (Durazzo et al., 2014). Interventions to treat tobacco dependence can be very diverse, based on either or both behavioural/ psychological strategies and various pharmacological treatments. Non-pharmacological interventions can have mixed results (Niaura, 2008). Counselling is the most frequently used approach, but others have also been explored, such as mindfulness-based approaches, cognitive behavioural therapy, behavioural activation therapy, motivational interviewing, contingency manage- ment, and exposure and/or aversion to smoking. Among the pharmacological therapies for tobacco cessation, nicotine replacement therapy, bupropion and varenicline are the most common, but low overall treatment efficacy and adverse effects are key limitations (Gómez-Coronado et al., 2018). Combinations of non-pharmacological and pharmacological approaches seem to be the most effective in supporting tobacco cessation (Gómez- Coronado et al., 2018). 17Evidence and recommendations Additional considerations include: • In keeping with interventions described in the WHO training package for tobacco dependence, people who make use of tobacco should be advised to quit and the appropriate programmes aimed at preventing tobacco use uptake, promoting tobacco cessation, as well as diagnosing and treating tobacco dependence, should be established (http://www.who.int/ tobacco/publications/building_capacity/training_ package/treatingtobaccodependence/en/). The interventions include behavioural interventions, as well as pharmacological ones (i.e. nicotine replacement therapy, bupropion, varenicline). • Individual level interventions should be provided in the context of population level tobacco cessation programmes. SUPPORTING EVIDENCE AND RATIONALE No systematic reviews comparing tobacco cessation interventions with no intervention were identified. A large body of observational evidence is available on tobacco smoking as a risk factor for cognitive impairment and dementia. These studies show an association between tobacco smoking (including in mid-life) and dementia, or cognitive decline, in later life (Beydoun et al., 2014; Di Marco et al., 2014; Lafortune et al., 2016; North et al., 2015; Xu et al., 2015; Zhong et al., 2015). Only limited adverse events have been reported and only for pharmacological interventions (Motooka et al., 2018). Therefore, any type of intervention aimed at tobacco cessation is likely to be more beneficial than detrimental. The GDG made a strong recommendation although evidence from experimental intervention trials is not available, since tobacco use has substantial established harm and the epidemiological/ observational evidence on tobacco use and increased risk of dementia fulfils most of the Bradford-Hill’s criteria for causation (Lafortune et al., 2016). The evidence is strong, the population attributable risk is high, reproducible in different settings and with different study designs, specific, and indicates a dose- response effect. In addition, criteria such as temporality (mid-life smoking is correlated to a higher risk of late life dementia) (Lafortune et al., 2016), coherence (experimental laboratory results are in keeping with the observational evidence) (Durazzo et al., 2014) and mecha- nistic evidence suggest that smoking causes brain damage, underpinning subsequent cognitive decline. RECOMMENDATIONS AND CONSIDERATIONS RECOMMENDATION: Interventions for tobacco cessation should be offered to adults who use tobacco since they may reduce the risk of cognitive decline and dementia in addition to other health benefits. Quality of evidence: low Strength of recommendation: strong 18 Risk reduction of cognitive decline and dementia: WHO guidelines 3.3 NUTRITIONAL INTERVENTIONS Population: Adults with normal cognition or MCI Intervention: Dietary supplements (e.g. B vitamins, antioxidants, omega-3 and ginkgo) Comparison: Care as usual/placebo or one treatment versus another Outcomes: • Critical – Cognitive function – Incident MCI – Dementia • Important – Quality of life – Functional level (ADL, IADL) – Adverse events – Drop-out rates 3.3a For adults with normal cognition or MCI, are nutritional interventions including dietary supplements more effective than usual care or no intervention in reducing the risk/progression of cognitive decline and/or dementia? 3.3b For adults with normal cognition or MCI, are nutritional interventions such as healthy dietary patterns (e.g. the Mediterranean diet) more effective than usual care or no intervention in reducing the risk/progression of cognitive decline and/or dementia? Population: Adults with normal cognition or MCI Intervention: Healthy dietary pattern (e.g. the Mediterranean diet) Comparison: Care as usual or no intervention Outcomes: • Critical – Cognitive function – Incident MCI – Dementia • Important – Quality of life – Functional level (ADL, IADL) – Adverse events – Drop-out rates BACKGROUND A healthy diet throughout the life course plays a crucial role in optimal development, and in maintaining health and preventing NCDs. Previous dietary intervention studies have shown that dietary changes are involved in prevention of many conditions that increase the risk of dementia, such as diabetes (Diabetes Prevention Program Research Group, 2002; Tuomilehto et al., 2001) and CVD (Rees et al., 2013). Mechanistic and animal models have 19Evidence and recommendations suggested a variety of pathways that link dietary factors to neuropathological changes in the development of dementia (Swaminathan & Jicha, 2014). Therefore, dietary factors may be involved in the development of dementia, both directly and through their role on other risk factors, and a healthy diet may have a great preventive potential for cognitive impairment. The Mediterranean diet is the most extensively studied dietary approach, in general as well as in relation to cognitive function. Several systematic reviews of observational studies have concluded that high adherence to the Mediterranean diet is associated with decreased risk of MCI and AD, but modest adherence is not (Singh et al., 2014; Wu & Sun, 2017). Moreover, among participants with normal cognition, higher adherence is associated with better episodic memory and global cognition (Loughrey et al., 2017). Other promising dietary approaches associated with better cognitive function include: dietary approaches to stop hypertension (DASH) (Berendsen et al., 2017; Morris et al., 2015a; 2015b; Wengreen et al., 2013); and the brain health-specific Mediterranean-DASH Intervention for Neurodegenerative Delay (MIND) diet. Concerning individual foods and nutrients, consumption of fruit and vegetables (Jiang et al., 2017; Wu et al., 2017) and fish (Bakre et al., 2018; Zhang et al., 2016) are most consistently associated with decreased risk of dementia. Higher fish consumption has been linked to lower memory decline among healthy participants in many studies (Samieri et al., 2018), as well as intake of polyunsaturated fatty acids (PUFA) (fish-derived) (Zhang et al., 2016). Other foods and nutrients that have been associated with reduced risk of dementia or cognitive impairment are nuts, olive oil and coffee (Solfrizzi et al., 2017). Evidence has also been reported concerning folate, vitamin E, carotenes, vitamin C and vitamin D (Balion et al., 2012; Dangour et al., 2010; Rafnsson et al., 2013; Travica et al., 2017), but findings are inconsistent. RECOMMENDATIONS AND CONSIDERATIONS RECOMMENDATION 1: The Mediterranean-like diet may be recommended to adults with normal cognition and MCI to reduce the risk of cognitive decline and/or dementia. Quality of evidence: moderate Strength of the recommendation: conditional RECOMMENDATION 2: Healthy, balanced diet should be recommended to all adults based on WHO recommendations on healthy diet. Quality of evidence: low to high (for different dietary components) Strength of the recommendation: strong RECOMMENDATION 3: Vitamins B and E, PUFA and multi-complex supplementation should not be recommended to reduce the risk of cognitive decline and/or dementia. Quality of evidence: moderate Strength of the recommendation: strong 20 Risk reduction of cognitive decline and dementia: WHO guidelines Additional considerations include: • The evidence and recommendations provided assume that the nutritional status and potential micronutrients deficiencies in both mid-life and old age have been assessed and treated. • A balanced and varied diet represents a natural source of polyphenols and protein. • The recommendation about vitamins B and E, PUFA and multi-complex supplementation applies to people without nutrient deficiency. SUPPORTING EVIDENCE AND RATIONALE Observational studies have consistently reported that a healthy diet is associated with better cognitive performance (Berendsen et al., 2017; Frith et al., 2018; Loughrey et al., 2017; Morris et al., 2015; Wengreen et al., 2013), but the evidence from clinical trials is more inconsistent (D’Cunha et al., 2018; Fitzpatrick-Lewis et al., 2015a; 2015b; Forbes et al., 2015; Radd-Vagenas et al., 2018; Solfrizzi et al., 2018). It is important to acknowledge that interventions with dietary modifications that improve several aspects of dietary intake at once are more likely to promote better cognition compared with supplementation with only some nutrients. Dietary factors may have synergistic effects that are only evident in combinations of foods ( Jacobs Jr et al., 2009). WHO recommendations on a healthy diet (http://www.who.int/en/news-room/fact-sheets/detail/healthy-diet) For adults, the WHO guidelines recommend the following. A healthy diet contains: • Fruits, vegetables, legumes (e.g. lentils, beans), nuts and whole grains (e.g. unprocessed maize, millet, oats, wheat, brown rice). • At least 400 g (five portions) of fruits and vegetables a day. Potatoes, sweet potatoes, cassava and other starchy roots are not classified as fruits or vegetables. • Less than 10% of total energy intake from free sugars which is equivalent to 50 g (or around 12 level teaspoons) for a person of healthy body weight consuming approximately 2000 calories per day, but ideally less than 5% of total energy intake for additional health benefits. Most free sugars are added to foods or drinks by the manufacturer, cook or consumer, and can also be found in sugars naturally present in honey, syrups, fruit juices and fruit juice concentrates. • Less than 30% of total energy intake from fats. Unsaturated fats (found in fish, avocado, nuts, sunflower, canola and olive oils) are preferable to saturated fats (found in fatty meat, butter, palm and coconut oil, cream, cheese, ghee and lard) and trans-fats of all kinds, including both industrially produced trans-fats (found in processed food, fast food, snack food, fried food, frozen pizza, pies, cookies, biscuits, wafers, margarines and spreads) and ruminant trans-fats (found in meat and dairy foods from ruminant animals, such as cows, sheep, goats, camels and others). It is suggested to reduce the intake of saturated fats to less than 10% of total energy intake and trans-fats to less than 1% of total energy intake. In particular, industrially produced trans-fats are not part of a healthy diet and should be avoided. • Less than 5 g of salt (equivalent to approximately 1 teaspoon) per day and use iodized salt. 21Evidence and recommendations Regarding nutritional interventions, such as dietary supplements or healthy dietary patterns (e.g. the Mediterranean diet) compared with usual care or no intervention, six systematic reviews were identified for nine different nutritional interventions. These interventions were: 1. Multi-supplement complexes versus placebo in adults with normal cognition (D’Cunha et al., 2018). 2. Multi-supplement complexes versus placebo in adults with MCI (Fitzpatrick-Lewis et al., 2015). 3. PUFA versus placebo (Forbes et al., 2015). 4. Vitamin B versus placebo (Forbes et al., 2015). 5. Vitamin E versus placebo (Forbes et al., 2015). 6. Polyphenols versus placebo (Solfrizzi et al., 2018). 7. Protein supplementation versus placebo (Solfrizzi et al., 2018). 8. Chicken essence versus placebo (Teoh et al., 2016). 9. Mediterranean diet versus alternate or usual diet (Radd-Vagenas et al., 2018). The outcomes of incident MCI and dementia were only reported for interventions involving multi- supplement complexes in adults with normal cognition and the Mediterranean diet (D’Cunha et al., 2018; Radd-Vagenas et al., 2018). However, neither of these interventions showed a direct effect in reducing the incidence of dementia and/or MCI. All of the interventions/comparisons reported cognitive outcomes. There was moderate quality evidence that the Mediterranean diet can improve verbal and visual memory (Radd-Vagenas et al., 2018). A meta-analysis showed results that approached significance for global cognition and consistently positive, but non-significant, results were reported for all other cognitive outcomes (attention, working memory, processing speed, language and executive function) (Radd-Vagenas et al., 2018). A consistent positive effect of polyphenols on cognitive performance was also found, however, the quality of the evidence was low (Solfrizzi et al., 2018). Similarly, protein supplementations were found to have a beneficial effect on cognition in older adults, but the results were inconsistent and the quality of the evidence was low (Solfrizzi et al., 2018). Overall, no effects were found for multi-complex (D’Cunha et al., 2018; Fitzpatrick-Lewis et al., 2015), vitamins B and E (Forbes et al., 2015), and PUFA supplementation (Forbes et al., 2015). Low-quality evidence was reported for protein and polyphenols supplementation (Solfrizzi et al., 2018), and moderate evidence of a beneficial effect of the Mediterranean diet was found (Radd-Vagenas et al., 2018). Three multi-supplement complex interventions: docosahexaenoic acid (DHA) + eicosapentaenoic acid (EPA) + vitamin E + soy phospholipids + tryptophan + melatonin; vitamin E + multivitamin; lyophilized royal jelly + gingko biloba + Panax ginseng; were examined and none showed an increased risk of any serious adverse event during the follow-up period (moderate quality evidence, Fitzpatrick-Lewis et al., 2015). The GDG concluded that the benefits of a Mediterranean diet and a balanced diet outweighed the harms and provided conditional and strong recommendations respectively. The GDG noted that vitamin E and protein supplementation at high doses have been associated with undesirable non- anticipated effects that outweigh the benefits and recommended against their use. 22 Risk reduction of cognitive decline and dementia: WHO guidelines Population: Adults with normal cognition or MCI and excessive use of alcohol Intervention: • Behavioural and psychological interventions to treat alcohol use disorders (e.g. motivational interviewing) • Pharmacological interventions to treat alcohol use disorders Comparison: Care as usual or no intervention Outcomes: • Critical – Cognitive function – Incident MCI – Dementia • Important – Quality of life – Functional level (ADL, IADL) – Adverse events – Drop-out rates For adults with normal cognition or MCI and alcohol use disorders, are behavioural and psychological interventions to treat alcohol use disorders more effective than usual care or no intervention in reducing the risk of cognitive decline and/or dementia? 3.4 INTERVENTIONS FOR ALCOHOL USE DISORDERS BACKGROUND Excessive alcohol consumption is common in many countries (Gell et al., 2015). In 2012, 5.9% of all deaths worldwide (about 3.3 million) were directly attributable to harmful use of alcohol (WHO, 2014). Furthermore, excessive consumption of alcohol is one of the leading causes of general disability globally (WHO, 2014), being a direct cause in more than 200 diseases including risk factors for dementia and injury conditions (WHO, 1992; WHO 2019a). There is extensive evidence on excessive alcohol as a risk factor for dementia and cognitive decline (Langballe et al., 2015; Sachdeva et al., 2016; Zhou et al., 2014). Several approaches have been applied in interventions aimed at hazardous and harmful use of alcohol. Pharmacological therapies with different types of drugs (e.g. opioid antagonists, ALDH2 inhibitors) have shown various degrees of efficacy for adults with alcohol use disorders, although none of them showed to be superior in comparison trials. Behaviour and psychological interventions have shown to be effective in alcohol use disorders, and especially among those with hazardous and harmful drinking. Screening and brief intervention in primary care is one of the most cost-effective means of reducing alcohol-attributable morbidity and deaths (Kaner, 2018). Interventions for alcohol use disorders have been described in the mhGAP Intervention guide - Version 2.0 for mental, neurological and substance use disorders in non-specialized health settings (http://www.who.int/mental_health/mhgap/mhGAP_ intervention_guide_02/en/). 23Evidence and recommendations RECOMMENDATIONS AND CONSIDERATIONS RECOMMENDATION Interventions aimed at reducing or ceasing hazardous and harmful drinking should be offered to adults with normal cognition and MCI to reduce the risk of cognitive decline and/or dementia in addition to other health benefits. Quality of evidence: moderate (for observational evidence) Strength of the recommendation: conditional WHO mhGAP Intervention guide - Version 2 for mental, neurological and substance use disorders in non-specialized health settings (http://www.who.int/mental_health/mhgap/mhGAP_intervention_guide_02/en/) The WHO mhGAP Intervention guide recommends the following: Harmful use of alcohol • Provide psychoeducation and emphasize that the level/pattern of alcohol use is causing harm to health. • Explore the person’s motivations for alcohol use. Conduct motivational interviewing. • Advise stopping alcohol completely or consuming at a non-harmful level (if a non-harmful level exists) and indicate your intention in supporting the person in doing so. Ask the person if they are ready to try to make this change. • Explore strategies for reducing or stopping use and strategies for reducing harm. • Address food, housing and employment needs. • Offer regular follow-up. Alcohol dependence • Thiamine during alcohol use. • Diazepam during alcohol detoxification to treat withdrawal symptoms. • Naltrexone, acamprosate or disulfiram to prevent relapse after detoxification. • Psychosocial interventions if available, e.g. cognitive behaviour therapy, motivational enhancement therapy, contingency management therapy, family counselling or therapy, problem-solving counselling or therapy; self-help groups. 24 Risk reduction of cognitive decline and dementia: WHO guidelines Additional considerations include: • Interventions can be based on lifestyle/ behavioural changes or pharmacological treatments in accordance with the WHO mhGAP guidelines. Lifestyle behavioural interventions are likely to be more acceptable and have fewer adverse events. • A U-shaped relationship between alcohol consumption and cognitive function has been reported. However, due to methodological limitations in most studies that describe this effect, it is not possible to assume that a light to moderate consumption of alcohol is, in fact, protective toward dementia and/or cognitive decline. This, in addition to other health risks and the social and economic burden associated with alcohol, do not favour a general recommendation of its use. • Individual level interventions should be provided in the context of WHO Global strategy to reduce harmful use of alcohol (WHO 2010) and population level interventions, through strengthening restrictions on alcohol availability, enforcing drink driving countermeasures, facilitating access to screening, brief interventions, and treatment, enforcing bans or comprehensive restrictions on alcohol advertising, sponsorship, and promotion, raising prices on alcohol through excise taxes and pricing policies. SUPPORTING EVIDENCE AND RATIONALE No systematic reviews were identified for interventions for hazardous and harmful alcohol consumption (behavioural, psychological and pharmacological interventions) and reduced the risk of cognitive decline and/or dementia. However, a large body of observational evidence is available on alcohol as a risk factor for cognitive decline and dementia (Beydoun et al., 2014; Hersi et al., 2017; Ilomaki et al., 2015; Lafortune et al., 2016; Piazza-Gardner et al., 2013; Xu et al., 2017). Generally, single studies did not always show similar results (mostly due to differences in study design) but the most consistent pattern is that of a U-shaped relationship between alcohol consumption and dementia and/or cognitive impairment, which clearly links excessive alcohol consumption to a significantly increased risk (Xu et al., 2017). A range of adverse events has also been reported for pharmacological interventions aimed at reducing excessive alcohol consumption while lifestyle interventions are mostly based on behavioural interventions and no evidence of adverse events (apart from those related to withdrawal syndrome) have been identified (NICE, 2011). Overall, the GDG concluded that the benefits outweighed the harms and, based on the strong observational evidence, made a conditional recommendation for interventions to reduce or cease hazardous and harmful alcohol use. 25Evidence and recommendations Population: Adults with normal cognition or MCI Intervention: • Cognitive stimulation • Cognitive training Comparison: Care as usual or no intervention Outcomes: • Critical – Cognitive function – Incident MCI – Dementia • Important – Quality of life – Functional level (ADL, IADL) – Adverse events – Drop-out rates For adults with normal cognition or MCI is cognitive stimulation or cognitive training more effective than usual care or no intervention in reducing the risk of cognitive decline and/or dementia? 3.5 COGNITIVE INTERVENTIONS BACKGROUND Dementia is preceded by cognitive decline. However, not everyone who is exposed to dementia risk factors will go on to develop cognitive impairment. The concept of cognitive reserve has been proposed as a protective factor that may reduce the risk of clinical onset of dementia and cognitive decline (Stern, 2012). Cognitive reserve refers to the brain’s ability to cope with or compensate for neuropathology or damage (Stern, 2012). Studies have shown that increased cognitive activity may stimulate (or increase) cognitive reserve and have a buffering effect against rapid cognitive decline (Stern & Munn, 2010) as well as a significant reduction in the risk of MCI or AD diagnosis in those who reported high compared with low levels of cognitive activities (combined OR = 0.38, 95% CI: 0.15–0.99) (Sattler, 2012). Increased cognitive activity can be achieved through cognitive stimulation therapy and/or cognitive training. Cognitive stimulation therapy refers to “participation in a range of activities aimed at improving cognitive and social functioning” (Clare & Woods, 2004), while cognitive training refers to “guided practice of specific standardized tasks designed to enhance particular cognitive functions” (Clare & Woods, 2004). The NIA (United States of America) identified cognitive training as an intervention aimed at preventing or delaying the onset of age-related cognitive decline, MCI, or clinical Alzheimer’s-type dementia (Kane et al., 2017). Additionally, the WHO ICOPE guidelines (http://www. who.int/ageing/publications/guidelines-icope/en/) recommend cognitive stimulation for older adults with cognitive impairment. These interventions were assessed against outcomes that were judged as critical and important for this population. 26 Risk reduction of cognitive decline and dementia: WHO guidelines SUPPORTING EVIDENCE AND RATIONALE For cognitive stimulation versus usual care or no intervention in healthy older adults, evidence was extracted from one systematic review (Strout et al., 2016). No evidence for adults with MCI was available. The review reported that half of the interventions evaluated proved to be effective in improving cognitive outcomes in at least one cognitive domain – executive function, attention, memory, language and/or processing speed (Strout et al., 2016). The quality of the evidence was low. The results were reported in narrative form and no meta-analysis was conducted. No evidence for incident MCI or dementia was available. For cognitive training versus usual care or no intervention in healthy older adults, evidence was extracted from one systematic review (Chiu et al., 2017). The review conducted a meta-analysis which showed that cognitive training in healthy older adults has a moderate positive effect on overall cognitive functioning. The quality of evidence was low. No evidence for incident MCI or dementia was available. For cognitive training versus usual care or no intervention in adults with MCI, evidence was extracted from two systematic reviews (Chandler et al., 2016; Sherman et al., 2017). With regards to cognitive function outcome, the quality of evidence is low showing that cognitive training in adults with MCI has a small positive effect on cognition. With regards to incident dementia outcome, the quality of evidence is very low as the results were narratively reported. It was reported that one study found that half of the control group, but none of the intervention group, developed dementia at the 8-month follow-up, while another found that more of the intervention group reported incident dementia at the 2-year follow-up (Chandler et al., 2016). With regards to quality of life and functional level, the quality of evidence is low showing that cognitive training in adults with MCI has a small positive effect on ADL but not quality of life. The evidence for cognitive interventions is mainly in studies with older adults. The GDG concluded that in this population the desirable effects of the intervention outweighed the undesirable effects and provided a conditional recommendation for cognitive training. The evidence for cognitive stimulation in reducing the risk of dementia was insufficient and no recommendation was made by the GDG. RECOMMENDATIONS AND CONSIDERATIONS RECOMMENDATION: Cognitive training may be offered to older adults with normal cognition and with MCI to reduce the risk of cognitive decline and/or dementia. Quality of evidence: very low to low Strength of the recommendation: conditional 27Evidence and recommendations Population: Adults with normal cognition or MCI Intervention: Comparison: Care as usual or no intervention Outcomes: • Critical – Cognitive function – Incident MCI – Dementia • Important – Quality of life – Functional level (ADL, IADL) – Adverse events – Drop-out rates For adults with normal cognition or MCI is preserving and promoting a high level of social activity more effective than usual care or no intervention in reducing the risk of cognitive decline and/or dementia? 3.6 SOCIAL ACTIVITY BACKGROUND Social engagement is an important predictor of well- being throughout life (Cherry et al., 2011). Social disengagement conversely, has been shown to place older individuals at increased risk of cognitive impairment and dementia (Fratiglioni et al., 2004). A systematic review and meta-analysis of longitudinal cohort studies showed that lower social participation, less frequent social contact and loneliness were associated with higher rates of incident dementia (Kuiper et al., 2015). The Lancet Commission on Dementia Prevention, Intervention, and Care identified social engagement as an intervention that could be used to prevent dementia (Livingston et al., 2017). RECOMMENDATIONS AND CONSIDERATIONS There is insufficient evidence for social activity and reduction of risk of cognitive decline/dementia. Social participation and social support are strongly connected to good health and well-being throughout life and social inclusion should be supported over the life-course. (Global age-friendly cities: a guide, http://www.who.int/ageing/publications/Global_age_friendly_ cities_Guide_English.pdf) 28 Risk reduction of cognitive decline and dementia: WHO guidelines SUPPORTING EVIDENCE AND RATIONALE For preservation and promotion of social activity including community and family engagement versus care as usual or no intervention, evidence was extracted from one systematic review examining adults with normal cognition (Kelly et al., 2017). No evidence for adults with MCI was available. For cognitive function outcomes, the quality of the evidence is very low. Three RCTs, which assessed the association between cognitive function and social activity, were deemed eligible. The review findings were reported narratively (Kelly et al., 2017). Overall cognition was measured by varied composite measures of global cognition, including the ADAS-cog, MMSE and MDRS. One of the three RCTs found social activity intervention to be significantly associated with improvements in cognitive function (Pitkala et al., 2011). No data were available for incident MCI or dementia, quality of life, functional level (ADL, IADL), adverse events or drop-outs. The GDG concluded that the evidence is limited and inconclusive, so no recommendation was made for social activity and risk of cognitive decline/dementia. Furthermore, there is a risk of bias arising from reverse causality whereby low social engagement prior to diagnosis of cognitive decline or dementia may be at least in part due to the disease process. The GDG did not make a recommendation against social activity as they concluded that social activity has a wide range of other benefits to health and well-being. 29Evidence and recommendations Population: Adults with normal cognition or MCI who are overweight or obese Intervention: Weight management • Non-pharmacological interventions, e.g. cognitive behavioural intervention strategies, lifestyle interventions • Pharmacological interventions, e.g. weight loss medication (e.g. orlistat) Comparison: Care as usual or no intervention Outcomes: • Critical – Cognitive function – Incident MCI – Dementia • Important – Quality of life – Functional level (ADL, IADL) – Adverse events – Drop-out rates For adults with normal cognition or MCI who are overweight or obese, are interventions for weight reduction (or control of obesity) more effective than usual care or no intervention in reducing the risk of cognitive decline and/or dementia? 3.7 WEIGHT MANAGEMENT BACKGROUND Overweight and obesity are some of the best characterized and established risks for a variety of NCDs, responsible for at least 2.8 million deaths each year worldwide, and of an estimated 35.8 million (2.3%) of global disability-adjusted life years (DALYs) (WHO, 2019b). In 2008, 35% of adults aged 20+ were overweight (BMI ≥ 25 kg/m2) (34% men and 35% of women), with significantly variable prevalence among world areas, with the United States of America, Europe and the Eastern Mediterranean regions with the highest concentration of people with overweight/ obesity (WHO, 2019b). Overweight and obesity, in particular, have been linked to a number of medical complications such as Type 2 diabetes (Chan et al., 1994), cancer (Renehan et al., 2015), premature mortality (Fontana & Hu, 2014), and CVD (Eckel, 1997), both as direct risk factors as well as risks for other cardiovascular risk factors, such as high cholesterol and hypertension. Obesity has been steadily rising, particularly among older adults in the last few decades (Nguyen & El-Serag, 2010) and although an increasing body of evidence suggests that overweight (25 < BMI < 30) in older adults could be more protective than normal weight in terms of overall mortality (Flicker et al., 2010), a link has also been established between excess of fat body mass and cognitive impairment (Xu et al., 2011). A recent systematic review and meta-analysis of observational studies conducted on a total of about 600 000 individuals showed that obesity (but not overweight) at mid-life increases the risk of dementia (RR = 1.33; 95% CI: 1.08–1.63) (Albanese et al., 2017). It has been suggested that weight loss could indirectly reduce the risk of dementia by improving a variety of metabolic factors linked with the pathogenesis of cognitive impairment and dementia (i.e. glucose 30 Risk reduction of cognitive decline and dementia: WHO guidelines tolerance, insulin sensitivity, blood pressure, oxidative stress, and inflammation) (Bennett et al., 2009). However, a direct beneficial effect of weight reduction intervention is also plausible. Although, so far, evidence of potential cognitive benefits of weight loss seem to be strongly associated with increased physical activity (Colcombe et al., 2006; Erickson et al., 2010), in 2011 a systematic review concluded that intentional weight loss can improve performance in some cognitive domains, at least in people with obesity (Siervo et al., 2011). Additional considerations include: • Lifestyle interventions that included both diet and physical activity components seemed to show the best results. • In addition to interventions at individual level, lifestyle interventions at the population level, such as activity parks, green spaces and infrastructure to support active commuting, need to be considered. • Being underweight in both late-mid-life and old age might be associated with a higher risk of dementia. However, it is likely that this association is explained, at least in part, by reverse causality, whereby brain pathology may cause weight loss before the clinical onset of dementia. • Unintentional weight loss and malnutrition are associated with poor health outcomes and should be investigated and treated at all ages. However, it is unlikely that interventions that favour weight gain in people who are underweight in either mid- or late life can reduce the risk of dementia or cognitive impairment. RECOMMENDATION: Interventions for mid-life overweight and/or obesity may be offered to reduce the risk of cognitive decline and/or dementia. Quality of evidence: low to moderate Strength of the recommendation: conditional WHO guidance on overweight and obesity outlined in Prevention and control of noncommunicable diseases: guidelines for primary health care in low-resource settings (2012) (http://www.who.int/nmh/publications/phc2012/en/) WHO guidance on overweight and obesity should be followed. • Advise overweight patients to reduce weight by following a balanced diet. • Advise patients to give preference to low glycaemic-index foods (beans, lentils, oats and unsweetened fruit) as the source of carbohydrates in their diet. • Advise patients to reduce sedentary behaviour and practise regular daily physical activity appropriate for their physical capabilities (e.g. walking). RECOMMENDATIONS AND CONSIDERATIONS 31Evidence and recommendations SUPPORTING EVIDENCE AND RATIONALE For weight reduction with behavioural and/or lifestyle interventions (or control of obesity) compared with usual care or no intervention, evidence was extracted from one systematic review examining adults with normal cognition who are overweight or obese (Veronese et al., 2017). No evidence for adults with MCI was available. There was low to moderate evidence that lifestyle interventions aimed at weight reduction could improve cognitive function in the attention, memory and language domains. Interventions were very short (ranging from 8 to 48 weeks). No data were found in relation to incident MCI and dementia outcomes. No evidence of adverse events was identified. For pharmacological interventions for weight reduction (or control of obesity) compared with usual care or no intervention, no systematic reviews were found. The GDG concluded that the benefits of the interventions outweighed the harms and provided a conditional recommendation. Since the observational evidence of a correlation between overweight/obesity and increased risk of dementia is stronger and more consistent in mid-life than in late life (Hersi et al., 2017; Lafortune et al., 2016; Pedditzi et al., 2016; Prickett et al., 2015; Xu et al., 2015), the GDG made a conditional recommendation for this population. 32 Risk reduction of cognitive decline and dementia: WHO guidelines Population: Adults with normal cognition or MCI with hypertension Intervention: Antihypertensive medication, lifestyle interventions Comparison: Placebo/no intervention Outcomes: • Critical – Cognitive function – Incident MCI – Dementia • Important – Quality of life – Functional level (ADL, IADL) – Adverse events – Drop-out rates For adults with normal cognition or MCI and hypertension, is treatment of hypertension more effective than placebo/no intervention in reducing the risk of cognitive decline/dementia? 3.8 MANAGEMENT OF HYPERTENSION BACKGROUND Hypertension in mid-life has been associated with an increased risk of late life dementia (Kivipelto et al., 2001). In particular, a pattern of increased blood pressure during mid-life followed by a rapid decrease in blood pressure later in life has been found in individuals who go on to develop dementia (Kivipelto et al., 2001; Launer et al., 2000; Stewart et al., 2009). There is mixed evidence relating to the reduction of blood pressure in late mid- or late life and subsequent cognitive decline or dementia, however, there is evidence to show that the reduction of hypertension can have substantial benefits in reducing cardiovascular morbidity and mortality and thus improving overall health of the ageing population (Musini et al., 2009). Hypertension can be prevented through a range of lifestyle factors, including eating a healthy diet, maintaining a healthy weight and participating in an adequate amount of physical activity. It can also be controlled through antihypertensive medication. However, the evidence for the effectiveness of blood pressure lowering treatments in reducing the risk of cognitive decline and dementia risk is mixed. RECOMMENDATION 1: Management of hypertension should be offered to adults with hypertension according to existing WHO guidelines. Quality of evidence: low to high (for different interventions) Strength of the recommendation: strong RECOMMENDATIONS AND CONSIDERATIONS 33Evidence and recommendations HEARTS Technical package for cardiovascular disease management in primary health care: evidence-based treatment protocols (http://apps.who.int/iris/bitstream/handle/10665/260421/WHO-NMH-NVI-18.2-eng.pdf?sequence=1) Medications used to treat hypertension • There are four main classes of antihypertensive medications: angiotensin converting enzyme (ACE) inhibitors; angiotensin receptor blockers (ARB); calcium channel blockers (CCB); and thiazide and thiazide-like diuretics. Any of these four classes of antihypertensive medication may be used unless there are specific contraindications. Proper treatment of hypertension usually requires a combination of hypertension medications. Notes on specific hypertension medications • Pregnant women and women of childbearing age not on effective contraception should not be given ACE inhibitors, ARBs or thiazide/thiazide-like diuretics; CCBs should be used. If not controlled with intensification dose of medication, refer to specialist. • Beta blockers are not recommended as first-line therapy. If a heart attack has been diagnosed within the previous three years, or there is atrial fibrillation or heart failure, then a beta blocker should be added to the starting dose of antihypertensive medication. Patients with angina may also benefit from treatment with a beta blocker. Other treatment considerations • If there is a prior heart attack or stroke, or the person is otherwise at high risk of CVD, start a statin at the same time as starting antihypertensive medication. (Statins should not be used in women who are or who may become pregnant.) • If there is a prior heart attack or ischemic stroke, start low-dose aspirin. • The hypertension protocols included in this module serve well for initiation and maintenance of successful treatment. If there are serious adverse events, lack of control of blood pressure, or if a major medical event intervenes, then referral to a specialist will be needed. • If the patient is already on another medication regimen, blood pressure is controlled to the target level, and the medications the patient is taking are accessible and affordable, there is no reason to change the regimen. • If the patient feels faint on standing, check blood pressure while standing. If the systolic blood pressure is consistently less than 110 mm Hg in a patient on medical treatment, consider reducing the dosage or number of medications used. RECOMMENDATION 2: Management of hypertension may be offered to adults with hypertension to reduce the risk of cognitive decline and/or dementia. Quality of evidence: very low (in relation to dementia outcomes) Strength of the recommendation: conditional 34 Risk reduction of cognitive decline and dementia: WHO guidelines SUPPORTING EVIDENCE AND RATIONALE For treatment of hypertension in the form of antihypertensive medication versus placebo or no intervention, evidence was extracted from two systematic reviews examining adults with normal cognition and hypertension (Parsons et al., 2016; Weiss et al., 2016). No evidence for adults with MCI was available. With regard to cognitive function and incident dementia outcomes, the quality of the evidence was low, which showed that antihypertensive therapy has no effect on cognitive decline or incidence of dementia. With regard to quality of life and functional level outcomes, the quality of evidence is very low, showing that antihypertensive therapy does not decrease quality of life or functional level. With regard to adverse events, the quality of evidence was very low, showing mixed findings with regard to antihypertensive use. There were no data on incident MCI and overall drop- out rates. Initial results from the SPRINT-MIND trial, a substudy of the Systolic Blood Pressure Intervention Trial (SPRINT) that aims to evaluate the effect of intensive blood pressure control on risk of dementia, support the possibility of a dose-response relationship between blood pressure and risk of cognitive decline or dementia (SPRINT-MIND 2019). Observational evidence suggests a strong association between hypertension and incident cognitive decline/dementia. For treatment of hypertension in the form of lifestyle interventions versus placebo or no intervention, no systematic reviews were found. The GDG made a strong recommendation for management of hypertension for its established health benefits and a conditional recommendation for hypertension management for reducing the risk of cognitive decline/dementia. The GDG concluded that though there is limited clinical trial evidence that treatment of hypertension reduces the risk of cognitive decline or dementia, the benefits outweighed the harms since the evidence suggests that intervention does not lower quality of life or functional level and there are mixed results regarding adverse effects which may depend on the drug used. Additionally, robust evidence for a causal relationship is available. 35Evidence and recommendations Population: Adults with normal cognition or MCI with diabetes mellitus Intervention: • Medications for glycaemic control • Diet and lifestyle interventions Comparison: Placebo/no intervention Outcomes: • Critical – Cognitive function – Incident MCI – Dementia • Important – Quality of life – Functional level (ADL, IADL) – Adverse events – Drop-out rates For adults with normal cognition or MCI and diabetes mellitus, is treatment of diabetes more effective than placebo/no intervention in reducing the risk of cognitive decline and/or dementia? 3.9 MANAGEMENT OF DIABETES BACKGROUND The presence of late life diabetes has been linked to an increased risk of dementia (Luchsinger, 2010; Prince et al., 2014; Profenno et al., 2010). However, the mechanism by which this occurs is unclear. Poor glucose control has been associated with lower cognitive functioning and greater cognitive decline (Yaffe et al., 2012). In addition, the complications associated with diabetes, such as nephropathy (kidney damage), retinopathy (eye damage), hearing impair- ment and CVD, have all been found to increase the risk of dementia (Bruce et al., 2014; Exalto et al., 2013). The literature examining interventions that aim to improve glycaemic control shows mixed findings with regard to cognitive outcomes (Launer et al., 2011; Luchsinger et al., 2011). In addition, the evidence on the effectiveness of medication for diabetes in reducing dementia risk is inconsistent (Cheng et al., 2014; Moore et al., 2013; Parikh et al., 2011). There is some evidence to suggest that treating the cardiovascular comor- bidities associated with diabetes, such as high choles- terol and hypertension, may mediate the risk for dementia (Johnson et al., 2012; Parikh et al., 2011). 36 Risk reduction of cognitive decline and dementia: WHO guidelines RECOMMENDATION 1: Management of diabetes in the form of medications and/or lifestyle interventions should be offered to adults with diabetes according to existing WHO guidelines. Quality of evidence: very low to moderate (for different interventions) Strength of the recommendation: strong RECOMMENDATION 2: Management of diabetes may be offered to adults with diabetes to reduce the risk of cognitive decline and/or dementia. Quality of evidence: very low Strength of the recommendation: conditional Package of essential noncommunicable (PEN) disease interventions for primary health care in low-resource settings (https://www.who.int/cardiovascular_diseases/publications/pen2010/en/). For individuals with diabetes, the WHO guidelines recommend the following treatments: Type 1 diabetes • Daily insulin injections (Level 1). Type 2 diabetes • Oral hypoglycaemic agents for Type 2 diabetes, if glycaemic targets are not achieved with modification of diet, maintenance of a healthy body weight and regular physical activity (Level 1). • Metformin as initial drug in overweight patients (Level 1) and non-overweight (Level 4). • Other classes of antihyperglycaemic agents, added to metformin if glycaemic targets are not met (Level 3). • Reduction of cardiovascular risk for those with diabetes and 10-year cardiovascular risk > 20% with aspirin, angiotensin converting enzyme inhibitor and statins (Level 1). RECOMMENDATIONS AND CONSIDERATIONS 37Evidence and recommendations SUPPORTING EVIDENCE AND RATIONALE For treatment of diabetes in the form of medications for glycaemic control versus placebo or no intervention, evidence was extracted from one systematic review examining adults with normal cognition and Type 2 diabetes (Areosa Sastre et al., 2017). No evidence for adults with MCI was available. The quality of the evidence was moderate for cognitive function outcomes and very low for incident dementia outcomes, which showed intensive as opposed to standard glycaemic control has an unclear effect on cognitive function and no effect on incident dementia. The evidence reviewed included data from a large study set across 215 collaborating centres in 20 countries in Asia, Australasia, Europe and North America. The quality of evidence for adverse events was very low, showing intensive glycaemic control increases the risk of hypoglycaemic events. No data on incident MCI, quality of life, functional outcomes or drop-out rates were available. Overall, in adults with normal cognition, the evidence may favour standard glycaemic control because intense glycaemic control has no effect on cognitive function but may result in increased episodes of hypoglycaemia. For treatment of diabetes in the form of diet and life- style interventions versus placebo or no intervention, evidence was extracted from one systematic review examining adults with normal cognition and Type 2 diabetes (Podolski et al., 2017). No evidence for adults with MCI was available. The quality of evidence was very low and the findings were mixed. No meta- analysis was conducted and there were no robust data on clinical significance. The GDG made a strong recommendation for management of diabetes for its established health benefits and a conditional recommendation for diabetes management for reducing the risk of cognitive decline/dementia. The GDG concluded that though there is limited clinical trial evidence on the management of diabetes to reduce the risk of cognitive decline or dementia, the benefits outweighed the harms and there is robust observational evidence to suggest diabetes increases the risk of cognitive decline and dementia. 38 Risk reduction of cognitive decline and dementia: WHO guidelines Population: Adults with normal cognition or MCI with dyslipidaemia Intervention: • Statins (e.g. simvastatin and pravastatin) • Lifestyle interventions Comparison: Placebo or no intervention Outcomes: • Critical – Cognitive function – Incident MCI – Dementia • Important – Quality of life – Functional level (ADL, IADL) – Adverse events – Drop-out rates For adults with normal cognition or mild cognitive impairment and dyslipidaemia, is treatment of dyslipidaemia more effective than placebo or no intervention in reducing the risk of cognitive decline and/or dementia? 3.10 MANAGEMENT OF DYSLIPIDAEMIA BACKGROUND Elevated serum cholesterol is one of the key modifiable cardiovascular risk factors. A third of ischaemic heart disease worldwide is attributable to dyslipidaemia and it is estimated to be the cause of 2.6 million deaths (4.5% of total) per year, as well as a considerable proportion of disability (WHO, 2019b). The prevalence of raised total cholesterol among countries seems to correlate with wealth: in high-income countries, more than 50% of adults have elevated total cholesterol level, more than double the rate in low-income countries (WHO, 2019c). The idea that raised level of blood cholesterol could be related to an increased risk of dementia was already introduced in the mid-1970s (Richardson et al., 2000). Since then, a number of epidemiological studies have demonstrated a close relationship between high serum cholesterol levels and the onset of AD/dementia (Kivipelto et al., 2002; Solomon et al., 2007; Whitmer et al., 2005), but results have been inconsistent, with other studies showing no or negative correlation (Mainous et al., 2005; Mielke et al., 2005). Based on the severity of the dyslipidaemia and CVD overall risk, lifestyle or pharmacological approaches can be undertaken to reduce blood cholesterol. Weight reduction and decreasing saturated fats in the diet (decreasing the consumption of food of animal origin) are the most common and effective lifestyle recommen- dations (Perk et al., 2012). However, dyslipidaemia is often controlled and managed pharmacologically, with statins being the drugs of first choice. Several observational studies have investigated the possible beneficial effect of statins therapy in preventing dementia, but bias and heterogeneity hampered the overall quality of the evidence (Song et al., 2013; Swiger et al., 2013; Wong et al., 2013). Recently, a re-analysis of statin use in AD patients from failed clinical trials suggested that the use of simvastatin may slow the progression of cognitive decline in some people (Geifman et al., 2017). 39Evidence and recommendations RECOMMENDATIONS AND CONSIDERATIONS RECOMMENDATION: Management of dyslipidaemia at mid-life may be offered to reduce the risk of cognitive decline and dementia. Quality of evidence: low Strength of the recommendation: conditional Additional considerations include: • Statin treatment in older adults should not be specifically initiated for preventing cognitive decline and/or dementia but may be used for other health benefits according to WHO’s Prevention and control of noncommunicable diseases: guidelines for primary health care in low-resource settings (http://www.who.int/nmh/publications/phc2012/en/). SUPPORTING EVIDENCE AND RATIONALE For control of dyslipidaemia through treatment with statins compared with placebo, evidence was extracted from one systematic review examining adults with normal cognition and dyslipidaemia (McGuinness et al., 2016). No evidence for adults with MCI was available. The quality of the evidence was moderate for cognitive function outcomes and low for incident dementia outcomes, showing that treatment with statins has no effect on either incident dementia and/or cognitive decline. There is moderate quality evidence that the treatment with statins does not increase the incidence of serious adverse events. A large body of observational evidence has linked dyslipidaemia to an increased risk of dementia and/or cognitive decline and found an association between control of dyslipidaemia and reduction of dementia and/or cognitive decline risk (Geifman et al., 2017; Hersi et al., 2017; Reitz, 2013; Song et al., 2013). Overall, indirect evidence suggests that managing dyslipidaemia in mid-life can help reduce the risk of cognitive decline and/or dementia. No studies were identified that specifically aimed at controlling dyslipidaemia through lifestyle interventions and included outcomes related to dementia and/or cognitive impairment. The GDG concluded that the desirable effects of dyslipidaemia treatment outweigh the undesirable effects and made a conditional recommendation. The observational evidence reported a stronger correlation between high cholesterol and dementia in mid-life rather than late life (Hersi et al., 2017; Reitz, 2013). The systematic review evidence that focused on clinical trials in older adults (65+) showed that statin treatment has no effect on cognition or dementia outcomes (McGuinness et al., 2016). Therefore, the GDG concluded that there were no grounds to recommend the use of statin and the control of cholesterol in late life but only in mid-life. 40 Risk reduction of cognitive decline and dementia: WHO guidelines Population: Adults with normal cognition or MCI with moderate to severe depressive disorder Intervention: • Pharmacological interventions to treat depression (antidepressant medication) • Psychological interventions to treat depression (e.g. cognitive behavioural therapy, problem-solving therapy, interpersonal therapy, behavioural activation) Comparison: Care as usual or placebo or no intervention Outcomes: • Critical – Cognitive function – Incident MCI – Dementia • Important – Quality of life – Functional level (ADL, IADL) – Adverse events – Drop-out rates For adults with normal cognition or mild cognitive impairment and depressive disorder, is treatment of depression more effective than usual care, placebo or no intervention in reducing the risk of cognitive decline and/or dementia? 3.11 MANAGEMENT OF DEPRESSION BACKGROUND There is a substantial body of evidence linking depression to cognitive decline and dementia. A review carried out as part of the World Alzheimer Report in 2014 combined 32 studies into a meta-analysis which looked at the effect of depression on the risk of incident dementia. This involved 62,568 participants with a median follow-up of 5 years (range 2 to 17). The review reported that the presence of depression nearly doubled the risk of dementia (pooled effect size = 1.97, 95% CI: 1.67–2.32) (Prince et al., 2014). The authors also carried out a meta-regression looking at follow-up time. They reported a trend toward smaller effect sizes in studies with longer follow-up suggesting that depression may have a prodromal role in dementia. It is noteworthy to mention that cognitive impairment may be the main symptom of depression in the elderly; a phenomenon that used to be called pseudodementia. There are several potential explanations for the link between depression and cognitive impairment or dementia. Some of these include associations between depression, noradrenergic changes and white matter lesions, depression which stems from insight into impairment at early stages of decline, depression highlighting underlying deficits, i.e. by reducing motivation and bringing its own cognitive deficits (Camus et al., 2004; Jorm, 2001; Kales et al., 2005; Schweitzer et al., 2002). 41Evidence and recommendations RECOMMENDATIONS AND CONSIDERATIONS There is currently insufficient evidence to recommend the use of antidepressant medicines for reducing the risk of cognitive decline and/or dementia. The management of depression, in the form of antidepressants and/or psychological interventions, should be provided to adults with depression according to existing WHO mhGAP guidelines. WHO mhGAP Intervention guide - Version 2 for mental, neurological and substance use disorders in non-specialized health settings (https://www.who.int/mental_health/mhgap/mhGAP_intervention_guide_02/en/) For adults with moderate to severe depressive disorder, the WHO guidelines recommend the following treatments: Psychosocial/non-pharmacological treatment and advice • Psychoeducation (for the person and his or her family, as appropriate). • Addressing current psychosocial stressors. • Reactivate social networks. • Brief psychological treatments, if available. • Offer regular follow-up. Antidepressant medication • Select an antidepressant from the National or WHO Formulary. Selective serotonin reuptake inhibitors (fluoxetine) and tricyclic antidepressants (amitriptyline) are antidepressants mentioned in the WHO Formulary and are on the WHO model list of essential medicines. • In selecting an antidepressant, consider the symptom pattern of the person, the side-effect profile of the medication, and the efficacy of previous antidepressant treatments, if any. • For co-morbid medical conditions, before prescribing antidepressants, consider potential for drug-disease or drug-drug interaction. Consult the National or the WHO Formulary. • Combining antidepressants with other psychotropic medication requires supervision by, or consultation with a specialist. 42 Risk reduction of cognitive decline and dementia: WHO guidelines SUPPORTING EVIDENCE AND RATIONALE For pharmacological interventions to treat depression (antidepressant medication) compared with usual care or placebo, evidence was extracted from one systematic review examining adults with normal cognition and major depressive disorder (Baune et al., 2018). No evidence for adults with MCI was available. The review conducted a network meta-analysis and reported standardized mean differences in the Digit Symbol Substitution Test as a measure of cognition function. The review reported that vortioxetine (versus placebo) improved cognitive functioning while duloxetine, sertraline, citalopram, escitalopram, phenelzine and nortriptyline showed no effect (Baune et al., 2018). The quality of the evidence was very low and no data were reported for incident MCI or dementia outcomes, quality of life, adverse events, functional level or drop-out rates. Overall, the true balance of effects is difficult to ascertain. The evidence favours the use of vortioxetine (but not other pharmacological interventions) to treat depression for reducing the risk of cognitive decline or dementia. However, no data on adverse effects were available, e.g. drug-related side-effects or interactions. For psychological interventions to treat depression compared with placebo or no intervention, no relevant systematic reviews were found. The GDG therefore concluded that there was insufficient evidence currently for depression manage- ment and reduction of risk of cognitive decline/ dementia. They also concluded that the management of depression is important for its other benefits and did not make a negative recommendation against this intervention. 43Evidence and recommendations Population: Adults with normal cognition or MCI with hearing loss Intervention: Interventions to treat hearing loss (e.g. hearing aids) Comparison: Care as usual or no intervention Outcomes: • Critical – Cognitive function – Incident MCI – Dementia • Important – Quality of life – Functional level (ADL, IADL) – Adverse events – Drop-out rates For adults with normal cognition or MCI and hearing loss, is treatment of hearing loss more effective than usual care, or no intervention in reducing the risk of cognitive decline and/or dementia? 3.12 MANAGEMENT OF HEARING LOSS BACKGROUND Hearing loss is a prevalent age-related disorder. As the fourth leading cause of years lived with disability in the global population (WHO, 2012), it is estimated to affect one in three adults aged 65 and older, with this statistic growing annually (Wilson et al., 2017). The implications of hearing loss, however, are often underestimated both at the individual and population level (Blustein et al., 2018). Hearing impairment has debilitating consequences on functional ability and social and emotional well-being. Deteriorations in hearing impact on individuals’ ability to communicate with others, which in turn can result in feelings of frustration, isolation, loneliness (Ciorba et al., 2012). Older adult populations who already experience the isolating effects of age-related factors, such as diminished mobility, driving cessation, death of partners or living alone, are particularly vulnerable to these psychosocial impacts. Hearing loss is also associated with increased risk of cognitive decline or dementia (Lin et al., 2013). A recent meta-analysis of prospective cohort studies showed that the relative risk of hearing impairment on incident Alzheimer’s and MCI was 2.82 (95% CI: 1.47–5.42). (Zheng et al., 2017). Additionally, a meta-analysis published by the Lancet Commission showed that hearing loss can almost double the risk of incident dementia (RR = 1.94, 95% CI: 1.38–2.73) (Livingston et al., 2017). Hearing loss and cognitive impairment or dementia, individually, and in combination, predict functional ability and burden of care. Hearing loss interventions, therefore, have the potential to substantially improve outcomes for older people on multiple domains. 44 Risk reduction of cognitive decline and dementia: WHO guidelines WHO Guidelines on integrated care for older people (ICOPE) (http://www.who.int/ageing/publications/guidelines-icope/en/) For older adults, WHO recommends the following: Screening followed by provision of hearing aids should be offered to older people for timely identification and management of hearing loss. Considerations for recommendation: • Community awareness about hearing loss and the positive benefits of audiological rehabilitation in older people, through community case finding and outreach activities, should be promoted. • Health care professionals should be encouraged to screen older adults for hearing loss by periodically questioning them about their hearing. Audiological examination, otoscopic examination and the whispered voice test are also recommended. • Hearing aids are the treatment of choice for older people with hearing loss, because they minimize reduction in hearing and improve daily functioning. • Medications should be reviewed for potential ototoxicity. • People with chronic otitis media or sudden hearing loss, or who fail any screening tests, should be referred to an otolaryngologist. There is insufficient evidence to recommend use of hearing aids to reduce the risk of cognitive decline and/or dementia. Screening followed by provision of hearing aids should be offered to older people for timely identification and management of hearing loss as recommended in the WHO ICOPE guidelines. RECOMMENDATIONS AND CONSIDERATIONS 45Evidence and recommendations SUPPORTING EVIDENCE AND RATIONALE For interventions to treat hearing loss (e.g. hearing aids) versus care as usual or no intervention, evidence was extracted from one systematic review examining adults with normal cognition and hearing loss (Cherko et al., 2016). No evidence for adults with MCI was available. For cognitive function and quality of life, the quality of evidence is very low. No meta-analyses were performed and results were reported narratively with no numerical data to support conclusions (Cherko et al., 2016). Based on two studies including measures of cognitive function, the review concluded that while hearing aids use was found to be associated with improvements in cognitive function, these benefits may be limited in that cognitive improvements have been shown to revert to baseline at 1 year follow-up. They also concluded that use of hearing aids in older people was associated with improvements in quality of life outcomes based on two studies. Overall, the evidence does not favour either the intervention or the comparison. Hearing aids may improve quality of life but the amount of evidence available is limited. No data are available for incident MCI or dementia, functional level (ADL, IADL), adverse events or drop-outs. The GDG concluded that there is currently insufficient evidence to recommend the use of hearing aids to reduce the risk of cognitive decline/dementia. The GDG also concluded that the use of hearing aids is important to correct hearing loss in older adults for their other benefits and recommend following the ICOPE guidelines in this regard. 46 Risk reduction of cognitive decline and dementia: WHO guidelines IMPLEME NTATION CONSIDE R ATIONS 4 47 Implementation considerations Countries will be supported to implement the guidelines through training of health care personnel and using centres of excellence on improved quality of care. The implementation will also be supported locally through the adoption of the Global action plan on the public health response to dementia 2017– 2025; the Comprehensive mental health action plan 2013–2020; and the Global action plan for the prevention and control of noncommunicable diseases 2013–2020 at country level. The national capacity building process will also be supported through WHO collaboration with international organizations and associations. Given that many of the interventions included in these guidelines are strongly related to the management of risk factors for CVD and diabetes, the implementation of these recommendations should be combined, whenever possible and in the relevant target population, with the ongoing prevention programmes to reduce the risk of these conditions. The optimal preventive effect may be obtained by addressing several risk factors at the same time. Collaboration among different stake- holders and multidisciplinary approaches will also be needed. The recommendations contained in these guidelines should be adapted into a locally appropriate document that can meet the needs of each country and its health services. WHO headquarters will work closely with the regional and country offices, as well as implementing partners and public health agencies at the national level, to ensure communication and country-specific adaptations of the guidelines, through regional and national meetings. As countries consider how to implement these guidelines, the budgetary and human resource requirements, and other health systems implications should be analysed to identify which inputs and systems are currently available, and which areas require additional investment. These may include training of health workers, supply of medicines and adaptations of health information systems to collect data on service utilization. To support country implementation, WHO will produce a series of subsidiary tools that will address clinical and service delivery aspects of the imple- mentation of the recommendations included in these guidelines. 48 Risk reduction of cognitive decline and dementia: WHO guidelines PUBLIC ATION, DISSEMINATION AND EVALUATION 5 49Publication, dissemination and evaluation 5.1 PUBLICATION AND DISSEMINATION The guidelines will be disseminated as a print publication and electronically on a dedicated internet space on the WHO website. The guidelines will be disseminated through both the mental health and NCD dissemination activities of the Global action plan on the public health response to dementia 2017–2025 (such as the Global Dementia Observatory knowledge exchange platform), the Comprehensive mental health action plan 2013–2020 and the Global action plan for the prevention and control of noncommunicable diseases 2013–2020. These guidelines will be appended to the mhGAP guidelines and disseminated through the mhGAP evidence resource centre and other mhGAP derivative products, including the mhGAP Intervention guide. Since these guidelines are linked to other WHO guidelines such as NCD and ICOPE guidelines and other resources on ageing, dissemination will occur along with these guidelines. The guidelines and products are developed in English, and will be translated into other WHO official languages for wider dissemination and in collaboration with WHO regional offices. Local adaptation is necessary to ensure that the guidelines are appropriate for the local conditions that affect the care of people with cognitive decline and dementia in health facilities and the community. Adaptation will include language translation and ensuring that the interventions are acceptable in the specific socio-cultural context and suitable for the local health system. The ADAPTE manual for guideline adaptation outlines the approach to be used.12 The acceptability and applicability of the recommendations will be examined in the specific cultural context, including the availability of health services, expertise and resources, and the organization of health services, as well as population characteristics, cultural beliefs and value judgments. Relevant departments in ministries of health will be notified of the guidelines through WHO regional and country offices. A briefing package will be prepared for technical officers outside of WHO headquarters that will include an executive summary and Q&A related to policy and programme implications. Dissemination will also be encouraged through WHO collaboration with international organizations and associations. In coordination with WHO Communications, the media will be notified of the new guidelines. Countries will be supported to implement the guidelines through the training of health care personnel on improved quality of care and using centres of excellence. Capacity-building activities will be undertaken through web-based platforms and regional workshops. Dissemination will be supported by the publication of selected systematic reviews and evidence in peer review journals, and presentations and workshops at key conferences and events. 12 http://www.g-i-n.net/document-store/working-groups-documents/adaptation/adapte-resource-toolkit-guideline-adaptation-2-0.pdf 50 Risk reduction of cognitive decline and dementia: WHO guidelines 5.2 MONITORING AND EVALUATION Following publication of these guidelines, WHO will continue to collect regular feedback from implemen- tation activities in order to evaluate their usefulness and impact. Information will be used to evaluate the quality of the guidelines and to identify areas where improvement is required. WHO’s Global Dementia Observatory, an online data and knowledge exchange platform for dementia, provides the framework for monitoring implementation of these guidelines13. 5.3 IMPLICATIONS FOR FURTHER RESEARCH The majority of the recommendations align with current guidelines for the treatment of pre-existing health conditions and dependencies. However, more evidence is needed to determine what the impact of these interventions are on the outcomes of incident MCI or dementia. No recommendations could be made for social activity and hearing loss due to insufficient evidence. Some trials are currently being conducted for hearing loss interventions. These guidelines may need to be updated once these results are released. However, currently there is little research being conducted that examines the impact of social activity on cognitive decline and dementia. Part of the difficulty in conducting this type of research is that social activity is difficult to define and quantify, and it is also difficult to differentiate it from the physical or mental activities which are often a component of this type of intervention. The development of standardized protocols for social activity interventions may therefore need to precede the running of clinical trials. Some of the evidence presented here is based on RCTs with relatively short follow-up periods (e.g. interventions for cognitive training, depression, social activity). This limits our ability to judge the potential impact of the interventions on the development of cognitive decline and dementia as they have long prodromal periods. More evidence needs to be gathered with longer term follow-up periods in order to more accurately estimate the impact of these interventions in reducing the risk of cognitive decline/ dementia in the long run. In addition, more research needs to be conducted to understand how timing affects the impact of these interventions on cognitive decline and dementia (e.g. mid-life versus late life physical activity). The prevalence of dementia is increasing in LMIC. However, the majority of clinical trials have been conducted in high-income countries, so there is very little evidence on the effectiveness of these interventions for LMIC. More attention needs to be given to understanding how best to reduce the risk of cognitive decline and dementia in LMIC. 13 Available at: https://www.who.int/mental_health/neurology/dementia/Global_Observatory/en/ 51 The PICO questions applied to gather evidence for the preparation of these guidelines included interventions on single risk factors. However, given the multifactor etiology of dementia, and the interaction of risk factors across the lifestyle of each individual, multidomain approaches have been increasingly researched and show potential to be more effective than single-factor strategies. Recently, three large multidomain RCTs – the Finnish Geriatric Intervention Study to Prevent Cognitive Impairment and Disability (FINGER); Effect of long-term omega-3 PUFA supplementation with or without multidomain intervention on cognitive function in elderly adults with memory complaints (MAPT); and Prevention of dementia by intensive vascular care (preDIVA) – have been completed (Ngandu et al., 2015; Andrieu et al., 2017; Moll von Charante et al., 2016). Although only the multidomain lifestyle intervention tested in FINGER reported significant results in the primary analysis, the overall findings from the three trials suggested that targeting individuals at increased risk could be the most effective strategy. In particular, other interventions showed significant results in participants with an elevated dementia risk score, in MAPT (as in FINGER), and individuals with untreated hypertension at baseline, in preDIVA, respectively. In the context of multidomain interventions, new technologies and e-health solutions could also provide useful tools for risk reduction, by broadening the reach of such interventions (Barbera et al., 2018). Given the heterogeneity of risk profiles among older populations, global initiatives, such as the World Wide FINGERS Network (www.wwfingers.com), have been launched recently with the specific purpose of testing similar interventions, which have been adapted in diverse geographical and cultural settings (Kivipelto et al., 2017). Further research on the efficacy of multidomain interventions that are adjusted to specific geographical and cultural contexts, in populations at increased risk, and by making use of novel e-health tools (if possible) is, therefore, needed. 5.4 FUTURE REVIEW AND UPDATE It is expected that the guidelines will be reviewed again in five years. New evidence in these areas is regularly monitored by the WHO Secretariat, in consultation with GDG members and technical experts identified for the evidence review process, WHO collaborating centres and academic institutions. With the increasing evidence from multidomain intervention trials expected to be reported in the coming years, the addition of a PICO question addressing such interventions should be considered in future revisions. Publication, dissemination and evaluation 52 Risk reduction of cognitive decline and dementia: WHO guidelines Albanese E, Launer LJ, Egger M, Prince MJ, Giannakopoulos P, Wolters, FJ et al. (2017). 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Corrado Barbui M European University of Verona, Italy Mental health research and training, public health, health systems strengthening 5. Adelina Comas-Herrera F European London School of Economics, United Kingdom Health economist, dementia research 6. Amit Dias M South-East Asia Department of Preventive and Social Medicine, Goa Medical College, India Dementia, public health in LMIC 7. Cleusa P Ferri F Americas Federal University of São Paulo, Brazil Research in dementia and 10/66 group, dementia risk factors in LMIC 8. Riadh Gouider M Eastern Alzheimer’s Centre, Razi Hospital, Tunis; Tunisian Society of Neurology, Tunisia Dementia research in areas of epidemiology, neuropsychological assessment and risk factors 9. Shinya Ishii M Western Pacific Health and Welfare Bureau for the Elderly; Ministry of Health, Labour and Welfare, Tokyo, Japan Health policy, neurology of Alzheimer’s disease and dementia 10. Yves Joanette M Americas Canadian Institutes of Health Research, Government of Canada Dementia research 11. Joseph Kibachio M African Ministry of Health, Nairobi, Kenya Public health, health policy, NCDs 12. Miia Kivipelto F European Karolinska Institutet, Stockholm University, Stockholm, Sweden Dementia research in the field of early diagnosis and prevention 13. Shanthi Mendis F South-East Asia Independent consultant in global health, Sri Lanka NCDs and cardiology, health policy development, capacity strengthening, implementation research particularly in LMIC 61Annex 1: Guideline development group members Name Gender WHO region Affiliation Area of expertise 14. Ayesha Motala F African University of KwaZulu-Natal, South Africa Epidemiology and genetics of diabetes mellitus 15. Ronald Petersen M Americas Mayo Clinic, United States of America Memory disorders, aging and Alzheimer's disease 16. Dorairaj Prabhakaran M South-East Asia Centre for Chronic Conditions and Injuries & Public Health Foundation of India Cardiovascular disease prevention, epidemiology, developmental origin, and biomarkers of cardiovascular diseases and diabetes 17. Martin Prince M European Health Foundation of India Public health aspects of ageing and chronic disease in LMIC, dementia, guideline development 18. Suzana Shahar F Western Pacific Universiti Kebangsaan, Malaysia Nutrition, micronutrients, dietary interventions 19. Ameenah Bibi Mia Sorefan F African Alzheimer’s Association of Mauritius; Ministry of Health & Quality of Life, Mauritius Ageing, dementia and Alzheimer’s disease 20. Kusumadewi Suharya (Dy) F Western Pacific Alzheimer’s Disease International, Indonesia Dementia and public health 21. Huali Wang F Western Pacific Dementia Care & Research Center, Peking University Institute of Mental Health, China Dementia research and education 62 Risk reduction of cognitive decline and dementia: WHO guidelines ANNEX 2: ASSESSMENT OF CONFLICT OF INTEREST INDIVIDUALS INVOLVED IN ASSESSMENT OF CONFLICT OF INTEREST: Tarun Dua, Programme Manager, Department of Mental Health and Substance Abuse, WHO headquarters. Neerja Chowdhary, Technical Officer, Department of Mental Health and Substance Abuse, WHO headquarters. To comply with WHO’s Conflict of Interest Policy, the Secretariat followed the revised Guidelines for Declaration of Interests (WHO Experts).14 Declarations of interest (DoI) were requested from: (a) all GDG members; (b) all external partners involved in the evidence review process; (c) all experts invited to review the evidence profiles. A letter requesting completion of a DoI form and submission of a curriculum vitae as well as was sent to all GDG members, the external review group and external partners. They were asked to agree to the publication of a summary of declarations in the guide- line. The GDG members were also required to complete a confidentiality undertaking. Once received, the WHO Secretariat reviewed the DoIs as well as additional information (internet and bibliographic database search) and evaluated if there are any conflicts of interest and if so, whether these require a management plan. In order to enhance its management of conflicts of interest as well as strengthen public trust and transparency in connection with WHO meetings and activities involving the provision of technical/normative advice, the names and brief biographies members being considered for participation in the GDG were disclosed for public notice and comment prior to the meeting. At the beginning of the GDG meeting, the DoI of each GDG member were presented and GDG members and external partners were asked to update their DoI with relevant changes by notifying the responsible technical officer. The follow up and suggested actions agreed upon to manage the conflicts of interest declared are summarized below: • If members declare interests that are relevant to the meeting, the WHO Secretariat will note any potential conflict of interest and summarize these and then decide whether and to what extent they can participate in the guideline development. • If the conflict is deemed to be significant, the WHO Secretariat will decide if the conflict necessitates exclusion of that person from participating in the guideline process or if their participation should be limited. • These decisions are made on a case-by-case basis. Below is a summary of the Declared conflicts of interest and how these were managed. A. GDG MEMBERS GDG Members with no relevant interests declared on the DOI form and no relevant interests found in the CV 1. Kaarin J Anstey, University of New South Wales, Sydney, Australia; 2. Kimberly Ashby-Mitchell, Caribbean Public Health Agency, Port of Spain, Trinidad and Tobago; 3. Corrado Barbui, University of Verona, Verona, Italy. 4. Amit Dias, Department of Preventive and Social Medicine, Goa Medical College Bambolim, Goa, India; 5. Suharya Dy (Kusumadewi), Alzheimer’s Disease International, Jakarta, Indonesia; 6. Cleusa P. Ferri, Federal University of Sao Paulo, Sao Paulo, Brazil. 7. Riadh Gouider, Razi Hospital, Faculty of Medicine, Tunis, Tunisia; 8. Shinya Ishii, Ministry of Health, Labour and Welfare, Tokyo, Japan; 14 WHO Office of Compliance, Risk Management and Ethics (CRE) http://intranet.who.int/homes/cre/ethics/doiexperts/ 63 9. Yves Joanette, Canadian Institute of Health Research, Government of Canada. 10. Joseph Kibachio, Ministry of health, Nairobi, Kenya; 11. Shanthi Mendis, Colombo, Sri Lanka; 12. Dorairaj Prabhakaran, Public Health Foundation of India, New Delhi, India; 13. Ameenah Bibi Mia Sorefan, Ministry of Health and Quality of Life, Quatre-Bornes, Mauritius GDG members who have declared an interest on the DOI form or where a potentially relevant interest has been noted from the CV Charles Alessi, Public Health England, London, United-Kingdom Dr Alessi declared that the travel costs for the GDG meeting were covered by his organization. Action: This interest was deemed insignificant or minimal and unlikely to affect, or be reasonably perceived to affect, Dr Alessi’s judgement in the development of the present guidelines. He is deemed to be participating in the guideline development process in an individual capacity and not representing any organization. No further action was necessary Adelina Comas-Herrera, London School of Economics, London, United-Kingdom Dr Comas-Herrera declared in her DoI from that she had received research support routed via her University on various research projects on dementia in 2015 and 2016. These amounts were used to pay her salary by the University. She also declared receiving a payment of US$1000 in 2017 to advise a pharmaceutical company, Axovant Sciences GmbH. The topic was on the availability of data on dementia costs for a medicine that has since been withdrawn due to lack of effectiveness. Action: It was felt that this interest is insignificant or minimal and unlikely to affect, or be reasonably perceived to affect, Dr Comas-Herera’s judgement in the development of the present guidelines. No further action was necessary. Miia Kivipelto, Karolinska Institutet, Stockholm, Sweden Dr Kivipelto declared in her DoI form that she currently serves on the Advisory Board of a Finnish company that focuses on early diagnosis and e-health solutions for which she received €2500. She is also on the Governance committee of AARP, a non-profit organization for healthy ageing for which she received €800. She also declared that she has received research grants related to risk factors for dementia and is a founding member of World-Wide Fingers, an interdisciplinary network to share experiences, harmonize data and plan joint international initiatives for the risk reduction of cognitive decline and dementia. Action: This interest was deemed insignificant or minimal and unlikely to affect, or be reasonably perceived to affect, Dr Kivipelto’s judgement in the development of the present guidelines. She is deemed to be participating in the guideline development process in an individual capacity and not representing any organization. No further action was necessary Ayesha Motala, University of KwaZulu-Natal, Durban, South Africa. Dr Motala declared that as a public servant working in a government institute, she seeks sponsorships to meetings from various organizations, especially when her scientific abstracts are accepted for presentations. The sponsorships are merely for attending the meetings, with no obligation to the sponsoring companies. Annex 2: Assessment of conflict of interest 64 Risk reduction of cognitive decline and dementia: WHO guidelines Details of such sponsorship for which she received a total amount of US$26 000: 4–8 December 2017: International Diabetes Federation (IDF) Congress, Abu Dhabi: Sanofi Aventis sponsorship for travel and accommodation; 11–15 September 2017: European Association for the Study of Diabetes (EASD) Congress, Lisbon: Pfizer sponsorship for travel and accommodation; 8–13 June 2018: American Diabetes Association (ADA), San Diego: Boehringer Ingelheim sponsorship for travel and accommodation: a member of her collaborating scientific team presented a paper. Action: It was felt that this interest is insignificant or minimal and unlikely to affect, or be reasonably perceived to affect, Dr Motala’s contribution as an external reviewer for these guidelines. No further action was necessary. Ronald C. Petersen, Mayo Clinic, Rochester, USA Dr Petersen declared that he is a clinical trials consultant for five pharmaceutical companies: from four of these (Roche Inc, Merck Inc, Genetech Inc and GE Healthcare) he receives less than US$ 10 000 and from one (Biogen Inc) he receives less that US$ 15 000 as consultancy fees. Action: It was felt that this interest is unlikely to affect, or be reasonably perceived to affect, Dr Petersen’s contribution as an external reviewer for these guidelines since these grants are not related to the topic of interest. No further action was necessary. Martin Prince, King’s College London, London, United Kingdom Professor Prince declared in his DOI form that he currently receives research support through a grant from the National Institute of Health Research (NIHR, UK) amounting to £7 million over four years. Professor Prince is the PI and 20% of his salary costs are charged to the grant. The work focuses on health systems strengthening in sub Saharan Africa and one theme relates to the topic of these guidelines i.e. integrated primary healthcare for multimorbid conditions. Action: It was felt that this interest is insignificant or minimal and unlikely to affect, or be reasonably perceived to affect, Professor Prince’s judgement in the development of the present guidelines. No further action was necessary Suzana Shahar, Universiti Kebangsaan Malaysia, Selangor, Malaysia Dr Sahar has declared in her DoI form that she has a clinical trial agreement through her University with Biotropics, a company that develops bio-resources into superior natural health product. The research involves evaluating the efficacy of Asian traditional herbs in improving cognition and mood. The funding amount is US$ 100 000 between 2014 and 2018. Action: It was felt that this interest is insignificant or minimal and unlikely to affect, or be reasonably perceived to affect, Dr Sahar’s contribution as an external reviewer for these guidelines. No further action was necessary Huali Wang, Dementia Care & Research Center, Peking University Institute of Mental Health, Beijing, China. Dr Wang declared in her DoI form that prior to 2016, she had worked as a consultant with Neowave Inc. to develop a tablet-based cognitive training program. She also declared that she had received support for travelling to meetings form Eisai China amounting to US$ 7000 prior to 2017. The meeting were all Alzheimer’s Disease International (ADI) conferences. 65 Action: It was felt that this interest is insignificant or minimal and unlikely to affect, or be reasonably perceived to affect, Dr Wang’s contribution as an external reviewer for these guidelines. No further action was necessary B. EXTERNAL REVIEW GROUP Members of the external review group with no relevant interests declared on the DOI form and no relevant interests found in the CV 1. Abdullah Al Khatami, Ministry of Health, Saudi Arabia 2. Alistair Burns, University of Manchester, UK 3. Linda Clare, University of Exeter, UK 4. Jacqueline Dominguez, Institute for dementia care Asia, Quezon city, Philippines 5. Maelënn Guerchet, The Global Observatory for Ageing and Dementia Care, King's College London, UK 6. Mariella Guerra, Institute of Memory, Depression and Related Disorders – IMEDER, Lima, Peru 7. Luis Miguel F. Gutiérrez Robledo, Instituto Nacional de Geriatría, Institutos Nacionales de Salud de México, Mexico City, Mexico 8. Vladimir Hachinski, University of Western Ontario in London, Ontario, Canada 9. Qurat ul Ain Khan, Aga Khan University Hospital, Karachi, Pakistan. 10. Sebastian Koehler, Maastricht University, The Netherlands 11. Jae-hong Lee, University of Ulsan College of Medicine, Seoul, Korea 12. Gill Livingstone, University college London, UK 13. Jean Claude Mbanya, Doctoral School of Life Sciences, Health and Environment, University of Yaoundé I, Cameroon. 14. James McKillop, Service user group representative, UK 15. Rajat Ray, National Drug Dependence Treatment Centre, All India Institute of Medical Sciences, New Delhi, India 16. Helen Rochford Brennan, European Working Group of people with dementia, Ireland 17. Kate Swaffer, Dementia Alliance International, Australia 18. Weili Xu, Karolinska Institute, Finland Members of the external review group who have declared an interest on the DOI form or where a potentially relevant interest has been noted from the CV Emiliano Albanese, Universita della Svizzera italiana, Switzerland Dr Albanese declared in his DoI form that he receives research support from the Economic and Research Council UK as part of the STRIDE (Strengthening responses to dementia in developing countries) research consortium which focuses on dementia research in low and middle income countries. The amount of US$ 50 000 is provided to the institution to which he is affiliated. Action: It was felt that this interest is insignificant or minimal and unlikely to affect, or be reasonably perceived to affect, Dr Albanese’s contribution as an external reviewer for these guidelines. No further action was necessary. Hillary Doxford, 3 Nations Dementia Working Group, UK Ms Doxford declared in her DoI form that she has served on a grant review panel assessing and prioritizing grant applications for funding dementia research projects for the National Institute for Health Research, UK. The income she received for this was £450. She is also a voluntary member of the Dementia Programme Board in the UK Department of Health and Social Care as a person with lived experience. Action: It was felt that this interest is insignificant or minimal and unlikely to affect, or be reasonably perceived to affect, Ms Doxford’s contribution as an external reviewer for these guidelines. No further action was necessary. Annex 2: Assessment of conflict of interest 66 Risk reduction of cognitive decline and dementia: WHO guidelines Elaine Rashbrook, Public Health England, UK Dr Rashbrook declared in her DoI form that she is employed by Public Health England (PHE), a government agency, as Consultant Specialist Life Course since 2015. PHE supports work on dementia risk reduction in line with the government strategy. There is no identified financial value for the work. Action: It was felt that this interest is insignificant or minimal and unlikely to affect, or be reasonably perceived to affect, Dr Rashbrook’s contribution as an external reviewer for these guidelines. She is deemed to be providing her review in an individual capacity and not representing any organization. No further action was necessary. Andrew Sommerlad, University College London, UK Dr Sommerlad declared in his DoI form that he receives research support from the Wellcome Trust in the form of a personal research fellowship to examiner whether social isolation is a risk factor for dementia The amount of funding is £201 311 from 2016 to 2019. Action: It was felt that this interest is insignificant or minimal and unlikely to affect, or be reasonably perceived to affect, Dr Sommerlad’s contribution as an external reviewer for these guidelines. No further action was necessary B. EXTERNAL PARTNERS External partners with no relevant interests declared on the DOI form and no relevant interests found in the CV 1. Mariagnese Barbera, University of Eastern Finland, Kuopio, Finland; 2. Nicole A. Ee, University of New South Wales, Sydney, Australia; 3. Jenni Kumlala, Karolinska Institutet, Stockholm, Sweden; 4. Ruth Peters, University of New South Wales, Sydney, Australia; 5. Lidan Zheng, University of New South Wales, Sydney, Australia. None of the external partners declared relevant interests on the DOI forms nor were relevant interests found in the CV.   67 ANNEX 3: SCOPING QUESTIONS INTERVENTIONS ADDRESSING LIFESTYLE AND BEHAVIOUR RISK FACTORS 1. Physical activity interventions For adults with normal cognition or mild cognitive impairment, are physical activity interventions more effective than usual care or no intervention in reducing the risk of cognitive decline and/or dementia? P: Adults (age above 18 years) with normal cognition or MCI I: Physical activity interventions (aerobic, resistance training or multicomponent physical activity) C: Care as usual or no intervention O: • Critical – Cognitive function – Incident MCI – Dementia 2. Tobacco cessation interventions For adults with normal cognition or mild cognitive impairment who use tobacco, are interventions for tobacco cessation more effective than usual care or no intervention in reducing the risk of cognitive decline and/or dementia? P: Adults with normal cognition or MCI who use tobacco I: Interventions for tobacco cessation (behavioural interventions and pharmacological interventions including nicotine replacement therapy, bupropion, varenicline) C: Care as usual or no intervention O: • Critical – Cognitive function – Incident MCI – Dementia 3. Nutritional interventions 3a. For adults with normal cognition or mild cognitive impairment, are nutritional interventions such as dietary supplements more effective than usual care or no intervention in reducing the risk of cognitive decline and/or dementia? P: Adults with normal cognition or MCI I: Dietary supplements (e.g. B vitamins, antioxidants, omega-3 and ginkgo); C: Care as usual or no intervention O: • Critical – Cognitive function – Incident MCI – Dementia • Important – Quality of life – Functional level (ADL, IADL) – Adverse events – Drop-out rates • Important – Quality of life – Functional level (ADL, IADL) – Adverse events – Drop-out rates • Important – Quality of life – Functional level (ADL, IADL) – Adverse events – Drop-out rates Annex 3: Scoping questions 68 Risk reduction of cognitive decline and dementia: WHO guidelines 3b. For adults with normal cognition or mild cognitive impairment, are nutritional interventions such as healthy dietary patterns (e.g. Mediterranean diet) more effective than usual care or no intervention in reducing the risk of cognitive decline and/or dementia? P: Adults with normal cognition or MCI I: Healthy dietary pattern (e.g. Mediterranean diet) C: Care as usual or no intervention O: • Critical – Cognitive function – Incident MCI – Dementia 4. Interventions for alcohol use disorders For adults with normal cognition or mild cognitive impairment and alcohol use disorders, are behavioural and psychological interventions to treat alcohol use disorders more effective than usual care or no intervention in reducing the risk of cognitive decline and/or dementia? P: Adults with normal cognition or MCI and excessive use of alcohol I: • Behavioural and psychological interventions to treat alcohol use disorders (e.g. motivational interviewing) • Pharmacological interventions to treat alcohol use disorders C: Care as usual or no intervention O: • Critical – Cognitive function – Incident MCI – Dementia • Important – Quality of life – Functional level (ADL, IADL) – Adverse events – Drop-out rates • Important – Quality of life – Functional level (ADL, IADL) – Adverse events – Drop-out rates 69 SPECIFIC INTERVENTIONS 5. Cognitive interventions For adults with normal cognition or mild cognitive impairment is cognitive stimulation or cognitive training more effective than usual care or no intervention in reducing the risk of cognitive decline and/ or dementia? P: Adults with normal cognition or MCI I: • Cognitive stimulation • Cognitive training C: Care as usual or no intervention O: • Critical – Cognitive function – Incident MCI – Dementia 6. Social activity For adults with normal cognition or mild cognitive impairment is preserving and promoting a high level of social activity more effective than usual care or no intervention in reducing the risk of cognitive decline and/or dementia? P: Adults with normal cognition or MCI I: Preservation and promotion of social activity including community and family engagement C: Care as usual or no intervention O: • Critical – Cognitive function – Incident MCI – Dementia • Important – Quality of life – Functional level (ADL, IADL) – Adverse events – Drop-out rates • Important – Quality of life – Functional level (ADL, IADL) – Adverse events – Drop-out rates Annex 3: Scoping questions 70 Risk reduction of cognitive decline and dementia: WHO guidelines INTERVENTIONS FOR HEALTH CONDITIONS 7. Weight management For adults with normal cognition or mild cognitive impairment who are overweight or obese, are interventions for weight reduction (or control of obesity) more effective than usual care or no intervention in reducing the risk of cognitive decline and/or dementia? P: Adults with normal cognition or MCI who are overweight or obese I: Weight management • Non-pharmacological interventions, e.g. cognitive-behavioural intervention strategies, lifestyle interventions • Pharmacological interventions, e.g. weight-loss medication (e.g. orlistat) C: Care as usual or no intervention O: • Critical – Cognitive function – Incident MCI – Dementia 8. Management of hypertension For adults with normal cognition or mild cognitive impairment and hypertension, is treatment of hypertension more effective than placebo/no intervention in reducing the risk of cognitive decline/dementia? P: Adults with normal cognition or MCI with hypertension I: Antihypertensive medication, lifestyle interventions C: Placebo/no intervention O: • Critical – Cognitive function – Incident MCI – Dementia 9. Management of diabetes mellitus For adults with normal cognition or mild cognitive impairment and diabetes mellitus, is treatment of diabetes more effective than placebo/no intervention in reducing the risk of cognitive decline and/or dementia? P: Adults with normal cognition or MCI with diabetes mellitus I: • Medications for glycaemic control • Diet and lifestyle interventions C: Placebo/no intervention O: • Critical – Cognitive function – Incident MCI – Dementia • Important – Quality of life – Functional level (ADL, IADL) – Adverse events – Drop-out rates • Important – Quality of life – Functional level (ADL, IADL) – Adverse events – Drop-out rates • Important – Quality of life – Functional level (ADL, IADL) – Adverse events – Drop-out rates 71Annex 3: Scoping questions 10. Management of dyslipidaemia For adults with normal cognition or mild cognitive impairment and dyslipidaemia, is treatment of dyslipidaemia more effective than placebo or no intervention in reducing the risk of cognitive decline and/or dementia? P: Adults with normal cognition or MCI with dyslipidaemia I: • Statins (e.g. simvastatin and pravastatin) • Lifestyle interventions C: Placebo or no intervention O: • Critical – Cognitive function – Incident MCI – Dementia 11. Management of depression For adults with normal cognition or mild cognitive impairment and depressive disorder, is treatment of depression more effective than usual care, placebo or no intervention in reducing the risk of cognitive decline and/or dementia? P: Adults with normal cognition or MCI with moderate to severe depressive disorder I: • Pharmacological interventions to treat depression (antidepressant medication) • Psychological interventions to treat depression (e.g. cognitive behavioural therapy, problem-solving therapy, interpersonal therapy, behavioural activation) C: Care as usual or placebo or no intervention O: • Critical – Cognitive function – Incident MCI – Dementia 12. Management of hearing loss For adults with normal cognition or mild cognitive impairment and hearing loss, is treatment of hearing loss more effective than usual care, or no intervention in reducing the risk of cognitive decline and/or dementia? P: Adults with normal cognition or MCI with hearing loss I: Interventions to treat hearing loss (e.g. hearing aids) C: Care as usual or no intervention O: • Critical – Cognitive function – Incident MCI – Dementia • Important – Quality of life – Functional level (ADL, IADL) – Adverse events – Drop-out rates • Important – Quality of life – Functional level (ADL, IADL) – Adverse events – Drop-out rates • Important – Quality of life – Functional level (ADL, IADL) – Adverse events – Drop-out rates 72 Risk reduction of cognitive decline and dementia: WHO guidelines ANNEX 4: EVIDENCE REVIEW METHODOLOGY Comprehensive searches of major bibliographic databases were conducted to identify one systematic review that matched each of the outcomes for each of the PICO questions. The aim was to identify systematic reviews that were timely, of high quality and relevant to each of the PICO questions. The search strategies differed slightly between the two teams (based in the Karolinska Institutet, Sweden and University of New South Wales, Australia. However, in general, the following process was employed: 1. Search for systematic reviews (including meta- analyses) that were published in the last 2 years for each of the PICO questions. The searches were run from April to June 2018. 2. If no relevant high-quality systematic reviews were identified from the 2 years for any of the PICO questions, the search was expanded to include systematic reviews from the last 5 years for that PICO question. For the relevant PICO questions, the 2016 AHRQ systematic review was also consulted. The aim of the AHRQ review was to examine interventions to prevent cognitive decline and dementia. The review systematically searched records between January 2009 and September 2016. 3. For the hearing loss question, there was very limited evidence available, therefore searches were expanded to include all systematic reviews ever published. 4. Based on the GDG’s feedback during the GDG meeting in July 2018, the searches were expanded to further include systematic reviews of obser- vational studies. The searches were re-run July to August 2018. The following bibliographic databases were searched: • Bibliographic • Medline • Cochrane • PsycInfo • Embase • NICE. Relevant to LMIC • Global Index Medicus/Global Health Library • WHO regional database • WHOLIS • Database of impact evaluations • AJOL • KoreaMed • IndMED • HrCak • ArabPsycNet • HERDIN NeON • EurasiaHealth. After the searches were run using the search strategies listed below, titles and abstracts of all results were screened in Endnote; subsequently the full texts of those papers were reviewed that could not be excluded based on the title/abstract review. GRADE EVIDENCE TABLES For each outcome of each PICO question, one or more systematic reviews were then selected to be used within the GRADE evidence tables. The following criteria were used when selecting which systematic review to use within the GRADE evidence tables: • Published in the last 5 years, ideally 2 years (timeliness). • High quality (i.e. measured using AMSTAR 215 criteria). 15 Shea BJ, Grimshaw JM, Wells GA, Boers M, Andersson N, Hamel C et al (2007). Development of AMSTAR: a measurement tool to assess the methodological quality of systematic reviews. BMC Medical Research Methodology. 7:10. 73Annex 3: Scoping questions • Closely relevant to the PICO question. • Comprehensive systematic reviews given preference, where possible. • Cochrane reviews or other meta-analyses given preference, where possible/appropriate. The GRADE methodology involves rating the quality of the studies included in the systematic review according to study design, risk of bias, inconsistency, indirectness, imprecision, and publication bias. Together with the effect sizes of studies, an overall “certainty of evidence” is provided of either very low, low, moderate or high. GRADE evidence tables were completed using the GRADEpro online tool.16 The same criteria were used as for the mhGAP Intervention guide when completing the GRADE evidence tables in terms of the assessment of the quality of studies (for risk of bias, inconsistency, indirectness, imprecision, and publication bias).17 SEARCH STRATEGIES Separate searches were performed for each of the 12 PICO questions. Where PICO questions included both pharmacological and non-pharmacological interventions, searches were run separately for these. Filters were used in the bibliographic databases where possible to restrict the searches to systematic reviews and meta-analyses, as well as to humans. No further restrictions were employed, for example in terms of language (apart from the publication date, as mentioned above). The “advanced search” option was selected in bibliographic databases, where possible. PICO 1 For adults with normal cognition or mild cognitive impairment, are physical activity interventions more effective than usual care or no intervention in reducing the risk of cognitive decline and/or dementia? Search strategy (dementia OR cognit* OR “mild cognitive impairment” OR “Alzheimer disease” OR “dementia vascular” OR “dementia multi-infarct” OR MCI OR “cognitive dysfunction” OR neuropsychologi* OR “Health-Related Quality” Of Life OR “life quality” OR “Activities Daily Living” OR “Chronic Limitation of Activity” OR “Limitation of Activity, Chronic” OR ADL OR “activities of daily living” OR “Drug-Related Side Effects and Adverse Reactions” OR “Adverse Drug Event” OR “Adverse Drug Reaction” OR “Long Term Adverse Effects” OR “Adverse Effects, Long Term Disease-Free Survival” OR “Event-Free Survival” OR “Adverse effects”) AND (Exercise OR “exercise therapy” OR “Acute Exercise” OR “Aerobic Exercise” OR “Exercise Training” OR “Exercise, Aerobic” OR “Exercise, Isometric” OR “Exercise, Physical” OR “Isometric Exercise OR Physical Activity” OR “resistance training”) PICO 2 For adults with normal cognition or mild cognitive impairment who use tobacco, are interventions for tobacco cessation more effective than usual care or no intervention in reducing the risk of cognitive decline and/or dementia? Search strategy (dementia OR cognit* OR mild cognitive impairment OR Alzheimer disease OR dementia vascular OR dementia multi-infarct OR MCI OR cognitive dysfunction OR neuropsychologi* OR Health-Related Quality Of Life OR life quality OR Activities, Daily Living OR Chronic Limitation of Activity OR Limitation 16 https://gradepro.org/ 17 See http://www.who.int/mental_health/mhgap/evidence/mhgap_ guideline_process_2009.pdf 74 Risk reduction of cognitive decline and dementia: WHO guidelines of Activity, Chronic OR ADL OR activities of daily living OR Drug-Related Side Effects and Adverse Reactions OR Adverse Drug Event OR Adverse Drug Reaction OR Long Term Adverse Effects OR Adverse Effects, Long Term Disease-Free Survival OR Event-Free Survival OR Adverse effects) AND (Tobacco OR smoking OR Tobacco use cessation OR giving up smoking OR quitting smoking OR stopping smoking OR smoking cessation OR smoking reduction OR tobacco use cessation products OR varenicline OR nicotinic agonists OR Nicotine Inhalant OR Nicotine Lozenge OR Nicotine Lozenges OR Nicotine Nasal Spray OR Nicotine Patch OR Nicotine Polacrilex OR Nicotine Replacement Products OR Nicotine Transdermal Patch OR Smoking Cessation Products) AND (Behavior OR behaviour OR drug therapy OR pharmacologic therapy OR pharmacotherapy OR Cognitive behavioural therapy OR Cognitive behavioural therapy OR Drug therapy OR cognitive therapy OR online therapy OR treatment) PICO 3 3a. For adults with normal cognition or mild cognitive impairment, are nutritional interventions such as dietary supplements more effective than usual care or no intervention in reducing the risk/ progression of cognitive decline and/or dementia? 3b. For adults with normal cognition or mild cognitive impairment, are nutritional interventions such as healthy dietary patterns (e.g. Mediterranean diet) more effective than usual care or no intervention in reducing the risk/progression of cognitive decline and/or dementia? Search strategy (dementia OR cognit* OR “mild cognitive impairment” OR “Alzheimer disease” OR Alzheimer* OR “dementia vascular” OR “dementia multi-infarct” OR MCI OR “cognitive dysfunction” OR neuropsychologi* OR “Health-Related Quality Of Life” OR “life quality” OR “quality of life” OR “Activities of Daily Living” OR “Chronic Limitation of Activity” OR “Limitation of Activity, Chronic” OR ADL OR “activities of daily living” OR “Drug-Related Side Effects and Adverse Reactions” OR “Adverse Drug Event” OR “Adverse Drug Reaction” OR “Long Term Adverse Effects” OR “Adverse Effects, Long Term” OR “Disease-Free Survival” OR “Event-Free Survival” OR “Adverse effects”) AND (“Dietary supple- ments” OR “Dietary Supplementations” OR “Food Supplementations” OR “Food Supplements” OR “Herbal Supplements” OR Neutraceuticals OR Nutraceuticals OR Nutriceuticals OR diet or vitamin or food) PICO 4 For adults with normal cognition or mild cognitive impairment and alcohol use disorders, are behavioural and psychological interventions to treat alcohol use disorders more effective than usual care or no intervention in reducing the risk of cognitive decline and/or dementia? Search strategy (dementia OR cognit* OR mild cognitive impairment OR Alzheimer disease OR dementia vascular OR dementia multi-infarct OR MCI OR cognitive dysfunction OR neuropsychologi* OR Health-Related Quality Of Life OR life quality OR Activities, Daily Living OR Chronic Limitation of Activity OR Limitation of Activity, Chronic OR ADL OR activities of daily living OR Drug-Related Side Effects and Adverse Reactions OR Adverse Drug Event OR Adverse Drug Reaction OR Long Term Adverse Effects OR Adverse Effects, Long Term Disease-Free Survival OR Event-Free Survival OR Adverse effects) AND (Alcohol drinking OR Binge drinking OR Drunkenness OR alcohol intoxication OR alcoholism OR alcohol withdrawal) AND (Add in Behavior OR behaviour OR drug therapy OR pharmacologic therapy OR pharmacotherapy OR Cognitive behavioural therapy OR Cognitive behavioural therapy OR Drug therapy OR cognitive therapy OR online therapy OR treatment) 75Annex 3: Scoping questions PICO 5 For adults with normal cognition or mild cognitive impairment is cognitive stimulation or cognitive training more effective than usual care or no intervention in reducing the risk of cognitive decline and/or dementia? Search strategy (systemati* or meta analys*) and (dementia or cognit* or MCI or neuropsycholog* or Alzheimer*) and ("Brain training" OR "cognitive training" OR "Brain fitness" OR Games OR "Memory training" OR (Stimulation AND cognit*) PICO 6 For adults with normal cognition or mild cognitive impairment is preserving and promoting a high level of social activity more effective than usual care or no intervention in reducing the risk of cognitive decline and/or dementia? Search strategy ("social interaction" or "social Networks" or "social processes" or "social behaviour" or "social behavior" or "community networks" or "social media" or family) and (dementia or cognit* or "mild cognitive impairment" or MCI or "cognitive dysfunction" or neuropsycholog* or Alzheime*) and (systemati* or meta-analys*) PICO 7 For adults with normal cognition or mild cognitive impairment who are overweight or obese, are interventions for weight reduction (or control of obesity) more effective than usual care or no intervention in reducing the risk of cognitive decline and/or dementia? Search strategy (dementia OR cognit* OR mild cognitive impairment OR Alzheimer disease OR dementia vascular OR dementia multi-infarct OR MCI OR cognitive dysfunction OR neuropsychologi* OR Health-Related Quality Of Life OR life quality OR Activities, Daily Living OR Chronic Limitation of Activity OR Limitation of Activity, Chronic OR ADL OR activities of daily living OR Drug-Related Side Effects and Adverse Reactions OR Adverse Drug Event OR Adverse Drug Reaction OR Long Term Adverse Effects OR Adverse Effects, Long Term Disease-Free Survival OR Event-Free Survival OR Adverse effects) AND (Overweight OR Body weight or Body mass index OR weight loss OR Body weight changes) AND (Behavior OR behaviour OR drug therapy OR pharmacologic therapy OR pharmacotherapy OR Cognitive behavioural therapy OR Cognitive behavioural therapy OR Drug therapy OR cognitive therapy OR online therapy OR treatment OR Appetite depressants) PICO 8 For adults with normal cognition or mild cognitive impairment and hypertension, is treatment of hypertension more effective than placebo/no intervention in reducing reduce the risk of cognitive decline/dementia? Search strategy (systemati* or meta-analys*) and (dementia or cognit* or "mild cognitive impairment" or MCI or "cognitive dysfunction" or neuropsycholog* or Alzheimer's or Alzheimer) and (behaviour or behavior or "drug therapy" or "pharmacologic therapy" or pharmacotherapy or "cognitive behavioural therapy" or "cognitive behavioral therapy" or "cognitive therapy" or "online therapy" or "anti-hypertensive" or antihypertensive or treatment) and (hypertension or "blood pressure" or systolic or diastolic or prehypertension) 76 Risk reduction of cognitive decline and dementia: WHO guidelines PICO 9 For adults with normal cognition or mild cognitive impairment and diabetes mellitus, is treatment of diabetes more effective than placebo/no intervention in reducing the risk of cognitive decline and/or dementia? Search strategy (systemati* or meta-analys*) and (dementia or cognit* or "mild cognitive impairment" or MCI or "cognitive dysfunction" or neuropsycholog* or Alzheime*) .ab. and diabetes.af. and ("hypoglycemic agents" or treatment or therapy or pharmacotherapy or behaviour or behavior) PICO 10 For adults with normal cognition or mild cognitive impairment and dyslipidaemia, is treatment of dyslipidaemia more effective than placebo or no intervention in reducing reduce the risk of cognitive decline and/or dementia? Search strategy (dementia OR cognit* OR mild cognitive impairment OR Alzheimer disease OR dementia vascular OR dementia multi-infarct OR MCI OR cognitive dysfunction OR neuropsychologi* OR Health-Related Quality Of Life OR life quality OR Activities, Daily Living OR Chronic Limitation of Activity OR Limitation of Activity, Chronic OR ADL OR activities of daily living OR Drug-Related Side Effects and Adverse Reactions OR Adverse Drug Event OR Adverse Drug Reaction OR Long Term Adverse Effects OR Adverse Effects, Long Term Disease-Free Survival OR Event-Free Survival OR Adverse effects) AND (Cholesterol OR Hypercholes-terolemia OR lipo- proteins OR HDL cholesterol OR LDL cholesterol OR triglycerides) AND (Behavior OR behaviour OR drug therapy OR pharmalogic therapy OR pharmacotherapy OR Cognitive behavioural therapy OR Cognitive behavioural therapy OR Drug therapy OR cognitive therapy OR online therapy OR treatment OR statins OR Hydroxymethylglutaryl-CoA Reductase Inhibitors OR Anticholesteremic agents) PICO 11 For adults with normal cognition or mild cognitive impairment and depressive disorder, is treatment of depression more effective than usual care, placebo or no intervention in reducing the risk of cognitive decline and/or dementia? Search strategy (depression or depressive) and (systemati* or meta- analys*) and (dementia or cognit* or "mild cognitive impairment" or MCI or "cognitive dysfunction" or neuropsycholog* or Alzheimer's or Alzheimer*) and (treatment or therapy or pharmacotherapy or antidepressan* or antidepressiv*) PICO 12 For adults with normal cognition or mild cognitive impairment and hearing loss, is treatment of hearing loss more effective than usual care, or no intervention in reducing the risk of cognitive decline and/or dementia? Search strategy (hearing aids OR Cochlear implants Or hearing implants) AND (hearing loss OR deafness OR hearing impairment OR hypoacusis OR intervention OR treatment) AND (dementia OR cognit* OR mild cognitive impairment OR Alzheimer's disease OR dementia vascular OR dementia multi-infarct OR MCI OR cognitive dysfunction OR neuropsycholog*) 77Glossary Adverse event Any untoward medical occurrence in a patient or clinical investigation subject caused by health care management. Aerobic exercise A type of physical exercise that requires free oxygen to adequately meet energy demands via the aerobic metabolism. During aerobic exercise, oxygen is used to “burn” fats and glucose in order to produce adenosine triphosphate, the basic energy carrier for all cells. This type of exercise improves physical fitness by promoting the circulation of oxygen through the blood, is associated with an increased rate of breathing, and includes any type of exercise that, when performed at levels of intensity sufficiently supported by the aerobic metabolism, can be performed for extended periods of time. Behavioural activation A behavioural treatment for depression in which the person with depression is guided to increase the number of rewarding activities in his or her life. Body mass index An objective measurement calculated as body mass (or weight in kg) divided by the square of the body height (in metres), universally expressed in units of kg/m2. BMI is used as approximate indicator of the amount of tissue mass (muscle, bone, and fat) in an individual. Based on the correlation between BMI and the degree of risk for certain disease, such as diabetes or atherosclerosis, BMI values are categorized as underweight, normal weight, overweight, or obese; obesity can also be subcategorized in moderate severe and morbid. Cognitive behavioural intervention/therapy A type of psychological therapy that involves identifying and correcting distorted maladaptive beliefs, while using thought exercises and real experiences to facilitate symptom reduction and improved functioning. Cognitive decline The physiological decay of brain functions such as memory, attention or learning ability, for example, which is associated with the normal ageing process. It differs from cognitive impairment in that anyone who ages develops some kind of cognitive decline, although at different degrees. Cognitive impairment, instead, is normally the result of a pathological event: injury, disease, or increased levels of cognitive decline. Cognitive function Cerebral activities, i.e. reasoning, memory, attention, and language that lead to the attainment of information and knowledge. Cognitive stimulation Participation in a range of activities designed to improve cognitive and social functioning. Cognitive training Guided practice of specific standardized tasks designed to enhance particular cognitive functions. Dementia Dementia, a group of disorders characterized by a decline from a previously attained cognitive level that affects activities of daily living or social functioning. Dietary supplements Dietary supplements include vitamins, minerals, fibre, fatty acids, or amino acids, among other substances. They are either intended to provide nutrients in order to increase their consumption, or to provide non-nutrient chemicals which are claimed to have a biologically beneficial effect. Health-related quality of life An individual’s or a group’s perceived physical and mental health over time. As a multidimensional concept, it includes domains related to physical, mental, emotional and social functioning, and it is a way to assess the impact of health status on quality of life. Mediterranean diet A diet which consists of a high intake of cereals, fruits, fish, legumes, and vegetables and low intake of meat and dairy. G LOSSARY 78 Risk reduction of cognitive decline and dementia: WHO guidelines Mild cognitive impairment A disorder characterized by impairment of memory, learning difficulties and reduced ability to concentrate on a task for more than brief periods. There is often a marked feeling of mental fatigue when mental tasks are attempted, and new learning is found to be subjectively difficult even when objectively successful. None of these symptoms are so severe that a diagnosis of either dementia or delirium can be made. Motivational interviewing An established evidence-based practice in the treatment of individuals with substance use disorders that focuses on exploring and resolving ambivalence and centres on motivational processes within the individual that facilitate change. Multidomain intervention Intervention normally aimed to prevent/address a certain disease or condition by acting simultaneously on a range of risk factors, which may be either correlated or independent from each other. Nicotine replacement therapy A type of treatment that makes use of special products which provide small, steady doses of nicotine to help stop cravings and relieve withdrawal symptoms when an individual is trying to stop using tobacco. These products include nicotine gum, nicotine inhaler, nicotine nasal spray, nicotine lozenges, and nicotine patch. They do not contain any of the other chemicals found in tobacco products. Physical activity Any bodily movement produced by skeletal muscles that requires energy expenditure – including activities undertaken while working, playing, carrying out household chores, travelling, and engaging in recreational pursuits Physical exercise: subcategory of physical activity that is planned, structured, repetitive, and aims to improve or maintain one or more components of physical fitness. Problem-solving therapy A type of psychological therapy where the patient systematically identifies his or her problems; generates alternative solutions for each problem; selects the best solution; develops and conducts a plan; and evaluates whether this has solved the problem. Quality of life An individual’s perception of their position in life in the context of the culture and value systems in which they live and in relation to their goals, expectations, standards and concerns. Resistance training A form of physical exercise that, by the moving of the limbs against high loads or fixed resistances, causes skeletal muscles contraction, building their strength, anaerobic endurance, and size. The external resistance can be represented by dumbbells, rubber exercise tubing, the own body weight, bricks, bottles of water, machine specifically designed to this purpose, or any other object that causes the muscles to contract. The forces involved must be such that relatively few repetitions are possible without a substantial rest period. Resistance or strength training is primarily an anaerobic activity, although some proponents have adapted it to provide the benefits of aerobic exercise through circuit training. Social activity Social activities are varied and difficult to define, however they may include meeting friends, attending events or functions, volunteering or participating in occupational duties or group recreational activities.

For further information, please contact: Department of Mental Health and Substance Abuse, World Health Organization Avenue Appia 20 CH-1211 Geneva 27 Switzerland Email: whodementia@who.int Website: www.who.int/mental_health/ neurology/dementia/en ISBN 978-92-4-155054-3

RISK REDUCTION OF COGNITIVE DECLINE AND DEMENTIA WHO GUIDELINES

iRISK REDUCTION OF COGNITIVE DECLINE AND DEMENTIA WHO GUIDELINES ii Risk reduction of cognitive decline and dementia: WHO guidelines Risk reduction of cognitive decline and dementia: WHO guidelines ISBN 978-92-4-155054-3 © World Health Organization 2019 Some rights reserved. This work is available under the Creative Commons Attribution-NonCommercial-ShareAlike 3.0 IGO licence (CC BY-NC-SA 3.0 IGO; https://creativecommons.org/licenses/by-nc-sa/3.0/igo). Under the terms of this licence, you may copy, redistribute and adapt the work for non-commercial purposes, provided the work is appropriately cited, as indicated below. In any use of this work, there should be no suggestion that WHO endorses any specific organization, products or services. The use of the WHO logo is not permitted. If you adapt the work, then you must license your work under the same or equivalent Creative Commons licence. 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If you wish to reuse material from this work that is attributed to a third party, such as tables, figures or images, it is your responsibility to determine whether permission is needed for that reuse and to obtain permission from the copyright holder. The risk of claims resulting from infringement of any third-party-owned component in the work rests solely with the user. General disclaimers. The designations employed and the presentation of the material in this publication do not imply the expression of any opinion whatsoever on the part of WHO concerning the legal status of any country, territory, city or area or of its authorities, or concerning the delimitation of its frontiers or boundaries. Dotted and dashed lines on maps represent approximate border lines for which there may not yet be full agreement. The mention of specific companies or of certain manufacturers’ products does not imply that they are endorsed or recommended by WHO in preference to others of a similar nature that are not mentioned. Errors and omissions excepted, the names of proprietary products are distinguished by initial capital letters. All reasonable precautions have been taken by WHO to verify the information contained in this publication. However, the published material is being distributed without warranty of any kind, either expressed or implied. The responsibility for the interpretation and use of the material lies with the reader. In no event shall WHO be liable for damages arising from its use. Design and layout: Erica Lefstad Printed in France iii FOREWORD ........................................................... v ACKNOWLEDGEMENTS ................................... vi ACRONYMS .......................................................... viii EXECUTIVE SUMMARY .................................... x 1. INTRODUCTION ........................................ xiv 1.1 Background and rationale for these guidelines ..... 1 1.2 Related WHO guidelines and tools ......................... 3 1.3 Target audience .................................................... 4 1.4 Goals and objectives ............................................ 4 1.5 Guiding principles ................................................ 5 2. GUIDELINE DEVELOPMENT PROCESS ........................................................ 6 2.1 Guideline development group ............................... 7 2.2 Declarations of interest by the GDG members and external reviewers ......................................... 7 2.3 Collaboration with external partners ..................... 8 2.4 Identifying, appraising and synthesizing available evidence ................................................ 8 2.5 Decision-making during the GDG meeting .............. 10 2.6 Document preparation and peer review ................ 11 3. EVIDENCE AND RECOMMENDATIONS ............................. 12 3.1 Physical activity interventions ............................. 13 3.2 Tobacco cessation interventions .......................... 16 3.3 Nutritional interventions ..................................... 18 3.4 Interventions for alcohol use disorders ................. 22 3.5 Cognitive interventions ....................................... 25 3.6 Social activity ...................................................... 27 3.7 Weight management ........................................... 29 3.8 Management of hypertension .............................. 32 3.9 Management of diabetes ...................................... 35 3.10 Management of dyslipidaemia ............................. 38 3.11 Management of depression ................................. 40 3.12 Management of hearing loss ................................ 43 4. IMPLEMENTATION CONSIDER ATIONS ................................... 46 5. PUBLICATION, DISSEMINATION AND EVALUATION ................................... 48 5.1 Publication and dissemination ............................... 49 5.2 Monitoring and evaluation ..................................... 50 5.3 Implications for further research ............................ 50 5.4 Future review and update ...................................... 51 REFERENCES ...................................................... 52 ANNEX 1: GUIDELINE DEVELOPMENT GROUP MEMBERS ........................................... 60 ANNEX 2: ASSESSMENT OF CONFLICT OF INTEREST ....................................................... 62 ANNEX 3: SCOPING QUESTIONS ............... 67 ANNEX 4: EVIDENCE REVIEW METHODOLOGY ................................................ 72 WEB ANNEX: EVIDENCE PROFILES (WHO/MSD/MER/19.1); https://www.who.int/mental_health/neurology/dementia/ guidelines_risk_ reduction/en/index.html GLOSSARY ............................................................ 77 CONTE NTS iv Risk reduction of cognitive decline and dementia: WHO guidelines vFOREWORD Dementia is a rapidly growing public health problem affecting around 50 million people around the world. There are nearly 10 million new cases every year and this figure is set to triple by 2050. Dementia is a major cause of disability and dependency among older people and can devastate the lives of affected individuals, their carers and families. Additionally, the disease inflicts a heavy economic burden on societies as a whole, with the costs of caring for people with dementia estimated to rise to US$ 2 trillion annually by 2030. While there is no curative treatment for dementia, the proactive management of modifiable risk factors can delay or slow onset or progression of the disease. In May 2017, the Seventieth World Health Assembly endorsed a Global Action Plan on the Public Health Response to Dementia 2017–2025, urging Member States to develop, as soon as feasible, ambitious national responses to address this challenge. Dementia risk reduction is one of the seven action areas in the global action plan. These new WHO guidelines provide the knowledge base for health care providers, governments, policy-makers and other stakeholders to reduce the risks of cognitive decline and dementia through a public health approach. As many of the risk factors for dementia are shared with those of non- communicable diseases, the key recommendations can be effectively integrated into programmes for tobacco cessation, cardiovascular disease risk reduction and nutrition. I urge all stakeholders to make the best use of these recommendations to improve the lives of people with dementia, their carers and their families. Dr Ren Minghui Assistant Director-General for Universal Health Coverage/Communicable and Noncommunicable Diseases, World Health Organization vi Risk reduction of cognitive decline and dementia: WHO guidelines GUIDELINE DEVELOPMENT GROUP Chair: Martin Prince, King’s College, London, United Kingdom. Members: Charles Alessi, Public Health England, London, United Kingdom; Kaarin J Anstey, University of New South Wales, Sydney, Australia; Kimberly Ashby-Mitchell, Caribbean Public Health Agency, Port of Spain, Trinidad and Tobago; Adelina Comas- Herrera, London School of Economics, London, United Kingdom; Amit Dias, Department of Preventive and Social Medicine, Goa Medical College Bambolim, Goa, India; Cleusa P Ferri, Federal University of São Paulo, São Paulo, Brazil; Riadh Gouider, Razi Hospital, Faculty of Medicine, Tunis, Tunisia; Shinya Ishii, Ministry of Health, Labour and Welfare, Tokyo, Japan; Yves Joanette, Canadian Institutes of Health Research, Government of Canada; Joseph Kibachio, Ministry of Health, Nairobi, Kenya; Miia Kivipelto, Karolinska Institutet, Stockholm, Sweden; Shanthi Mendis, Colombo, Sri Lanka; Ayesha Motala, University of KwaZulu-Natal, Durban, South Africa; Ronald C Petersen, Mayo Clinic, Rochester, United States of America; Dorairaj Prabhakaran, Public Health Foundation of India, New Delhi, India; Suzana Shahar, Universiti Kebangsaan Malaysia, Selangor, Malaysia; Ameenah Bibi Mia Sorefan, Ministry of Health and Quality of Life, Quatre-Bornes, Mauritius; Kusumadewi Suharya (Dy), Alzheimer’s Disease International, Jakarta, Indonesia; Huali Wang, Dementia Care & Research Center, Peking University Institute of Mental Health, Beijing, China. Grade methodologist: Corrado Barbui, University of Verona, Italy. EXTERNAL REVIEW GROUP Abdullah Al Khatami, Ministry of Health, Saudi Arabia; Emiliano Albanese, Università della Svizzera italiana, Switzerland; Alistair Burns, University of Manchester, United Kingdom; Linda Clare, University of Exeter, United Kingdom; Jacqueline Dominguez, Institute for Dementia Care Asia, Quezon City, Philippines; Hillary Doxford, 3 Nations Dementia Working Group, United Kingdom; Maelënn Guerchet, Global Observatory for Ageing and Dementia Care, King’s College London, United Kingdom; Mariella Guerra, Institute of Memory, Depression and Related Disorders, Lima, Peru; Luis Miguel F Gutiérrez Robledo, Instituto Nacional de Geriatría, Institutos Nacionales de Salud de México, Mexico City, Mexico; Vladimir Hachinski, University of Western Ontario in London, Ontario, Canada; Qurat-ul Ain Khan, Aga Khan University Hospital, Karachi, Pakistan; Sebastian Koehler, Maastricht University, The Netherlands; Jae-hong Lee, University of Ulsan College of Medicine, Seoul, Republic of Korea; Gill Livingstone, University College London, United Kingdom; Jean Claude Mbanya, Doctoral School of Life Sciences, Health and Environment, University of Yaoundé I, Cameroon; James McKillop, service user group representative, United Kingdom; Elaine Rashbrook, Public Health England, United Kingdom; Rajat Ray, National Drug Dependence Treatment Centre, All India Institute of Medical Sciences, New Delhi, India; Helen Rochford Brennan, European Working Group of People with Dementia, Ireland; Andrew Sommerlad, University College London, United Kingdom; Kate Swaffer, Dementia Alliance International, Australia; Weili Xu, Karolinska Institutet, Finland. WHO GUIDELINE STEERING GROUP Overall coordination: Tarun Dua, Programme Manager, Department of Mental Health and Substance Abuse; Neerja Chowdhary, Technical Officer, Department of Mental Health and Substance Abuse. WHO headquarters members: Katthyana Aparicio Reyes, Department of Service Delivery and Safety; Islene Araujo de Carvalho, Department of Ageing and Life Course; Lubna Bhatti, Department of Prevention of Noncommunicable Diseases; Fiona Bull, Department of Prevention of Noncommunicable Diseases; Shelly Chadha, Department of Management of Noncommunicable Diseases, Disability, Violence and Injury Prevention; Alarcos Cieza, Department of Management of Noncommunicable Diseases, Disability, Violence and Injury Prevention; Stéfanie Fréel, Department of Mental Health and Substance Abuse; Maria Garcia Casal, Department of Nutrition for Health and Development; Angela Luzia Herscheid, ACK NOWLE DG E M E NTS viiAcknowledgements Department of Mental Health and Substance Abuse; Michal Herz, Department of Mental Health and Substance Abuse; Dzmitry Krupchanka, Department of Mental Health and Substance Abuse; Artin Mahdanian, Department of Mental Health and Substance Abuse; Shanthi Pal, Department of Essential Medicines and Health Products; Anne Margriet Pot, Department of Ageing and Life Course; Gojka Roglic, Department of Management of Noncommunicable Diseases, Disability, Violence and Injury Prevention; Katrin Seeher, Department of Mental Health and Substance Abuse. WHO regional office advisors: Nazneen Anwar, WHO Regional Office for South-East Asia; Dan Chisholm, WHO Regional Office for Europe; Devora Kestel, WHO Regional Office for the Americas; Sebastiana Da Gama Nkomo, WHO Regional Office for Africa; Khalid Saeed, WHO Regional Office for the Eastern Mediterranean; Martin Vandendyck, WHO Regional Office for the Western Pacific. WHO evidence review and synthesis teams: Mariagnese Barbera, University of Eastern Finland, Kuopio, Finland; Nicole A Ee, University of New South Wales, Sydney, Australia; Jenni Kumlala, Karolinska Institutet, Stockholm, Sweden; Ruth Peters, University of New South Wales, Sydney, Australia; Lidan Zheng, University of New South Wales, Sydney, Australia. FUNDING SOURCE Funds received from Public Health England, United Kingdom; Centers for Disease Control and Prevention, United States of America; and the WHO Core Voluntary Contributions Account were used for the development of these guidelines. viii Risk reduction of cognitive decline and dementia: WHO guidelines ACE angiotensin converting enzyme AD Alzheimer disease ADAS-cog Alzheimer Disease Assessment Scale-Cog ADL activities of daily living AHRQ Agency for Healthcare Research and Quality (United States of America) ARB angiotensin receptor blocker BMI body mass index CCB calcium channel blocker CI confidence interval CVRF cardiovascular risk factors CVD cardiovascular disease DALYs disability-adjusted life years DASH dietary approaches to stop hypertension DoI declaration of interest EMBASE Excerpta Medica dataBASE ERG external review group GDG guideline development group (WHO) GDP gross domestic product GRADE Grading of Recommendations Assessment, Development and Evaluation HIV human immunodeficiency virus IADL instrumental activities of daily living ICOPE Integrated Care for Older People (WHO) LMIC low- and middle-income countries MCI mild cognitive impairment MDRS Mattis Dementia Rating Scale MeSH Medical Subject Headings mhGAP Mental Health Gap Action Programme (WHO) MMSE Mini Mental State Examination NCDs noncommunicable diseases NIA National Institute on Aging (United States of America) NICE National Institute of Health and Care Excellence (United Kingdom) OR odds ratio ACRONYMS ixAcronyms PEN Package of Essential Noncommunicable Disease Interventions (WHO) PICO population, intervention, comparison, outcome PUFA polyunsaturated fatty acids RCT randomized controlled trial RR relative risk SMD standardized mean difference x Risk reduction of cognitive decline and dementia: WHO guidelines E XECUTIVE SUMMARY INTRODUCTION Dementia is a rapidly growing global public health problem. Worldwide, around 50 million people have dementia, with approximately 60% living in low- and middle-income countries (LMIC). Every year, there are nearly 10 million new cases. The total number of people with dementia is projected to reach 82 million in 2030 and 152 million in 2050. Dementia leads to increased costs for governments, communities, families and individuals, and to loss in productivity for economies. In 2015, the total global societal cost of dementia was estimated to be US$ 818 billion, equiv- alent to 1.1% of global gross domestic product (GDP). Crucially, while age is the strongest known risk factor for cognitive decline, dementia is not a natural or inevi- table consequence of ageing. Several recent studies have shown a relationship between the development of cognitive impairment and dementia with lifestyle- related risk factors, such as physical inactivity, tobacco use, unhealthy diets and harmful use of alcohol. Certain medical conditions are associated with an increased risk of developing dementia, including hypertension, diabetes, hypercholesterolemia, obesity and depression. Other potentially modifiable risk factors include social isolation and cognitive inactivity. The existence of potentially modifiable risk factors means that prevention of dementia is possible through a public health approach, including the implementation of key interventions that delay or slow cognitive decline or dementia. In May 2017, the Seventieth World Health Assembly endorsed the Global action plan on the public health response to dementia 2017–2025 (WHO, 2017a). The action plan includes seven strategic action areas and xiExecutive Summary dementia risk reduction is one of them. The action plan calls upon the WHO Secretariat to strengthen, share and disseminate an evidence base to support policy interventions for reducing potentially modifiable risk factors for dementia. This involves providing a database of available evidence on the prevalence of those risk factors and the impact of reducing them; and supporting the formulation and implementation of evidence-based, multisectoral interventions for reducing the risk of dementia. The risk reduction guidelines for cognitive decline and dementia are aligned with WHO’s mandate to provide evidence-based guidance for a public health response to dementia. GUIDELINE DEVELOPMENT METHODS The process of development of these guidelines followed the WHO handbook for guideline development and involved: 1. recruitment of the guideline development group (GDG); 2. declaration of interest by GDG members and peer reviewers; 3. scoping review to formulate questions and select outcomes; 4. identification, appraisal and synthesis of available evidence; 5. formulation of recommendations with inputs from a wide range of stakeholders; and 6. preparation of documents and plans for dissemination. The GDG, an international group of experts, provided input into the scope of the guidelines and assisted the steering group in developing the key questions. A total of 12 PICO (population, intervention, comparison and outcome) questions were developed. To address the PICO questions, a series of searches for systematic reviews was conducted and Grading of Recommendations Assessment, Development and Evaluation (GRADE) evidence profiles prepared. During a meeting at WHO headquarters in Geneva, 2–3 July 2018, the GDG discussed the evidence, sought clarifications and interpreted the findings in order to develop recommendations. The GDG considered the balance of benefit and harm of each intervention; values and preferences; costs and resource use; and other relevant practical issues for providers in LMIC. When making a strong recommendation, the GDG was confident that the desirable effects of the inter- vention outweigh any undesirable effects. When the GDG was uncertain about the balance between the desirable and undesirable effects, the GDG issued a conditional recommendation. Strong recommenda- tions imply that most individuals would want the intervention and should receive it, while conditional recommendations imply that different choices may be appropriate for individual patients and they may require assistance at arriving at management decisions. The GDG members reached a unanimous agreement on all the recommendations and ratings. xii Risk reduction of cognitive decline and dementia: WHO guidelines SUMMARY OF RECOMMENDATIONS Physical activity interventions Physical activity should be recommended to adults with normal cognition to reduce the risk of cognitive decline. Quality of evidence: moderate Strength of the recommendation: strong Physical activity may be recommended to adults with mild cognitive impairment to reduce the risk of cognitive decline. Quality of evidence: low Strength of the recommendation: conditional Tobacco cessation interventions Interventions for tobacco cessation should be offered to adults who use tobacco since they may reduce the risk of cognitive decline and dementia in addition to other health benefits. Quality of evidence: low Strength of the recommendation: strong Nutritional interventions The Mediterranean-like diet may be recommended to adults with normal cognition and mild cognitive impairment to reduce the risk of cognitive decline and/or dementia. Quality of evidence: moderate Strength of the recommendation: conditional A healthy, balanced diet should be recommended to all adults based on WHO recommendations on healthy diet. Quality of evidence: low to high (for different dietary components) Strength of the recommendation: conditional Vitamins B and E, polyunsaturated fatty acids and multi-complex supplementation should not be recommended to reduce the risk of cognitive decline and/or dementia. Quality of evidence: moderate Strength of the recommendation: strong Interventions for alcohol use disorders Interventions aimed at reducing or ceasing hazardous and harmful drinking should be offered to adults with normal cognition and mild cognitive impairment to reduce the risk of cognitive decline and/or dementia in addition to other health benefits. Quality of evidence: moderate (for observational evidence) Strength of the recommendation: conditional Cognitive interventions Cognitive training may be offered to older adults with normal cognition and with mild cognitive impairment to reduce the risk of cognitive decline and/or dementia. Quality of evidence: very low to low Strength of the recommendation: conditional Social activity There is insufficient evidence for social activity and reduction of risk of cognitive decline/dementia. Social participation and social support are strongly connected to good health and well- being throughout life and social inclusion should be supported over the life-course. xiiiExecutive Summary Weight management Interventions for mid-life overweight and/or obesity may be offered to reduce the risk of cognitive decline and/or dementia. Quality of evidence: low to moderate Strength of the recommendation: conditional Management of hypertension Management of hypertension should be offered to adults with hypertension according to existing WHO guidelines. Quality of evidence: low to high (for different interventions) Strength of the recommendation: strong Management of hypertension may be offered to adults with hypertension to reduce the risk of cognitive decline and/or dementia. Quality of evidence: very low (in relation to dementia outcomes) Strength of the recommendation: conditional Management of diabetes mellitus The management of diabetes in the form of medications and/or lifestyle interventions should be offered to adults with diabetes according to existing WHO guidelines. Quality of evidence: very low to moderate (for different interventions) Strength of the recommendation: strong The management of diabetes may be offered to adults with diabetes to reduce the risk of cognitive decline and/or dementia. Quality of evidence: very low Strength of the recommendation: conditional Management of dyslipidaemia Management of dyslipidaemia at mid-life may be offered to reduce the risk of cognitive decline and dementia. Quality of evidence: low Strength of the recommendation: conditional Management of depression There is currently insufficient evidence to recommend the use of antidepressant medicines for reducing the risk of cognitive decline and/or dementia. The management of depression in the form of antidepressants and/or psychological interventions should be provided to adults with depression according to existing WHO mhGAP guidelines. Management of hearing loss There is insufficient evidence to recommend use of hearing aids to reduce the risk of cognitive decline and/or dementia. Screening followed by provision of hearing aids should be offered to older people for timely identification and management of hearing loss as recommended in the WHO ICOPE guidelines. xiv Risk reduction of cognitive decline and dementia: WHO guidelines 1 INTRODUC TION 1Introduction 1.1 BACKGROUND AND RATIONALE FOR THESE GUIDELINES Dementia, a group of disorders characterized by a decline from a previously attained cognitive level that affects activities of daily living (ADL) and social functioning, poses one of the greatest global challenges for health and social care in the 21st century. In 2015, dementia affected 50 million people worldwide (or roughly 5% of the world’s elderly population, i.e. those above the age of 60 years). The number of people with dementia is expected to increase to 82 million in 2030 and 152 million by 2050 with the estimated proportion of the population aged 60 and over with dementia at a given time between 5 to 8% 1 because dementia rises exponentially during old age and the world’s population is ageing. These projections assume constant age- and sex-specific prevalence of dementia over time, and, accordingly, the steepest rises are expected especially in low- and middle- income countries (LMIC), where the demographic changes will be more marked. Dementia is a major cause of disability and dependency among older people worldwide, and it has a significant impact not only on individuals but also on carers, families, communities and societies. Dementia accounts for 11.9% of the years lived with disability due to a noncommunicable disease (NCD) worldwide. Dementia leads to increased costs for governments, communities, families and individuals, and to loss in productivity for economies. The annual global cost of dementia is estimated to be US$ 818 billion (OECD, 2015; WHO, 2017b). Nearly 85% of costs are related to family and social, rather than medical, care (GBD 2015 Neurological Disorders Collaborator Group, 2017). Most health systems are ill-equipped and under-resourced to respond to the current needs associated with dementia. Thus, societal ageing and the associated increases in dementia prevalence will likely have major health-service implications for the care of people with dementia and support for affected families. There are many different causes and types of demen- tia. Primary dementias include: dementia due to Alzheimer disease (AD), vascular dementia, dementia with Lewy bodies and frontotemporal dementia (in which the decline in cognitive abilities itself is mostly due to an underlying neurodegenera-tive process and not directly caused by other etiologies). Alzheimer disease is the most common, followed by vascular dementia and dementia with Lewy bodies. Mixed dementia with features of more than one type is also common, especially in older adults, while frontotemporal dementia is a less common form but relatively more frequent before old age. Secondary dementias are those caused by, or closely related to, some other recognizable disease, such as HIV, head injury, multiple sclerosis, thyroid disorders or vitamin B12 deficiency. In these secondary dementias, cognitive impairment is typically accompanied by symptoms and signs in other organ systems and the treatment focuses on management of the underlying disease. For the scope of these guidelines we refer to primary dementias. Though early treatment of some diseases may have the potential to prevent the onset of secondary dementias, we are not including these 1 WHO & King’s College London (2017). Global prevalence of dementia – updated figures 2017. Available at: https://www.who.int/news-room/fact-sheets/detail/dementia 2 Risk reduction of cognitive decline and dementia: WHO guidelines secondary dementias in the scope of these guidelines since there are prevention or appropriate management and treatment strategies for most of these specific diseases and conditions, which effectively reduce dementia-related signs and symptoms. However, late-onset dementia is a heterogeneous and multifactorial condition and some factors (i.e. head trauma, B12 deficiency earlier in life) may also contribute to the development of dementia later in life (not only secondary dementia). RISK FACTORS FOR DEMENTIA Non-modifiable risk factors for dementia include gene polymorphisms, age, gender, race/ethnicity and family history. Crucially, while age is the strongest known risk factor for cognitive decline, dementia is not a natural or inevitable consequence of ageing. During the last two decades, several studies have shown a relationship between the development of cognitive impairment and dementia with educational attainment, and lifestyle-related risk factors, such as physical inactivity, tobacco use, unhealthy diets and harmful use of alcohol. Further, certain medical conditions are associated with an increased risk of developing dementia, including hypertension, diabetes, hypercholesterolemia, obesity and depression. Other potentially modifiable risk factors may include social isolation and cognitive inactivity. The risk factors included in the scope of these guidelines were chosen based on recent systematic reviews and guidelines, i.e. National Institute of Health and Care Excellence (United Kingdom) (NICE, 2015); the United States of America Agency for Healthcare Research and Quality (AHRQ) systematic review (Kane et al., 2017); the World Alzheimer report 2014 (Prince, et al., 2014) and the report by the Lancet Commission on Dementia Prevention, Intervention, and Care (Livingston et al., 2017). The current focus on modifiable risk factors is justified by their potential to be targeted for prevention of dementia, and/or the delay of the progression of cognitive decline. NEED FOR THESE GUIDELINES The existence of potentially modifiable risk factors means that prevention of dementia is possible through a public health approach, including the implementation of key interventions that delay or slow cognitive decline or dementia. In May 2017, the Seventieth World Health Assembly endorsed the Global action plan on the public health response to dementia 2017–2025 (WHO, 2017a). The vision of the action plan is a world in which dementia is prevented and people with dementia and their carers live well and receive the care and support they need to fulfil their potential with dignity, respect, autonomy and equality. The goal of the action plan is to improve the lives of people with dementia, their carers and families, while decreasing the impact of dementia on them as well as on communities and countries. The action plan includes seven strategic action areas, and dementia risk reduction is one of them. The action plan calls upon the WHO Secretariat to strengthen, share and disseminate an evidence base to support policy interventions for reducing potentially modifiable risk factors for dementia. This involves providing a database of available evidence on the prevalence of those risk factors and the impact of reducing them; and supporting the formulation and implementation of evidence-based, multi-sectoral interventions for reducing the risk of dementia. These current guidelines represent the first steps to support countries as they develop approaches to delay or prevent the onset of dementia. 3Introduction The risk reduction guidelines for cognitive decline and dementia are aligned with WHO’s mandate to provide evidence-based guidance for a public health response to dementia. By supporting health and social care professionals, particularly by improving their capacity to provide evidence-based, multisectoral, gender and culturally appropriate interventions to the general population, including modifiable dementia risk factors that are shared with other NCDs, the risk of developing dementia can be potentially reduced, or its progression delayed. Thus, the guidelines align with WHO’s work in the area of prevention and management of NCDs, which aims to support countries to reduce the incidence, morbidity and mortality of NCDs. WHO has collaborated with a range of stakeholders, including international and national public health agencies working in the area of prevention of NCDs and dementia. The guidelines are in close conceptual and strategic synergy with other WHO action plans and strategies, i.e. the Comprehensive mental health action plan 2013– 2020,2 the Global action plan for the prevention and control of noncommunicable diseases 2013–2020,3 the Global strategy and action plan on ageing and health 2016–2020,4 the Global strategy to reduce harmful use of alcohol5 and the Global strategy on diet, physical activity and health.6 Furthermore, this work is aligned with the WHO move towards making health services more people-centred. Finally, the work will contribute to the attainment of Sustainable Development Goal 3, target 3.8, i.e. achieve universal health coverage, including financial risk protection, access to quality essential healthcare services and access to safe, effective, quality and affordable essential medicines and vaccines for all (UN, 2019). 1.2 RELATED WHO GUIDELINES AND TOOLS Several existing WHO guidelines and tools designed for the general population are relevant for addressing health conditions that may increase the risk of cognitive decline or dementia in individuals with normal cognition or mild cognitive impairment (MCI). The following WHO guidelines and tools were consulted when developing the current guidelines: • mhGAP Intervention guide – Version 2.0 for mental, neurological and substance use disorders in non- specialized health settings. Geneva: WHO, 2016. http://www.who.int/mental_health/mhgap/mhGAP_ intervention_guide_02/en/ • Prevention and control of noncommunicable diseases: guidelines for primary health care in low- resource settings. Geneva: WHO, 2012. http://apps. who.int/iris/bitstream/10665/76173/1/9789241548397_ eng.pdf • Package of essential noncommunicable (PEN) disease interventions for primary health care in low-resource settings. Geneva: WHO, 2010. http:// www.who.int/cardiovascular_diseases/publications/ pen2010/en/ • Global recommendations on physical activity for health. Geneva: WHO, 2010. http://www.who.int/ dietphysicalactivity/publications/9789241599979/en/ • Integrated care for older people (ICOPE): Recommendations on interventions to improve physical and mental capacities of older people at community level. Geneva: WHO, 2016. 2 Available at http://www.who.int/mental_health/action_plan_2013/en/ 3 Available at http://www.who.int/nmh/publications/ncd-action-plan/en/ 4 Available at http://who.int/ageing/global-strategy/en/ 5 Available at http://www.who.int/substance_abuse/activities/gsrhua/en/ 6 Available at http://www.who.int/dietphysicalactivity/Indicators%20English.pdf 4 Risk reduction of cognitive decline and dementia: WHO guidelines • HEARTS Technical package for cardiovascular disease management in primary health care: evidence-based treatment protocols. http://www. who.int/cardiovascular_diseases/hearts/en/ • Global age-friendly cities: a guide. Geneva: WHO, 2007. http://www.who.int/ageing/publications/Global_ age_friendly_cities_Guide_English.pdf • Recommendations on healthy diet. Geneva: WHO, 2019. http://www.who.int/en/news- room/fact-sheets/detail/healthy-diet • Strengthening health systems for treating tobacco dependence in primary care. Geneva: WHO, 2013. http://www.who.int/tobacco/publications/building_ capacity/training_package/treatingtobaccodependence/en/ • Framework on integrated people-centred health services. Geneva: WHO, 2016. http://apps.who.int/ gb/ebwha/pdf_files/WHA69/A69_39-en.pdf?ua=1 These existing WHO guidelines and tools address some of the interventions that are included in the scope of the current guidelines, but they do not include cognitive decline or dementia as outcomes. Where the current guidelines overlap with the other guidelines, e.g. ICOPE guidelines, which provide recommendations on cognitive interventions in people with MCI, we have referred to these existing recommendations, rather than developing new ones. The current guidelines, therefore, complement, but do not duplicate, existing work. 1.3 TARGET AUDIENCE The guidelines are primarily targeted at health care providers working at a first or second level facility or at district level, including basic outpatient and inpatient services. The health care providers could be doctors, nurses or other cadres of health workers. Quality improvement teams at all levels of the system will benefit from the work. In addition, the guidelines and their derivative products have implications for policy-makers, health care planners and programme managers at national and international level, as well as the general population. 1.4 GOALS AND OBJECTIVES • To provide evidence-based recommendations on lifestyle behaviours and interventions to delay or prevent cognitive decline and dementia in the general population. • To provide evidence-based recommendations on management of specific physical and mental health conditions to delay or prevent cognitive decline and dementia. 5Introduction These guidelines provide up-to-date WHO evidence- based recommendations to facilitate implementing the Global action plan on the public health response to dementia 2017–2025, the Comprehensive mental health action plan 2013–2020 and WHO’s Mental Health Gap Action Programme (mhGAP),7 the Global action plan for the prevention and control of noncommunicable diseases 2013–2020,8 the Global strategy and action plan on ageing and health 2016–2020,9 the Global strategy to reduce harmful use of alcohol,10 and the Global strategy on diet, physical activity and health.11 1.5 GUIDING PRINCIPLES The following principles have informed the development of these guidelines and should guide their implementation: • The guidelines should expedite the achievement of the goals outlined in the Global action plan on the public health response to dementia 2017–2025, as well as target 3.4 of the Sustainable Development Goals, which focuses on reducing the premature mortality from NCDs and the promotion of mental health and well-being (UN, 2019). • The process of developing these guidelines, and their subsequent implementation, should concretely foster the right to equal levels of health for people at risk of cognitive decline and dementia and promote their active involvement. • The recommendations should be implemented with accompanying efforts to safeguard the human rights of persons living with cognitive decline and dementia, including reduction of stigma and discrimination, reducing barriers to seek health and social care services, and ensuring informed decision-making in treatment choices. Implementation of the recommendations should be tailored to the local context, including the availability of financial and human resources. However, the inequities addressed in these guidelines are common across all countries, and should be made a priority in health services. 7 Available at http://www.who.int/mental_health/action_plan_2013/en/ 8 Available at http://www.who.int/nmh/publications/ncd-action-plan/en/ 9 Available at http://who.int/ageing/global-strategy/en/ 10 Available at http://www.who.int/substance_abuse/activities/gsrhua/en/ 11 Available at http://www.who.int/dietphysicalactivity/Indicators%20English.pdf 6 Risk reduction of cognitive decline and dementia: WHO guidelines GUIDE LINE DEVE LOPME NT PROCESS 2 7Guideline development process The process of developing these guidelines followed the WHO Handbook for guideline development (2nd edition, http://apps.who.int/ medicinedocs/en/m/abstract/Js22083en/). It consisted of the following steps. 2.1 GUIDELINE DEVELOPMENT GROUP A WHO guideline steering group, led by the Department of Mental Health and Substance Abuse, was established with representatives from WHO regional offices and relevant WHO departments and programmes. The guideline steering group provided overall support to the guideline development process. Two additional groups were established: a guideline development group (GDG) and an external review group (ERG). The GDG included a panel of academicians and clinicians with multidisciplinary expertise on the conditions covered by the guidelines. Consideration was given to geographic diversity and gender balance (see Annex 1). As a respected researcher in the field, the Chairperson was selected for their extensive experience of guideline development methodology, and their participation in other guideline development groups. Each potential GDG member was asked to complete the WHO declaration of interest (DoI) form. These were reviewed by the steering group. 2.2 DECLARATIONS OF INTEREST BY THE GDG MEMBERS AND EXTERNAL REVIEWERS All GDG members, peer reviewers and systematic review team members were requested to complete the DoI prior to the evidence review process for guideline development. Invitations to participate in the GDG meeting were sent only after the DoI had been reviewed and approved. The GDG members were also required to complete a confidentiality undertaking. Once received, the WHO Secretariat reviewed the DoIs, as well as additional information (internet and bibliographic database search), and evaluated if there were any conflicts of interest and if so, whether these required a management plan. The group composition was finalized after this process. The names and brief biographies of the members being considered for participation in the GDG were disclosed for public notice and comment prior to the meeting. At the beginning of the GDG meeting, the DoI of each GDG member were presented and GDG members, as well as external partners, were asked to update their DoI with relevant changes by notifying the WHO Secretariat. Declarations of interest were reassessed for potential conflict before the face-to-face meeting in Geneva. None of the members had major conflicts of interest. All decisions were documented (see Annex 2). 8 Risk reduction of cognitive decline and dementia: WHO guidelines 2.3 COLLABORATION WITH EXTERNAL PARTNERS The Center for Alzheimer Research at the Karolinska Institutet, Stockholm, Sweden, and the School of Psychology at the University of New South Wales and Neuroscience Research, Australia, supported the development of the guidelines by conducting the evidence review and synthesis. 2.4 IDENTIFYING, APPRAISING AND SYNTHESIZING AVAILABLE EVIDENCE The procedure of the scoping review to identify the draft population, intervention, comparison, outcome (PICO) questions consisted of the identification of potentially modifiable risk factors and interventions for cognitive decline or dementia. These interventions are summarized in existing WHO guidelines listed earlier, such as the Prevention and control of noncommunicable diseases; Package of essential noncommunicable (PEN) disease interventions for primary health care in low-resource settings; and Integrated care for older people (ICOPE) guidelines. These guidelines, however, do not include cognitive decline or dementia as outcomes. Among recent summary reports, the Lancet Commission on Dementia Prevention, Intervention, and Care report summarizes the emerging knowledge on dementia risk factors and interventions (Livingston et al., 2017). The risk factors and interventions reported in this set of systematic reviews included education, exercise, maintaining social engagement, reducing smoking, and management of hearing loss, depression, hypertension, diabetes and obesity. Another systematic review requested and supported by the National Institute on Aging (NIA) at the National Institutes of Health, United States of America, also identified risk factors and evidence for interventions, specifically cognitive training, blood pressure management and exercise (Kane et al., 2017). The interventions reported in these reviews have formed the basis of the interventions included in the PICO questions. The population in these guidelines considered adults with normal cognition as well as those with MCI. We use the term MCI to refer to a disorder characterized by impairment of memory, learning difficulties and reduced ability to concentrate on a task for more than brief periods, beyond what is expected in normal ageing. There is often a marked feeling of mental fatigue when mental tasks are attempted, and new learning is found to be subjectively difficult even when objectively successful. None of these symptoms is so severe that a diagnosis of dementia can be made. Individuals diagnosed with MCI, however, are at greater risk of developing dementia; the inclusion of adults with MCI in these guidelines will enable the use of interventions to slow the progression of cognitive decline, i.e. the transition from MCI to dementia itself. 9The scope of these guidelines is prevention/risk reduction of cognitive decline or dementia (main outcomes of interest). Cognitive decline is defined as a noticeable and measurable loss or abnormality in attention functions, memory functions or higher level cognitive functions (including attention, language and reasoning). Dementia is a syndrome that includes cognitive decline and other symptoms and can be diagnosed based on ICD-10 criteria. It involves a decline in memory with impairment of at least one other cognitive function, such as skilled movements (limb apraxia), language (aphasia) or executive function (e.g. planning, attention and abstract reasoning). This decline should represent a change from previous behaviour, and impair social and/or occupational functioning. As stated in the background section, when we use the word dementia in this document, we are referring to the primary or neurodegenerative dementias. The GDG provided input into the scope of the guidelines and assisted the steering group in developing the key questions. Twelve PICO-structured questions were developed (Annex 3). Outcomes were rated by GDG members according to their importance, as “critical”, “important” or “unimportant”. Those outcomes rated as critical and important were selected for inclusion into the PICO. Regular communication and discussions with the GDG were held by email and teleconferences, respectively. The systematic review team developed protocols to review the evidence that existed for the inter- ventions to reduce the risk of cognitive decline and/ or dementia (as outlined in the PICO questions) for adults with normal cognition or MCI (Annex 4). Existing relevant systematic reviews were identified for each of the PICO questions. The steering group assessed the quality of existing reviews using the assessment of multiple systematic reviews (AMSTAR) checklist. Systematic reviews found to be of high quality were also assessed for timeliness to ensure that the most current evidence was used. The Grading of Recommendations Assessment, Development and Evaluation (GRADE) methodology (Guyatt et al., 2011), as well as the WHO Handbook for guideline development, were used to develop the evidence profiles. The quality assessment of the evidence was performed according to GRADE considering study design – randomized controlled trials (RCT) or observational studies, risk of bias, inconsistency, indirectness, imprecision and risk of reporting bias. Evidence was characterized as either high, moderate, low or very low. Guideline development process 10 Risk reduction of cognitive decline and dementia: WHO guidelines 2.5 DECISION-MAKING DURING THE GDG MEETING The GDG met at the WHO headquarters in Geneva, 2–3 July 2018. The evidence review was sent out in advance and it was summarized in a presentation during the meeting. The GDG members discussed the evidence, clarified points and interpreted the findings in order to develop recommendations based on the draft prepared by the WHO Secretariat. The GDG considered the relevance of the recommendations for adults with normal cognition or MCI based on the GRADE Evidence-to-Decision (EtD) framework (Alonso-Coello et al., 2016), considering the balance of benefit and harm of each intervention; values and preferences of the individuals involved; costs and resource use; acceptability of the intervention to health care providers in LMIC; feasibility of implementation; and impact on equity and human rights. No surveys or formal cost-effectiveness studies to determine resource constraints were conducted but discussions of these domains were informed by the combined expertise and experience of the GDG members. Equity and human rights were considered by specifically searching databases that include studies from LMIC, examining data for disaggregation for specific subgroups. Potential differential effects of the interventions on different subgroups of people related to economic status, employment or occupation, education, place of residence, gender or ethnicity were considered by the GDG. Taking into account these considerations, when making a strong recommendation, the GDG was confident that the desirable effects of the intervention outweigh any undesirable effects. When the GDG was uncertain about the balance between the desirable and undesirable effects, the GDG issued a conditional recommendation. Strong recommendations imply that most individuals would want the intervention and should receive it, while conditional recommendations imply that different choices may be appropriate for individual patients and they may require assistance at arriving at management decisions. In some instances, even when the quality of evidence was low or very low, it was agreed that if the recommendation would be of general benefit, and this was seen to outweigh the harms, it may still be rated as strong. In the event of a disagreement, the Chair and the Methodologist would ascertain whether the dispute was related to the interpretation of the data or to the way that the recommendation was formulated. If a consensus agreement was not reached, the GDG members agreed to a majority vote of 70%, to determine a decision. WHO staff members present at the meeting, as well as other external technical experts involved in the collection and review of the evidence, were excluded from voting. The GDG members reached a consensus agreement on all recommendations and ratings and voting was not needed. 11 2.6 DOCUMENT PREPARATION AND PEER REVIEW The draft guideline and evidence profiles prepared by WHO staff and the GDG were circulated to the ERG and the steering group. The role of the ERG was to identify any errors or missing data and to comment on clarity, setting-specific issues and implications for implementation rather than changing the recommen- dations. All inputs and remarks were discussed and agreed with the GDG by email. 12 Risk reduction of cognitive decline and dementia: WHO guidelines This section provides an overview of each PICO question described under the following headings: background; recommendations and additional considerations; supporting evidence for the recommendations and the rationale for the recommendations based on the evidence synthesized as well as criteria listed in the EtD tables. Complete evidence profiles for each PICO question including the GRADE tables and the EtD tables are included in the Web Annex. EVIDE NCE AND RECOMME NDATIONS 3 13Evidence and recommendations Population: Adults (age above 18 years) with normal cognition or MCI Intervention: Physical activity interventions (aerobic, resistance training or multicomponent physical activity) Comparison: Care as usual or no intervention Outcomes: • Critical – Cognitive function – Incident MCI – Dementia • Important – Quality of life – Functional level (ADL, IADL) – Adverse events – Drop-out rates For adults with normal cognition or MCI, are physical activity interventions more effective than usual care or no intervention in reducing the risk of cognitive decline and/or dementia? 3.1 PHYSICAL ACTIVITY INTERVENTIONS BACKGROUND A physically active lifestyle is linked to brain health. In large observational studies with follow-up periods extending decades, physically active people seem less likely to develop cognitive decline, all-cause dementia, vascular dementia and Alzheimer disease when compared with inactive people (Gallaway et al., 2017; Hamer & Chida, 2009; Sofi et al., 2011; Stephen et al., 2017). Especially, the highest levels of physical exercise seem to be most protective (Hamer & Chida, 2009; Sofi et al., 2011). Physical activity seems to have beneficial effects on brain structures, which may underlie this association (Rovio et al., 2010). Other potential mechanisms underlying the association are most likely indirect, such as the positive effects of physical exercise on other modifiable cardiovascular risk factors (CVRFs), including hypertension, insulin resistance and high cholesterol levels as well as other biological mechanisms, including but not limited to enhancing the immune system function, anti-inflammatory properties, and increasing neurotrophic factors. Physical activity interventions are described in WHO’s Global recommendations on physical activity for health (2010). RECOMMENDATIONS AND CONSIDERATIONS RECOMMENDATION 1: Physical activity should be recommended to adults with normal cognition to reduce the risk of cognitive decline. Quality of evidence: moderate Strength of the recommendation: strong 14 Risk reduction of cognitive decline and dementia: WHO guidelines RECOMMENDATION 2: Physical activity may be recommended to adults with MCI to reduce the risk of cognitive decline. Quality of evidence: low Strength of the recommendation: conditional WHO’s Global recommendations on physical activity for health (2010) (http://www.who.int/dietphysicalactivity/publications/9789241599979/en/) Below is an extract from these recommendations for adults 65 years and above: For adults 65 years and above, physical activity includes recreational or leisure-time physical activity, transportation (e.g. walking or cycling), occupational (if the person is still engaged in work), household chores, play, games, sports or planned exercise, in the context of daily, family, and community activities. In order to improve cardiorespiratory and muscular fitness, bone and functional health, and reduce the risk of NCDs, depression and cognitive decline, the following are recommended: 1. Adults aged 65 years and above should do at least 150 minutes of moderate-intensity aerobic physical activity throughout the week, or do at least 75 minutes of vigorous-intensity aerobic physical activity throughout the week, or an equivalent combination of moderate- and vigorous-intensity activity. 2. Aerobic activity should be performed in bouts of at least 10 minutes’ duration. 3. For additional health benefits, adults aged 65 years and above should increase their moderate- intensity aerobic physical activity to 300 minutes per week, or engage in 150 minutes of vigorous-intensity aerobic physical activity per week, or an equivalent combination of moderate- and vigorous-intensity activity. 4. Adults of this age group with poor mobility should perform physical activity to enhance balance and prevent falls on 3 or more days per week. 5. Muscle-strengthening activities should be done involving major muscle groups, on 2 or more days per week. 6. When adults of this age group cannot do the recommended amounts of physical activity due to health conditions, they should be as physically active as their abilities and conditions allow. Overall, across all the age groups, the benefits of implementing the above recommendations, and of being physically active, outweigh the harms. At the recommended level of 150 minutes per week of moderate-intensity activity, musculoskeletal injury rates appear to be uncommon. In a population- based approach, in order to decrease the risks of musculoskeletal injuries, it would be appropriate to encourage a moderate start with gradual progress to higher levels of physical activity. 15Evidence and recommendations Additional considerations include: • Physical activity is easily available for everybody and has a large range of beneficial effects. • Aerobic activity plays a key role in the beneficial effect of physical activity. SUPPORTING EVIDENCE AND RATIONALE For physical activity interventions (e.g. aerobic, resistance training or multicomponent physical activity) compared with usual care or no intervention, four systematic reviews were identified for six different physical activity interventions (Barha et al., 2017; Barreto et al., 2017; Northey et al., 2018; Song et al., 2018). These were: 1. Aerobic exercise intervention versus usual care or no intervention in adults with normal cognition. 2. Training exercise intervention versus usual care or no intervention in adults with normal cognition. 3. Multimodal exercise intervention versus usual care or no intervention in adults with normal cognition. 4. Aerobic exercise intervention versus usual care or no intervention in adults with MCI. 5. Training exercise intervention versus usual care or no intervention in adults with MCI. 6. Multimodal exercise intervention versus usual care or no intervention in adults with MCI. For cognitive outcomes in healthy adults, there is moderate quality evidence which indicates that physical activity interventions have a positive effect on cognition. There is low to moderate quality evidence that suggests that physical activity does not affect risk of MCI and dementia. For cognitive outcomes in adults with MCI, there is low quality evidence that indicates that physical activity interventions have a positive effect on cognition. However, these benefits are not consistent across all cognitive domains. The evidence shows that the effect size is larger for aerobic training versus resistance training and there is stronger evidence for adults with normal cognition (especially aerobic training) than in adults with MCI. The GDG concluded that the desirable effects of physical activity outweighed the undesirable effects. Overall, low to moderate quality evidence has shown that physical activity has a small but beneficial effect on cognition. Even in MCI populations, low quality evidence suggests cognitive benefits of physical exercise. The effect of these interventions seems to be mostly due to aerobic exercise. Based on the quality of evidence, a strong recommendation was made for healthy adults and a conditional one for adults with MCI. 16 Risk reduction of cognitive decline and dementia: WHO guidelines Population: Adults with normal cognition or MCI who use tobacco Intervention: Interventions for tobacco cessation (behavioural interventions and pharmacological interventions including nicotine replacement therapy, bupropion, varenicline) Comparison: Care as usual or no intervention Outcomes: • Critical – Cognitive function – Incident MCI – Dementia • Important – Quality of life – Functional level (ADL, IADL) – Adverse events – Drop-out rates For adults with normal cognition or MCI who use tobacco, are interventions for tobacco cessation more effective than usual care or no intervention in reducing the risk of cognitive decline and/or dementia? 3.2 TOBACCO CESSATION INTERVENTIONS BACKGROUND Tobacco dependence is the leading cause of preventable death globally, causing an estimated 5 million deaths per year (WHO, 2011) and worldwide medical costs ranging in billions of US dollars (Lightwood et al., 2000). Tobacco is the major risk factor for a number of conditions, including many types of cancers, cardiovascular diseases (CVDs) and risk factors, and respiratory disorders (US Department of Health Human Services, 2004), and tobacco cessation has been demonstrated to significantly reduce these health risks (Pirie et al., 2013). Tobacco cessation has also been associated with reduced depression, anxiety and stress, and improved mood and quality of life compared with continuing to smoke (Taylor et al., 2014). Tobacco dependence is also associated with other disorders and age-related conditions, such as frailty and work ability in older people (Amorim et al., 2014; Kojima et al., 2015), as well as dementia and cognitive decline (Durazzo et al., 2014). Interventions to treat tobacco dependence can be very diverse, based on either or both behavioural/ psychological strategies and various pharmacological treatments. Non-pharmacological interventions can have mixed results (Niaura, 2008). Counselling is the most frequently used approach, but others have also been explored, such as mindfulness-based approaches, cognitive behavioural therapy, behavioural activation therapy, motivational interviewing, contingency manage- ment, and exposure and/or aversion to smoking. Among the pharmacological therapies for tobacco cessation, nicotine replacement therapy, bupropion and varenicline are the most common, but low overall treatment efficacy and adverse effects are key limitations (Gómez-Coronado et al., 2018). Combinations of non-pharmacological and pharmacological approaches seem to be the most effective in supporting tobacco cessation (Gómez- Coronado et al., 2018). 17Evidence and recommendations Additional considerations include: • In keeping with interventions described in the WHO training package for tobacco dependence, people who make use of tobacco should be advised to quit and the appropriate programmes aimed at preventing tobacco use uptake, promoting tobacco cessation, as well as diagnosing and treating tobacco dependence, should be established (http://www.who.int/ tobacco/publications/building_capacity/training_ package/treatingtobaccodependence/en/). The interventions include behavioural interventions, as well as pharmacological ones (i.e. nicotine replacement therapy, bupropion, varenicline). • Individual level interventions should be provided in the context of population level tobacco cessation programmes. SUPPORTING EVIDENCE AND RATIONALE No systematic reviews comparing tobacco cessation interventions with no intervention were identified. A large body of observational evidence is available on tobacco smoking as a risk factor for cognitive impairment and dementia. These studies show an association between tobacco smoking (including in mid-life) and dementia, or cognitive decline, in later life (Beydoun et al., 2014; Di Marco et al., 2014; Lafortune et al., 2016; North et al., 2015; Xu et al., 2015; Zhong et al., 2015). Only limited adverse events have been reported and only for pharmacological interventions (Motooka et al., 2018). Therefore, any type of intervention aimed at tobacco cessation is likely to be more beneficial than detrimental. The GDG made a strong recommendation although evidence from experimental intervention trials is not available, since tobacco use has substantial established harm and the epidemiological/ observational evidence on tobacco use and increased risk of dementia fulfils most of the Bradford-Hill’s criteria for causation (Lafortune et al., 2016). The evidence is strong, the population attributable risk is high, reproducible in different settings and with different study designs, specific, and indicates a dose- response effect. In addition, criteria such as temporality (mid-life smoking is correlated to a higher risk of late life dementia) (Lafortune et al., 2016), coherence (experimental laboratory results are in keeping with the observational evidence) (Durazzo et al., 2014) and mecha- nistic evidence suggest that smoking causes brain damage, underpinning subsequent cognitive decline. RECOMMENDATIONS AND CONSIDERATIONS RECOMMENDATION: Interventions for tobacco cessation should be offered to adults who use tobacco since they may reduce the risk of cognitive decline and dementia in addition to other health benefits. Quality of evidence: low Strength of recommendation: strong 18 Risk reduction of cognitive decline and dementia: WHO guidelines 3.3 NUTRITIONAL INTERVENTIONS Population: Adults with normal cognition or MCI Intervention: Dietary supplements (e.g. B vitamins, antioxidants, omega-3 and ginkgo) Comparison: Care as usual/placebo or one treatment versus another Outcomes: • Critical – Cognitive function – Incident MCI – Dementia • Important – Quality of life – Functional level (ADL, IADL) – Adverse events – Drop-out rates 3.3a For adults with normal cognition or MCI, are nutritional interventions including dietary supplements more effective than usual care or no intervention in reducing the risk/progression of cognitive decline and/or dementia? 3.3b For adults with normal cognition or MCI, are nutritional interventions such as healthy dietary patterns (e.g. the Mediterranean diet) more effective than usual care or no intervention in reducing the risk/progression of cognitive decline and/or dementia? Population: Adults with normal cognition or MCI Intervention: Healthy dietary pattern (e.g. the Mediterranean diet) Comparison: Care as usual or no intervention Outcomes: • Critical – Cognitive function – Incident MCI – Dementia • Important – Quality of life – Functional level (ADL, IADL) – Adverse events – Drop-out rates BACKGROUND A healthy diet throughout the life course plays a crucial role in optimal development, and in maintaining health and preventing NCDs. Previous dietary intervention studies have shown that dietary changes are involved in prevention of many conditions that increase the risk of dementia, such as diabetes (Diabetes Prevention Program Research Group, 2002; Tuomilehto et al., 2001) and CVD (Rees et al., 2013). Mechanistic and animal models have 19Evidence and recommendations suggested a variety of pathways that link dietary factors to neuropathological changes in the development of dementia (Swaminathan & Jicha, 2014). Therefore, dietary factors may be involved in the development of dementia, both directly and through their role on other risk factors, and a healthy diet may have a great preventive potential for cognitive impairment. The Mediterranean diet is the most extensively studied dietary approach, in general as well as in relation to cognitive function. Several systematic reviews of observational studies have concluded that high adherence to the Mediterranean diet is associated with decreased risk of MCI and AD, but modest adherence is not (Singh et al., 2014; Wu & Sun, 2017). Moreover, among participants with normal cognition, higher adherence is associated with better episodic memory and global cognition (Loughrey et al., 2017). Other promising dietary approaches associated with better cognitive function include: dietary approaches to stop hypertension (DASH) (Berendsen et al., 2017; Morris et al., 2015a; 2015b; Wengreen et al., 2013); and the brain health-specific Mediterranean-DASH Intervention for Neurodegenerative Delay (MIND) diet. Concerning individual foods and nutrients, consumption of fruit and vegetables (Jiang et al., 2017; Wu et al., 2017) and fish (Bakre et al., 2018; Zhang et al., 2016) are most consistently associated with decreased risk of dementia. Higher fish consumption has been linked to lower memory decline among healthy participants in many studies (Samieri et al., 2018), as well as intake of polyunsaturated fatty acids (PUFA) (fish-derived) (Zhang et al., 2016). Other foods and nutrients that have been associated with reduced risk of dementia or cognitive impairment are nuts, olive oil and coffee (Solfrizzi et al., 2017). Evidence has also been reported concerning folate, vitamin E, carotenes, vitamin C and vitamin D (Balion et al., 2012; Dangour et al., 2010; Rafnsson et al., 2013; Travica et al., 2017), but findings are inconsistent. RECOMMENDATIONS AND CONSIDERATIONS RECOMMENDATION 1: The Mediterranean-like diet may be recommended to adults with normal cognition and MCI to reduce the risk of cognitive decline and/or dementia. Quality of evidence: moderate Strength of the recommendation: conditional RECOMMENDATION 2: Healthy, balanced diet should be recommended to all adults based on WHO recommendations on healthy diet. Quality of evidence: low to high (for different dietary components) Strength of the recommendation: strong RECOMMENDATION 3: Vitamins B and E, PUFA and multi-complex supplementation should not be recommended to reduce the risk of cognitive decline and/or dementia. Quality of evidence: moderate Strength of the recommendation: strong 20 Risk reduction of cognitive decline and dementia: WHO guidelines Additional considerations include: • The evidence and recommendations provided assume that the nutritional status and potential micronutrients deficiencies in both mid-life and old age have been assessed and treated. • A balanced and varied diet represents a natural source of polyphenols and protein. • The recommendation about vitamins B and E, PUFA and multi-complex supplementation applies to people without nutrient deficiency. SUPPORTING EVIDENCE AND RATIONALE Observational studies have consistently reported that a healthy diet is associated with better cognitive performance (Berendsen et al., 2017; Frith et al., 2018; Loughrey et al., 2017; Morris et al., 2015; Wengreen et al., 2013), but the evidence from clinical trials is more inconsistent (D’Cunha et al., 2018; Fitzpatrick-Lewis et al., 2015a; 2015b; Forbes et al., 2015; Radd-Vagenas et al., 2018; Solfrizzi et al., 2018). It is important to acknowledge that interventions with dietary modifications that improve several aspects of dietary intake at once are more likely to promote better cognition compared with supplementation with only some nutrients. Dietary factors may have synergistic effects that are only evident in combinations of foods ( Jacobs Jr et al., 2009). WHO recommendations on a healthy diet (http://www.who.int/en/news-room/fact-sheets/detail/healthy-diet) For adults, the WHO guidelines recommend the following. A healthy diet contains: • Fruits, vegetables, legumes (e.g. lentils, beans), nuts and whole grains (e.g. unprocessed maize, millet, oats, wheat, brown rice). • At least 400 g (five portions) of fruits and vegetables a day. Potatoes, sweet potatoes, cassava and other starchy roots are not classified as fruits or vegetables. • Less than 10% of total energy intake from free sugars which is equivalent to 50 g (or around 12 level teaspoons) for a person of healthy body weight consuming approximately 2000 calories per day, but ideally less than 5% of total energy intake for additional health benefits. Most free sugars are added to foods or drinks by the manufacturer, cook or consumer, and can also be found in sugars naturally present in honey, syrups, fruit juices and fruit juice concentrates. • Less than 30% of total energy intake from fats. Unsaturated fats (found in fish, avocado, nuts, sunflower, canola and olive oils) are preferable to saturated fats (found in fatty meat, butter, palm and coconut oil, cream, cheese, ghee and lard) and trans-fats of all kinds, including both industrially produced trans-fats (found in processed food, fast food, snack food, fried food, frozen pizza, pies, cookies, biscuits, wafers, margarines and spreads) and ruminant trans-fats (found in meat and dairy foods from ruminant animals, such as cows, sheep, goats, camels and others). It is suggested to reduce the intake of saturated fats to less than 10% of total energy intake and trans-fats to less than 1% of total energy intake. In particular, industrially produced trans-fats are not part of a healthy diet and should be avoided. • Less than 5 g of salt (equivalent to approximately 1 teaspoon) per day and use iodized salt. 21Evidence and recommendations Regarding nutritional interventions, such as dietary supplements or healthy dietary patterns (e.g. the Mediterranean diet) compared with usual care or no intervention, six systematic reviews were identified for nine different nutritional interventions. These interventions were: 1. Multi-supplement complexes versus placebo in adults with normal cognition (D’Cunha et al., 2018). 2. Multi-supplement complexes versus placebo in adults with MCI (Fitzpatrick-Lewis et al., 2015). 3. PUFA versus placebo (Forbes et al., 2015). 4. Vitamin B versus placebo (Forbes et al., 2015). 5. Vitamin E versus placebo (Forbes et al., 2015). 6. Polyphenols versus placebo (Solfrizzi et al., 2018). 7. Protein supplementation versus placebo (Solfrizzi et al., 2018). 8. Chicken essence versus placebo (Teoh et al., 2016). 9. Mediterranean diet versus alternate or usual diet (Radd-Vagenas et al., 2018). The outcomes of incident MCI and dementia were only reported for interventions involving multi- supplement complexes in adults with normal cognition and the Mediterranean diet (D’Cunha et al., 2018; Radd-Vagenas et al., 2018). However, neither of these interventions showed a direct effect in reducing the incidence of dementia and/or MCI. All of the interventions/comparisons reported cognitive outcomes. There was moderate quality evidence that the Mediterranean diet can improve verbal and visual memory (Radd-Vagenas et al., 2018). A meta-analysis showed results that approached significance for global cognition and consistently positive, but non-significant, results were reported for all other cognitive outcomes (attention, working memory, processing speed, language and executive function) (Radd-Vagenas et al., 2018). A consistent positive effect of polyphenols on cognitive performance was also found, however, the quality of the evidence was low (Solfrizzi et al., 2018). Similarly, protein supplementations were found to have a beneficial effect on cognition in older adults, but the results were inconsistent and the quality of the evidence was low (Solfrizzi et al., 2018). Overall, no effects were found for multi-complex (D’Cunha et al., 2018; Fitzpatrick-Lewis et al., 2015), vitamins B and E (Forbes et al., 2015), and PUFA supplementation (Forbes et al., 2015). Low-quality evidence was reported for protein and polyphenols supplementation (Solfrizzi et al., 2018), and moderate evidence of a beneficial effect of the Mediterranean diet was found (Radd-Vagenas et al., 2018). Three multi-supplement complex interventions: docosahexaenoic acid (DHA) + eicosapentaenoic acid (EPA) + vitamin E + soy phospholipids + tryptophan + melatonin; vitamin E + multivitamin; lyophilized royal jelly + gingko biloba + Panax ginseng; were examined and none showed an increased risk of any serious adverse event during the follow-up period (moderate quality evidence, Fitzpatrick-Lewis et al., 2015). The GDG concluded that the benefits of a Mediterranean diet and a balanced diet outweighed the harms and provided conditional and strong recommendations respectively. The GDG noted that vitamin E and protein supplementation at high doses have been associated with undesirable non- anticipated effects that outweigh the benefits and recommended against their use. 22 Risk reduction of cognitive decline and dementia: WHO guidelines Population: Adults with normal cognition or MCI and excessive use of alcohol Intervention: • Behavioural and psychological interventions to treat alcohol use disorders (e.g. motivational interviewing) • Pharmacological interventions to treat alcohol use disorders Comparison: Care as usual or no intervention Outcomes: • Critical – Cognitive function – Incident MCI – Dementia • Important – Quality of life – Functional level (ADL, IADL) – Adverse events – Drop-out rates For adults with normal cognition or MCI and alcohol use disorders, are behavioural and psychological interventions to treat alcohol use disorders more effective than usual care or no intervention in reducing the risk of cognitive decline and/or dementia? 3.4 INTERVENTIONS FOR ALCOHOL USE DISORDERS BACKGROUND Excessive alcohol consumption is common in many countries (Gell et al., 2015). In 2012, 5.9% of all deaths worldwide (about 3.3 million) were directly attributable to harmful use of alcohol (WHO, 2014). Furthermore, excessive consumption of alcohol is one of the leading causes of general disability globally (WHO, 2014), being a direct cause in more than 200 diseases including risk factors for dementia and injury conditions (WHO, 1992; WHO 2019a). There is extensive evidence on excessive alcohol as a risk factor for dementia and cognitive decline (Langballe et al., 2015; Sachdeva et al., 2016; Zhou et al., 2014). Several approaches have been applied in interventions aimed at hazardous and harmful use of alcohol. Pharmacological therapies with different types of drugs (e.g. opioid antagonists, ALDH2 inhibitors) have shown various degrees of efficacy for adults with alcohol use disorders, although none of them showed to be superior in comparison trials. Behaviour and psychological interventions have shown to be effective in alcohol use disorders, and especially among those with hazardous and harmful drinking. Screening and brief intervention in primary care is one of the most cost-effective means of reducing alcohol-attributable morbidity and deaths (Kaner, 2018). Interventions for alcohol use disorders have been described in the mhGAP Intervention guide - Version 2.0 for mental, neurological and substance use disorders in non-specialized health settings (http://www.who.int/mental_health/mhgap/mhGAP_ intervention_guide_02/en/). 23Evidence and recommendations RECOMMENDATIONS AND CONSIDERATIONS RECOMMENDATION Interventions aimed at reducing or ceasing hazardous and harmful drinking should be offered to adults with normal cognition and MCI to reduce the risk of cognitive decline and/or dementia in addition to other health benefits. Quality of evidence: moderate (for observational evidence) Strength of the recommendation: conditional WHO mhGAP Intervention guide - Version 2 for mental, neurological and substance use disorders in non-specialized health settings (http://www.who.int/mental_health/mhgap/mhGAP_intervention_guide_02/en/) The WHO mhGAP Intervention guide recommends the following: Harmful use of alcohol • Provide psychoeducation and emphasize that the level/pattern of alcohol use is causing harm to health. • Explore the person’s motivations for alcohol use. Conduct motivational interviewing. • Advise stopping alcohol completely or consuming at a non-harmful level (if a non-harmful level exists) and indicate your intention in supporting the person in doing so. Ask the person if they are ready to try to make this change. • Explore strategies for reducing or stopping use and strategies for reducing harm. • Address food, housing and employment needs. • Offer regular follow-up. Alcohol dependence • Thiamine during alcohol use. • Diazepam during alcohol detoxification to treat withdrawal symptoms. • Naltrexone, acamprosate or disulfiram to prevent relapse after detoxification. • Psychosocial interventions if available, e.g. cognitive behaviour therapy, motivational enhancement therapy, contingency management therapy, family counselling or therapy, problem-solving counselling or therapy; self-help groups. 24 Risk reduction of cognitive decline and dementia: WHO guidelines Additional considerations include: • Interventions can be based on lifestyle/ behavioural changes or pharmacological treatments in accordance with the WHO mhGAP guidelines. Lifestyle behavioural interventions are likely to be more acceptable and have fewer adverse events. • A U-shaped relationship between alcohol consumption and cognitive function has been reported. However, due to methodological limitations in most studies that describe this effect, it is not possible to assume that a light to moderate consumption of alcohol is, in fact, protective toward dementia and/or cognitive decline. This, in addition to other health risks and the social and economic burden associated with alcohol, do not favour a general recommendation of its use. • Individual level interventions should be provided in the context of WHO Global strategy to reduce harmful use of alcohol (WHO 2010) and population level interventions, through strengthening restrictions on alcohol availability, enforcing drink driving countermeasures, facilitating access to screening, brief interventions, and treatment, enforcing bans or comprehensive restrictions on alcohol advertising, sponsorship, and promotion, raising prices on alcohol through excise taxes and pricing policies. SUPPORTING EVIDENCE AND RATIONALE No systematic reviews were identified for interventions for hazardous and harmful alcohol consumption (behavioural, psychological and pharmacological interventions) and reduced the risk of cognitive decline and/or dementia. However, a large body of observational evidence is available on alcohol as a risk factor for cognitive decline and dementia (Beydoun et al., 2014; Hersi et al., 2017; Ilomaki et al., 2015; Lafortune et al., 2016; Piazza-Gardner et al., 2013; Xu et al., 2017). Generally, single studies did not always show similar results (mostly due to differences in study design) but the most consistent pattern is that of a U-shaped relationship between alcohol consumption and dementia and/or cognitive impairment, which clearly links excessive alcohol consumption to a significantly increased risk (Xu et al., 2017). A range of adverse events has also been reported for pharmacological interventions aimed at reducing excessive alcohol consumption while lifestyle interventions are mostly based on behavioural interventions and no evidence of adverse events (apart from those related to withdrawal syndrome) have been identified (NICE, 2011). Overall, the GDG concluded that the benefits outweighed the harms and, based on the strong observational evidence, made a conditional recommendation for interventions to reduce or cease hazardous and harmful alcohol use. 25Evidence and recommendations Population: Adults with normal cognition or MCI Intervention: • Cognitive stimulation • Cognitive training Comparison: Care as usual or no intervention Outcomes: • Critical – Cognitive function – Incident MCI – Dementia • Important – Quality of life – Functional level (ADL, IADL) – Adverse events – Drop-out rates For adults with normal cognition or MCI is cognitive stimulation or cognitive training more effective than usual care or no intervention in reducing the risk of cognitive decline and/or dementia? 3.5 COGNITIVE INTERVENTIONS BACKGROUND Dementia is preceded by cognitive decline. However, not everyone who is exposed to dementia risk factors will go on to develop cognitive impairment. The concept of cognitive reserve has been proposed as a protective factor that may reduce the risk of clinical onset of dementia and cognitive decline (Stern, 2012). Cognitive reserve refers to the brain’s ability to cope with or compensate for neuropathology or damage (Stern, 2012). Studies have shown that increased cognitive activity may stimulate (or increase) cognitive reserve and have a buffering effect against rapid cognitive decline (Stern & Munn, 2010) as well as a significant reduction in the risk of MCI or AD diagnosis in those who reported high compared with low levels of cognitive activities (combined OR = 0.38, 95% CI: 0.15–0.99) (Sattler, 2012). Increased cognitive activity can be achieved through cognitive stimulation therapy and/or cognitive training. Cognitive stimulation therapy refers to “participation in a range of activities aimed at improving cognitive and social functioning” (Clare & Woods, 2004), while cognitive training refers to “guided practice of specific standardized tasks designed to enhance particular cognitive functions” (Clare & Woods, 2004). The NIA (United States of America) identified cognitive training as an intervention aimed at preventing or delaying the onset of age-related cognitive decline, MCI, or clinical Alzheimer’s-type dementia (Kane et al., 2017). Additionally, the WHO ICOPE guidelines (http://www. who.int/ageing/publications/guidelines-icope/en/) recommend cognitive stimulation for older adults with cognitive impairment. These interventions were assessed against outcomes that were judged as critical and important for this population. 26 Risk reduction of cognitive decline and dementia: WHO guidelines SUPPORTING EVIDENCE AND RATIONALE For cognitive stimulation versus usual care or no intervention in healthy older adults, evidence was extracted from one systematic review (Strout et al., 2016). No evidence for adults with MCI was available. The review reported that half of the interventions evaluated proved to be effective in improving cognitive outcomes in at least one cognitive domain – executive function, attention, memory, language and/or processing speed (Strout et al., 2016). The quality of the evidence was low. The results were reported in narrative form and no meta-analysis was conducted. No evidence for incident MCI or dementia was available. For cognitive training versus usual care or no intervention in healthy older adults, evidence was extracted from one systematic review (Chiu et al., 2017). The review conducted a meta-analysis which showed that cognitive training in healthy older adults has a moderate positive effect on overall cognitive functioning. The quality of evidence was low. No evidence for incident MCI or dementia was available. For cognitive training versus usual care or no intervention in adults with MCI, evidence was extracted from two systematic reviews (Chandler et al., 2016; Sherman et al., 2017). With regards to cognitive function outcome, the quality of evidence is low showing that cognitive training in adults with MCI has a small positive effect on cognition. With regards to incident dementia outcome, the quality of evidence is very low as the results were narratively reported. It was reported that one study found that half of the control group, but none of the intervention group, developed dementia at the 8-month follow-up, while another found that more of the intervention group reported incident dementia at the 2-year follow-up (Chandler et al., 2016). With regards to quality of life and functional level, the quality of evidence is low showing that cognitive training in adults with MCI has a small positive effect on ADL but not quality of life. The evidence for cognitive interventions is mainly in studies with older adults. The GDG concluded that in this population the desirable effects of the intervention outweighed the undesirable effects and provided a conditional recommendation for cognitive training. The evidence for cognitive stimulation in reducing the risk of dementia was insufficient and no recommendation was made by the GDG. RECOMMENDATIONS AND CONSIDERATIONS RECOMMENDATION: Cognitive training may be offered to older adults with normal cognition and with MCI to reduce the risk of cognitive decline and/or dementia. Quality of evidence: very low to low Strength of the recommendation: conditional 27Evidence and recommendations Population: Adults with normal cognition or MCI Intervention: Comparison: Care as usual or no intervention Outcomes: • Critical – Cognitive function – Incident MCI – Dementia • Important – Quality of life – Functional level (ADL, IADL) – Adverse events – Drop-out rates For adults with normal cognition or MCI is preserving and promoting a high level of social activity more effective than usual care or no intervention in reducing the risk of cognitive decline and/or dementia? 3.6 SOCIAL ACTIVITY BACKGROUND Social engagement is an important predictor of well- being throughout life (Cherry et al., 2011). Social disengagement conversely, has been shown to place older individuals at increased risk of cognitive impairment and dementia (Fratiglioni et al., 2004). A systematic review and meta-analysis of longitudinal cohort studies showed that lower social participation, less frequent social contact and loneliness were associated with higher rates of incident dementia (Kuiper et al., 2015). The Lancet Commission on Dementia Prevention, Intervention, and Care identified social engagement as an intervention that could be used to prevent dementia (Livingston et al., 2017). RECOMMENDATIONS AND CONSIDERATIONS There is insufficient evidence for social activity and reduction of risk of cognitive decline/dementia. Social participation and social support are strongly connected to good health and well-being throughout life and social inclusion should be supported over the life-course. (Global age-friendly cities: a guide, http://www.who.int/ageing/publications/Global_age_friendly_ cities_Guide_English.pdf) 28 Risk reduction of cognitive decline and dementia: WHO guidelines SUPPORTING EVIDENCE AND RATIONALE For preservation and promotion of social activity including community and family engagement versus care as usual or no intervention, evidence was extracted from one systematic review examining adults with normal cognition (Kelly et al., 2017). No evidence for adults with MCI was available. For cognitive function outcomes, the quality of the evidence is very low. Three RCTs, which assessed the association between cognitive function and social activity, were deemed eligible. The review findings were reported narratively (Kelly et al., 2017). Overall cognition was measured by varied composite measures of global cognition, including the ADAS-cog, MMSE and MDRS. One of the three RCTs found social activity intervention to be significantly associated with improvements in cognitive function (Pitkala et al., 2011). No data were available for incident MCI or dementia, quality of life, functional level (ADL, IADL), adverse events or drop-outs. The GDG concluded that the evidence is limited and inconclusive, so no recommendation was made for social activity and risk of cognitive decline/dementia. Furthermore, there is a risk of bias arising from reverse causality whereby low social engagement prior to diagnosis of cognitive decline or dementia may be at least in part due to the disease process. The GDG did not make a recommendation against social activity as they concluded that social activity has a wide range of other benefits to health and well-being. 29Evidence and recommendations Population: Adults with normal cognition or MCI who are overweight or obese Intervention: Weight management • Non-pharmacological interventions, e.g. cognitive behavioural intervention strategies, lifestyle interventions • Pharmacological interventions, e.g. weight loss medication (e.g. orlistat) Comparison: Care as usual or no intervention Outcomes: • Critical – Cognitive function – Incident MCI – Dementia • Important – Quality of life – Functional level (ADL, IADL) – Adverse events – Drop-out rates For adults with normal cognition or MCI who are overweight or obese, are interventions for weight reduction (or control of obesity) more effective than usual care or no intervention in reducing the risk of cognitive decline and/or dementia? 3.7 WEIGHT MANAGEMENT BACKGROUND Overweight and obesity are some of the best characterized and established risks for a variety of NCDs, responsible for at least 2.8 million deaths each year worldwide, and of an estimated 35.8 million (2.3%) of global disability-adjusted life years (DALYs) (WHO, 2019b). In 2008, 35% of adults aged 20+ were overweight (BMI ≥ 25 kg/m2) (34% men and 35% of women), with significantly variable prevalence among world areas, with the United States of America, Europe and the Eastern Mediterranean regions with the highest concentration of people with overweight/ obesity (WHO, 2019b). Overweight and obesity, in particular, have been linked to a number of medical complications such as Type 2 diabetes (Chan et al., 1994), cancer (Renehan et al., 2015), premature mortality (Fontana & Hu, 2014), and CVD (Eckel, 1997), both as direct risk factors as well as risks for other cardiovascular risk factors, such as high cholesterol and hypertension. Obesity has been steadily rising, particularly among older adults in the last few decades (Nguyen & El-Serag, 2010) and although an increasing body of evidence suggests that overweight (25 < BMI < 30) in older adults could be more protective than normal weight in terms of overall mortality (Flicker et al., 2010), a link has also been established between excess of fat body mass and cognitive impairment (Xu et al., 2011). A recent systematic review and meta-analysis of observational studies conducted on a total of about 600 000 individuals showed that obesity (but not overweight) at mid-life increases the risk of dementia (RR = 1.33; 95% CI: 1.08–1.63) (Albanese et al., 2017). It has been suggested that weight loss could indirectly reduce the risk of dementia by improving a variety of metabolic factors linked with the pathogenesis of cognitive impairment and dementia (i.e. glucose 30 Risk reduction of cognitive decline and dementia: WHO guidelines tolerance, insulin sensitivity, blood pressure, oxidative stress, and inflammation) (Bennett et al., 2009). However, a direct beneficial effect of weight reduction intervention is also plausible. Although, so far, evidence of potential cognitive benefits of weight loss seem to be strongly associated with increased physical activity (Colcombe et al., 2006; Erickson et al., 2010), in 2011 a systematic review concluded that intentional weight loss can improve performance in some cognitive domains, at least in people with obesity (Siervo et al., 2011). Additional considerations include: • Lifestyle interventions that included both diet and physical activity components seemed to show the best results. • In addition to interventions at individual level, lifestyle interventions at the population level, such as activity parks, green spaces and infrastructure to support active commuting, need to be considered. • Being underweight in both late-mid-life and old age might be associated with a higher risk of dementia. However, it is likely that this association is explained, at least in part, by reverse causality, whereby brain pathology may cause weight loss before the clinical onset of dementia. • Unintentional weight loss and malnutrition are associated with poor health outcomes and should be investigated and treated at all ages. However, it is unlikely that interventions that favour weight gain in people who are underweight in either mid- or late life can reduce the risk of dementia or cognitive impairment. RECOMMENDATION: Interventions for mid-life overweight and/or obesity may be offered to reduce the risk of cognitive decline and/or dementia. Quality of evidence: low to moderate Strength of the recommendation: conditional WHO guidance on overweight and obesity outlined in Prevention and control of noncommunicable diseases: guidelines for primary health care in low-resource settings (2012) (http://www.who.int/nmh/publications/phc2012/en/) WHO guidance on overweight and obesity should be followed. • Advise overweight patients to reduce weight by following a balanced diet. • Advise patients to give preference to low glycaemic-index foods (beans, lentils, oats and unsweetened fruit) as the source of carbohydrates in their diet. • Advise patients to reduce sedentary behaviour and practise regular daily physical activity appropriate for their physical capabilities (e.g. walking). RECOMMENDATIONS AND CONSIDERATIONS 31Evidence and recommendations SUPPORTING EVIDENCE AND RATIONALE For weight reduction with behavioural and/or lifestyle interventions (or control of obesity) compared with usual care or no intervention, evidence was extracted from one systematic review examining adults with normal cognition who are overweight or obese (Veronese et al., 2017). No evidence for adults with MCI was available. There was low to moderate evidence that lifestyle interventions aimed at weight reduction could improve cognitive function in the attention, memory and language domains. Interventions were very short (ranging from 8 to 48 weeks). No data were found in relation to incident MCI and dementia outcomes. No evidence of adverse events was identified. For pharmacological interventions for weight reduction (or control of obesity) compared with usual care or no intervention, no systematic reviews were found. The GDG concluded that the benefits of the interventions outweighed the harms and provided a conditional recommendation. Since the observational evidence of a correlation between overweight/obesity and increased risk of dementia is stronger and more consistent in mid-life than in late life (Hersi et al., 2017; Lafortune et al., 2016; Pedditzi et al., 2016; Prickett et al., 2015; Xu et al., 2015), the GDG made a conditional recommendation for this population. 32 Risk reduction of cognitive decline and dementia: WHO guidelines Population: Adults with normal cognition or MCI with hypertension Intervention: Antihypertensive medication, lifestyle interventions Comparison: Placebo/no intervention Outcomes: • Critical – Cognitive function – Incident MCI – Dementia • Important – Quality of life – Functional level (ADL, IADL) – Adverse events – Drop-out rates For adults with normal cognition or MCI and hypertension, is treatment of hypertension more effective than placebo/no intervention in reducing the risk of cognitive decline/dementia? 3.8 MANAGEMENT OF HYPERTENSION BACKGROUND Hypertension in mid-life has been associated with an increased risk of late life dementia (Kivipelto et al., 2001). In particular, a pattern of increased blood pressure during mid-life followed by a rapid decrease in blood pressure later in life has been found in individuals who go on to develop dementia (Kivipelto et al., 2001; Launer et al., 2000; Stewart et al., 2009). There is mixed evidence relating to the reduction of blood pressure in late mid- or late life and subsequent cognitive decline or dementia, however, there is evidence to show that the reduction of hypertension can have substantial benefits in reducing cardiovascular morbidity and mortality and thus improving overall health of the ageing population (Musini et al., 2009). Hypertension can be prevented through a range of lifestyle factors, including eating a healthy diet, maintaining a healthy weight and participating in an adequate amount of physical activity. It can also be controlled through antihypertensive medication. However, the evidence for the effectiveness of blood pressure lowering treatments in reducing the risk of cognitive decline and dementia risk is mixed. RECOMMENDATION 1: Management of hypertension should be offered to adults with hypertension according to existing WHO guidelines. Quality of evidence: low to high (for different interventions) Strength of the recommendation: strong RECOMMENDATIONS AND CONSIDERATIONS 33Evidence and recommendations HEARTS Technical package for cardiovascular disease management in primary health care: evidence-based treatment protocols (http://apps.who.int/iris/bitstream/handle/10665/260421/WHO-NMH-NVI-18.2-eng.pdf?sequence=1) Medications used to treat hypertension • There are four main classes of antihypertensive medications: angiotensin converting enzyme (ACE) inhibitors; angiotensin receptor blockers (ARB); calcium channel blockers (CCB); and thiazide and thiazide-like diuretics. Any of these four classes of antihypertensive medication may be used unless there are specific contraindications. Proper treatment of hypertension usually requires a combination of hypertension medications. Notes on specific hypertension medications • Pregnant women and women of childbearing age not on effective contraception should not be given ACE inhibitors, ARBs or thiazide/thiazide-like diuretics; CCBs should be used. If not controlled with intensification dose of medication, refer to specialist. • Beta blockers are not recommended as first-line therapy. If a heart attack has been diagnosed within the previous three years, or there is atrial fibrillation or heart failure, then a beta blocker should be added to the starting dose of antihypertensive medication. Patients with angina may also benefit from treatment with a beta blocker. Other treatment considerations • If there is a prior heart attack or stroke, or the person is otherwise at high risk of CVD, start a statin at the same time as starting antihypertensive medication. (Statins should not be used in women who are or who may become pregnant.) • If there is a prior heart attack or ischemic stroke, start low-dose aspirin. • The hypertension protocols included in this module serve well for initiation and maintenance of successful treatment. If there are serious adverse events, lack of control of blood pressure, or if a major medical event intervenes, then referral to a specialist will be needed. • If the patient is already on another medication regimen, blood pressure is controlled to the target level, and the medications the patient is taking are accessible and affordable, there is no reason to change the regimen. • If the patient feels faint on standing, check blood pressure while standing. If the systolic blood pressure is consistently less than 110 mm Hg in a patient on medical treatment, consider reducing the dosage or number of medications used. RECOMMENDATION 2: Management of hypertension may be offered to adults with hypertension to reduce the risk of cognitive decline and/or dementia. Quality of evidence: very low (in relation to dementia outcomes) Strength of the recommendation: conditional 34 Risk reduction of cognitive decline and dementia: WHO guidelines SUPPORTING EVIDENCE AND RATIONALE For treatment of hypertension in the form of antihypertensive medication versus placebo or no intervention, evidence was extracted from two systematic reviews examining adults with normal cognition and hypertension (Parsons et al., 2016; Weiss et al., 2016). No evidence for adults with MCI was available. With regard to cognitive function and incident dementia outcomes, the quality of the evidence was low, which showed that antihypertensive therapy has no effect on cognitive decline or incidence of dementia. With regard to quality of life and functional level outcomes, the quality of evidence is very low, showing that antihypertensive therapy does not decrease quality of life or functional level. With regard to adverse events, the quality of evidence was very low, showing mixed findings with regard to antihypertensive use. There were no data on incident MCI and overall drop- out rates. Initial results from the SPRINT-MIND trial, a substudy of the Systolic Blood Pressure Intervention Trial (SPRINT) that aims to evaluate the effect of intensive blood pressure control on risk of dementia, support the possibility of a dose-response relationship between blood pressure and risk of cognitive decline or dementia (SPRINT-MIND 2019). Observational evidence suggests a strong association between hypertension and incident cognitive decline/dementia. For treatment of hypertension in the form of lifestyle interventions versus placebo or no intervention, no systematic reviews were found. The GDG made a strong recommendation for management of hypertension for its established health benefits and a conditional recommendation for hypertension management for reducing the risk of cognitive decline/dementia. The GDG concluded that though there is limited clinical trial evidence that treatment of hypertension reduces the risk of cognitive decline or dementia, the benefits outweighed the harms since the evidence suggests that intervention does not lower quality of life or functional level and there are mixed results regarding adverse effects which may depend on the drug used. Additionally, robust evidence for a causal relationship is available. 35Evidence and recommendations Population: Adults with normal cognition or MCI with diabetes mellitus Intervention: • Medications for glycaemic control • Diet and lifestyle interventions Comparison: Placebo/no intervention Outcomes: • Critical – Cognitive function – Incident MCI – Dementia • Important – Quality of life – Functional level (ADL, IADL) – Adverse events – Drop-out rates For adults with normal cognition or MCI and diabetes mellitus, is treatment of diabetes more effective than placebo/no intervention in reducing the risk of cognitive decline and/or dementia? 3.9 MANAGEMENT OF DIABETES BACKGROUND The presence of late life diabetes has been linked to an increased risk of dementia (Luchsinger, 2010; Prince et al., 2014; Profenno et al., 2010). However, the mechanism by which this occurs is unclear. Poor glucose control has been associated with lower cognitive functioning and greater cognitive decline (Yaffe et al., 2012). In addition, the complications associated with diabetes, such as nephropathy (kidney damage), retinopathy (eye damage), hearing impair- ment and CVD, have all been found to increase the risk of dementia (Bruce et al., 2014; Exalto et al., 2013). The literature examining interventions that aim to improve glycaemic control shows mixed findings with regard to cognitive outcomes (Launer et al., 2011; Luchsinger et al., 2011). In addition, the evidence on the effectiveness of medication for diabetes in reducing dementia risk is inconsistent (Cheng et al., 2014; Moore et al., 2013; Parikh et al., 2011). There is some evidence to suggest that treating the cardiovascular comor- bidities associated with diabetes, such as high choles- terol and hypertension, may mediate the risk for dementia (Johnson et al., 2012; Parikh et al., 2011). 36 Risk reduction of cognitive decline and dementia: WHO guidelines RECOMMENDATION 1: Management of diabetes in the form of medications and/or lifestyle interventions should be offered to adults with diabetes according to existing WHO guidelines. Quality of evidence: very low to moderate (for different interventions) Strength of the recommendation: strong RECOMMENDATION 2: Management of diabetes may be offered to adults with diabetes to reduce the risk of cognitive decline and/or dementia. Quality of evidence: very low Strength of the recommendation: conditional Package of essential noncommunicable (PEN) disease interventions for primary health care in low-resource settings (https://www.who.int/cardiovascular_diseases/publications/pen2010/en/). For individuals with diabetes, the WHO guidelines recommend the following treatments: Type 1 diabetes • Daily insulin injections (Level 1). Type 2 diabetes • Oral hypoglycaemic agents for Type 2 diabetes, if glycaemic targets are not achieved with modification of diet, maintenance of a healthy body weight and regular physical activity (Level 1). • Metformin as initial drug in overweight patients (Level 1) and non-overweight (Level 4). • Other classes of antihyperglycaemic agents, added to metformin if glycaemic targets are not met (Level 3). • Reduction of cardiovascular risk for those with diabetes and 10-year cardiovascular risk > 20% with aspirin, angiotensin converting enzyme inhibitor and statins (Level 1). RECOMMENDATIONS AND CONSIDERATIONS 37Evidence and recommendations SUPPORTING EVIDENCE AND RATIONALE For treatment of diabetes in the form of medications for glycaemic control versus placebo or no intervention, evidence was extracted from one systematic review examining adults with normal cognition and Type 2 diabetes (Areosa Sastre et al., 2017). No evidence for adults with MCI was available. The quality of the evidence was moderate for cognitive function outcomes and very low for incident dementia outcomes, which showed intensive as opposed to standard glycaemic control has an unclear effect on cognitive function and no effect on incident dementia. The evidence reviewed included data from a large study set across 215 collaborating centres in 20 countries in Asia, Australasia, Europe and North America. The quality of evidence for adverse events was very low, showing intensive glycaemic control increases the risk of hypoglycaemic events. No data on incident MCI, quality of life, functional outcomes or drop-out rates were available. Overall, in adults with normal cognition, the evidence may favour standard glycaemic control because intense glycaemic control has no effect on cognitive function but may result in increased episodes of hypoglycaemia. For treatment of diabetes in the form of diet and life- style interventions versus placebo or no intervention, evidence was extracted from one systematic review examining adults with normal cognition and Type 2 diabetes (Podolski et al., 2017). No evidence for adults with MCI was available. The quality of evidence was very low and the findings were mixed. No meta- analysis was conducted and there were no robust data on clinical significance. The GDG made a strong recommendation for management of diabetes for its established health benefits and a conditional recommendation for diabetes management for reducing the risk of cognitive decline/dementia. The GDG concluded that though there is limited clinical trial evidence on the management of diabetes to reduce the risk of cognitive decline or dementia, the benefits outweighed the harms and there is robust observational evidence to suggest diabetes increases the risk of cognitive decline and dementia. 38 Risk reduction of cognitive decline and dementia: WHO guidelines Population: Adults with normal cognition or MCI with dyslipidaemia Intervention: • Statins (e.g. simvastatin and pravastatin) • Lifestyle interventions Comparison: Placebo or no intervention Outcomes: • Critical – Cognitive function – Incident MCI – Dementia • Important – Quality of life – Functional level (ADL, IADL) – Adverse events – Drop-out rates For adults with normal cognition or mild cognitive impairment and dyslipidaemia, is treatment of dyslipidaemia more effective than placebo or no intervention in reducing the risk of cognitive decline and/or dementia? 3.10 MANAGEMENT OF DYSLIPIDAEMIA BACKGROUND Elevated serum cholesterol is one of the key modifiable cardiovascular risk factors. A third of ischaemic heart disease worldwide is attributable to dyslipidaemia and it is estimated to be the cause of 2.6 million deaths (4.5% of total) per year, as well as a considerable proportion of disability (WHO, 2019b). The prevalence of raised total cholesterol among countries seems to correlate with wealth: in high-income countries, more than 50% of adults have elevated total cholesterol level, more than double the rate in low-income countries (WHO, 2019c). The idea that raised level of blood cholesterol could be related to an increased risk of dementia was already introduced in the mid-1970s (Richardson et al., 2000). Since then, a number of epidemiological studies have demonstrated a close relationship between high serum cholesterol levels and the onset of AD/dementia (Kivipelto et al., 2002; Solomon et al., 2007; Whitmer et al., 2005), but results have been inconsistent, with other studies showing no or negative correlation (Mainous et al., 2005; Mielke et al., 2005). Based on the severity of the dyslipidaemia and CVD overall risk, lifestyle or pharmacological approaches can be undertaken to reduce blood cholesterol. Weight reduction and decreasing saturated fats in the diet (decreasing the consumption of food of animal origin) are the most common and effective lifestyle recommen- dations (Perk et al., 2012). However, dyslipidaemia is often controlled and managed pharmacologically, with statins being the drugs of first choice. Several observational studies have investigated the possible beneficial effect of statins therapy in preventing dementia, but bias and heterogeneity hampered the overall quality of the evidence (Song et al., 2013; Swiger et al., 2013; Wong et al., 2013). Recently, a re-analysis of statin use in AD patients from failed clinical trials suggested that the use of simvastatin may slow the progression of cognitive decline in some people (Geifman et al., 2017). 39Evidence and recommendations RECOMMENDATIONS AND CONSIDERATIONS RECOMMENDATION: Management of dyslipidaemia at mid-life may be offered to reduce the risk of cognitive decline and dementia. Quality of evidence: low Strength of the recommendation: conditional Additional considerations include: • Statin treatment in older adults should not be specifically initiated for preventing cognitive decline and/or dementia but may be used for other health benefits according to WHO’s Prevention and control of noncommunicable diseases: guidelines for primary health care in low-resource settings (http://www.who.int/nmh/publications/phc2012/en/). SUPPORTING EVIDENCE AND RATIONALE For control of dyslipidaemia through treatment with statins compared with placebo, evidence was extracted from one systematic review examining adults with normal cognition and dyslipidaemia (McGuinness et al., 2016). No evidence for adults with MCI was available. The quality of the evidence was moderate for cognitive function outcomes and low for incident dementia outcomes, showing that treatment with statins has no effect on either incident dementia and/or cognitive decline. There is moderate quality evidence that the treatment with statins does not increase the incidence of serious adverse events. A large body of observational evidence has linked dyslipidaemia to an increased risk of dementia and/or cognitive decline and found an association between control of dyslipidaemia and reduction of dementia and/or cognitive decline risk (Geifman et al., 2017; Hersi et al., 2017; Reitz, 2013; Song et al., 2013). Overall, indirect evidence suggests that managing dyslipidaemia in mid-life can help reduce the risk of cognitive decline and/or dementia. No studies were identified that specifically aimed at controlling dyslipidaemia through lifestyle interventions and included outcomes related to dementia and/or cognitive impairment. The GDG concluded that the desirable effects of dyslipidaemia treatment outweigh the undesirable effects and made a conditional recommendation. The observational evidence reported a stronger correlation between high cholesterol and dementia in mid-life rather than late life (Hersi et al., 2017; Reitz, 2013). The systematic review evidence that focused on clinical trials in older adults (65+) showed that statin treatment has no effect on cognition or dementia outcomes (McGuinness et al., 2016). Therefore, the GDG concluded that there were no grounds to recommend the use of statin and the control of cholesterol in late life but only in mid-life. 40 Risk reduction of cognitive decline and dementia: WHO guidelines Population: Adults with normal cognition or MCI with moderate to severe depressive disorder Intervention: • Pharmacological interventions to treat depression (antidepressant medication) • Psychological interventions to treat depression (e.g. cognitive behavioural therapy, problem-solving therapy, interpersonal therapy, behavioural activation) Comparison: Care as usual or placebo or no intervention Outcomes: • Critical – Cognitive function – Incident MCI – Dementia • Important – Quality of life – Functional level (ADL, IADL) – Adverse events – Drop-out rates For adults with normal cognition or mild cognitive impairment and depressive disorder, is treatment of depression more effective than usual care, placebo or no intervention in reducing the risk of cognitive decline and/or dementia? 3.11 MANAGEMENT OF DEPRESSION BACKGROUND There is a substantial body of evidence linking depression to cognitive decline and dementia. A review carried out as part of the World Alzheimer Report in 2014 combined 32 studies into a meta-analysis which looked at the effect of depression on the risk of incident dementia. This involved 62,568 participants with a median follow-up of 5 years (range 2 to 17). The review reported that the presence of depression nearly doubled the risk of dementia (pooled effect size = 1.97, 95% CI: 1.67–2.32) (Prince et al., 2014). The authors also carried out a meta-regression looking at follow-up time. They reported a trend toward smaller effect sizes in studies with longer follow-up suggesting that depression may have a prodromal role in dementia. It is noteworthy to mention that cognitive impairment may be the main symptom of depression in the elderly; a phenomenon that used to be called pseudodementia. There are several potential explanations for the link between depression and cognitive impairment or dementia. Some of these include associations between depression, noradrenergic changes and white matter lesions, depression which stems from insight into impairment at early stages of decline, depression highlighting underlying deficits, i.e. by reducing motivation and bringing its own cognitive deficits (Camus et al., 2004; Jorm, 2001; Kales et al., 2005; Schweitzer et al., 2002). 41Evidence and recommendations RECOMMENDATIONS AND CONSIDERATIONS There is currently insufficient evidence to recommend the use of antidepressant medicines for reducing the risk of cognitive decline and/or dementia. The management of depression, in the form of antidepressants and/or psychological interventions, should be provided to adults with depression according to existing WHO mhGAP guidelines. WHO mhGAP Intervention guide - Version 2 for mental, neurological and substance use disorders in non-specialized health settings (https://www.who.int/mental_health/mhgap/mhGAP_intervention_guide_02/en/) For adults with moderate to severe depressive disorder, the WHO guidelines recommend the following treatments: Psychosocial/non-pharmacological treatment and advice • Psychoeducation (for the person and his or her family, as appropriate). • Addressing current psychosocial stressors. • Reactivate social networks. • Brief psychological treatments, if available. • Offer regular follow-up. Antidepressant medication • Select an antidepressant from the National or WHO Formulary. Selective serotonin reuptake inhibitors (fluoxetine) and tricyclic antidepressants (amitriptyline) are antidepressants mentioned in the WHO Formulary and are on the WHO model list of essential medicines. • In selecting an antidepressant, consider the symptom pattern of the person, the side-effect profile of the medication, and the efficacy of previous antidepressant treatments, if any. • For co-morbid medical conditions, before prescribing antidepressants, consider potential for drug-disease or drug-drug interaction. Consult the National or the WHO Formulary. • Combining antidepressants with other psychotropic medication requires supervision by, or consultation with a specialist. 42 Risk reduction of cognitive decline and dementia: WHO guidelines SUPPORTING EVIDENCE AND RATIONALE For pharmacological interventions to treat depression (antidepressant medication) compared with usual care or placebo, evidence was extracted from one systematic review examining adults with normal cognition and major depressive disorder (Baune et al., 2018). No evidence for adults with MCI was available. The review conducted a network meta-analysis and reported standardized mean differences in the Digit Symbol Substitution Test as a measure of cognition function. The review reported that vortioxetine (versus placebo) improved cognitive functioning while duloxetine, sertraline, citalopram, escitalopram, phenelzine and nortriptyline showed no effect (Baune et al., 2018). The quality of the evidence was very low and no data were reported for incident MCI or dementia outcomes, quality of life, adverse events, functional level or drop-out rates. Overall, the true balance of effects is difficult to ascertain. The evidence favours the use of vortioxetine (but not other pharmacological interventions) to treat depression for reducing the risk of cognitive decline or dementia. However, no data on adverse effects were available, e.g. drug-related side-effects or interactions. For psychological interventions to treat depression compared with placebo or no intervention, no relevant systematic reviews were found. The GDG therefore concluded that there was insufficient evidence currently for depression manage- ment and reduction of risk of cognitive decline/ dementia. They also concluded that the management of depression is important for its other benefits and did not make a negative recommendation against this intervention. 43Evidence and recommendations Population: Adults with normal cognition or MCI with hearing loss Intervention: Interventions to treat hearing loss (e.g. hearing aids) Comparison: Care as usual or no intervention Outcomes: • Critical – Cognitive function – Incident MCI – Dementia • Important – Quality of life – Functional level (ADL, IADL) – Adverse events – Drop-out rates For adults with normal cognition or MCI and hearing loss, is treatment of hearing loss more effective than usual care, or no intervention in reducing the risk of cognitive decline and/or dementia? 3.12 MANAGEMENT OF HEARING LOSS BACKGROUND Hearing loss is a prevalent age-related disorder. As the fourth leading cause of years lived with disability in the global population (WHO, 2012), it is estimated to affect one in three adults aged 65 and older, with this statistic growing annually (Wilson et al., 2017). The implications of hearing loss, however, are often underestimated both at the individual and population level (Blustein et al., 2018). Hearing impairment has debilitating consequences on functional ability and social and emotional well-being. Deteriorations in hearing impact on individuals’ ability to communicate with others, which in turn can result in feelings of frustration, isolation, loneliness (Ciorba et al., 2012). Older adult populations who already experience the isolating effects of age-related factors, such as diminished mobility, driving cessation, death of partners or living alone, are particularly vulnerable to these psychosocial impacts. Hearing loss is also associated with increased risk of cognitive decline or dementia (Lin et al., 2013). A recent meta-analysis of prospective cohort studies showed that the relative risk of hearing impairment on incident Alzheimer’s and MCI was 2.82 (95% CI: 1.47–5.42). (Zheng et al., 2017). Additionally, a meta-analysis published by the Lancet Commission showed that hearing loss can almost double the risk of incident dementia (RR = 1.94, 95% CI: 1.38–2.73) (Livingston et al., 2017). Hearing loss and cognitive impairment or dementia, individually, and in combination, predict functional ability and burden of care. Hearing loss interventions, therefore, have the potential to substantially improve outcomes for older people on multiple domains. 44 Risk reduction of cognitive decline and dementia: WHO guidelines WHO Guidelines on integrated care for older people (ICOPE) (http://www.who.int/ageing/publications/guidelines-icope/en/) For older adults, WHO recommends the following: Screening followed by provision of hearing aids should be offered to older people for timely identification and management of hearing loss. Considerations for recommendation: • Community awareness about hearing loss and the positive benefits of audiological rehabilitation in older people, through community case finding and outreach activities, should be promoted. • Health care professionals should be encouraged to screen older adults for hearing loss by periodically questioning them about their hearing. Audiological examination, otoscopic examination and the whispered voice test are also recommended. • Hearing aids are the treatment of choice for older people with hearing loss, because they minimize reduction in hearing and improve daily functioning. • Medications should be reviewed for potential ototoxicity. • People with chronic otitis media or sudden hearing loss, or who fail any screening tests, should be referred to an otolaryngologist. There is insufficient evidence to recommend use of hearing aids to reduce the risk of cognitive decline and/or dementia. Screening followed by provision of hearing aids should be offered to older people for timely identification and management of hearing loss as recommended in the WHO ICOPE guidelines. RECOMMENDATIONS AND CONSIDERATIONS 45Evidence and recommendations SUPPORTING EVIDENCE AND RATIONALE For interventions to treat hearing loss (e.g. hearing aids) versus care as usual or no intervention, evidence was extracted from one systematic review examining adults with normal cognition and hearing loss (Cherko et al., 2016). No evidence for adults with MCI was available. For cognitive function and quality of life, the quality of evidence is very low. No meta-analyses were performed and results were reported narratively with no numerical data to support conclusions (Cherko et al., 2016). Based on two studies including measures of cognitive function, the review concluded that while hearing aids use was found to be associated with improvements in cognitive function, these benefits may be limited in that cognitive improvements have been shown to revert to baseline at 1 year follow-up. They also concluded that use of hearing aids in older people was associated with improvements in quality of life outcomes based on two studies. Overall, the evidence does not favour either the intervention or the comparison. Hearing aids may improve quality of life but the amount of evidence available is limited. No data are available for incident MCI or dementia, functional level (ADL, IADL), adverse events or drop-outs. The GDG concluded that there is currently insufficient evidence to recommend the use of hearing aids to reduce the risk of cognitive decline/dementia. The GDG also concluded that the use of hearing aids is important to correct hearing loss in older adults for their other benefits and recommend following the ICOPE guidelines in this regard. 46 Risk reduction of cognitive decline and dementia: WHO guidelines IMPLEME NTATION CONSIDE R ATIONS 4 47 Implementation considerations Countries will be supported to implement the guidelines through training of health care personnel and using centres of excellence on improved quality of care. The implementation will also be supported locally through the adoption of the Global action plan on the public health response to dementia 2017– 2025; the Comprehensive mental health action plan 2013–2020; and the Global action plan for the prevention and control of noncommunicable diseases 2013–2020 at country level. The national capacity building process will also be supported through WHO collaboration with international organizations and associations. Given that many of the interventions included in these guidelines are strongly related to the management of risk factors for CVD and diabetes, the implementation of these recommendations should be combined, whenever possible and in the relevant target population, with the ongoing prevention programmes to reduce the risk of these conditions. The optimal preventive effect may be obtained by addressing several risk factors at the same time. Collaboration among different stake- holders and multidisciplinary approaches will also be needed. The recommendations contained in these guidelines should be adapted into a locally appropriate document that can meet the needs of each country and its health services. WHO headquarters will work closely with the regional and country offices, as well as implementing partners and public health agencies at the national level, to ensure communication and country-specific adaptations of the guidelines, through regional and national meetings. As countries consider how to implement these guidelines, the budgetary and human resource requirements, and other health systems implications should be analysed to identify which inputs and systems are currently available, and which areas require additional investment. These may include training of health workers, supply of medicines and adaptations of health information systems to collect data on service utilization. To support country implementation, WHO will produce a series of subsidiary tools that will address clinical and service delivery aspects of the imple- mentation of the recommendations included in these guidelines. 48 Risk reduction of cognitive decline and dementia: WHO guidelines PUBLIC ATION, DISSEMINATION AND EVALUATION 5 49Publication, dissemination and evaluation 5.1 PUBLICATION AND DISSEMINATION The guidelines will be disseminated as a print publication and electronically on a dedicated internet space on the WHO website. The guidelines will be disseminated through both the mental health and NCD dissemination activities of the Global action plan on the public health response to dementia 2017–2025 (such as the Global Dementia Observatory knowledge exchange platform), the Comprehensive mental health action plan 2013–2020 and the Global action plan for the prevention and control of noncommunicable diseases 2013–2020. These guidelines will be appended to the mhGAP guidelines and disseminated through the mhGAP evidence resource centre and other mhGAP derivative products, including the mhGAP Intervention guide. Since these guidelines are linked to other WHO guidelines such as NCD and ICOPE guidelines and other resources on ageing, dissemination will occur along with these guidelines. The guidelines and products are developed in English, and will be translated into other WHO official languages for wider dissemination and in collaboration with WHO regional offices. Local adaptation is necessary to ensure that the guidelines are appropriate for the local conditions that affect the care of people with cognitive decline and dementia in health facilities and the community. Adaptation will include language translation and ensuring that the interventions are acceptable in the specific socio-cultural context and suitable for the local health system. The ADAPTE manual for guideline adaptation outlines the approach to be used.12 The acceptability and applicability of the recommendations will be examined in the specific cultural context, including the availability of health services, expertise and resources, and the organization of health services, as well as population characteristics, cultural beliefs and value judgments. Relevant departments in ministries of health will be notified of the guidelines through WHO regional and country offices. A briefing package will be prepared for technical officers outside of WHO headquarters that will include an executive summary and Q&A related to policy and programme implications. Dissemination will also be encouraged through WHO collaboration with international organizations and associations. In coordination with WHO Communications, the media will be notified of the new guidelines. Countries will be supported to implement the guidelines through the training of health care personnel on improved quality of care and using centres of excellence. Capacity-building activities will be undertaken through web-based platforms and regional workshops. Dissemination will be supported by the publication of selected systematic reviews and evidence in peer review journals, and presentations and workshops at key conferences and events. 12 http://www.g-i-n.net/document-store/working-groups-documents/adaptation/adapte-resource-toolkit-guideline-adaptation-2-0.pdf 50 Risk reduction of cognitive decline and dementia: WHO guidelines 5.2 MONITORING AND EVALUATION Following publication of these guidelines, WHO will continue to collect regular feedback from implemen- tation activities in order to evaluate their usefulness and impact. Information will be used to evaluate the quality of the guidelines and to identify areas where improvement is required. WHO’s Global Dementia Observatory, an online data and knowledge exchange platform for dementia, provides the framework for monitoring implementation of these guidelines13. 5.3 IMPLICATIONS FOR FURTHER RESEARCH The majority of the recommendations align with current guidelines for the treatment of pre-existing health conditions and dependencies. However, more evidence is needed to determine what the impact of these interventions are on the outcomes of incident MCI or dementia. No recommendations could be made for social activity and hearing loss due to insufficient evidence. Some trials are currently being conducted for hearing loss interventions. These guidelines may need to be updated once these results are released. However, currently there is little research being conducted that examines the impact of social activity on cognitive decline and dementia. Part of the difficulty in conducting this type of research is that social activity is difficult to define and quantify, and it is also difficult to differentiate it from the physical or mental activities which are often a component of this type of intervention. The development of standardized protocols for social activity interventions may therefore need to precede the running of clinical trials. Some of the evidence presented here is based on RCTs with relatively short follow-up periods (e.g. interventions for cognitive training, depression, social activity). This limits our ability to judge the potential impact of the interventions on the development of cognitive decline and dementia as they have long prodromal periods. More evidence needs to be gathered with longer term follow-up periods in order to more accurately estimate the impact of these interventions in reducing the risk of cognitive decline/ dementia in the long run. In addition, more research needs to be conducted to understand how timing affects the impact of these interventions on cognitive decline and dementia (e.g. mid-life versus late life physical activity). The prevalence of dementia is increasing in LMIC. However, the majority of clinical trials have been conducted in high-income countries, so there is very little evidence on the effectiveness of these interventions for LMIC. More attention needs to be given to understanding how best to reduce the risk of cognitive decline and dementia in LMIC. 13 Available at: https://www.who.int/mental_health/neurology/dementia/Global_Observatory/en/ 51 The PICO questions applied to gather evidence for the preparation of these guidelines included interventions on single risk factors. However, given the multifactor etiology of dementia, and the interaction of risk factors across the lifestyle of each individual, multidomain approaches have been increasingly researched and show potential to be more effective than single-factor strategies. Recently, three large multidomain RCTs – the Finnish Geriatric Intervention Study to Prevent Cognitive Impairment and Disability (FINGER); Effect of long-term omega-3 PUFA supplementation with or without multidomain intervention on cognitive function in elderly adults with memory complaints (MAPT); and Prevention of dementia by intensive vascular care (preDIVA) – have been completed (Ngandu et al., 2015; Andrieu et al., 2017; Moll von Charante et al., 2016). Although only the multidomain lifestyle intervention tested in FINGER reported significant results in the primary analysis, the overall findings from the three trials suggested that targeting individuals at increased risk could be the most effective strategy. In particular, other interventions showed significant results in participants with an elevated dementia risk score, in MAPT (as in FINGER), and individuals with untreated hypertension at baseline, in preDIVA, respectively. In the context of multidomain interventions, new technologies and e-health solutions could also provide useful tools for risk reduction, by broadening the reach of such interventions (Barbera et al., 2018). Given the heterogeneity of risk profiles among older populations, global initiatives, such as the World Wide FINGERS Network (www.wwfingers.com), have been launched recently with the specific purpose of testing similar interventions, which have been adapted in diverse geographical and cultural settings (Kivipelto et al., 2017). Further research on the efficacy of multidomain interventions that are adjusted to specific geographical and cultural contexts, in populations at increased risk, and by making use of novel e-health tools (if possible) is, therefore, needed. 5.4 FUTURE REVIEW AND UPDATE It is expected that the guidelines will be reviewed again in five years. New evidence in these areas is regularly monitored by the WHO Secretariat, in consultation with GDG members and technical experts identified for the evidence review process, WHO collaborating centres and academic institutions. With the increasing evidence from multidomain intervention trials expected to be reported in the coming years, the addition of a PICO question addressing such interventions should be considered in future revisions. Publication, dissemination and evaluation 52 Risk reduction of cognitive decline and dementia: WHO guidelines Albanese E, Launer LJ, Egger M, Prince MJ, Giannakopoulos P, Wolters, FJ et al. (2017). 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Corrado Barbui M European University of Verona, Italy Mental health research and training, public health, health systems strengthening 5. Adelina Comas-Herrera F European London School of Economics, United Kingdom Health economist, dementia research 6. Amit Dias M South-East Asia Department of Preventive and Social Medicine, Goa Medical College, India Dementia, public health in LMIC 7. Cleusa P Ferri F Americas Federal University of São Paulo, Brazil Research in dementia and 10/66 group, dementia risk factors in LMIC 8. Riadh Gouider M Eastern Alzheimer’s Centre, Razi Hospital, Tunis; Tunisian Society of Neurology, Tunisia Dementia research in areas of epidemiology, neuropsychological assessment and risk factors 9. Shinya Ishii M Western Pacific Health and Welfare Bureau for the Elderly; Ministry of Health, Labour and Welfare, Tokyo, Japan Health policy, neurology of Alzheimer’s disease and dementia 10. Yves Joanette M Americas Canadian Institutes of Health Research, Government of Canada Dementia research 11. Joseph Kibachio M African Ministry of Health, Nairobi, Kenya Public health, health policy, NCDs 12. Miia Kivipelto F European Karolinska Institutet, Stockholm University, Stockholm, Sweden Dementia research in the field of early diagnosis and prevention 13. Shanthi Mendis F South-East Asia Independent consultant in global health, Sri Lanka NCDs and cardiology, health policy development, capacity strengthening, implementation research particularly in LMIC 61Annex 1: Guideline development group members Name Gender WHO region Affiliation Area of expertise 14. Ayesha Motala F African University of KwaZulu-Natal, South Africa Epidemiology and genetics of diabetes mellitus 15. Ronald Petersen M Americas Mayo Clinic, United States of America Memory disorders, aging and Alzheimer's disease 16. Dorairaj Prabhakaran M South-East Asia Centre for Chronic Conditions and Injuries & Public Health Foundation of India Cardiovascular disease prevention, epidemiology, developmental origin, and biomarkers of cardiovascular diseases and diabetes 17. Martin Prince M European Health Foundation of India Public health aspects of ageing and chronic disease in LMIC, dementia, guideline development 18. Suzana Shahar F Western Pacific Universiti Kebangsaan, Malaysia Nutrition, micronutrients, dietary interventions 19. Ameenah Bibi Mia Sorefan F African Alzheimer’s Association of Mauritius; Ministry of Health & Quality of Life, Mauritius Ageing, dementia and Alzheimer’s disease 20. Kusumadewi Suharya (Dy) F Western Pacific Alzheimer’s Disease International, Indonesia Dementia and public health 21. Huali Wang F Western Pacific Dementia Care & Research Center, Peking University Institute of Mental Health, China Dementia research and education 62 Risk reduction of cognitive decline and dementia: WHO guidelines ANNEX 2: ASSESSMENT OF CONFLICT OF INTEREST INDIVIDUALS INVOLVED IN ASSESSMENT OF CONFLICT OF INTEREST: Tarun Dua, Programme Manager, Department of Mental Health and Substance Abuse, WHO headquarters. Neerja Chowdhary, Technical Officer, Department of Mental Health and Substance Abuse, WHO headquarters. To comply with WHO’s Conflict of Interest Policy, the Secretariat followed the revised Guidelines for Declaration of Interests (WHO Experts).14 Declarations of interest (DoI) were requested from: (a) all GDG members; (b) all external partners involved in the evidence review process; (c) all experts invited to review the evidence profiles. A letter requesting completion of a DoI form and submission of a curriculum vitae as well as was sent to all GDG members, the external review group and external partners. They were asked to agree to the publication of a summary of declarations in the guide- line. The GDG members were also required to complete a confidentiality undertaking. Once received, the WHO Secretariat reviewed the DoIs as well as additional information (internet and bibliographic database search) and evaluated if there are any conflicts of interest and if so, whether these require a management plan. In order to enhance its management of conflicts of interest as well as strengthen public trust and transparency in connection with WHO meetings and activities involving the provision of technical/normative advice, the names and brief biographies members being considered for participation in the GDG were disclosed for public notice and comment prior to the meeting. At the beginning of the GDG meeting, the DoI of each GDG member were presented and GDG members and external partners were asked to update their DoI with relevant changes by notifying the responsible technical officer. The follow up and suggested actions agreed upon to manage the conflicts of interest declared are summarized below: • If members declare interests that are relevant to the meeting, the WHO Secretariat will note any potential conflict of interest and summarize these and then decide whether and to what extent they can participate in the guideline development. • If the conflict is deemed to be significant, the WHO Secretariat will decide if the conflict necessitates exclusion of that person from participating in the guideline process or if their participation should be limited. • These decisions are made on a case-by-case basis. Below is a summary of the Declared conflicts of interest and how these were managed. A. GDG MEMBERS GDG Members with no relevant interests declared on the DOI form and no relevant interests found in the CV 1. Kaarin J Anstey, University of New South Wales, Sydney, Australia; 2. Kimberly Ashby-Mitchell, Caribbean Public Health Agency, Port of Spain, Trinidad and Tobago; 3. Corrado Barbui, University of Verona, Verona, Italy. 4. Amit Dias, Department of Preventive and Social Medicine, Goa Medical College Bambolim, Goa, India; 5. Suharya Dy (Kusumadewi), Alzheimer’s Disease International, Jakarta, Indonesia; 6. Cleusa P. Ferri, Federal University of Sao Paulo, Sao Paulo, Brazil. 7. Riadh Gouider, Razi Hospital, Faculty of Medicine, Tunis, Tunisia; 8. Shinya Ishii, Ministry of Health, Labour and Welfare, Tokyo, Japan; 14 WHO Office of Compliance, Risk Management and Ethics (CRE) http://intranet.who.int/homes/cre/ethics/doiexperts/ 63 9. Yves Joanette, Canadian Institute of Health Research, Government of Canada. 10. Joseph Kibachio, Ministry of health, Nairobi, Kenya; 11. Shanthi Mendis, Colombo, Sri Lanka; 12. Dorairaj Prabhakaran, Public Health Foundation of India, New Delhi, India; 13. Ameenah Bibi Mia Sorefan, Ministry of Health and Quality of Life, Quatre-Bornes, Mauritius GDG members who have declared an interest on the DOI form or where a potentially relevant interest has been noted from the CV Charles Alessi, Public Health England, London, United-Kingdom Dr Alessi declared that the travel costs for the GDG meeting were covered by his organization. Action: This interest was deemed insignificant or minimal and unlikely to affect, or be reasonably perceived to affect, Dr Alessi’s judgement in the development of the present guidelines. He is deemed to be participating in the guideline development process in an individual capacity and not representing any organization. No further action was necessary Adelina Comas-Herrera, London School of Economics, London, United-Kingdom Dr Comas-Herrera declared in her DoI from that she had received research support routed via her University on various research projects on dementia in 2015 and 2016. These amounts were used to pay her salary by the University. She also declared receiving a payment of US$1000 in 2017 to advise a pharmaceutical company, Axovant Sciences GmbH. The topic was on the availability of data on dementia costs for a medicine that has since been withdrawn due to lack of effectiveness. Action: It was felt that this interest is insignificant or minimal and unlikely to affect, or be reasonably perceived to affect, Dr Comas-Herera’s judgement in the development of the present guidelines. No further action was necessary. Miia Kivipelto, Karolinska Institutet, Stockholm, Sweden Dr Kivipelto declared in her DoI form that she currently serves on the Advisory Board of a Finnish company that focuses on early diagnosis and e-health solutions for which she received €2500. She is also on the Governance committee of AARP, a non-profit organization for healthy ageing for which she received €800. She also declared that she has received research grants related to risk factors for dementia and is a founding member of World-Wide Fingers, an interdisciplinary network to share experiences, harmonize data and plan joint international initiatives for the risk reduction of cognitive decline and dementia. Action: This interest was deemed insignificant or minimal and unlikely to affect, or be reasonably perceived to affect, Dr Kivipelto’s judgement in the development of the present guidelines. She is deemed to be participating in the guideline development process in an individual capacity and not representing any organization. No further action was necessary Ayesha Motala, University of KwaZulu-Natal, Durban, South Africa. Dr Motala declared that as a public servant working in a government institute, she seeks sponsorships to meetings from various organizations, especially when her scientific abstracts are accepted for presentations. The sponsorships are merely for attending the meetings, with no obligation to the sponsoring companies. Annex 2: Assessment of conflict of interest 64 Risk reduction of cognitive decline and dementia: WHO guidelines Details of such sponsorship for which she received a total amount of US$26 000: 4–8 December 2017: International Diabetes Federation (IDF) Congress, Abu Dhabi: Sanofi Aventis sponsorship for travel and accommodation; 11–15 September 2017: European Association for the Study of Diabetes (EASD) Congress, Lisbon: Pfizer sponsorship for travel and accommodation; 8–13 June 2018: American Diabetes Association (ADA), San Diego: Boehringer Ingelheim sponsorship for travel and accommodation: a member of her collaborating scientific team presented a paper. Action: It was felt that this interest is insignificant or minimal and unlikely to affect, or be reasonably perceived to affect, Dr Motala’s contribution as an external reviewer for these guidelines. No further action was necessary. Ronald C. Petersen, Mayo Clinic, Rochester, USA Dr Petersen declared that he is a clinical trials consultant for five pharmaceutical companies: from four of these (Roche Inc, Merck Inc, Genetech Inc and GE Healthcare) he receives less than US$ 10 000 and from one (Biogen Inc) he receives less that US$ 15 000 as consultancy fees. Action: It was felt that this interest is unlikely to affect, or be reasonably perceived to affect, Dr Petersen’s contribution as an external reviewer for these guidelines since these grants are not related to the topic of interest. No further action was necessary. Martin Prince, King’s College London, London, United Kingdom Professor Prince declared in his DOI form that he currently receives research support through a grant from the National Institute of Health Research (NIHR, UK) amounting to £7 million over four years. Professor Prince is the PI and 20% of his salary costs are charged to the grant. The work focuses on health systems strengthening in sub Saharan Africa and one theme relates to the topic of these guidelines i.e. integrated primary healthcare for multimorbid conditions. Action: It was felt that this interest is insignificant or minimal and unlikely to affect, or be reasonably perceived to affect, Professor Prince’s judgement in the development of the present guidelines. No further action was necessary Suzana Shahar, Universiti Kebangsaan Malaysia, Selangor, Malaysia Dr Sahar has declared in her DoI form that she has a clinical trial agreement through her University with Biotropics, a company that develops bio-resources into superior natural health product. The research involves evaluating the efficacy of Asian traditional herbs in improving cognition and mood. The funding amount is US$ 100 000 between 2014 and 2018. Action: It was felt that this interest is insignificant or minimal and unlikely to affect, or be reasonably perceived to affect, Dr Sahar’s contribution as an external reviewer for these guidelines. No further action was necessary Huali Wang, Dementia Care & Research Center, Peking University Institute of Mental Health, Beijing, China. Dr Wang declared in her DoI form that prior to 2016, she had worked as a consultant with Neowave Inc. to develop a tablet-based cognitive training program. She also declared that she had received support for travelling to meetings form Eisai China amounting to US$ 7000 prior to 2017. The meeting were all Alzheimer’s Disease International (ADI) conferences. 65 Action: It was felt that this interest is insignificant or minimal and unlikely to affect, or be reasonably perceived to affect, Dr Wang’s contribution as an external reviewer for these guidelines. No further action was necessary B. EXTERNAL REVIEW GROUP Members of the external review group with no relevant interests declared on the DOI form and no relevant interests found in the CV 1. Abdullah Al Khatami, Ministry of Health, Saudi Arabia 2. Alistair Burns, University of Manchester, UK 3. Linda Clare, University of Exeter, UK 4. Jacqueline Dominguez, Institute for dementia care Asia, Quezon city, Philippines 5. Maelënn Guerchet, The Global Observatory for Ageing and Dementia Care, King's College London, UK 6. Mariella Guerra, Institute of Memory, Depression and Related Disorders – IMEDER, Lima, Peru 7. Luis Miguel F. Gutiérrez Robledo, Instituto Nacional de Geriatría, Institutos Nacionales de Salud de México, Mexico City, Mexico 8. Vladimir Hachinski, University of Western Ontario in London, Ontario, Canada 9. Qurat ul Ain Khan, Aga Khan University Hospital, Karachi, Pakistan. 10. Sebastian Koehler, Maastricht University, The Netherlands 11. Jae-hong Lee, University of Ulsan College of Medicine, Seoul, Korea 12. Gill Livingstone, University college London, UK 13. Jean Claude Mbanya, Doctoral School of Life Sciences, Health and Environment, University of Yaoundé I, Cameroon. 14. James McKillop, Service user group representative, UK 15. Rajat Ray, National Drug Dependence Treatment Centre, All India Institute of Medical Sciences, New Delhi, India 16. Helen Rochford Brennan, European Working Group of people with dementia, Ireland 17. Kate Swaffer, Dementia Alliance International, Australia 18. Weili Xu, Karolinska Institute, Finland Members of the external review group who have declared an interest on the DOI form or where a potentially relevant interest has been noted from the CV Emiliano Albanese, Universita della Svizzera italiana, Switzerland Dr Albanese declared in his DoI form that he receives research support from the Economic and Research Council UK as part of the STRIDE (Strengthening responses to dementia in developing countries) research consortium which focuses on dementia research in low and middle income countries. The amount of US$ 50 000 is provided to the institution to which he is affiliated. Action: It was felt that this interest is insignificant or minimal and unlikely to affect, or be reasonably perceived to affect, Dr Albanese’s contribution as an external reviewer for these guidelines. No further action was necessary. Hillary Doxford, 3 Nations Dementia Working Group, UK Ms Doxford declared in her DoI form that she has served on a grant review panel assessing and prioritizing grant applications for funding dementia research projects for the National Institute for Health Research, UK. The income she received for this was £450. She is also a voluntary member of the Dementia Programme Board in the UK Department of Health and Social Care as a person with lived experience. Action: It was felt that this interest is insignificant or minimal and unlikely to affect, or be reasonably perceived to affect, Ms Doxford’s contribution as an external reviewer for these guidelines. No further action was necessary. Annex 2: Assessment of conflict of interest 66 Risk reduction of cognitive decline and dementia: WHO guidelines Elaine Rashbrook, Public Health England, UK Dr Rashbrook declared in her DoI form that she is employed by Public Health England (PHE), a government agency, as Consultant Specialist Life Course since 2015. PHE supports work on dementia risk reduction in line with the government strategy. There is no identified financial value for the work. Action: It was felt that this interest is insignificant or minimal and unlikely to affect, or be reasonably perceived to affect, Dr Rashbrook’s contribution as an external reviewer for these guidelines. She is deemed to be providing her review in an individual capacity and not representing any organization. No further action was necessary. Andrew Sommerlad, University College London, UK Dr Sommerlad declared in his DoI form that he receives research support from the Wellcome Trust in the form of a personal research fellowship to examiner whether social isolation is a risk factor for dementia The amount of funding is £201 311 from 2016 to 2019. Action: It was felt that this interest is insignificant or minimal and unlikely to affect, or be reasonably perceived to affect, Dr Sommerlad’s contribution as an external reviewer for these guidelines. No further action was necessary B. EXTERNAL PARTNERS External partners with no relevant interests declared on the DOI form and no relevant interests found in the CV 1. Mariagnese Barbera, University of Eastern Finland, Kuopio, Finland; 2. Nicole A. Ee, University of New South Wales, Sydney, Australia; 3. Jenni Kumlala, Karolinska Institutet, Stockholm, Sweden; 4. Ruth Peters, University of New South Wales, Sydney, Australia; 5. Lidan Zheng, University of New South Wales, Sydney, Australia. None of the external partners declared relevant interests on the DOI forms nor were relevant interests found in the CV.   67 ANNEX 3: SCOPING QUESTIONS INTERVENTIONS ADDRESSING LIFESTYLE AND BEHAVIOUR RISK FACTORS 1. Physical activity interventions For adults with normal cognition or mild cognitive impairment, are physical activity interventions more effective than usual care or no intervention in reducing the risk of cognitive decline and/or dementia? P: Adults (age above 18 years) with normal cognition or MCI I: Physical activity interventions (aerobic, resistance training or multicomponent physical activity) C: Care as usual or no intervention O: • Critical – Cognitive function – Incident MCI – Dementia 2. Tobacco cessation interventions For adults with normal cognition or mild cognitive impairment who use tobacco, are interventions for tobacco cessation more effective than usual care or no intervention in reducing the risk of cognitive decline and/or dementia? P: Adults with normal cognition or MCI who use tobacco I: Interventions for tobacco cessation (behavioural interventions and pharmacological interventions including nicotine replacement therapy, bupropion, varenicline) C: Care as usual or no intervention O: • Critical – Cognitive function – Incident MCI – Dementia 3. Nutritional interventions 3a. For adults with normal cognition or mild cognitive impairment, are nutritional interventions such as dietary supplements more effective than usual care or no intervention in reducing the risk of cognitive decline and/or dementia? P: Adults with normal cognition or MCI I: Dietary supplements (e.g. B vitamins, antioxidants, omega-3 and ginkgo); C: Care as usual or no intervention O: • Critical – Cognitive function – Incident MCI – Dementia • Important – Quality of life – Functional level (ADL, IADL) – Adverse events – Drop-out rates • Important – Quality of life – Functional level (ADL, IADL) – Adverse events – Drop-out rates • Important – Quality of life – Functional level (ADL, IADL) – Adverse events – Drop-out rates Annex 3: Scoping questions 68 Risk reduction of cognitive decline and dementia: WHO guidelines 3b. For adults with normal cognition or mild cognitive impairment, are nutritional interventions such as healthy dietary patterns (e.g. Mediterranean diet) more effective than usual care or no intervention in reducing the risk of cognitive decline and/or dementia? P: Adults with normal cognition or MCI I: Healthy dietary pattern (e.g. Mediterranean diet) C: Care as usual or no intervention O: • Critical – Cognitive function – Incident MCI – Dementia 4. Interventions for alcohol use disorders For adults with normal cognition or mild cognitive impairment and alcohol use disorders, are behavioural and psychological interventions to treat alcohol use disorders more effective than usual care or no intervention in reducing the risk of cognitive decline and/or dementia? P: Adults with normal cognition or MCI and excessive use of alcohol I: • Behavioural and psychological interventions to treat alcohol use disorders (e.g. motivational interviewing) • Pharmacological interventions to treat alcohol use disorders C: Care as usual or no intervention O: • Critical – Cognitive function – Incident MCI – Dementia • Important – Quality of life – Functional level (ADL, IADL) – Adverse events – Drop-out rates • Important – Quality of life – Functional level (ADL, IADL) – Adverse events – Drop-out rates 69 SPECIFIC INTERVENTIONS 5. Cognitive interventions For adults with normal cognition or mild cognitive impairment is cognitive stimulation or cognitive training more effective than usual care or no intervention in reducing the risk of cognitive decline and/ or dementia? P: Adults with normal cognition or MCI I: • Cognitive stimulation • Cognitive training C: Care as usual or no intervention O: • Critical – Cognitive function – Incident MCI – Dementia 6. Social activity For adults with normal cognition or mild cognitive impairment is preserving and promoting a high level of social activity more effective than usual care or no intervention in reducing the risk of cognitive decline and/or dementia? P: Adults with normal cognition or MCI I: Preservation and promotion of social activity including community and family engagement C: Care as usual or no intervention O: • Critical – Cognitive function – Incident MCI – Dementia • Important – Quality of life – Functional level (ADL, IADL) – Adverse events – Drop-out rates • Important – Quality of life – Functional level (ADL, IADL) – Adverse events – Drop-out rates Annex 3: Scoping questions 70 Risk reduction of cognitive decline and dementia: WHO guidelines INTERVENTIONS FOR HEALTH CONDITIONS 7. Weight management For adults with normal cognition or mild cognitive impairment who are overweight or obese, are interventions for weight reduction (or control of obesity) more effective than usual care or no intervention in reducing the risk of cognitive decline and/or dementia? P: Adults with normal cognition or MCI who are overweight or obese I: Weight management • Non-pharmacological interventions, e.g. cognitive-behavioural intervention strategies, lifestyle interventions • Pharmacological interventions, e.g. weight-loss medication (e.g. orlistat) C: Care as usual or no intervention O: • Critical – Cognitive function – Incident MCI – Dementia 8. Management of hypertension For adults with normal cognition or mild cognitive impairment and hypertension, is treatment of hypertension more effective than placebo/no intervention in reducing the risk of cognitive decline/dementia? P: Adults with normal cognition or MCI with hypertension I: Antihypertensive medication, lifestyle interventions C: Placebo/no intervention O: • Critical – Cognitive function – Incident MCI – Dementia 9. Management of diabetes mellitus For adults with normal cognition or mild cognitive impairment and diabetes mellitus, is treatment of diabetes more effective than placebo/no intervention in reducing the risk of cognitive decline and/or dementia? P: Adults with normal cognition or MCI with diabetes mellitus I: • Medications for glycaemic control • Diet and lifestyle interventions C: Placebo/no intervention O: • Critical – Cognitive function – Incident MCI – Dementia • Important – Quality of life – Functional level (ADL, IADL) – Adverse events – Drop-out rates • Important – Quality of life – Functional level (ADL, IADL) – Adverse events – Drop-out rates • Important – Quality of life – Functional level (ADL, IADL) – Adverse events – Drop-out rates 71Annex 3: Scoping questions 10. Management of dyslipidaemia For adults with normal cognition or mild cognitive impairment and dyslipidaemia, is treatment of dyslipidaemia more effective than placebo or no intervention in reducing the risk of cognitive decline and/or dementia? P: Adults with normal cognition or MCI with dyslipidaemia I: • Statins (e.g. simvastatin and pravastatin) • Lifestyle interventions C: Placebo or no intervention O: • Critical – Cognitive function – Incident MCI – Dementia 11. Management of depression For adults with normal cognition or mild cognitive impairment and depressive disorder, is treatment of depression more effective than usual care, placebo or no intervention in reducing the risk of cognitive decline and/or dementia? P: Adults with normal cognition or MCI with moderate to severe depressive disorder I: • Pharmacological interventions to treat depression (antidepressant medication) • Psychological interventions to treat depression (e.g. cognitive behavioural therapy, problem-solving therapy, interpersonal therapy, behavioural activation) C: Care as usual or placebo or no intervention O: • Critical – Cognitive function – Incident MCI – Dementia 12. Management of hearing loss For adults with normal cognition or mild cognitive impairment and hearing loss, is treatment of hearing loss more effective than usual care, or no intervention in reducing the risk of cognitive decline and/or dementia? P: Adults with normal cognition or MCI with hearing loss I: Interventions to treat hearing loss (e.g. hearing aids) C: Care as usual or no intervention O: • Critical – Cognitive function – Incident MCI – Dementia • Important – Quality of life – Functional level (ADL, IADL) – Adverse events – Drop-out rates • Important – Quality of life – Functional level (ADL, IADL) – Adverse events – Drop-out rates • Important – Quality of life – Functional level (ADL, IADL) – Adverse events – Drop-out rates 72 Risk reduction of cognitive decline and dementia: WHO guidelines ANNEX 4: EVIDENCE REVIEW METHODOLOGY Comprehensive searches of major bibliographic databases were conducted to identify one systematic review that matched each of the outcomes for each of the PICO questions. The aim was to identify systematic reviews that were timely, of high quality and relevant to each of the PICO questions. The search strategies differed slightly between the two teams (based in the Karolinska Institutet, Sweden and University of New South Wales, Australia. However, in general, the following process was employed: 1. Search for systematic reviews (including meta- analyses) that were published in the last 2 years for each of the PICO questions. The searches were run from April to June 2018. 2. If no relevant high-quality systematic reviews were identified from the 2 years for any of the PICO questions, the search was expanded to include systematic reviews from the last 5 years for that PICO question. For the relevant PICO questions, the 2016 AHRQ systematic review was also consulted. The aim of the AHRQ review was to examine interventions to prevent cognitive decline and dementia. The review systematically searched records between January 2009 and September 2016. 3. For the hearing loss question, there was very limited evidence available, therefore searches were expanded to include all systematic reviews ever published. 4. Based on the GDG’s feedback during the GDG meeting in July 2018, the searches were expanded to further include systematic reviews of obser- vational studies. The searches were re-run July to August 2018. The following bibliographic databases were searched: • Bibliographic • Medline • Cochrane • PsycInfo • Embase • NICE. Relevant to LMIC • Global Index Medicus/Global Health Library • WHO regional database • WHOLIS • Database of impact evaluations • AJOL • KoreaMed • IndMED • HrCak • ArabPsycNet • HERDIN NeON • EurasiaHealth. After the searches were run using the search strategies listed below, titles and abstracts of all results were screened in Endnote; subsequently the full texts of those papers were reviewed that could not be excluded based on the title/abstract review. GRADE EVIDENCE TABLES For each outcome of each PICO question, one or more systematic reviews were then selected to be used within the GRADE evidence tables. The following criteria were used when selecting which systematic review to use within the GRADE evidence tables: • Published in the last 5 years, ideally 2 years (timeliness). • High quality (i.e. measured using AMSTAR 215 criteria). 15 Shea BJ, Grimshaw JM, Wells GA, Boers M, Andersson N, Hamel C et al (2007). Development of AMSTAR: a measurement tool to assess the methodological quality of systematic reviews. BMC Medical Research Methodology. 7:10. 73Annex 3: Scoping questions • Closely relevant to the PICO question. • Comprehensive systematic reviews given preference, where possible. • Cochrane reviews or other meta-analyses given preference, where possible/appropriate. The GRADE methodology involves rating the quality of the studies included in the systematic review according to study design, risk of bias, inconsistency, indirectness, imprecision, and publication bias. Together with the effect sizes of studies, an overall “certainty of evidence” is provided of either very low, low, moderate or high. GRADE evidence tables were completed using the GRADEpro online tool.16 The same criteria were used as for the mhGAP Intervention guide when completing the GRADE evidence tables in terms of the assessment of the quality of studies (for risk of bias, inconsistency, indirectness, imprecision, and publication bias).17 SEARCH STRATEGIES Separate searches were performed for each of the 12 PICO questions. Where PICO questions included both pharmacological and non-pharmacological interventions, searches were run separately for these. Filters were used in the bibliographic databases where possible to restrict the searches to systematic reviews and meta-analyses, as well as to humans. No further restrictions were employed, for example in terms of language (apart from the publication date, as mentioned above). The “advanced search” option was selected in bibliographic databases, where possible. PICO 1 For adults with normal cognition or mild cognitive impairment, are physical activity interventions more effective than usual care or no intervention in reducing the risk of cognitive decline and/or dementia? Search strategy (dementia OR cognit* OR “mild cognitive impairment” OR “Alzheimer disease” OR “dementia vascular” OR “dementia multi-infarct” OR MCI OR “cognitive dysfunction” OR neuropsychologi* OR “Health-Related Quality” Of Life OR “life quality” OR “Activities Daily Living” OR “Chronic Limitation of Activity” OR “Limitation of Activity, Chronic” OR ADL OR “activities of daily living” OR “Drug-Related Side Effects and Adverse Reactions” OR “Adverse Drug Event” OR “Adverse Drug Reaction” OR “Long Term Adverse Effects” OR “Adverse Effects, Long Term Disease-Free Survival” OR “Event-Free Survival” OR “Adverse effects”) AND (Exercise OR “exercise therapy” OR “Acute Exercise” OR “Aerobic Exercise” OR “Exercise Training” OR “Exercise, Aerobic” OR “Exercise, Isometric” OR “Exercise, Physical” OR “Isometric Exercise OR Physical Activity” OR “resistance training”) PICO 2 For adults with normal cognition or mild cognitive impairment who use tobacco, are interventions for tobacco cessation more effective than usual care or no intervention in reducing the risk of cognitive decline and/or dementia? Search strategy (dementia OR cognit* OR mild cognitive impairment OR Alzheimer disease OR dementia vascular OR dementia multi-infarct OR MCI OR cognitive dysfunction OR neuropsychologi* OR Health-Related Quality Of Life OR life quality OR Activities, Daily Living OR Chronic Limitation of Activity OR Limitation 16 https://gradepro.org/ 17 See http://www.who.int/mental_health/mhgap/evidence/mhgap_ guideline_process_2009.pdf 74 Risk reduction of cognitive decline and dementia: WHO guidelines of Activity, Chronic OR ADL OR activities of daily living OR Drug-Related Side Effects and Adverse Reactions OR Adverse Drug Event OR Adverse Drug Reaction OR Long Term Adverse Effects OR Adverse Effects, Long Term Disease-Free Survival OR Event-Free Survival OR Adverse effects) AND (Tobacco OR smoking OR Tobacco use cessation OR giving up smoking OR quitting smoking OR stopping smoking OR smoking cessation OR smoking reduction OR tobacco use cessation products OR varenicline OR nicotinic agonists OR Nicotine Inhalant OR Nicotine Lozenge OR Nicotine Lozenges OR Nicotine Nasal Spray OR Nicotine Patch OR Nicotine Polacrilex OR Nicotine Replacement Products OR Nicotine Transdermal Patch OR Smoking Cessation Products) AND (Behavior OR behaviour OR drug therapy OR pharmacologic therapy OR pharmacotherapy OR Cognitive behavioural therapy OR Cognitive behavioural therapy OR Drug therapy OR cognitive therapy OR online therapy OR treatment) PICO 3 3a. For adults with normal cognition or mild cognitive impairment, are nutritional interventions such as dietary supplements more effective than usual care or no intervention in reducing the risk/ progression of cognitive decline and/or dementia? 3b. For adults with normal cognition or mild cognitive impairment, are nutritional interventions such as healthy dietary patterns (e.g. Mediterranean diet) more effective than usual care or no intervention in reducing the risk/progression of cognitive decline and/or dementia? Search strategy (dementia OR cognit* OR “mild cognitive impairment” OR “Alzheimer disease” OR Alzheimer* OR “dementia vascular” OR “dementia multi-infarct” OR MCI OR “cognitive dysfunction” OR neuropsychologi* OR “Health-Related Quality Of Life” OR “life quality” OR “quality of life” OR “Activities of Daily Living” OR “Chronic Limitation of Activity” OR “Limitation of Activity, Chronic” OR ADL OR “activities of daily living” OR “Drug-Related Side Effects and Adverse Reactions” OR “Adverse Drug Event” OR “Adverse Drug Reaction” OR “Long Term Adverse Effects” OR “Adverse Effects, Long Term” OR “Disease-Free Survival” OR “Event-Free Survival” OR “Adverse effects”) AND (“Dietary supple- ments” OR “Dietary Supplementations” OR “Food Supplementations” OR “Food Supplements” OR “Herbal Supplements” OR Neutraceuticals OR Nutraceuticals OR Nutriceuticals OR diet or vitamin or food) PICO 4 For adults with normal cognition or mild cognitive impairment and alcohol use disorders, are behavioural and psychological interventions to treat alcohol use disorders more effective than usual care or no intervention in reducing the risk of cognitive decline and/or dementia? Search strategy (dementia OR cognit* OR mild cognitive impairment OR Alzheimer disease OR dementia vascular OR dementia multi-infarct OR MCI OR cognitive dysfunction OR neuropsychologi* OR Health-Related Quality Of Life OR life quality OR Activities, Daily Living OR Chronic Limitation of Activity OR Limitation of Activity, Chronic OR ADL OR activities of daily living OR Drug-Related Side Effects and Adverse Reactions OR Adverse Drug Event OR Adverse Drug Reaction OR Long Term Adverse Effects OR Adverse Effects, Long Term Disease-Free Survival OR Event-Free Survival OR Adverse effects) AND (Alcohol drinking OR Binge drinking OR Drunkenness OR alcohol intoxication OR alcoholism OR alcohol withdrawal) AND (Add in Behavior OR behaviour OR drug therapy OR pharmacologic therapy OR pharmacotherapy OR Cognitive behavioural therapy OR Cognitive behavioural therapy OR Drug therapy OR cognitive therapy OR online therapy OR treatment) 75Annex 3: Scoping questions PICO 5 For adults with normal cognition or mild cognitive impairment is cognitive stimulation or cognitive training more effective than usual care or no intervention in reducing the risk of cognitive decline and/or dementia? Search strategy (systemati* or meta analys*) and (dementia or cognit* or MCI or neuropsycholog* or Alzheimer*) and ("Brain training" OR "cognitive training" OR "Brain fitness" OR Games OR "Memory training" OR (Stimulation AND cognit*) PICO 6 For adults with normal cognition or mild cognitive impairment is preserving and promoting a high level of social activity more effective than usual care or no intervention in reducing the risk of cognitive decline and/or dementia? Search strategy ("social interaction" or "social Networks" or "social processes" or "social behaviour" or "social behavior" or "community networks" or "social media" or family) and (dementia or cognit* or "mild cognitive impairment" or MCI or "cognitive dysfunction" or neuropsycholog* or Alzheime*) and (systemati* or meta-analys*) PICO 7 For adults with normal cognition or mild cognitive impairment who are overweight or obese, are interventions for weight reduction (or control of obesity) more effective than usual care or no intervention in reducing the risk of cognitive decline and/or dementia? Search strategy (dementia OR cognit* OR mild cognitive impairment OR Alzheimer disease OR dementia vascular OR dementia multi-infarct OR MCI OR cognitive dysfunction OR neuropsychologi* OR Health-Related Quality Of Life OR life quality OR Activities, Daily Living OR Chronic Limitation of Activity OR Limitation of Activity, Chronic OR ADL OR activities of daily living OR Drug-Related Side Effects and Adverse Reactions OR Adverse Drug Event OR Adverse Drug Reaction OR Long Term Adverse Effects OR Adverse Effects, Long Term Disease-Free Survival OR Event-Free Survival OR Adverse effects) AND (Overweight OR Body weight or Body mass index OR weight loss OR Body weight changes) AND (Behavior OR behaviour OR drug therapy OR pharmacologic therapy OR pharmacotherapy OR Cognitive behavioural therapy OR Cognitive behavioural therapy OR Drug therapy OR cognitive therapy OR online therapy OR treatment OR Appetite depressants) PICO 8 For adults with normal cognition or mild cognitive impairment and hypertension, is treatment of hypertension more effective than placebo/no intervention in reducing reduce the risk of cognitive decline/dementia? Search strategy (systemati* or meta-analys*) and (dementia or cognit* or "mild cognitive impairment" or MCI or "cognitive dysfunction" or neuropsycholog* or Alzheimer's or Alzheimer) and (behaviour or behavior or "drug therapy" or "pharmacologic therapy" or pharmacotherapy or "cognitive behavioural therapy" or "cognitive behavioral therapy" or "cognitive therapy" or "online therapy" or "anti-hypertensive" or antihypertensive or treatment) and (hypertension or "blood pressure" or systolic or diastolic or prehypertension) 76 Risk reduction of cognitive decline and dementia: WHO guidelines PICO 9 For adults with normal cognition or mild cognitive impairment and diabetes mellitus, is treatment of diabetes more effective than placebo/no intervention in reducing the risk of cognitive decline and/or dementia? Search strategy (systemati* or meta-analys*) and (dementia or cognit* or "mild cognitive impairment" or MCI or "cognitive dysfunction" or neuropsycholog* or Alzheime*) .ab. and diabetes.af. and ("hypoglycemic agents" or treatment or therapy or pharmacotherapy or behaviour or behavior) PICO 10 For adults with normal cognition or mild cognitive impairment and dyslipidaemia, is treatment of dyslipidaemia more effective than placebo or no intervention in reducing reduce the risk of cognitive decline and/or dementia? Search strategy (dementia OR cognit* OR mild cognitive impairment OR Alzheimer disease OR dementia vascular OR dementia multi-infarct OR MCI OR cognitive dysfunction OR neuropsychologi* OR Health-Related Quality Of Life OR life quality OR Activities, Daily Living OR Chronic Limitation of Activity OR Limitation of Activity, Chronic OR ADL OR activities of daily living OR Drug-Related Side Effects and Adverse Reactions OR Adverse Drug Event OR Adverse Drug Reaction OR Long Term Adverse Effects OR Adverse Effects, Long Term Disease-Free Survival OR Event-Free Survival OR Adverse effects) AND (Cholesterol OR Hypercholes-terolemia OR lipo- proteins OR HDL cholesterol OR LDL cholesterol OR triglycerides) AND (Behavior OR behaviour OR drug therapy OR pharmalogic therapy OR pharmacotherapy OR Cognitive behavioural therapy OR Cognitive behavioural therapy OR Drug therapy OR cognitive therapy OR online therapy OR treatment OR statins OR Hydroxymethylglutaryl-CoA Reductase Inhibitors OR Anticholesteremic agents) PICO 11 For adults with normal cognition or mild cognitive impairment and depressive disorder, is treatment of depression more effective than usual care, placebo or no intervention in reducing the risk of cognitive decline and/or dementia? Search strategy (depression or depressive) and (systemati* or meta- analys*) and (dementia or cognit* or "mild cognitive impairment" or MCI or "cognitive dysfunction" or neuropsycholog* or Alzheimer's or Alzheimer*) and (treatment or therapy or pharmacotherapy or antidepressan* or antidepressiv*) PICO 12 For adults with normal cognition or mild cognitive impairment and hearing loss, is treatment of hearing loss more effective than usual care, or no intervention in reducing the risk of cognitive decline and/or dementia? Search strategy (hearing aids OR Cochlear implants Or hearing implants) AND (hearing loss OR deafness OR hearing impairment OR hypoacusis OR intervention OR treatment) AND (dementia OR cognit* OR mild cognitive impairment OR Alzheimer's disease OR dementia vascular OR dementia multi-infarct OR MCI OR cognitive dysfunction OR neuropsycholog*) 77Glossary Adverse event Any untoward medical occurrence in a patient or clinical investigation subject caused by health care management. Aerobic exercise A type of physical exercise that requires free oxygen to adequately meet energy demands via the aerobic metabolism. During aerobic exercise, oxygen is used to “burn” fats and glucose in order to produce adenosine triphosphate, the basic energy carrier for all cells. This type of exercise improves physical fitness by promoting the circulation of oxygen through the blood, is associated with an increased rate of breathing, and includes any type of exercise that, when performed at levels of intensity sufficiently supported by the aerobic metabolism, can be performed for extended periods of time. Behavioural activation A behavioural treatment for depression in which the person with depression is guided to increase the number of rewarding activities in his or her life. Body mass index An objective measurement calculated as body mass (or weight in kg) divided by the square of the body height (in metres), universally expressed in units of kg/m2. BMI is used as approximate indicator of the amount of tissue mass (muscle, bone, and fat) in an individual. Based on the correlation between BMI and the degree of risk for certain disease, such as diabetes or atherosclerosis, BMI values are categorized as underweight, normal weight, overweight, or obese; obesity can also be subcategorized in moderate severe and morbid. Cognitive behavioural intervention/therapy A type of psychological therapy that involves identifying and correcting distorted maladaptive beliefs, while using thought exercises and real experiences to facilitate symptom reduction and improved functioning. Cognitive decline The physiological decay of brain functions such as memory, attention or learning ability, for example, which is associated with the normal ageing process. It differs from cognitive impairment in that anyone who ages develops some kind of cognitive decline, although at different degrees. Cognitive impairment, instead, is normally the result of a pathological event: injury, disease, or increased levels of cognitive decline. Cognitive function Cerebral activities, i.e. reasoning, memory, attention, and language that lead to the attainment of information and knowledge. Cognitive stimulation Participation in a range of activities designed to improve cognitive and social functioning. Cognitive training Guided practice of specific standardized tasks designed to enhance particular cognitive functions. Dementia Dementia, a group of disorders characterized by a decline from a previously attained cognitive level that affects activities of daily living or social functioning. Dietary supplements Dietary supplements include vitamins, minerals, fibre, fatty acids, or amino acids, among other substances. They are either intended to provide nutrients in order to increase their consumption, or to provide non-nutrient chemicals which are claimed to have a biologically beneficial effect. Health-related quality of life An individual’s or a group’s perceived physical and mental health over time. As a multidimensional concept, it includes domains related to physical, mental, emotional and social functioning, and it is a way to assess the impact of health status on quality of life. Mediterranean diet A diet which consists of a high intake of cereals, fruits, fish, legumes, and vegetables and low intake of meat and dairy. G LOSSARY 78 Risk reduction of cognitive decline and dementia: WHO guidelines Mild cognitive impairment A disorder characterized by impairment of memory, learning difficulties and reduced ability to concentrate on a task for more than brief periods. There is often a marked feeling of mental fatigue when mental tasks are attempted, and new learning is found to be subjectively difficult even when objectively successful. None of these symptoms are so severe that a diagnosis of either dementia or delirium can be made. Motivational interviewing An established evidence-based practice in the treatment of individuals with substance use disorders that focuses on exploring and resolving ambivalence and centres on motivational processes within the individual that facilitate change. Multidomain intervention Intervention normally aimed to prevent/address a certain disease or condition by acting simultaneously on a range of risk factors, which may be either correlated or independent from each other. Nicotine replacement therapy A type of treatment that makes use of special products which provide small, steady doses of nicotine to help stop cravings and relieve withdrawal symptoms when an individual is trying to stop using tobacco. These products include nicotine gum, nicotine inhaler, nicotine nasal spray, nicotine lozenges, and nicotine patch. They do not contain any of the other chemicals found in tobacco products. Physical activity Any bodily movement produced by skeletal muscles that requires energy expenditure – including activities undertaken while working, playing, carrying out household chores, travelling, and engaging in recreational pursuits Physical exercise: subcategory of physical activity that is planned, structured, repetitive, and aims to improve or maintain one or more components of physical fitness. Problem-solving therapy A type of psychological therapy where the patient systematically identifies his or her problems; generates alternative solutions for each problem; selects the best solution; develops and conducts a plan; and evaluates whether this has solved the problem. Quality of life An individual’s perception of their position in life in the context of the culture and value systems in which they live and in relation to their goals, expectations, standards and concerns. Resistance training A form of physical exercise that, by the moving of the limbs against high loads or fixed resistances, causes skeletal muscles contraction, building their strength, anaerobic endurance, and size. The external resistance can be represented by dumbbells, rubber exercise tubing, the own body weight, bricks, bottles of water, machine specifically designed to this purpose, or any other object that causes the muscles to contract. The forces involved must be such that relatively few repetitions are possible without a substantial rest period. Resistance or strength training is primarily an anaerobic activity, although some proponents have adapted it to provide the benefits of aerobic exercise through circuit training. Social activity Social activities are varied and difficult to define, however they may include meeting friends, attending events or functions, volunteering or participating in occupational duties or group recreational activities.

For further information, please contact: Department of Mental Health and Substance Abuse, World Health Organization Avenue Appia 20 CH-1211 Geneva 27 Switzerland Email: whodementia@who.int Website: www.who.int/mental_health/ neurology/dementia/en ISBN 978-92-4-155054-3

RISK REDUCTION OF COGNITIVE DECLINE AND DEMENTIA WHO GUIDELINES

iRISK REDUCTION OF COGNITIVE DECLINE AND DEMENTIA WHO GUIDELINES ii Risk reduction of cognitive decline and dementia: WHO guidelines Risk reduction of cognitive decline and dementia: WHO guidelines ISBN 978-92-4-155054-3 © World Health Organization 2019 Some rights reserved. This work is available under the Creative Commons Attribution-NonCommercial-ShareAlike 3.0 IGO licence (CC BY-NC-SA 3.0 IGO; https://creativecommons.org/licenses/by-nc-sa/3.0/igo). Under the terms of this licence, you may copy, redistribute and adapt the work for non-commercial purposes, provided the work is appropriately cited, as indicated below. In any use of this work, there should be no suggestion that WHO endorses any specific organization, products or services. The use of the WHO logo is not permitted. If you adapt the work, then you must license your work under the same or equivalent Creative Commons licence. 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If you wish to reuse material from this work that is attributed to a third party, such as tables, figures or images, it is your responsibility to determine whether permission is needed for that reuse and to obtain permission from the copyright holder. The risk of claims resulting from infringement of any third-party-owned component in the work rests solely with the user. General disclaimers. The designations employed and the presentation of the material in this publication do not imply the expression of any opinion whatsoever on the part of WHO concerning the legal status of any country, territory, city or area or of its authorities, or concerning the delimitation of its frontiers or boundaries. Dotted and dashed lines on maps represent approximate border lines for which there may not yet be full agreement. The mention of specific companies or of certain manufacturers’ products does not imply that they are endorsed or recommended by WHO in preference to others of a similar nature that are not mentioned. Errors and omissions excepted, the names of proprietary products are distinguished by initial capital letters. All reasonable precautions have been taken by WHO to verify the information contained in this publication. However, the published material is being distributed without warranty of any kind, either expressed or implied. The responsibility for the interpretation and use of the material lies with the reader. In no event shall WHO be liable for damages arising from its use. Design and layout: Erica Lefstad Printed in France iii FOREWORD ........................................................... v ACKNOWLEDGEMENTS ................................... vi ACRONYMS .......................................................... viii EXECUTIVE SUMMARY .................................... x 1. INTRODUCTION ........................................ xiv 1.1 Background and rationale for these guidelines ..... 1 1.2 Related WHO guidelines and tools ......................... 3 1.3 Target audience .................................................... 4 1.4 Goals and objectives ............................................ 4 1.5 Guiding principles ................................................ 5 2. GUIDELINE DEVELOPMENT PROCESS ........................................................ 6 2.1 Guideline development group ............................... 7 2.2 Declarations of interest by the GDG members and external reviewers ......................................... 7 2.3 Collaboration with external partners ..................... 8 2.4 Identifying, appraising and synthesizing available evidence ................................................ 8 2.5 Decision-making during the GDG meeting .............. 10 2.6 Document preparation and peer review ................ 11 3. EVIDENCE AND RECOMMENDATIONS ............................. 12 3.1 Physical activity interventions ............................. 13 3.2 Tobacco cessation interventions .......................... 16 3.3 Nutritional interventions ..................................... 18 3.4 Interventions for alcohol use disorders ................. 22 3.5 Cognitive interventions ....................................... 25 3.6 Social activity ...................................................... 27 3.7 Weight management ........................................... 29 3.8 Management of hypertension .............................. 32 3.9 Management of diabetes ...................................... 35 3.10 Management of dyslipidaemia ............................. 38 3.11 Management of depression ................................. 40 3.12 Management of hearing loss ................................ 43 4. IMPLEMENTATION CONSIDER ATIONS ................................... 46 5. PUBLICATION, DISSEMINATION AND EVALUATION ................................... 48 5.1 Publication and dissemination ............................... 49 5.2 Monitoring and evaluation ..................................... 50 5.3 Implications for further research ............................ 50 5.4 Future review and update ...................................... 51 REFERENCES ...................................................... 52 ANNEX 1: GUIDELINE DEVELOPMENT GROUP MEMBERS ........................................... 60 ANNEX 2: ASSESSMENT OF CONFLICT OF INTEREST ....................................................... 62 ANNEX 3: SCOPING QUESTIONS ............... 67 ANNEX 4: EVIDENCE REVIEW METHODOLOGY ................................................ 72 WEB ANNEX: EVIDENCE PROFILES (WHO/MSD/MER/19.1); https://www.who.int/mental_health/neurology/dementia/ guidelines_risk_ reduction/en/index.html GLOSSARY ............................................................ 77 CONTE NTS iv Risk reduction of cognitive decline and dementia: WHO guidelines vFOREWORD Dementia is a rapidly growing public health problem affecting around 50 million people around the world. There are nearly 10 million new cases every year and this figure is set to triple by 2050. Dementia is a major cause of disability and dependency among older people and can devastate the lives of affected individuals, their carers and families. Additionally, the disease inflicts a heavy economic burden on societies as a whole, with the costs of caring for people with dementia estimated to rise to US$ 2 trillion annually by 2030. While there is no curative treatment for dementia, the proactive management of modifiable risk factors can delay or slow onset or progression of the disease. In May 2017, the Seventieth World Health Assembly endorsed a Global Action Plan on the Public Health Response to Dementia 2017–2025, urging Member States to develop, as soon as feasible, ambitious national responses to address this challenge. Dementia risk reduction is one of the seven action areas in the global action plan. These new WHO guidelines provide the knowledge base for health care providers, governments, policy-makers and other stakeholders to reduce the risks of cognitive decline and dementia through a public health approach. As many of the risk factors for dementia are shared with those of non- communicable diseases, the key recommendations can be effectively integrated into programmes for tobacco cessation, cardiovascular disease risk reduction and nutrition. I urge all stakeholders to make the best use of these recommendations to improve the lives of people with dementia, their carers and their families. Dr Ren Minghui Assistant Director-General for Universal Health Coverage/Communicable and Noncommunicable Diseases, World Health Organization vi Risk reduction of cognitive decline and dementia: WHO guidelines GUIDELINE DEVELOPMENT GROUP Chair: Martin Prince, King’s College, London, United Kingdom. Members: Charles Alessi, Public Health England, London, United Kingdom; Kaarin J Anstey, University of New South Wales, Sydney, Australia; Kimberly Ashby-Mitchell, Caribbean Public Health Agency, Port of Spain, Trinidad and Tobago; Adelina Comas- Herrera, London School of Economics, London, United Kingdom; Amit Dias, Department of Preventive and Social Medicine, Goa Medical College Bambolim, Goa, India; Cleusa P Ferri, Federal University of São Paulo, São Paulo, Brazil; Riadh Gouider, Razi Hospital, Faculty of Medicine, Tunis, Tunisia; Shinya Ishii, Ministry of Health, Labour and Welfare, Tokyo, Japan; Yves Joanette, Canadian Institutes of Health Research, Government of Canada; Joseph Kibachio, Ministry of Health, Nairobi, Kenya; Miia Kivipelto, Karolinska Institutet, Stockholm, Sweden; Shanthi Mendis, Colombo, Sri Lanka; Ayesha Motala, University of KwaZulu-Natal, Durban, South Africa; Ronald C Petersen, Mayo Clinic, Rochester, United States of America; Dorairaj Prabhakaran, Public Health Foundation of India, New Delhi, India; Suzana Shahar, Universiti Kebangsaan Malaysia, Selangor, Malaysia; Ameenah Bibi Mia Sorefan, Ministry of Health and Quality of Life, Quatre-Bornes, Mauritius; Kusumadewi Suharya (Dy), Alzheimer’s Disease International, Jakarta, Indonesia; Huali Wang, Dementia Care & Research Center, Peking University Institute of Mental Health, Beijing, China. Grade methodologist: Corrado Barbui, University of Verona, Italy. EXTERNAL REVIEW GROUP Abdullah Al Khatami, Ministry of Health, Saudi Arabia; Emiliano Albanese, Università della Svizzera italiana, Switzerland; Alistair Burns, University of Manchester, United Kingdom; Linda Clare, University of Exeter, United Kingdom; Jacqueline Dominguez, Institute for Dementia Care Asia, Quezon City, Philippines; Hillary Doxford, 3 Nations Dementia Working Group, United Kingdom; Maelënn Guerchet, Global Observatory for Ageing and Dementia Care, King’s College London, United Kingdom; Mariella Guerra, Institute of Memory, Depression and Related Disorders, Lima, Peru; Luis Miguel F Gutiérrez Robledo, Instituto Nacional de Geriatría, Institutos Nacionales de Salud de México, Mexico City, Mexico; Vladimir Hachinski, University of Western Ontario in London, Ontario, Canada; Qurat-ul Ain Khan, Aga Khan University Hospital, Karachi, Pakistan; Sebastian Koehler, Maastricht University, The Netherlands; Jae-hong Lee, University of Ulsan College of Medicine, Seoul, Republic of Korea; Gill Livingstone, University College London, United Kingdom; Jean Claude Mbanya, Doctoral School of Life Sciences, Health and Environment, University of Yaoundé I, Cameroon; James McKillop, service user group representative, United Kingdom; Elaine Rashbrook, Public Health England, United Kingdom; Rajat Ray, National Drug Dependence Treatment Centre, All India Institute of Medical Sciences, New Delhi, India; Helen Rochford Brennan, European Working Group of People with Dementia, Ireland; Andrew Sommerlad, University College London, United Kingdom; Kate Swaffer, Dementia Alliance International, Australia; Weili Xu, Karolinska Institutet, Finland. WHO GUIDELINE STEERING GROUP Overall coordination: Tarun Dua, Programme Manager, Department of Mental Health and Substance Abuse; Neerja Chowdhary, Technical Officer, Department of Mental Health and Substance Abuse. WHO headquarters members: Katthyana Aparicio Reyes, Department of Service Delivery and Safety; Islene Araujo de Carvalho, Department of Ageing and Life Course; Lubna Bhatti, Department of Prevention of Noncommunicable Diseases; Fiona Bull, Department of Prevention of Noncommunicable Diseases; Shelly Chadha, Department of Management of Noncommunicable Diseases, Disability, Violence and Injury Prevention; Alarcos Cieza, Department of Management of Noncommunicable Diseases, Disability, Violence and Injury Prevention; Stéfanie Fréel, Department of Mental Health and Substance Abuse; Maria Garcia Casal, Department of Nutrition for Health and Development; Angela Luzia Herscheid, ACK NOWLE DG E M E NTS viiAcknowledgements Department of Mental Health and Substance Abuse; Michal Herz, Department of Mental Health and Substance Abuse; Dzmitry Krupchanka, Department of Mental Health and Substance Abuse; Artin Mahdanian, Department of Mental Health and Substance Abuse; Shanthi Pal, Department of Essential Medicines and Health Products; Anne Margriet Pot, Department of Ageing and Life Course; Gojka Roglic, Department of Management of Noncommunicable Diseases, Disability, Violence and Injury Prevention; Katrin Seeher, Department of Mental Health and Substance Abuse. WHO regional office advisors: Nazneen Anwar, WHO Regional Office for South-East Asia; Dan Chisholm, WHO Regional Office for Europe; Devora Kestel, WHO Regional Office for the Americas; Sebastiana Da Gama Nkomo, WHO Regional Office for Africa; Khalid Saeed, WHO Regional Office for the Eastern Mediterranean; Martin Vandendyck, WHO Regional Office for the Western Pacific. WHO evidence review and synthesis teams: Mariagnese Barbera, University of Eastern Finland, Kuopio, Finland; Nicole A Ee, University of New South Wales, Sydney, Australia; Jenni Kumlala, Karolinska Institutet, Stockholm, Sweden; Ruth Peters, University of New South Wales, Sydney, Australia; Lidan Zheng, University of New South Wales, Sydney, Australia. FUNDING SOURCE Funds received from Public Health England, United Kingdom; Centers for Disease Control and Prevention, United States of America; and the WHO Core Voluntary Contributions Account were used for the development of these guidelines. viii Risk reduction of cognitive decline and dementia: WHO guidelines ACE angiotensin converting enzyme AD Alzheimer disease ADAS-cog Alzheimer Disease Assessment Scale-Cog ADL activities of daily living AHRQ Agency for Healthcare Research and Quality (United States of America) ARB angiotensin receptor blocker BMI body mass index CCB calcium channel blocker CI confidence interval CVRF cardiovascular risk factors CVD cardiovascular disease DALYs disability-adjusted life years DASH dietary approaches to stop hypertension DoI declaration of interest EMBASE Excerpta Medica dataBASE ERG external review group GDG guideline development group (WHO) GDP gross domestic product GRADE Grading of Recommendations Assessment, Development and Evaluation HIV human immunodeficiency virus IADL instrumental activities of daily living ICOPE Integrated Care for Older People (WHO) LMIC low- and middle-income countries MCI mild cognitive impairment MDRS Mattis Dementia Rating Scale MeSH Medical Subject Headings mhGAP Mental Health Gap Action Programme (WHO) MMSE Mini Mental State Examination NCDs noncommunicable diseases NIA National Institute on Aging (United States of America) NICE National Institute of Health and Care Excellence (United Kingdom) OR odds ratio ACRONYMS ixAcronyms PEN Package of Essential Noncommunicable Disease Interventions (WHO) PICO population, intervention, comparison, outcome PUFA polyunsaturated fatty acids RCT randomized controlled trial RR relative risk SMD standardized mean difference x Risk reduction of cognitive decline and dementia: WHO guidelines E XECUTIVE SUMMARY INTRODUCTION Dementia is a rapidly growing global public health problem. Worldwide, around 50 million people have dementia, with approximately 60% living in low- and middle-income countries (LMIC). Every year, there are nearly 10 million new cases. The total number of people with dementia is projected to reach 82 million in 2030 and 152 million in 2050. Dementia leads to increased costs for governments, communities, families and individuals, and to loss in productivity for economies. In 2015, the total global societal cost of dementia was estimated to be US$ 818 billion, equiv- alent to 1.1% of global gross domestic product (GDP). Crucially, while age is the strongest known risk factor for cognitive decline, dementia is not a natural or inevi- table consequence of ageing. Several recent studies have shown a relationship between the development of cognitive impairment and dementia with lifestyle- related risk factors, such as physical inactivity, tobacco use, unhealthy diets and harmful use of alcohol. Certain medical conditions are associated with an increased risk of developing dementia, including hypertension, diabetes, hypercholesterolemia, obesity and depression. Other potentially modifiable risk factors include social isolation and cognitive inactivity. The existence of potentially modifiable risk factors means that prevention of dementia is possible through a public health approach, including the implementation of key interventions that delay or slow cognitive decline or dementia. In May 2017, the Seventieth World Health Assembly endorsed the Global action plan on the public health response to dementia 2017–2025 (WHO, 2017a). The action plan includes seven strategic action areas and xiExecutive Summary dementia risk reduction is one of them. The action plan calls upon the WHO Secretariat to strengthen, share and disseminate an evidence base to support policy interventions for reducing potentially modifiable risk factors for dementia. This involves providing a database of available evidence on the prevalence of those risk factors and the impact of reducing them; and supporting the formulation and implementation of evidence-based, multisectoral interventions for reducing the risk of dementia. The risk reduction guidelines for cognitive decline and dementia are aligned with WHO’s mandate to provide evidence-based guidance for a public health response to dementia. GUIDELINE DEVELOPMENT METHODS The process of development of these guidelines followed the WHO handbook for guideline development and involved: 1. recruitment of the guideline development group (GDG); 2. declaration of interest by GDG members and peer reviewers; 3. scoping review to formulate questions and select outcomes; 4. identification, appraisal and synthesis of available evidence; 5. formulation of recommendations with inputs from a wide range of stakeholders; and 6. preparation of documents and plans for dissemination. The GDG, an international group of experts, provided input into the scope of the guidelines and assisted the steering group in developing the key questions. A total of 12 PICO (population, intervention, comparison and outcome) questions were developed. To address the PICO questions, a series of searches for systematic reviews was conducted and Grading of Recommendations Assessment, Development and Evaluation (GRADE) evidence profiles prepared. During a meeting at WHO headquarters in Geneva, 2–3 July 2018, the GDG discussed the evidence, sought clarifications and interpreted the findings in order to develop recommendations. The GDG considered the balance of benefit and harm of each intervention; values and preferences; costs and resource use; and other relevant practical issues for providers in LMIC. When making a strong recommendation, the GDG was confident that the desirable effects of the inter- vention outweigh any undesirable effects. When the GDG was uncertain about the balance between the desirable and undesirable effects, the GDG issued a conditional recommendation. Strong recommenda- tions imply that most individuals would want the intervention and should receive it, while conditional recommendations imply that different choices may be appropriate for individual patients and they may require assistance at arriving at management decisions. The GDG members reached a unanimous agreement on all the recommendations and ratings. xii Risk reduction of cognitive decline and dementia: WHO guidelines SUMMARY OF RECOMMENDATIONS Physical activity interventions Physical activity should be recommended to adults with normal cognition to reduce the risk of cognitive decline. Quality of evidence: moderate Strength of the recommendation: strong Physical activity may be recommended to adults with mild cognitive impairment to reduce the risk of cognitive decline. Quality of evidence: low Strength of the recommendation: conditional Tobacco cessation interventions Interventions for tobacco cessation should be offered to adults who use tobacco since they may reduce the risk of cognitive decline and dementia in addition to other health benefits. Quality of evidence: low Strength of the recommendation: strong Nutritional interventions The Mediterranean-like diet may be recommended to adults with normal cognition and mild cognitive impairment to reduce the risk of cognitive decline and/or dementia. Quality of evidence: moderate Strength of the recommendation: conditional A healthy, balanced diet should be recommended to all adults based on WHO recommendations on healthy diet. Quality of evidence: low to high (for different dietary components) Strength of the recommendation: strong Vitamins B and E, polyunsaturated fatty acids and multi-complex supplementation should not be recommended to reduce the risk of cognitive decline and/or dementia. Quality of evidence: moderate Strength of the recommendation: strong Interventions for alcohol use disorders Interventions aimed at reducing or ceasing hazardous and harmful drinking should be offered to adults with normal cognition and mild cognitive impairment to reduce the risk of cognitive decline and/or dementia in addition to other health benefits. Quality of evidence: moderate (for observational evidence) Strength of the recommendation: conditional Cognitive interventions Cognitive training may be offered to older adults with normal cognition and with mild cognitive impairment to reduce the risk of cognitive decline and/or dementia. Quality of evidence: very low to low Strength of the recommendation: conditional Social activity There is insufficient evidence for social activity and reduction of risk of cognitive decline/dementia. Social participation and social support are strongly connected to good health and well- being throughout life and social inclusion should be supported over the life-course. xiiiExecutive Summary Weight management Interventions for mid-life overweight and/or obesity may be offered to reduce the risk of cognitive decline and/or dementia. Quality of evidence: low to moderate Strength of the recommendation: conditional Management of hypertension Management of hypertension should be offered to adults with hypertension according to existing WHO guidelines. Quality of evidence: low to high (for different interventions) Strength of the recommendation: strong Management of hypertension may be offered to adults with hypertension to reduce the risk of cognitive decline and/or dementia. Quality of evidence: very low (in relation to dementia outcomes) Strength of the recommendation: conditional Management of diabetes mellitus The management of diabetes in the form of medications and/or lifestyle interventions should be offered to adults with diabetes according to existing WHO guidelines. Quality of evidence: very low to moderate (for different interventions) Strength of the recommendation: strong The management of diabetes may be offered to adults with diabetes to reduce the risk of cognitive decline and/or dementia. Quality of evidence: very low Strength of the recommendation: conditional Management of dyslipidaemia Management of dyslipidaemia at mid-life may be offered to reduce the risk of cognitive decline and dementia. Quality of evidence: low Strength of the recommendation: conditional Management of depression There is currently insufficient evidence to recommend the use of antidepressant medicines for reducing the risk of cognitive decline and/or dementia. The management of depression in the form of antidepressants and/or psychological interventions should be provided to adults with depression according to existing WHO mhGAP guidelines. Management of hearing loss There is insufficient evidence to recommend use of hearing aids to reduce the risk of cognitive decline and/or dementia. Screening followed by provision of hearing aids should be offered to older people for timely identification and management of hearing loss as recommended in the WHO ICOPE guidelines. xiv Risk reduction of cognitive decline and dementia: WHO guidelines 1 INTRODUC TION 1Introduction 1.1 BACKGROUND AND RATIONALE FOR THESE GUIDELINES Dementia, a group of disorders characterized by a decline from a previously attained cognitive level that affects activities of daily living (ADL) and social functioning, poses one of the greatest global challenges for health and social care in the 21st century. In 2015, dementia affected 50 million people worldwide (or roughly 5% of the world’s elderly population, i.e. those above the age of 60 years). The number of people with dementia is expected to increase to 82 million in 2030 and 152 million by 2050 with the estimated proportion of the population aged 60 and over with dementia at a given time between 5 to 8% 1 because dementia rises exponentially during old age and the world’s population is ageing. These projections assume constant age- and sex-specific prevalence of dementia over time, and, accordingly, the steepest rises are expected especially in low- and middle- income countries (LMIC), where the demographic changes will be more marked. Dementia is a major cause of disability and dependency among older people worldwide, and it has a significant impact not only on individuals but also on carers, families, communities and societies. Dementia accounts for 11.9% of the years lived with disability due to a noncommunicable disease (NCD) worldwide. Dementia leads to increased costs for governments, communities, families and individuals, and to loss in productivity for economies. The annual global cost of dementia is estimated to be US$ 818 billion (OECD, 2015; WHO, 2017b). Nearly 85% of costs are related to family and social, rather than medical, care (GBD 2015 Neurological Disorders Collaborator Group, 2017). Most health systems are ill-equipped and under-resourced to respond to the current needs associated with dementia. Thus, societal ageing and the associated increases in dementia prevalence will likely have major health-service implications for the care of people with dementia and support for affected families. There are many different causes and types of demen- tia. Primary dementias include: dementia due to Alzheimer disease (AD), vascular dementia, dementia with Lewy bodies and frontotemporal dementia (in which the decline in cognitive abilities itself is mostly due to an underlying neurodegenera-tive process and not directly caused by other etiologies). Alzheimer disease is the most common, followed by vascular dementia and dementia with Lewy bodies. Mixed dementia with features of more than one type is also common, especially in older adults, while frontotemporal dementia is a less common form but relatively more frequent before old age. Secondary dementias are those caused by, or closely related to, some other recognizable disease, such as HIV, head injury, multiple sclerosis, thyroid disorders or vitamin B12 deficiency. In these secondary dementias, cognitive impairment is typically accompanied by symptoms and signs in other organ systems and the treatment focuses on management of the underlying disease. For the scope of these guidelines we refer to primary dementias. Though early treatment of some diseases may have the potential to prevent the onset of secondary dementias, we are not including these 1 WHO & King’s College London (2017). Global prevalence of dementia – updated figures 2017. Available at: https://www.who.int/news-room/fact-sheets/detail/dementia 2 Risk reduction of cognitive decline and dementia: WHO guidelines secondary dementias in the scope of these guidelines since there are prevention or appropriate management and treatment strategies for most of these specific diseases and conditions, which effectively reduce dementia-related signs and symptoms. However, late-onset dementia is a heterogeneous and multifactorial condition and some factors (i.e. head trauma, B12 deficiency earlier in life) may also contribute to the development of dementia later in life (not only secondary dementia). RISK FACTORS FOR DEMENTIA Non-modifiable risk factors for dementia include gene polymorphisms, age, gender, race/ethnicity and family history. Crucially, while age is the strongest known risk factor for cognitive decline, dementia is not a natural or inevitable consequence of ageing. During the last two decades, several studies have shown a relationship between the development of cognitive impairment and dementia with educational attainment, and lifestyle-related risk factors, such as physical inactivity, tobacco use, unhealthy diets and harmful use of alcohol. Further, certain medical conditions are associated with an increased risk of developing dementia, including hypertension, diabetes, hypercholesterolemia, obesity and depression. Other potentially modifiable risk factors may include social isolation and cognitive inactivity. The risk factors included in the scope of these guidelines were chosen based on recent systematic reviews and guidelines, i.e. National Institute of Health and Care Excellence (United Kingdom) (NICE, 2015); the United States of America Agency for Healthcare Research and Quality (AHRQ) systematic review (Kane et al., 2017); the World Alzheimer report 2014 (Prince, et al., 2014) and the report by the Lancet Commission on Dementia Prevention, Intervention, and Care (Livingston et al., 2017). The current focus on modifiable risk factors is justified by their potential to be targeted for prevention of dementia, and/or the delay of the progression of cognitive decline. NEED FOR THESE GUIDELINES The existence of potentially modifiable risk factors means that prevention of dementia is possible through a public health approach, including the implementation of key interventions that delay or slow cognitive decline or dementia. In May 2017, the Seventieth World Health Assembly endorsed the Global action plan on the public health response to dementia 2017–2025 (WHO, 2017a). The vision of the action plan is a world in which dementia is prevented and people with dementia and their carers live well and receive the care and support they need to fulfil their potential with dignity, respect, autonomy and equality. The goal of the action plan is to improve the lives of people with dementia, their carers and families, while decreasing the impact of dementia on them as well as on communities and countries. The action plan includes seven strategic action areas, and dementia risk reduction is one of them. The action plan calls upon the WHO Secretariat to strengthen, share and disseminate an evidence base to support policy interventions for reducing potentially modifiable risk factors for dementia. This involves providing a database of available evidence on the prevalence of those risk factors and the impact of reducing them; and supporting the formulation and implementation of evidence-based, multi-sectoral interventions for reducing the risk of dementia. These current guidelines represent the first steps to support countries as they develop approaches to delay or prevent the onset of dementia. 3Introduction The risk reduction guidelines for cognitive decline and dementia are aligned with WHO’s mandate to provide evidence-based guidance for a public health response to dementia. By supporting health and social care professionals, particularly by improving their capacity to provide evidence-based, multisectoral, gender and culturally appropriate interventions to the general population, including modifiable dementia risk factors that are shared with other NCDs, the risk of developing dementia can be potentially reduced, or its progression delayed. Thus, the guidelines align with WHO’s work in the area of prevention and management of NCDs, which aims to support countries to reduce the incidence, morbidity and mortality of NCDs. WHO has collaborated with a range of stakeholders, including international and national public health agencies working in the area of prevention of NCDs and dementia. The guidelines are in close conceptual and strategic synergy with other WHO action plans and strategies, i.e. the Comprehensive mental health action plan 2013– 2020,2 the Global action plan for the prevention and control of noncommunicable diseases 2013–2020,3 the Global strategy and action plan on ageing and health 2016–2020,4 the Global strategy to reduce harmful use of alcohol5 and the Global strategy on diet, physical activity and health.6 Furthermore, this work is aligned with the WHO move towards making health services more people-centred. Finally, the work will contribute to the attainment of Sustainable Development Goal 3, target 3.8, i.e. achieve universal health coverage, including financial risk protection, access to quality essential healthcare services and access to safe, effective, quality and affordable essential medicines and vaccines for all (UN, 2019). 1.2 RELATED WHO GUIDELINES AND TOOLS Several existing WHO guidelines and tools designed for the general population are relevant for addressing health conditions that may increase the risk of cognitive decline or dementia in individuals with normal cognition or mild cognitive impairment (MCI). The following WHO guidelines and tools were consulted when developing the current guidelines: • mhGAP Intervention guide – Version 2.0 for mental, neurological and substance use disorders in non- specialized health settings. Geneva: WHO, 2016. http://www.who.int/mental_health/mhgap/mhGAP_ intervention_guide_02/en/ • Prevention and control of noncommunicable diseases: guidelines for primary health care in low- resource settings. Geneva: WHO, 2012. http://apps. who.int/iris/bitstream/10665/76173/1/9789241548397_ eng.pdf • Package of essential noncommunicable (PEN) disease interventions for primary health care in low-resource settings. Geneva: WHO, 2010. http:// www.who.int/cardiovascular_diseases/publications/ pen2010/en/ • Global recommendations on physical activity for health. Geneva: WHO, 2010. http://www.who.int/ dietphysicalactivity/publications/9789241599979/en/ • Integrated care for older people (ICOPE): Recommendations on interventions to improve physical and mental capacities of older people at community level. Geneva: WHO, 2016. 2 Available at http://www.who.int/mental_health/action_plan_2013/en/ 3 Available at http://www.who.int/nmh/publications/ncd-action-plan/en/ 4 Available at http://who.int/ageing/global-strategy/en/ 5 Available at http://www.who.int/substance_abuse/activities/gsrhua/en/ 6 Available at http://www.who.int/dietphysicalactivity/Indicators%20English.pdf 4 Risk reduction of cognitive decline and dementia: WHO guidelines • HEARTS Technical package for cardiovascular disease management in primary health care: evidence-based treatment protocols. http://www. who.int/cardiovascular_diseases/hearts/en/ • Global age-friendly cities: a guide. Geneva: WHO, 2007. http://www.who.int/ageing/publications/Global_ age_friendly_cities_Guide_English.pdf • Recommendations on healthy diet. Geneva: WHO, 2019. http://www.who.int/en/news- room/fact-sheets/detail/healthy-diet • Strengthening health systems for treating tobacco dependence in primary care. Geneva: WHO, 2013. http://www.who.int/tobacco/publications/building_ capacity/training_package/treatingtobaccodependence/en/ • Framework on integrated people-centred health services. Geneva: WHO, 2016. http://apps.who.int/ gb/ebwha/pdf_files/WHA69/A69_39-en.pdf?ua=1 These existing WHO guidelines and tools address some of the interventions that are included in the scope of the current guidelines, but they do not include cognitive decline or dementia as outcomes. Where the current guidelines overlap with the other guidelines, e.g. ICOPE guidelines, which provide recommendations on cognitive interventions in people with MCI, we have referred to these existing recommendations, rather than developing new ones. The current guidelines, therefore, complement, but do not duplicate, existing work. 1.3 TARGET AUDIENCE The guidelines are primarily targeted at health care providers working at a first or second level facility or at district level, including basic outpatient and inpatient services. The health care providers could be doctors, nurses or other cadres of health workers. Quality improvement teams at all levels of the system will benefit from the work. In addition, the guidelines and their derivative products have implications for policy-makers, health care planners and programme managers at national and international level, as well as the general population. 1.4 GOALS AND OBJECTIVES • To provide evidence-based recommendations on lifestyle behaviours and interventions to delay or prevent cognitive decline and dementia in the general population. • To provide evidence-based recommendations on management of specific physical and mental health conditions to delay or prevent cognitive decline and dementia. 5Introduction These guidelines provide up-to-date WHO evidence- based recommendations to facilitate implementing the Global action plan on the public health response to dementia 2017–2025, the Comprehensive mental health action plan 2013–2020 and WHO’s Mental Health Gap Action Programme (mhGAP),7 the Global action plan for the prevention and control of noncommunicable diseases 2013–2020,8 the Global strategy and action plan on ageing and health 2016–2020,9 the Global strategy to reduce harmful use of alcohol,10 and the Global strategy on diet, physical activity and health.11 1.5 GUIDING PRINCIPLES The following principles have informed the development of these guidelines and should guide their implementation: • The guidelines should expedite the achievement of the goals outlined in the Global action plan on the public health response to dementia 2017–2025, as well as target 3.4 of the Sustainable Development Goals, which focuses on reducing the premature mortality from NCDs and the promotion of mental health and well-being (UN, 2019). • The process of developing these guidelines, and their subsequent implementation, should concretely foster the right to equal levels of health for people at risk of cognitive decline and dementia and promote their active involvement. • The recommendations should be implemented with accompanying efforts to safeguard the human rights of persons living with cognitive decline and dementia, including reduction of stigma and discrimination, reducing barriers to seek health and social care services, and ensuring informed decision-making in treatment choices. Implementation of the recommendations should be tailored to the local context, including the availability of financial and human resources. However, the inequities addressed in these guidelines are common across all countries, and should be made a priority in health services. 7 Available at http://www.who.int/mental_health/action_plan_2013/en/ 8 Available at http://www.who.int/nmh/publications/ncd-action-plan/en/ 9 Available at http://who.int/ageing/global-strategy/en/ 10 Available at http://www.who.int/substance_abuse/activities/gsrhua/en/ 11 Available at http://www.who.int/dietphysicalactivity/Indicators%20English.pdf 6 Risk reduction of cognitive decline and dementia: WHO guidelines GUIDE LINE DEVE LOPME NT PROCESS 2 7Guideline development process The process of developing these guidelines followed the WHO Handbook for guideline development (2nd edition, http://apps.who.int/ medicinedocs/en/m/abstract/Js22083en/). It consisted of the following steps. 2.1 GUIDELINE DEVELOPMENT GROUP A WHO guideline steering group, led by the Department of Mental Health and Substance Abuse, was established with representatives from WHO regional offices and relevant WHO departments and programmes. The guideline steering group provided overall support to the guideline development process. Two additional groups were established: a guideline development group (GDG) and an external review group (ERG). The GDG included a panel of academicians and clinicians with multidisciplinary expertise on the conditions covered by the guidelines. Consideration was given to geographic diversity and gender balance (see Annex 1). As a respected researcher in the field, the Chairperson was selected for their extensive experience of guideline development methodology, and their participation in other guideline development groups. Each potential GDG member was asked to complete the WHO declaration of interest (DoI) form. These were reviewed by the steering group. 2.2 DECLARATIONS OF INTEREST BY THE GDG MEMBERS AND EXTERNAL REVIEWERS All GDG members, peer reviewers and systematic review team members were requested to complete the DoI prior to the evidence review process for guideline development. Invitations to participate in the GDG meeting were sent only after the DoI had been reviewed and approved. The GDG members were also required to complete a confidentiality undertaking. Once received, the WHO Secretariat reviewed the DoIs, as well as additional information (internet and bibliographic database search), and evaluated if there were any conflicts of interest and if so, whether these required a management plan. The group composition was finalized after this process. The names and brief biographies of the members being considered for participation in the GDG were disclosed for public notice and comment prior to the meeting. At the beginning of the GDG meeting, the DoI of each GDG member were presented and GDG members, as well as external partners, were asked to update their DoI with relevant changes by notifying the WHO Secretariat. Declarations of interest were reassessed for potential conflict before the face-to-face meeting in Geneva. None of the members had major conflicts of interest. All decisions were documented (see Annex 2). 8 Risk reduction of cognitive decline and dementia: WHO guidelines 2.3 COLLABORATION WITH EXTERNAL PARTNERS The Center for Alzheimer Research at the Karolinska Institutet, Stockholm, Sweden, and the School of Psychology at the University of New South Wales and Neuroscience Research, Australia, supported the development of the guidelines by conducting the evidence review and synthesis. 2.4 IDENTIFYING, APPRAISING AND SYNTHESIZING AVAILABLE EVIDENCE The procedure of the scoping review to identify the draft population, intervention, comparison, outcome (PICO) questions consisted of the identification of potentially modifiable risk factors and interventions for cognitive decline or dementia. These interventions are summarized in existing WHO guidelines listed earlier, such as the Prevention and control of noncommunicable diseases; Package of essential noncommunicable (PEN) disease interventions for primary health care in low-resource settings; and Integrated care for older people (ICOPE) guidelines. These guidelines, however, do not include cognitive decline or dementia as outcomes. Among recent summary reports, the Lancet Commission on Dementia Prevention, Intervention, and Care report summarizes the emerging knowledge on dementia risk factors and interventions (Livingston et al., 2017). The risk factors and interventions reported in this set of systematic reviews included education, exercise, maintaining social engagement, reducing smoking, and management of hearing loss, depression, hypertension, diabetes and obesity. Another systematic review requested and supported by the National Institute on Aging (NIA) at the National Institutes of Health, United States of America, also identified risk factors and evidence for interventions, specifically cognitive training, blood pressure management and exercise (Kane et al., 2017). The interventions reported in these reviews have formed the basis of the interventions included in the PICO questions. The population in these guidelines considered adults with normal cognition as well as those with MCI. We use the term MCI to refer to a disorder characterized by impairment of memory, learning difficulties and reduced ability to concentrate on a task for more than brief periods, beyond what is expected in normal ageing. There is often a marked feeling of mental fatigue when mental tasks are attempted, and new learning is found to be subjectively difficult even when objectively successful. None of these symptoms is so severe that a diagnosis of dementia can be made. Individuals diagnosed with MCI, however, are at greater risk of developing dementia; the inclusion of adults with MCI in these guidelines will enable the use of interventions to slow the progression of cognitive decline, i.e. the transition from MCI to dementia itself. 9The scope of these guidelines is prevention/risk reduction of cognitive decline or dementia (main outcomes of interest). Cognitive decline is defined as a noticeable and measurable loss or abnormality in attention functions, memory functions or higher level cognitive functions (including attention, language and reasoning). Dementia is a syndrome that includes cognitive decline and other symptoms and can be diagnosed based on ICD-10 criteria. It involves a decline in memory with impairment of at least one other cognitive function, such as skilled movements (limb apraxia), language (aphasia) or executive function (e.g. planning, attention and abstract reasoning). This decline should represent a change from previous behaviour, and impair social and/or occupational functioning. As stated in the background section, when we use the word dementia in this document, we are referring to the primary or neurodegenerative dementias. The GDG provided input into the scope of the guidelines and assisted the steering group in developing the key questions. Twelve PICO-structured questions were developed (Annex 3). Outcomes were rated by GDG members according to their importance, as “critical”, “important” or “unimportant”. Those outcomes rated as critical and important were selected for inclusion into the PICO. Regular communication and discussions with the GDG were held by email and teleconferences, respectively. The systematic review team developed protocols to review the evidence that existed for the inter- ventions to reduce the risk of cognitive decline and/ or dementia (as outlined in the PICO questions) for adults with normal cognition or MCI (Annex 4). Existing relevant systematic reviews were identified for each of the PICO questions. The steering group assessed the quality of existing reviews using the assessment of multiple systematic reviews (AMSTAR) checklist. Systematic reviews found to be of high quality were also assessed for timeliness to ensure that the most current evidence was used. The Grading of Recommendations Assessment, Development and Evaluation (GRADE) methodology (Guyatt et al., 2011), as well as the WHO Handbook for guideline development, were used to develop the evidence profiles. The quality assessment of the evidence was performed according to GRADE considering study design – randomized controlled trials (RCT) or observational studies, risk of bias, inconsistency, indirectness, imprecision and risk of reporting bias. Evidence was characterized as either high, moderate, low or very low. Guideline development process 10 Risk reduction of cognitive decline and dementia: WHO guidelines 2.5 DECISION-MAKING DURING THE GDG MEETING The GDG met at the WHO headquarters in Geneva, 2–3 July 2018. The evidence review was sent out in advance and it was summarized in a presentation during the meeting. The GDG members discussed the evidence, clarified points and interpreted the findings in order to develop recommendations based on the draft prepared by the WHO Secretariat. The GDG considered the relevance of the recommendations for adults with normal cognition or MCI based on the GRADE Evidence-to-Decision (EtD) framework (Alonso-Coello et al., 2016), considering the balance of benefit and harm of each intervention; values and preferences of the individuals involved; costs and resource use; acceptability of the intervention to health care providers in LMIC; feasibility of implementation; and impact on equity and human rights. No surveys or formal cost-effectiveness studies to determine resource constraints were conducted but discussions of these domains were informed by the combined expertise and experience of the GDG members. Equity and human rights were considered by specifically searching databases that include studies from LMIC, examining data for disaggregation for specific subgroups. Potential differential effects of the interventions on different subgroups of people related to economic status, employment or occupation, education, place of residence, gender or ethnicity were considered by the GDG. Taking into account these considerations, when making a strong recommendation, the GDG was confident that the desirable effects of the intervention outweigh any undesirable effects. When the GDG was uncertain about the balance between the desirable and undesirable effects, the GDG issued a conditional recommendation. Strong recommendations imply that most individuals would want the intervention and should receive it, while conditional recommendations imply that different choices may be appropriate for individual patients and they may require assistance at arriving at management decisions. In some instances, even when the quality of evidence was low or very low, it was agreed that if the recommendation would be of general benefit, and this was seen to outweigh the harms, it may still be rated as strong. In the event of a disagreement, the Chair and the Methodologist would ascertain whether the dispute was related to the interpretation of the data or to the way that the recommendation was formulated. If a consensus agreement was not reached, the GDG members agreed to a majority vote of 70%, to determine a decision. WHO staff members present at the meeting, as well as other external technical experts involved in the collection and review of the evidence, were excluded from voting. The GDG members reached a consensus agreement on all recommendations and ratings and voting was not needed. 11 2.6 DOCUMENT PREPARATION AND PEER REVIEW The draft guideline and evidence profiles prepared by WHO staff and the GDG were circulated to the ERG and the steering group. The role of the ERG was to identify any errors or missing data and to comment on clarity, setting-specific issues and implications for implementation rather than changing the recommen- dations. All inputs and remarks were discussed and agreed with the GDG by email. 12 Risk reduction of cognitive decline and dementia: WHO guidelines This section provides an overview of each PICO question described under the following headings: background; recommendations and additional considerations; supporting evidence for the recommendations and the rationale for the recommendations based on the evidence synthesized as well as criteria listed in the EtD tables. Complete evidence profiles for each PICO question including the GRADE tables and the EtD tables are included in the Web Annex. EVIDE NCE AND RECOMME NDATIONS 3 13Evidence and recommendations Population: Adults (age above 18 years) with normal cognition or MCI Intervention: Physical activity interventions (aerobic, resistance training or multicomponent physical activity) Comparison: Care as usual or no intervention Outcomes: • Critical – Cognitive function – Incident MCI – Dementia • Important – Quality of life – Functional level (ADL, IADL) – Adverse events – Drop-out rates For adults with normal cognition or MCI, are physical activity interventions more effective than usual care or no intervention in reducing the risk of cognitive decline and/or dementia? 3.1 PHYSICAL ACTIVITY INTERVENTIONS BACKGROUND A physically active lifestyle is linked to brain health. In large observational studies with follow-up periods extending decades, physically active people seem less likely to develop cognitive decline, all-cause dementia, vascular dementia and Alzheimer disease when compared with inactive people (Gallaway et al., 2017; Hamer & Chida, 2009; Sofi et al., 2011; Stephen et al., 2017). Especially, the highest levels of physical exercise seem to be most protective (Hamer & Chida, 2009; Sofi et al., 2011). Physical activity seems to have beneficial effects on brain structures, which may underlie this association (Rovio et al., 2010). Other potential mechanisms underlying the association are most likely indirect, such as the positive effects of physical exercise on other modifiable cardiovascular risk factors (CVRFs), including hypertension, insulin resistance and high cholesterol levels as well as other biological mechanisms, including but not limited to enhancing the immune system function, anti-inflammatory properties, and increasing neurotrophic factors. Physical activity interventions are described in WHO’s Global recommendations on physical activity for health (2010). RECOMMENDATIONS AND CONSIDERATIONS RECOMMENDATION 1: Physical activity should be recommended to adults with normal cognition to reduce the risk of cognitive decline. Quality of evidence: moderate Strength of the recommendation: strong 14 Risk reduction of cognitive decline and dementia: WHO guidelines RECOMMENDATION 2: Physical activity may be recommended to adults with MCI to reduce the risk of cognitive decline. Quality of evidence: low Strength of the recommendation: conditional WHO’s Global recommendations on physical activity for health (2010) (http://www.who.int/dietphysicalactivity/publications/9789241599979/en/) Below is an extract from these recommendations for adults 65 years and above: For adults 65 years and above, physical activity includes recreational or leisure-time physical activity, transportation (e.g. walking or cycling), occupational (if the person is still engaged in work), household chores, play, games, sports or planned exercise, in the context of daily, family, and community activities. In order to improve cardiorespiratory and muscular fitness, bone and functional health, and reduce the risk of NCDs, depression and cognitive decline, the following are recommended: 1. Adults aged 65 years and above should do at least 150 minutes of moderate-intensity aerobic physical activity throughout the week, or do at least 75 minutes of vigorous-intensity aerobic physical activity throughout the week, or an equivalent combination of moderate- and vigorous-intensity activity. 2. Aerobic activity should be performed in bouts of at least 10 minutes’ duration. 3. For additional health benefits, adults aged 65 years and above should increase their moderate- intensity aerobic physical activity to 300 minutes per week, or engage in 150 minutes of vigorous-intensity aerobic physical activity per week, or an equivalent combination of moderate- and vigorous-intensity activity. 4. Adults of this age group with poor mobility should perform physical activity to enhance balance and prevent falls on 3 or more days per week. 5. Muscle-strengthening activities should be done involving major muscle groups, on 2 or more days per week. 6. When adults of this age group cannot do the recommended amounts of physical activity due to health conditions, they should be as physically active as their abilities and conditions allow. Overall, across all the age groups, the benefits of implementing the above recommendations, and of being physically active, outweigh the harms. At the recommended level of 150 minutes per week of moderate-intensity activity, musculoskeletal injury rates appear to be uncommon. In a population- based approach, in order to decrease the risks of musculoskeletal injuries, it would be appropriate to encourage a moderate start with gradual progress to higher levels of physical activity. 15Evidence and recommendations Additional considerations include: • Physical activity is easily available for everybody and has a large range of beneficial effects. • Aerobic activity plays a key role in the beneficial effect of physical activity. SUPPORTING EVIDENCE AND RATIONALE For physical activity interventions (e.g. aerobic, resistance training or multicomponent physical activity) compared with usual care or no intervention, four systematic reviews were identified for six different physical activity interventions (Barha et al., 2017; Barreto et al., 2017; Northey et al., 2018; Song et al., 2018). These were: 1. Aerobic exercise intervention versus usual care or no intervention in adults with normal cognition. 2. Training exercise intervention versus usual care or no intervention in adults with normal cognition. 3. Multimodal exercise intervention versus usual care or no intervention in adults with normal cognition. 4. Aerobic exercise intervention versus usual care or no intervention in adults with MCI. 5. Training exercise intervention versus usual care or no intervention in adults with MCI. 6. Multimodal exercise intervention versus usual care or no intervention in adults with MCI. For cognitive outcomes in healthy adults, there is moderate quality evidence which indicates that physical activity interventions have a positive effect on cognition. There is low to moderate quality evidence that suggests that physical activity does not affect risk of MCI and dementia. For cognitive outcomes in adults with MCI, there is low quality evidence that indicates that physical activity interventions have a positive effect on cognition. However, these benefits are not consistent across all cognitive domains. The evidence shows that the effect size is larger for aerobic training versus resistance training and there is stronger evidence for adults with normal cognition (especially aerobic training) than in adults with MCI. The GDG concluded that the desirable effects of physical activity outweighed the undesirable effects. Overall, low to moderate quality evidence has shown that physical activity has a small but beneficial effect on cognition. Even in MCI populations, low quality evidence suggests cognitive benefits of physical exercise. The effect of these interventions seems to be mostly due to aerobic exercise. Based on the quality of evidence, a strong recommendation was made for healthy adults and a conditional one for adults with MCI. 16 Risk reduction of cognitive decline and dementia: WHO guidelines Population: Adults with normal cognition or MCI who use tobacco Intervention: Interventions for tobacco cessation (behavioural interventions and pharmacological interventions including nicotine replacement therapy, bupropion, varenicline) Comparison: Care as usual or no intervention Outcomes: • Critical – Cognitive function – Incident MCI – Dementia • Important – Quality of life – Functional level (ADL, IADL) – Adverse events – Drop-out rates For adults with normal cognition or MCI who use tobacco, are interventions for tobacco cessation more effective than usual care or no intervention in reducing the risk of cognitive decline and/or dementia? 3.2 TOBACCO CESSATION INTERVENTIONS BACKGROUND Tobacco dependence is the leading cause of preventable death globally, causing an estimated 5 million deaths per year (WHO, 2011) and worldwide medical costs ranging in billions of US dollars (Lightwood et al., 2000). Tobacco is the major risk factor for a number of conditions, including many types of cancers, cardiovascular diseases (CVDs) and risk factors, and respiratory disorders (US Department of Health Human Services, 2004), and tobacco cessation has been demonstrated to significantly reduce these health risks (Pirie et al., 2013). Tobacco cessation has also been associated with reduced depression, anxiety and stress, and improved mood and quality of life compared with continuing to smoke (Taylor et al., 2014). Tobacco dependence is also associated with other disorders and age-related conditions, such as frailty and work ability in older people (Amorim et al., 2014; Kojima et al., 2015), as well as dementia and cognitive decline (Durazzo et al., 2014). Interventions to treat tobacco dependence can be very diverse, based on either or both behavioural/ psychological strategies and various pharmacological treatments. Non-pharmacological interventions can have mixed results (Niaura, 2008). Counselling is the most frequently used approach, but others have also been explored, such as mindfulness-based approaches, cognitive behavioural therapy, behavioural activation therapy, motivational interviewing, contingency manage- ment, and exposure and/or aversion to smoking. Among the pharmacological therapies for tobacco cessation, nicotine replacement therapy, bupropion and varenicline are the most common, but low overall treatment efficacy and adverse effects are key limitations (Gómez-Coronado et al., 2018). Combinations of non-pharmacological and pharmacological approaches seem to be the most effective in supporting tobacco cessation (Gómez- Coronado et al., 2018). 17Evidence and recommendations Additional considerations include: • In keeping with interventions described in the WHO training package for tobacco dependence, people who make use of tobacco should be advised to quit and the appropriate programmes aimed at preventing tobacco use uptake, promoting tobacco cessation, as well as diagnosing and treating tobacco dependence, should be established (http://www.who.int/ tobacco/publications/building_capacity/training_ package/treatingtobaccodependence/en/). The interventions include behavioural interventions, as well as pharmacological ones (i.e. nicotine replacement therapy, bupropion, varenicline). • Individual level interventions should be provided in the context of population level tobacco cessation programmes. SUPPORTING EVIDENCE AND RATIONALE No systematic reviews comparing tobacco cessation interventions with no intervention were identified. A large body of observational evidence is available on tobacco smoking as a risk factor for cognitive impairment and dementia. These studies show an association between tobacco smoking (including in mid-life) and dementia, or cognitive decline, in later life (Beydoun et al., 2014; Di Marco et al., 2014; Lafortune et al., 2016; North et al., 2015; Xu et al., 2015; Zhong et al., 2015). Only limited adverse events have been reported and only for pharmacological interventions (Motooka et al., 2018). Therefore, any type of intervention aimed at tobacco cessation is likely to be more beneficial than detrimental. The GDG made a strong recommendation although evidence from experimental intervention trials is not available, since tobacco use has substantial established harm and the epidemiological/ observational evidence on tobacco use and increased risk of dementia fulfils most of the Bradford-Hill’s criteria for causation (Lafortune et al., 2016). The evidence is strong, the population attributable risk is high, reproducible in different settings and with different study designs, specific, and indicates a dose- response effect. In addition, criteria such as temporality (mid-life smoking is correlated to a higher risk of late life dementia) (Lafortune et al., 2016), coherence (experimental laboratory results are in keeping with the observational evidence) (Durazzo et al., 2014) and mecha- nistic evidence suggest that smoking causes brain damage, underpinning subsequent cognitive decline. RECOMMENDATIONS AND CONSIDERATIONS RECOMMENDATION: Interventions for tobacco cessation should be offered to adults who use tobacco since they may reduce the risk of cognitive decline and dementia in addition to other health benefits. Quality of evidence: low Strength of recommendation: strong 18 Risk reduction of cognitive decline and dementia: WHO guidelines 3.3 NUTRITIONAL INTERVENTIONS Population: Adults with normal cognition or MCI Intervention: Dietary supplements (e.g. B vitamins, antioxidants, omega-3 and ginkgo) Comparison: Care as usual/placebo or one treatment versus another Outcomes: • Critical – Cognitive function – Incident MCI – Dementia • Important – Quality of life – Functional level (ADL, IADL) – Adverse events – Drop-out rates 3.3a For adults with normal cognition or MCI, are nutritional interventions including dietary supplements more effective than usual care or no intervention in reducing the risk/progression of cognitive decline and/or dementia? 3.3b For adults with normal cognition or MCI, are nutritional interventions such as healthy dietary patterns (e.g. the Mediterranean diet) more effective than usual care or no intervention in reducing the risk/progression of cognitive decline and/or dementia? Population: Adults with normal cognition or MCI Intervention: Healthy dietary pattern (e.g. the Mediterranean diet) Comparison: Care as usual or no intervention Outcomes: • Critical – Cognitive function – Incident MCI – Dementia • Important – Quality of life – Functional level (ADL, IADL) – Adverse events – Drop-out rates BACKGROUND A healthy diet throughout the life course plays a crucial role in optimal development, and in maintaining health and preventing NCDs. Previous dietary intervention studies have shown that dietary changes are involved in prevention of many conditions that increase the risk of dementia, such as diabetes (Diabetes Prevention Program Research Group, 2002; Tuomilehto et al., 2001) and CVD (Rees et al., 2013). Mechanistic and animal models have 19Evidence and recommendations suggested a variety of pathways that link dietary factors to neuropathological changes in the development of dementia (Swaminathan & Jicha, 2014). Therefore, dietary factors may be involved in the development of dementia, both directly and through their role on other risk factors, and a healthy diet may have a great preventive potential for cognitive impairment. The Mediterranean diet is the most extensively studied dietary approach, in general as well as in relation to cognitive function. Several systematic reviews of observational studies have concluded that high adherence to the Mediterranean diet is associated with decreased risk of MCI and AD, but modest adherence is not (Singh et al., 2014; Wu & Sun, 2017). Moreover, among participants with normal cognition, higher adherence is associated with better episodic memory and global cognition (Loughrey et al., 2017). Other promising dietary approaches associated with better cognitive function include: dietary approaches to stop hypertension (DASH) (Berendsen et al., 2017; Morris et al., 2015a; 2015b; Wengreen et al., 2013); and the brain health-specific Mediterranean-DASH Intervention for Neurodegenerative Delay (MIND) diet. Concerning individual foods and nutrients, consumption of fruit and vegetables (Jiang et al., 2017; Wu et al., 2017) and fish (Bakre et al., 2018; Zhang et al., 2016) are most consistently associated with decreased risk of dementia. Higher fish consumption has been linked to lower memory decline among healthy participants in many studies (Samieri et al., 2018), as well as intake of polyunsaturated fatty acids (PUFA) (fish-derived) (Zhang et al., 2016). Other foods and nutrients that have been associated with reduced risk of dementia or cognitive impairment are nuts, olive oil and coffee (Solfrizzi et al., 2017). Evidence has also been reported concerning folate, vitamin E, carotenes, vitamin C and vitamin D (Balion et al., 2012; Dangour et al., 2010; Rafnsson et al., 2013; Travica et al., 2017), but findings are inconsistent. RECOMMENDATIONS AND CONSIDERATIONS RECOMMENDATION 1: The Mediterranean-like diet may be recommended to adults with normal cognition and MCI to reduce the risk of cognitive decline and/or dementia. Quality of evidence: moderate Strength of the recommendation: conditional RECOMMENDATION 2: Healthy, balanced diet should be recommended to all adults based on WHO recommendations on healthy diet. Quality of evidence: low to high (for different dietary components) Strength of the recommendation: strong RECOMMENDATION 3: Vitamins B and E, PUFA and multi-complex supplementation should not be recommended to reduce the risk of cognitive decline and/or dementia. Quality of evidence: moderate Strength of the recommendation: strong 20 Risk reduction of cognitive decline and dementia: WHO guidelines Additional considerations include: • The evidence and recommendations provided assume that the nutritional status and potential micronutrients deficiencies in both mid-life and old age have been assessed and treated. • A balanced and varied diet represents a natural source of polyphenols and protein. • The recommendation about vitamins B and E, PUFA and multi-complex supplementation applies to people without nutrient deficiency. SUPPORTING EVIDENCE AND RATIONALE Observational studies have consistently reported that a healthy diet is associated with better cognitive performance (Berendsen et al., 2017; Frith et al., 2018; Loughrey et al., 2017; Morris et al., 2015; Wengreen et al., 2013), but the evidence from clinical trials is more inconsistent (D’Cunha et al., 2018; Fitzpatrick-Lewis et al., 2015a; 2015b; Forbes et al., 2015; Radd-Vagenas et al., 2018; Solfrizzi et al., 2018). It is important to acknowledge that interventions with dietary modifications that improve several aspects of dietary intake at once are more likely to promote better cognition compared with supplementation with only some nutrients. Dietary factors may have synergistic effects that are only evident in combinations of foods ( Jacobs Jr et al., 2009). WHO recommendations on a healthy diet (http://www.who.int/en/news-room/fact-sheets/detail/healthy-diet) For adults, the WHO guidelines recommend the following. A healthy diet contains: • Fruits, vegetables, legumes (e.g. lentils, beans), nuts and whole grains (e.g. unprocessed maize, millet, oats, wheat, brown rice). • At least 400 g (five portions) of fruits and vegetables a day. Potatoes, sweet potatoes, cassava and other starchy roots are not classified as fruits or vegetables. • Less than 10% of total energy intake from free sugars which is equivalent to 50 g (or around 12 level teaspoons) for a person of healthy body weight consuming approximately 2000 calories per day, but ideally less than 5% of total energy intake for additional health benefits. Most free sugars are added to foods or drinks by the manufacturer, cook or consumer, and can also be found in sugars naturally present in honey, syrups, fruit juices and fruit juice concentrates. • Less than 30% of total energy intake from fats. Unsaturated fats (found in fish, avocado, nuts, sunflower, canola and olive oils) are preferable to saturated fats (found in fatty meat, butter, palm and coconut oil, cream, cheese, ghee and lard) and trans-fats of all kinds, including both industrially produced trans-fats (found in processed food, fast food, snack food, fried food, frozen pizza, pies, cookies, biscuits, wafers, margarines and spreads) and ruminant trans-fats (found in meat and dairy foods from ruminant animals, such as cows, sheep, goats, camels and others). It is suggested to reduce the intake of saturated fats to less than 10% of total energy intake and trans-fats to less than 1% of total energy intake. In particular, industrially produced trans-fats are not part of a healthy diet and should be avoided. • Less than 5 g of salt (equivalent to approximately 1 teaspoon) per day and use iodized salt. 21Evidence and recommendations Regarding nutritional interventions, such as dietary supplements or healthy dietary patterns (e.g. the Mediterranean diet) compared with usual care or no intervention, six systematic reviews were identified for nine different nutritional interventions. These interventions were: 1. Multi-supplement complexes versus placebo in adults with normal cognition (D’Cunha et al., 2018). 2. Multi-supplement complexes versus placebo in adults with MCI (Fitzpatrick-Lewis et al., 2015). 3. PUFA versus placebo (Forbes et al., 2015). 4. Vitamin B versus placebo (Forbes et al., 2015). 5. Vitamin E versus placebo (Forbes et al., 2015). 6. Polyphenols versus placebo (Solfrizzi et al., 2018). 7. Protein supplementation versus placebo (Solfrizzi et al., 2018). 8. Chicken essence versus placebo (Teoh et al., 2016). 9. Mediterranean diet versus alternate or usual diet (Radd-Vagenas et al., 2018). The outcomes of incident MCI and dementia were only reported for interventions involving multi- supplement complexes in adults with normal cognition and the Mediterranean diet (D’Cunha et al., 2018; Radd-Vagenas et al., 2018). However, neither of these interventions showed a direct effect in reducing the incidence of dementia and/or MCI. All of the interventions/comparisons reported cognitive outcomes. There was moderate quality evidence that the Mediterranean diet can improve verbal and visual memory (Radd-Vagenas et al., 2018). A meta-analysis showed results that approached significance for global cognition and consistently positive, but non-significant, results were reported for all other cognitive outcomes (attention, working memory, processing speed, language and executive function) (Radd-Vagenas et al., 2018). A consistent positive effect of polyphenols on cognitive performance was also found, however, the quality of the evidence was low (Solfrizzi et al., 2018). Similarly, protein supplementations were found to have a beneficial effect on cognition in older adults, but the results were inconsistent and the quality of the evidence was low (Solfrizzi et al., 2018). Overall, no effects were found for multi-complex (D’Cunha et al., 2018; Fitzpatrick-Lewis et al., 2015), vitamins B and E (Forbes et al., 2015), and PUFA supplementation (Forbes et al., 2015). Low-quality evidence was reported for protein and polyphenols supplementation (Solfrizzi et al., 2018), and moderate evidence of a beneficial effect of the Mediterranean diet was found (Radd-Vagenas et al., 2018). Three multi-supplement complex interventions: docosahexaenoic acid (DHA) + eicosapentaenoic acid (EPA) + vitamin E + soy phospholipids + tryptophan + melatonin; vitamin E + multivitamin; lyophilized royal jelly + gingko biloba + Panax ginseng; were examined and none showed an increased risk of any serious adverse event during the follow-up period (moderate quality evidence, Fitzpatrick-Lewis et al., 2015). The GDG concluded that the benefits of a Mediterranean diet and a balanced diet outweighed the harms and provided conditional and strong recommendations respectively. The GDG noted that vitamin E and protein supplementation at high doses have been associated with undesirable non- anticipated effects that outweigh the benefits and recommended against their use. 22 Risk reduction of cognitive decline and dementia: WHO guidelines Population: Adults with normal cognition or MCI and excessive use of alcohol Intervention: • Behavioural and psychological interventions to treat alcohol use disorders (e.g. motivational interviewing) • Pharmacological interventions to treat alcohol use disorders Comparison: Care as usual or no intervention Outcomes: • Critical – Cognitive function – Incident MCI – Dementia • Important – Quality of life – Functional level (ADL, IADL) – Adverse events – Drop-out rates For adults with normal cognition or MCI and alcohol use disorders, are behavioural and psychological interventions to treat alcohol use disorders more effective than usual care or no intervention in reducing the risk of cognitive decline and/or dementia? 3.4 INTERVENTIONS FOR ALCOHOL USE DISORDERS BACKGROUND Excessive alcohol consumption is common in many countries (Gell et al., 2015). In 2012, 5.9% of all deaths worldwide (about 3.3 million) were directly attributable to harmful use of alcohol (WHO, 2014). Furthermore, excessive consumption of alcohol is one of the leading causes of general disability globally (WHO, 2014), being a direct cause in more than 200 diseases including risk factors for dementia and injury conditions (WHO, 1992; WHO 2019a). There is extensive evidence on excessive alcohol as a risk factor for dementia and cognitive decline (Langballe et al., 2015; Sachdeva et al., 2016; Zhou et al., 2014). Several approaches have been applied in interventions aimed at hazardous and harmful use of alcohol. Pharmacological therapies with different types of drugs (e.g. opioid antagonists, ALDH2 inhibitors) have shown various degrees of efficacy for adults with alcohol use disorders, although none of them showed to be superior in comparison trials. Behaviour and psychological interventions have shown to be effective in alcohol use disorders, and especially among those with hazardous and harmful drinking. Screening and brief intervention in primary care is one of the most cost-effective means of reducing alcohol-attributable morbidity and deaths (Kaner, 2018). Interventions for alcohol use disorders have been described in the mhGAP Intervention guide - Version 2.0 for mental, neurological and substance use disorders in non-specialized health settings (http://www.who.int/mental_health/mhgap/mhGAP_ intervention_guide_02/en/). 23Evidence and recommendations RECOMMENDATIONS AND CONSIDERATIONS RECOMMENDATION Interventions aimed at reducing or ceasing hazardous and harmful drinking should be offered to adults with normal cognition and MCI to reduce the risk of cognitive decline and/or dementia in addition to other health benefits. Quality of evidence: moderate (for observational evidence) Strength of the recommendation: conditional WHO mhGAP Intervention guide - Version 2 for mental, neurological and substance use disorders in non-specialized health settings (http://www.who.int/mental_health/mhgap/mhGAP_intervention_guide_02/en/) The WHO mhGAP Intervention guide recommends the following: Harmful use of alcohol • Provide psychoeducation and emphasize that the level/pattern of alcohol use is causing harm to health. • Explore the person’s motivations for alcohol use. Conduct motivational interviewing. • Advise stopping alcohol completely or consuming at a non-harmful level (if a non-harmful level exists) and indicate your intention in supporting the person in doing so. Ask the person if they are ready to try to make this change. • Explore strategies for reducing or stopping use and strategies for reducing harm. • Address food, housing and employment needs. • Offer regular follow-up. Alcohol dependence • Thiamine during alcohol use. • Diazepam during alcohol detoxification to treat withdrawal symptoms. • Naltrexone, acamprosate or disulfiram to prevent relapse after detoxification. • Psychosocial interventions if available, e.g. cognitive behaviour therapy, motivational enhancement therapy, contingency management therapy, family counselling or therapy, problem-solving counselling or therapy; self-help groups. 24 Risk reduction of cognitive decline and dementia: WHO guidelines Additional considerations include: • Interventions can be based on lifestyle/ behavioural changes or pharmacological treatments in accordance with the WHO mhGAP guidelines. Lifestyle behavioural interventions are likely to be more acceptable and have fewer adverse events. • A U-shaped relationship between alcohol consumption and cognitive function has been reported. However, due to methodological limitations in most studies that describe this effect, it is not possible to assume that a light to moderate consumption of alcohol is, in fact, protective toward dementia and/or cognitive decline. This, in addition to other health risks and the social and economic burden associated with alcohol, do not favour a general recommendation of its use. • Individual level interventions should be provided in the context of WHO Global strategy to reduce harmful use of alcohol (WHO 2010) and population level interventions, through strengthening restrictions on alcohol availability, enforcing drink driving countermeasures, facilitating access to screening, brief interventions, and treatment, enforcing bans or comprehensive restrictions on alcohol advertising, sponsorship, and promotion, raising prices on alcohol through excise taxes and pricing policies. SUPPORTING EVIDENCE AND RATIONALE No systematic reviews were identified for interventions for hazardous and harmful alcohol consumption (behavioural, psychological and pharmacological interventions) and reduced the risk of cognitive decline and/or dementia. However, a large body of observational evidence is available on alcohol as a risk factor for cognitive decline and dementia (Beydoun et al., 2014; Hersi et al., 2017; Ilomaki et al., 2015; Lafortune et al., 2016; Piazza-Gardner et al., 2013; Xu et al., 2017). Generally, single studies did not always show similar results (mostly due to differences in study design) but the most consistent pattern is that of a U-shaped relationship between alcohol consumption and dementia and/or cognitive impairment, which clearly links excessive alcohol consumption to a significantly increased risk (Xu et al., 2017). A range of adverse events has also been reported for pharmacological interventions aimed at reducing excessive alcohol consumption while lifestyle interventions are mostly based on behavioural interventions and no evidence of adverse events (apart from those related to withdrawal syndrome) have been identified (NICE, 2011). Overall, the GDG concluded that the benefits outweighed the harms and, based on the strong observational evidence, made a conditional recommendation for interventions to reduce or cease hazardous and harmful alcohol use. 25Evidence and recommendations Population: Adults with normal cognition or MCI Intervention: • Cognitive stimulation • Cognitive training Comparison: Care as usual or no intervention Outcomes: • Critical – Cognitive function – Incident MCI – Dementia • Important – Quality of life – Functional level (ADL, IADL) – Adverse events – Drop-out rates For adults with normal cognition or MCI is cognitive stimulation or cognitive training more effective than usual care or no intervention in reducing the risk of cognitive decline and/or dementia? 3.5 COGNITIVE INTERVENTIONS BACKGROUND Dementia is preceded by cognitive decline. However, not everyone who is exposed to dementia risk factors will go on to develop cognitive impairment. The concept of cognitive reserve has been proposed as a protective factor that may reduce the risk of clinical onset of dementia and cognitive decline (Stern, 2012). Cognitive reserve refers to the brain’s ability to cope with or compensate for neuropathology or damage (Stern, 2012). Studies have shown that increased cognitive activity may stimulate (or increase) cognitive reserve and have a buffering effect against rapid cognitive decline (Stern & Munn, 2010) as well as a significant reduction in the risk of MCI or AD diagnosis in those who reported high compared with low levels of cognitive activities (combined OR = 0.38, 95% CI: 0.15–0.99) (Sattler, 2012). Increased cognitive activity can be achieved through cognitive stimulation therapy and/or cognitive training. Cognitive stimulation therapy refers to “participation in a range of activities aimed at improving cognitive and social functioning” (Clare & Woods, 2004), while cognitive training refers to “guided practice of specific standardized tasks designed to enhance particular cognitive functions” (Clare & Woods, 2004). The NIA (United States of America) identified cognitive training as an intervention aimed at preventing or delaying the onset of age-related cognitive decline, MCI, or clinical Alzheimer’s-type dementia (Kane et al., 2017). Additionally, the WHO ICOPE guidelines (http://www. who.int/ageing/publications/guidelines-icope/en/) recommend cognitive stimulation for older adults with cognitive impairment. These interventions were assessed against outcomes that were judged as critical and important for this population. 26 Risk reduction of cognitive decline and dementia: WHO guidelines SUPPORTING EVIDENCE AND RATIONALE For cognitive stimulation versus usual care or no intervention in healthy older adults, evidence was extracted from one systematic review (Strout et al., 2016). No evidence for adults with MCI was available. The review reported that half of the interventions evaluated proved to be effective in improving cognitive outcomes in at least one cognitive domain – executive function, attention, memory, language and/or processing speed (Strout et al., 2016). The quality of the evidence was low. The results were reported in narrative form and no meta-analysis was conducted. No evidence for incident MCI or dementia was available. For cognitive training versus usual care or no intervention in healthy older adults, evidence was extracted from one systematic review (Chiu et al., 2017). The review conducted a meta-analysis which showed that cognitive training in healthy older adults has a moderate positive effect on overall cognitive functioning. The quality of evidence was low. No evidence for incident MCI or dementia was available. For cognitive training versus usual care or no intervention in adults with MCI, evidence was extracted from two systematic reviews (Chandler et al., 2016; Sherman et al., 2017). With regards to cognitive function outcome, the quality of evidence is low showing that cognitive training in adults with MCI has a small positive effect on cognition. With regards to incident dementia outcome, the quality of evidence is very low as the results were narratively reported. It was reported that one study found that half of the control group, but none of the intervention group, developed dementia at the 8-month follow-up, while another found that more of the intervention group reported incident dementia at the 2-year follow-up (Chandler et al., 2016). With regards to quality of life and functional level, the quality of evidence is low showing that cognitive training in adults with MCI has a small positive effect on ADL but not quality of life. The evidence for cognitive interventions is mainly in studies with older adults. The GDG concluded that in this population the desirable effects of the intervention outweighed the undesirable effects and provided a conditional recommendation for cognitive training. The evidence for cognitive stimulation in reducing the risk of dementia was insufficient and no recommendation was made by the GDG. RECOMMENDATIONS AND CONSIDERATIONS RECOMMENDATION: Cognitive training may be offered to older adults with normal cognition and with MCI to reduce the risk of cognitive decline and/or dementia. Quality of evidence: very low to low Strength of the recommendation: conditional 27Evidence and recommendations Population: Adults with normal cognition or MCI Intervention: Comparison: Care as usual or no intervention Outcomes: • Critical – Cognitive function – Incident MCI – Dementia • Important – Quality of life – Functional level (ADL, IADL) – Adverse events – Drop-out rates For adults with normal cognition or MCI is preserving and promoting a high level of social activity more effective than usual care or no intervention in reducing the risk of cognitive decline and/or dementia? 3.6 SOCIAL ACTIVITY BACKGROUND Social engagement is an important predictor of well- being throughout life (Cherry et al., 2011). Social disengagement conversely, has been shown to place older individuals at increased risk of cognitive impairment and dementia (Fratiglioni et al., 2004). A systematic review and meta-analysis of longitudinal cohort studies showed that lower social participation, less frequent social contact and loneliness were associated with higher rates of incident dementia (Kuiper et al., 2015). The Lancet Commission on Dementia Prevention, Intervention, and Care identified social engagement as an intervention that could be used to prevent dementia (Livingston et al., 2017). RECOMMENDATIONS AND CONSIDERATIONS There is insufficient evidence for social activity and reduction of risk of cognitive decline/dementia. Social participation and social support are strongly connected to good health and well-being throughout life and social inclusion should be supported over the life-course. (Global age-friendly cities: a guide, http://www.who.int/ageing/publications/Global_age_friendly_ cities_Guide_English.pdf) 28 Risk reduction of cognitive decline and dementia: WHO guidelines SUPPORTING EVIDENCE AND RATIONALE For preservation and promotion of social activity including community and family engagement versus care as usual or no intervention, evidence was extracted from one systematic review examining adults with normal cognition (Kelly et al., 2017). No evidence for adults with MCI was available. For cognitive function outcomes, the quality of the evidence is very low. Three RCTs, which assessed the association between cognitive function and social activity, were deemed eligible. The review findings were reported narratively (Kelly et al., 2017). Overall cognition was measured by varied composite measures of global cognition, including the ADAS-cog, MMSE and MDRS. One of the three RCTs found social activity intervention to be significantly associated with improvements in cognitive function (Pitkala et al., 2011). No data were available for incident MCI or dementia, quality of life, functional level (ADL, IADL), adverse events or drop-outs. The GDG concluded that the evidence is limited and inconclusive, so no recommendation was made for social activity and risk of cognitive decline/dementia. Furthermore, there is a risk of bias arising from reverse causality whereby low social engagement prior to diagnosis of cognitive decline or dementia may be at least in part due to the disease process. The GDG did not make a recommendation against social activity as they concluded that social activity has a wide range of other benefits to health and well-being. 29Evidence and recommendations Population: Adults with normal cognition or MCI who are overweight or obese Intervention: Weight management • Non-pharmacological interventions, e.g. cognitive behavioural intervention strategies, lifestyle interventions • Pharmacological interventions, e.g. weight loss medication (e.g. orlistat) Comparison: Care as usual or no intervention Outcomes: • Critical – Cognitive function – Incident MCI – Dementia • Important – Quality of life – Functional level (ADL, IADL) – Adverse events – Drop-out rates For adults with normal cognition or MCI who are overweight or obese, are interventions for weight reduction (or control of obesity) more effective than usual care or no intervention in reducing the risk of cognitive decline and/or dementia? 3.7 WEIGHT MANAGEMENT BACKGROUND Overweight and obesity are some of the best characterized and established risks for a variety of NCDs, responsible for at least 2.8 million deaths each year worldwide, and of an estimated 35.8 million (2.3%) of global disability-adjusted life years (DALYs) (WHO, 2019b). In 2008, 35% of adults aged 20+ were overweight (BMI ≥ 25 kg/m2) (34% men and 35% of women), with significantly variable prevalence among world areas, with the United States of America, Europe and the Eastern Mediterranean regions with the highest concentration of people with overweight/ obesity (WHO, 2019b). Overweight and obesity, in particular, have been linked to a number of medical complications such as Type 2 diabetes (Chan et al., 1994), cancer (Renehan et al., 2015), premature mortality (Fontana & Hu, 2014), and CVD (Eckel, 1997), both as direct risk factors as well as risks for other cardiovascular risk factors, such as high cholesterol and hypertension. Obesity has been steadily rising, particularly among older adults in the last few decades (Nguyen & El-Serag, 2010) and although an increasing body of evidence suggests that overweight (25 < BMI < 30) in older adults could be more protective than normal weight in terms of overall mortality (Flicker et al., 2010), a link has also been established between excess of fat body mass and cognitive impairment (Xu et al., 2011). A recent systematic review and meta-analysis of observational studies conducted on a total of about 600 000 individuals showed that obesity (but not overweight) at mid-life increases the risk of dementia (RR = 1.33; 95% CI: 1.08–1.63) (Albanese et al., 2017). It has been suggested that weight loss could indirectly reduce the risk of dementia by improving a variety of metabolic factors linked with the pathogenesis of cognitive impairment and dementia (i.e. glucose 30 Risk reduction of cognitive decline and dementia: WHO guidelines tolerance, insulin sensitivity, blood pressure, oxidative stress, and inflammation) (Bennett et al., 2009). However, a direct beneficial effect of weight reduction intervention is also plausible. Although, so far, evidence of potential cognitive benefits of weight loss seem to be strongly associated with increased physical activity (Colcombe et al., 2006; Erickson et al., 2010), in 2011 a systematic review concluded that intentional weight loss can improve performance in some cognitive domains, at least in people with obesity (Siervo et al., 2011). Additional considerations include: • Lifestyle interventions that included both diet and physical activity components seemed to show the best results. • In addition to interventions at individual level, lifestyle interventions at the population level, such as activity parks, green spaces and infrastructure to support active commuting, need to be considered. • Being underweight in both late-mid-life and old age might be associated with a higher risk of dementia. However, it is likely that this association is explained, at least in part, by reverse causality, whereby brain pathology may cause weight loss before the clinical onset of dementia. • Unintentional weight loss and malnutrition are associated with poor health outcomes and should be investigated and treated at all ages. However, it is unlikely that interventions that favour weight gain in people who are underweight in either mid- or late life can reduce the risk of dementia or cognitive impairment. RECOMMENDATION: Interventions for mid-life overweight and/or obesity may be offered to reduce the risk of cognitive decline and/or dementia. Quality of evidence: low to moderate Strength of the recommendation: conditional WHO guidance on overweight and obesity outlined in Prevention and control of noncommunicable diseases: guidelines for primary health care in low-resource settings (2012) (http://www.who.int/nmh/publications/phc2012/en/) WHO guidance on overweight and obesity should be followed. • Advise overweight patients to reduce weight by following a balanced diet. • Advise patients to give preference to low glycaemic-index foods (beans, lentils, oats and unsweetened fruit) as the source of carbohydrates in their diet. • Advise patients to reduce sedentary behaviour and practise regular daily physical activity appropriate for their physical capabilities (e.g. walking). RECOMMENDATIONS AND CONSIDERATIONS 31Evidence and recommendations SUPPORTING EVIDENCE AND RATIONALE For weight reduction with behavioural and/or lifestyle interventions (or control of obesity) compared with usual care or no intervention, evidence was extracted from one systematic review examining adults with normal cognition who are overweight or obese (Veronese et al., 2017). No evidence for adults with MCI was available. There was low to moderate evidence that lifestyle interventions aimed at weight reduction could improve cognitive function in the attention, memory and language domains. Interventions were very short (ranging from 8 to 48 weeks). No data were found in relation to incident MCI and dementia outcomes. No evidence of adverse events was identified. For pharmacological interventions for weight reduction (or control of obesity) compared with usual care or no intervention, no systematic reviews were found. The GDG concluded that the benefits of the interventions outweighed the harms and provided a conditional recommendation. Since the observational evidence of a correlation between overweight/obesity and increased risk of dementia is stronger and more consistent in mid-life than in late life (Hersi et al., 2017; Lafortune et al., 2016; Pedditzi et al., 2016; Prickett et al., 2015; Xu et al., 2015), the GDG made a conditional recommendation for this population. 32 Risk reduction of cognitive decline and dementia: WHO guidelines Population: Adults with normal cognition or MCI with hypertension Intervention: Antihypertensive medication, lifestyle interventions Comparison: Placebo/no intervention Outcomes: • Critical – Cognitive function – Incident MCI – Dementia • Important – Quality of life – Functional level (ADL, IADL) – Adverse events – Drop-out rates For adults with normal cognition or MCI and hypertension, is treatment of hypertension more effective than placebo/no intervention in reducing the risk of cognitive decline/dementia? 3.8 MANAGEMENT OF HYPERTENSION BACKGROUND Hypertension in mid-life has been associated with an increased risk of late life dementia (Kivipelto et al., 2001). In particular, a pattern of increased blood pressure during mid-life followed by a rapid decrease in blood pressure later in life has been found in individuals who go on to develop dementia (Kivipelto et al., 2001; Launer et al., 2000; Stewart et al., 2009). There is mixed evidence relating to the reduction of blood pressure in late mid- or late life and subsequent cognitive decline or dementia, however, there is evidence to show that the reduction of hypertension can have substantial benefits in reducing cardiovascular morbidity and mortality and thus improving overall health of the ageing population (Musini et al., 2009). Hypertension can be prevented through a range of lifestyle factors, including eating a healthy diet, maintaining a healthy weight and participating in an adequate amount of physical activity. It can also be controlled through antihypertensive medication. However, the evidence for the effectiveness of blood pressure lowering treatments in reducing the risk of cognitive decline and dementia risk is mixed. RECOMMENDATION 1: Management of hypertension should be offered to adults with hypertension according to existing WHO guidelines. Quality of evidence: low to high (for different interventions) Strength of the recommendation: strong RECOMMENDATIONS AND CONSIDERATIONS 33Evidence and recommendations HEARTS Technical package for cardiovascular disease management in primary health care: evidence-based treatment protocols (http://apps.who.int/iris/bitstream/handle/10665/260421/WHO-NMH-NVI-18.2-eng.pdf?sequence=1) Medications used to treat hypertension • There are four main classes of antihypertensive medications: angiotensin converting enzyme (ACE) inhibitors; angiotensin receptor blockers (ARB); calcium channel blockers (CCB); and thiazide and thiazide-like diuretics. Any of these four classes of antihypertensive medication may be used unless there are specific contraindications. Proper treatment of hypertension usually requires a combination of hypertension medications. Notes on specific hypertension medications • Pregnant women and women of childbearing age not on effective contraception should not be given ACE inhibitors, ARBs or thiazide/thiazide-like diuretics; CCBs should be used. If not controlled with intensification dose of medication, refer to specialist. • Beta blockers are not recommended as first-line therapy. If a heart attack has been diagnosed within the previous three years, or there is atrial fibrillation or heart failure, then a beta blocker should be added to the starting dose of antihypertensive medication. Patients with angina may also benefit from treatment with a beta blocker. Other treatment considerations • If there is a prior heart attack or stroke, or the person is otherwise at high risk of CVD, start a statin at the same time as starting antihypertensive medication. (Statins should not be used in women who are or who may become pregnant.) • If there is a prior heart attack or ischemic stroke, start low-dose aspirin. • The hypertension protocols included in this module serve well for initiation and maintenance of successful treatment. If there are serious adverse events, lack of control of blood pressure, or if a major medical event intervenes, then referral to a specialist will be needed. • If the patient is already on another medication regimen, blood pressure is controlled to the target level, and the medications the patient is taking are accessible and affordable, there is no reason to change the regimen. • If the patient feels faint on standing, check blood pressure while standing. If the systolic blood pressure is consistently less than 110 mm Hg in a patient on medical treatment, consider reducing the dosage or number of medications used. RECOMMENDATION 2: Management of hypertension may be offered to adults with hypertension to reduce the risk of cognitive decline and/or dementia. Quality of evidence: very low (in relation to dementia outcomes) Strength of the recommendation: conditional 34 Risk reduction of cognitive decline and dementia: WHO guidelines SUPPORTING EVIDENCE AND RATIONALE For treatment of hypertension in the form of antihypertensive medication versus placebo or no intervention, evidence was extracted from two systematic reviews examining adults with normal cognition and hypertension (Parsons et al., 2016; Weiss et al., 2016). No evidence for adults with MCI was available. With regard to cognitive function and incident dementia outcomes, the quality of the evidence was low, which showed that antihypertensive therapy has no effect on cognitive decline or incidence of dementia. With regard to quality of life and functional level outcomes, the quality of evidence is very low, showing that antihypertensive therapy does not decrease quality of life or functional level. With regard to adverse events, the quality of evidence was very low, showing mixed findings with regard to antihypertensive use. There were no data on incident MCI and overall drop- out rates. Initial results from the SPRINT-MIND trial, a substudy of the Systolic Blood Pressure Intervention Trial (SPRINT) that aims to evaluate the effect of intensive blood pressure control on risk of dementia, support the possibility of a dose-response relationship between blood pressure and risk of cognitive decline or dementia (SPRINT-MIND 2019). Observational evidence suggests a strong association between hypertension and incident cognitive decline/dementia. For treatment of hypertension in the form of lifestyle interventions versus placebo or no intervention, no systematic reviews were found. The GDG made a strong recommendation for management of hypertension for its established health benefits and a conditional recommendation for hypertension management for reducing the risk of cognitive decline/dementia. The GDG concluded that though there is limited clinical trial evidence that treatment of hypertension reduces the risk of cognitive decline or dementia, the benefits outweighed the harms since the evidence suggests that intervention does not lower quality of life or functional level and there are mixed results regarding adverse effects which may depend on the drug used. Additionally, robust evidence for a causal relationship is available. 35Evidence and recommendations Population: Adults with normal cognition or MCI with diabetes mellitus Intervention: • Medications for glycaemic control • Diet and lifestyle interventions Comparison: Placebo/no intervention Outcomes: • Critical – Cognitive function – Incident MCI – Dementia • Important – Quality of life – Functional level (ADL, IADL) – Adverse events – Drop-out rates For adults with normal cognition or MCI and diabetes mellitus, is treatment of diabetes more effective than placebo/no intervention in reducing the risk of cognitive decline and/or dementia? 3.9 MANAGEMENT OF DIABETES BACKGROUND The presence of late life diabetes has been linked to an increased risk of dementia (Luchsinger, 2010; Prince et al., 2014; Profenno et al., 2010). However, the mechanism by which this occurs is unclear. Poor glucose control has been associated with lower cognitive functioning and greater cognitive decline (Yaffe et al., 2012). In addition, the complications associated with diabetes, such as nephropathy (kidney damage), retinopathy (eye damage), hearing impair- ment and CVD, have all been found to increase the risk of dementia (Bruce et al., 2014; Exalto et al., 2013). The literature examining interventions that aim to improve glycaemic control shows mixed findings with regard to cognitive outcomes (Launer et al., 2011; Luchsinger et al., 2011). In addition, the evidence on the effectiveness of medication for diabetes in reducing dementia risk is inconsistent (Cheng et al., 2014; Moore et al., 2013; Parikh et al., 2011). There is some evidence to suggest that treating the cardiovascular comor- bidities associated with diabetes, such as high choles- terol and hypertension, may mediate the risk for dementia (Johnson et al., 2012; Parikh et al., 2011). 36 Risk reduction of cognitive decline and dementia: WHO guidelines RECOMMENDATION 1: Management of diabetes in the form of medications and/or lifestyle interventions should be offered to adults with diabetes according to existing WHO guidelines. Quality of evidence: very low to moderate (for different interventions) Strength of the recommendation: strong RECOMMENDATION 2: Management of diabetes may be offered to adults with diabetes to reduce the risk of cognitive decline and/or dementia. Quality of evidence: very low Strength of the recommendation: conditional Package of essential noncommunicable (PEN) disease interventions for primary health care in low-resource settings (https://www.who.int/cardiovascular_diseases/publications/pen2010/en/). For individuals with diabetes, the WHO guidelines recommend the following treatments: Type 1 diabetes • Daily insulin injections (Level 1). Type 2 diabetes • Oral hypoglycaemic agents for Type 2 diabetes, if glycaemic targets are not achieved with modification of diet, maintenance of a healthy body weight and regular physical activity (Level 1). • Metformin as initial drug in overweight patients (Level 1) and non-overweight (Level 4). • Other classes of antihyperglycaemic agents, added to metformin if glycaemic targets are not met (Level 3). • Reduction of cardiovascular risk for those with diabetes and 10-year cardiovascular risk > 20% with aspirin, angiotensin converting enzyme inhibitor and statins (Level 1). RECOMMENDATIONS AND CONSIDERATIONS 37Evidence and recommendations SUPPORTING EVIDENCE AND RATIONALE For treatment of diabetes in the form of medications for glycaemic control versus placebo or no intervention, evidence was extracted from one systematic review examining adults with normal cognition and Type 2 diabetes (Areosa Sastre et al., 2017). No evidence for adults with MCI was available. The quality of the evidence was moderate for cognitive function outcomes and very low for incident dementia outcomes, which showed intensive as opposed to standard glycaemic control has an unclear effect on cognitive function and no effect on incident dementia. The evidence reviewed included data from a large study set across 215 collaborating centres in 20 countries in Asia, Australasia, Europe and North America. The quality of evidence for adverse events was very low, showing intensive glycaemic control increases the risk of hypoglycaemic events. No data on incident MCI, quality of life, functional outcomes or drop-out rates were available. Overall, in adults with normal cognition, the evidence may favour standard glycaemic control because intense glycaemic control has no effect on cognitive function but may result in increased episodes of hypoglycaemia. For treatment of diabetes in the form of diet and life- style interventions versus placebo or no intervention, evidence was extracted from one systematic review examining adults with normal cognition and Type 2 diabetes (Podolski et al., 2017). No evidence for adults with MCI was available. The quality of evidence was very low and the findings were mixed. No meta- analysis was conducted and there were no robust data on clinical significance. The GDG made a strong recommendation for management of diabetes for its established health benefits and a conditional recommendation for diabetes management for reducing the risk of cognitive decline/dementia. The GDG concluded that though there is limited clinical trial evidence on the management of diabetes to reduce the risk of cognitive decline or dementia, the benefits outweighed the harms and there is robust observational evidence to suggest diabetes increases the risk of cognitive decline and dementia. 38 Risk reduction of cognitive decline and dementia: WHO guidelines Population: Adults with normal cognition or MCI with dyslipidaemia Intervention: • Statins (e.g. simvastatin and pravastatin) • Lifestyle interventions Comparison: Placebo or no intervention Outcomes: • Critical – Cognitive function – Incident MCI – Dementia • Important – Quality of life – Functional level (ADL, IADL) – Adverse events – Drop-out rates For adults with normal cognition or mild cognitive impairment and dyslipidaemia, is treatment of dyslipidaemia more effective than placebo or no intervention in reducing the risk of cognitive decline and/or dementia? 3.10 MANAGEMENT OF DYSLIPIDAEMIA BACKGROUND Elevated serum cholesterol is one of the key modifiable cardiovascular risk factors. A third of ischaemic heart disease worldwide is attributable to dyslipidaemia and it is estimated to be the cause of 2.6 million deaths (4.5% of total) per year, as well as a considerable proportion of disability (WHO, 2019b). The prevalence of raised total cholesterol among countries seems to correlate with wealth: in high-income countries, more than 50% of adults have elevated total cholesterol level, more than double the rate in low-income countries (WHO, 2019c). The idea that raised level of blood cholesterol could be related to an increased risk of dementia was already introduced in the mid-1970s (Richardson et al., 2000). Since then, a number of epidemiological studies have demonstrated a close relationship between high serum cholesterol levels and the onset of AD/dementia (Kivipelto et al., 2002; Solomon et al., 2007; Whitmer et al., 2005), but results have been inconsistent, with other studies showing no or negative correlation (Mainous et al., 2005; Mielke et al., 2005). Based on the severity of the dyslipidaemia and CVD overall risk, lifestyle or pharmacological approaches can be undertaken to reduce blood cholesterol. Weight reduction and decreasing saturated fats in the diet (decreasing the consumption of food of animal origin) are the most common and effective lifestyle recommen- dations (Perk et al., 2012). However, dyslipidaemia is often controlled and managed pharmacologically, with statins being the drugs of first choice. Several observational studies have investigated the possible beneficial effect of statins therapy in preventing dementia, but bias and heterogeneity hampered the overall quality of the evidence (Song et al., 2013; Swiger et al., 2013; Wong et al., 2013). Recently, a re-analysis of statin use in AD patients from failed clinical trials suggested that the use of simvastatin may slow the progression of cognitive decline in some people (Geifman et al., 2017). 39Evidence and recommendations RECOMMENDATIONS AND CONSIDERATIONS RECOMMENDATION: Management of dyslipidaemia at mid-life may be offered to reduce the risk of cognitive decline and dementia. Quality of evidence: low Strength of the recommendation: conditional Additional considerations include: • Statin treatment in older adults should not be specifically initiated for preventing cognitive decline and/or dementia but may be used for other health benefits according to WHO’s Prevention and control of noncommunicable diseases: guidelines for primary health care in low-resource settings (http://www.who.int/nmh/publications/phc2012/en/). SUPPORTING EVIDENCE AND RATIONALE For control of dyslipidaemia through treatment with statins compared with placebo, evidence was extracted from one systematic review examining adults with normal cognition and dyslipidaemia (McGuinness et al., 2016). No evidence for adults with MCI was available. The quality of the evidence was moderate for cognitive function outcomes and low for incident dementia outcomes, showing that treatment with statins has no effect on either incident dementia and/or cognitive decline. There is moderate quality evidence that the treatment with statins does not increase the incidence of serious adverse events. A large body of observational evidence has linked dyslipidaemia to an increased risk of dementia and/or cognitive decline and found an association between control of dyslipidaemia and reduction of dementia and/or cognitive decline risk (Geifman et al., 2017; Hersi et al., 2017; Reitz, 2013; Song et al., 2013). Overall, indirect evidence suggests that managing dyslipidaemia in mid-life can help reduce the risk of cognitive decline and/or dementia. No studies were identified that specifically aimed at controlling dyslipidaemia through lifestyle interventions and included outcomes related to dementia and/or cognitive impairment. The GDG concluded that the desirable effects of dyslipidaemia treatment outweigh the undesirable effects and made a conditional recommendation. The observational evidence reported a stronger correlation between high cholesterol and dementia in mid-life rather than late life (Hersi et al., 2017; Reitz, 2013). The systematic review evidence that focused on clinical trials in older adults (65+) showed that statin treatment has no effect on cognition or dementia outcomes (McGuinness et al., 2016). Therefore, the GDG concluded that there were no grounds to recommend the use of statin and the control of cholesterol in late life but only in mid-life. 40 Risk reduction of cognitive decline and dementia: WHO guidelines Population: Adults with normal cognition or MCI with moderate to severe depressive disorder Intervention: • Pharmacological interventions to treat depression (antidepressant medication) • Psychological interventions to treat depression (e.g. cognitive behavioural therapy, problem-solving therapy, interpersonal therapy, behavioural activation) Comparison: Care as usual or placebo or no intervention Outcomes: • Critical – Cognitive function – Incident MCI – Dementia • Important – Quality of life – Functional level (ADL, IADL) – Adverse events – Drop-out rates For adults with normal cognition or mild cognitive impairment and depressive disorder, is treatment of depression more effective than usual care, placebo or no intervention in reducing the risk of cognitive decline and/or dementia? 3.11 MANAGEMENT OF DEPRESSION BACKGROUND There is a substantial body of evidence linking depression to cognitive decline and dementia. A review carried out as part of the World Alzheimer Report in 2014 combined 32 studies into a meta-analysis which looked at the effect of depression on the risk of incident dementia. This involved 62,568 participants with a median follow-up of 5 years (range 2 to 17). The review reported that the presence of depression nearly doubled the risk of dementia (pooled effect size = 1.97, 95% CI: 1.67–2.32) (Prince et al., 2014). The authors also carried out a meta-regression looking at follow-up time. They reported a trend toward smaller effect sizes in studies with longer follow-up suggesting that depression may have a prodromal role in dementia. It is noteworthy to mention that cognitive impairment may be the main symptom of depression in the elderly; a phenomenon that used to be called pseudodementia. There are several potential explanations for the link between depression and cognitive impairment or dementia. Some of these include associations between depression, noradrenergic changes and white matter lesions, depression which stems from insight into impairment at early stages of decline, depression highlighting underlying deficits, i.e. by reducing motivation and bringing its own cognitive deficits (Camus et al., 2004; Jorm, 2001; Kales et al., 2005; Schweitzer et al., 2002). 41Evidence and recommendations RECOMMENDATIONS AND CONSIDERATIONS There is currently insufficient evidence to recommend the use of antidepressant medicines for reducing the risk of cognitive decline and/or dementia. The management of depression, in the form of antidepressants and/or psychological interventions, should be provided to adults with depression according to existing WHO mhGAP guidelines. WHO mhGAP Intervention guide - Version 2 for mental, neurological and substance use disorders in non-specialized health settings (https://www.who.int/mental_health/mhgap/mhGAP_intervention_guide_02/en/) For adults with moderate to severe depressive disorder, the WHO guidelines recommend the following treatments: Psychosocial/non-pharmacological treatment and advice • Psychoeducation (for the person and his or her family, as appropriate). • Addressing current psychosocial stressors. • Reactivate social networks. • Brief psychological treatments, if available. • Offer regular follow-up. Antidepressant medication • Select an antidepressant from the National or WHO Formulary. Selective serotonin reuptake inhibitors (fluoxetine) and tricyclic antidepressants (amitriptyline) are antidepressants mentioned in the WHO Formulary and are on the WHO model list of essential medicines. • In selecting an antidepressant, consider the symptom pattern of the person, the side-effect profile of the medication, and the efficacy of previous antidepressant treatments, if any. • For co-morbid medical conditions, before prescribing antidepressants, consider potential for drug-disease or drug-drug interaction. Consult the National or the WHO Formulary. • Combining antidepressants with other psychotropic medication requires supervision by, or consultation with a specialist. 42 Risk reduction of cognitive decline and dementia: WHO guidelines SUPPORTING EVIDENCE AND RATIONALE For pharmacological interventions to treat depression (antidepressant medication) compared with usual care or placebo, evidence was extracted from one systematic review examining adults with normal cognition and major depressive disorder (Baune et al., 2018). No evidence for adults with MCI was available. The review conducted a network meta-analysis and reported standardized mean differences in the Digit Symbol Substitution Test as a measure of cognition function. The review reported that vortioxetine (versus placebo) improved cognitive functioning while duloxetine, sertraline, citalopram, escitalopram, phenelzine and nortriptyline showed no effect (Baune et al., 2018). The quality of the evidence was very low and no data were reported for incident MCI or dementia outcomes, quality of life, adverse events, functional level or drop-out rates. Overall, the true balance of effects is difficult to ascertain. The evidence favours the use of vortioxetine (but not other pharmacological interventions) to treat depression for reducing the risk of cognitive decline or dementia. However, no data on adverse effects were available, e.g. drug-related side-effects or interactions. For psychological interventions to treat depression compared with placebo or no intervention, no relevant systematic reviews were found. The GDG therefore concluded that there was insufficient evidence currently for depression manage- ment and reduction of risk of cognitive decline/ dementia. They also concluded that the management of depression is important for its other benefits and did not make a negative recommendation against this intervention. 43Evidence and recommendations Population: Adults with normal cognition or MCI with hearing loss Intervention: Interventions to treat hearing loss (e.g. hearing aids) Comparison: Care as usual or no intervention Outcomes: • Critical – Cognitive function – Incident MCI – Dementia • Important – Quality of life – Functional level (ADL, IADL) – Adverse events – Drop-out rates For adults with normal cognition or MCI and hearing loss, is treatment of hearing loss more effective than usual care, or no intervention in reducing the risk of cognitive decline and/or dementia? 3.12 MANAGEMENT OF HEARING LOSS BACKGROUND Hearing loss is a prevalent age-related disorder. As the fourth leading cause of years lived with disability in the global population (WHO, 2012), it is estimated to affect one in three adults aged 65 and older, with this statistic growing annually (Wilson et al., 2017). The implications of hearing loss, however, are often underestimated both at the individual and population level (Blustein et al., 2018). Hearing impairment has debilitating consequences on functional ability and social and emotional well-being. Deteriorations in hearing impact on individuals’ ability to communicate with others, which in turn can result in feelings of frustration, isolation, loneliness (Ciorba et al., 2012). Older adult populations who already experience the isolating effects of age-related factors, such as diminished mobility, driving cessation, death of partners or living alone, are particularly vulnerable to these psychosocial impacts. Hearing loss is also associated with increased risk of cognitive decline or dementia (Lin et al., 2013). A recent meta-analysis of prospective cohort studies showed that the relative risk of hearing impairment on incident Alzheimer’s and MCI was 2.82 (95% CI: 1.47–5.42). (Zheng et al., 2017). Additionally, a meta-analysis published by the Lancet Commission showed that hearing loss can almost double the risk of incident dementia (RR = 1.94, 95% CI: 1.38–2.73) (Livingston et al., 2017). Hearing loss and cognitive impairment or dementia, individually, and in combination, predict functional ability and burden of care. Hearing loss interventions, therefore, have the potential to substantially improve outcomes for older people on multiple domains. 44 Risk reduction of cognitive decline and dementia: WHO guidelines WHO Guidelines on integrated care for older people (ICOPE) (http://www.who.int/ageing/publications/guidelines-icope/en/) For older adults, WHO recommends the following: Screening followed by provision of hearing aids should be offered to older people for timely identification and management of hearing loss. Considerations for recommendation: • Community awareness about hearing loss and the positive benefits of audiological rehabilitation in older people, through community case finding and outreach activities, should be promoted. • Health care professionals should be encouraged to screen older adults for hearing loss by periodically questioning them about their hearing. Audiological examination, otoscopic examination and the whispered voice test are also recommended. • Hearing aids are the treatment of choice for older people with hearing loss, because they minimize reduction in hearing and improve daily functioning. • Medications should be reviewed for potential ototoxicity. • People with chronic otitis media or sudden hearing loss, or who fail any screening tests, should be referred to an otolaryngologist. There is insufficient evidence to recommend use of hearing aids to reduce the risk of cognitive decline and/or dementia. Screening followed by provision of hearing aids should be offered to older people for timely identification and management of hearing loss as recommended in the WHO ICOPE guidelines. RECOMMENDATIONS AND CONSIDERATIONS 45Evidence and recommendations SUPPORTING EVIDENCE AND RATIONALE For interventions to treat hearing loss (e.g. hearing aids) versus care as usual or no intervention, evidence was extracted from one systematic review examining adults with normal cognition and hearing loss (Cherko et al., 2016). No evidence for adults with MCI was available. For cognitive function and quality of life, the quality of evidence is very low. No meta-analyses were performed and results were reported narratively with no numerical data to support conclusions (Cherko et al., 2016). Based on two studies including measures of cognitive function, the review concluded that while hearing aids use was found to be associated with improvements in cognitive function, these benefits may be limited in that cognitive improvements have been shown to revert to baseline at 1 year follow-up. They also concluded that use of hearing aids in older people was associated with improvements in quality of life outcomes based on two studies. Overall, the evidence does not favour either the intervention or the comparison. Hearing aids may improve quality of life but the amount of evidence available is limited. No data are available for incident MCI or dementia, functional level (ADL, IADL), adverse events or drop-outs. The GDG concluded that there is currently insufficient evidence to recommend the use of hearing aids to reduce the risk of cognitive decline/dementia. The GDG also concluded that the use of hearing aids is important to correct hearing loss in older adults for their other benefits and recommend following the ICOPE guidelines in this regard. 46 Risk reduction of cognitive decline and dementia: WHO guidelines IMPLEME NTATION CONSIDE R ATIONS 4 47 Implementation considerations Countries will be supported to implement the guidelines through training of health care personnel and using centres of excellence on improved quality of care. The implementation will also be supported locally through the adoption of the Global action plan on the public health response to dementia 2017– 2025; the Comprehensive mental health action plan 2013–2020; and the Global action plan for the prevention and control of noncommunicable diseases 2013–2020 at country level. The national capacity building process will also be supported through WHO collaboration with international organizations and associations. Given that many of the interventions included in these guidelines are strongly related to the management of risk factors for CVD and diabetes, the implementation of these recommendations should be combined, whenever possible and in the relevant target population, with the ongoing prevention programmes to reduce the risk of these conditions. The optimal preventive effect may be obtained by addressing several risk factors at the same time. Collaboration among different stake- holders and multidisciplinary approaches will also be needed. The recommendations contained in these guidelines should be adapted into a locally appropriate document that can meet the needs of each country and its health services. WHO headquarters will work closely with the regional and country offices, as well as implementing partners and public health agencies at the national level, to ensure communication and country-specific adaptations of the guidelines, through regional and national meetings. As countries consider how to implement these guidelines, the budgetary and human resource requirements, and other health systems implications should be analysed to identify which inputs and systems are currently available, and which areas require additional investment. These may include training of health workers, supply of medicines and adaptations of health information systems to collect data on service utilization. To support country implementation, WHO will produce a series of subsidiary tools that will address clinical and service delivery aspects of the imple- mentation of the recommendations included in these guidelines. 48 Risk reduction of cognitive decline and dementia: WHO guidelines PUBLIC ATION, DISSEMINATION AND EVALUATION 5 49Publication, dissemination and evaluation 5.1 PUBLICATION AND DISSEMINATION The guidelines will be disseminated as a print publication and electronically on a dedicated internet space on the WHO website. The guidelines will be disseminated through both the mental health and NCD dissemination activities of the Global action plan on the public health response to dementia 2017–2025 (such as the Global Dementia Observatory knowledge exchange platform), the Comprehensive mental health action plan 2013–2020 and the Global action plan for the prevention and control of noncommunicable diseases 2013–2020. These guidelines will be appended to the mhGAP guidelines and disseminated through the mhGAP evidence resource centre and other mhGAP derivative products, including the mhGAP Intervention guide. Since these guidelines are linked to other WHO guidelines such as NCD and ICOPE guidelines and other resources on ageing, dissemination will occur along with these guidelines. The guidelines and products are developed in English, and will be translated into other WHO official languages for wider dissemination and in collaboration with WHO regional offices. Local adaptation is necessary to ensure that the guidelines are appropriate for the local conditions that affect the care of people with cognitive decline and dementia in health facilities and the community. Adaptation will include language translation and ensuring that the interventions are acceptable in the specific socio-cultural context and suitable for the local health system. The ADAPTE manual for guideline adaptation outlines the approach to be used.12 The acceptability and applicability of the recommendations will be examined in the specific cultural context, including the availability of health services, expertise and resources, and the organization of health services, as well as population characteristics, cultural beliefs and value judgments. Relevant departments in ministries of health will be notified of the guidelines through WHO regional and country offices. A briefing package will be prepared for technical officers outside of WHO headquarters that will include an executive summary and Q&A related to policy and programme implications. Dissemination will also be encouraged through WHO collaboration with international organizations and associations. In coordination with WHO Communications, the media will be notified of the new guidelines. Countries will be supported to implement the guidelines through the training of health care personnel on improved quality of care and using centres of excellence. Capacity-building activities will be undertaken through web-based platforms and regional workshops. Dissemination will be supported by the publication of selected systematic reviews and evidence in peer review journals, and presentations and workshops at key conferences and events. 12 http://www.g-i-n.net/document-store/working-groups-documents/adaptation/adapte-resource-toolkit-guideline-adaptation-2-0.pdf 50 Risk reduction of cognitive decline and dementia: WHO guidelines 5.2 MONITORING AND EVALUATION Following publication of these guidelines, WHO will continue to collect regular feedback from implemen- tation activities in order to evaluate their usefulness and impact. Information will be used to evaluate the quality of the guidelines and to identify areas where improvement is required. WHO’s Global Dementia Observatory, an online data and knowledge exchange platform for dementia, provides the framework for monitoring implementation of these guidelines13. 5.3 IMPLICATIONS FOR FURTHER RESEARCH The majority of the recommendations align with current guidelines for the treatment of pre-existing health conditions and dependencies. However, more evidence is needed to determine what the impact of these interventions are on the outcomes of incident MCI or dementia. No recommendations could be made for social activity and hearing loss due to insufficient evidence. Some trials are currently being conducted for hearing loss interventions. These guidelines may need to be updated once these results are released. However, currently there is little research being conducted that examines the impact of social activity on cognitive decline and dementia. Part of the difficulty in conducting this type of research is that social activity is difficult to define and quantify, and it is also difficult to differentiate it from the physical or mental activities which are often a component of this type of intervention. The development of standardized protocols for social activity interventions may therefore need to precede the running of clinical trials. Some of the evidence presented here is based on RCTs with relatively short follow-up periods (e.g. interventions for cognitive training, depression, social activity). This limits our ability to judge the potential impact of the interventions on the development of cognitive decline and dementia as they have long prodromal periods. More evidence needs to be gathered with longer term follow-up periods in order to more accurately estimate the impact of these interventions in reducing the risk of cognitive decline/ dementia in the long run. In addition, more research needs to be conducted to understand how timing affects the impact of these interventions on cognitive decline and dementia (e.g. mid-life versus late life physical activity). The prevalence of dementia is increasing in LMIC. However, the majority of clinical trials have been conducted in high-income countries, so there is very little evidence on the effectiveness of these interventions for LMIC. More attention needs to be given to understanding how best to reduce the risk of cognitive decline and dementia in LMIC. 13 Available at: https://www.who.int/mental_health/neurology/dementia/Global_Observatory/en/ 51 The PICO questions applied to gather evidence for the preparation of these guidelines included interventions on single risk factors. However, given the multifactor etiology of dementia, and the interaction of risk factors across the lifestyle of each individual, multidomain approaches have been increasingly researched and show potential to be more effective than single-factor strategies. Recently, three large multidomain RCTs – the Finnish Geriatric Intervention Study to Prevent Cognitive Impairment and Disability (FINGER); Effect of long-term omega-3 PUFA supplementation with or without multidomain intervention on cognitive function in elderly adults with memory complaints (MAPT); and Prevention of dementia by intensive vascular care (preDIVA) – have been completed (Ngandu et al., 2015; Andrieu et al., 2017; Moll von Charante et al., 2016). Although only the multidomain lifestyle intervention tested in FINGER reported significant results in the primary analysis, the overall findings from the three trials suggested that targeting individuals at increased risk could be the most effective strategy. In particular, other interventions showed significant results in participants with an elevated dementia risk score, in MAPT (as in FINGER), and individuals with untreated hypertension at baseline, in preDIVA, respectively. In the context of multidomain interventions, new technologies and e-health solutions could also provide useful tools for risk reduction, by broadening the reach of such interventions (Barbera et al., 2018). Given the heterogeneity of risk profiles among older populations, global initiatives, such as the World Wide FINGERS Network (www.wwfingers.com), have been launched recently with the specific purpose of testing similar interventions, which have been adapted in diverse geographical and cultural settings (Kivipelto et al., 2017). Further research on the efficacy of multidomain interventions that are adjusted to specific geographical and cultural contexts, in populations at increased risk, and by making use of novel e-health tools (if possible) is, therefore, needed. 5.4 FUTURE REVIEW AND UPDATE It is expected that the guidelines will be reviewed again in five years. New evidence in these areas is regularly monitored by the WHO Secretariat, in consultation with GDG members and technical experts identified for the evidence review process, WHO collaborating centres and academic institutions. With the increasing evidence from multidomain intervention trials expected to be reported in the coming years, the addition of a PICO question addressing such interventions should be considered in future revisions. Publication, dissemination and evaluation 52 Risk reduction of cognitive decline and dementia: WHO guidelines Albanese E, Launer LJ, Egger M, Prince MJ, Giannakopoulos P, Wolters, FJ et al. (2017). 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Corrado Barbui M European University of Verona, Italy Mental health research and training, public health, health systems strengthening 5. Adelina Comas-Herrera F European London School of Economics, United Kingdom Health economist, dementia research 6. Amit Dias M South-East Asia Department of Preventive and Social Medicine, Goa Medical College, India Dementia, public health in LMIC 7. Cleusa P Ferri F Americas Federal University of São Paulo, Brazil Research in dementia and 10/66 group, dementia risk factors in LMIC 8. Riadh Gouider M Eastern Alzheimer’s Centre, Razi Hospital, Tunis; Tunisian Society of Neurology, Tunisia Dementia research in areas of epidemiology, neuropsychological assessment and risk factors 9. Shinya Ishii M Western Pacific Health and Welfare Bureau for the Elderly; Ministry of Health, Labour and Welfare, Tokyo, Japan Health policy, neurology of Alzheimer’s disease and dementia 10. Yves Joanette M Americas Canadian Institutes of Health Research, Government of Canada Dementia research 11. Joseph Kibachio M African Ministry of Health, Nairobi, Kenya Public health, health policy, NCDs 12. Miia Kivipelto F European Karolinska Institutet, Stockholm University, Stockholm, Sweden Dementia research in the field of early diagnosis and prevention 13. Shanthi Mendis F South-East Asia Independent consultant in global health, Sri Lanka NCDs and cardiology, health policy development, capacity strengthening, implementation research particularly in LMIC 61Annex 1: Guideline development group members Name Gender WHO region Affiliation Area of expertise 14. Ayesha Motala F African University of KwaZulu-Natal, South Africa Epidemiology and genetics of diabetes mellitus 15. Ronald Petersen M Americas Mayo Clinic, United States of America Memory disorders, aging and Alzheimer's disease 16. Dorairaj Prabhakaran M South-East Asia Centre for Chronic Conditions and Injuries & Public Health Foundation of India Cardiovascular disease prevention, epidemiology, developmental origin, and biomarkers of cardiovascular diseases and diabetes 17. Martin Prince M European Health Foundation of India Public health aspects of ageing and chronic disease in LMIC, dementia, guideline development 18. Suzana Shahar F Western Pacific Universiti Kebangsaan, Malaysia Nutrition, micronutrients, dietary interventions 19. Ameenah Bibi Mia Sorefan F African Alzheimer’s Association of Mauritius; Ministry of Health & Quality of Life, Mauritius Ageing, dementia and Alzheimer’s disease 20. Kusumadewi Suharya (Dy) F Western Pacific Alzheimer’s Disease International, Indonesia Dementia and public health 21. Huali Wang F Western Pacific Dementia Care & Research Center, Peking University Institute of Mental Health, China Dementia research and education 62 Risk reduction of cognitive decline and dementia: WHO guidelines ANNEX 2: ASSESSMENT OF CONFLICT OF INTEREST INDIVIDUALS INVOLVED IN ASSESSMENT OF CONFLICT OF INTEREST: Tarun Dua, Programme Manager, Department of Mental Health and Substance Abuse, WHO headquarters. Neerja Chowdhary, Technical Officer, Department of Mental Health and Substance Abuse, WHO headquarters. To comply with WHO’s Conflict of Interest Policy, the Secretariat followed the revised Guidelines for Declaration of Interests (WHO Experts).14 Declarations of interest (DoI) were requested from: (a) all GDG members; (b) all external partners involved in the evidence review process; (c) all experts invited to review the evidence profiles. A letter requesting completion of a DoI form and submission of a curriculum vitae as well as was sent to all GDG members, the external review group and external partners. They were asked to agree to the publication of a summary of declarations in the guide- line. The GDG members were also required to complete a confidentiality undertaking. Once received, the WHO Secretariat reviewed the DoIs as well as additional information (internet and bibliographic database search) and evaluated if there are any conflicts of interest and if so, whether these require a management plan. In order to enhance its management of conflicts of interest as well as strengthen public trust and transparency in connection with WHO meetings and activities involving the provision of technical/normative advice, the names and brief biographies members being considered for participation in the GDG were disclosed for public notice and comment prior to the meeting. At the beginning of the GDG meeting, the DoI of each GDG member were presented and GDG members and external partners were asked to update their DoI with relevant changes by notifying the responsible technical officer. The follow up and suggested actions agreed upon to manage the conflicts of interest declared are summarized below: • If members declare interests that are relevant to the meeting, the WHO Secretariat will note any potential conflict of interest and summarize these and then decide whether and to what extent they can participate in the guideline development. • If the conflict is deemed to be significant, the WHO Secretariat will decide if the conflict necessitates exclusion of that person from participating in the guideline process or if their participation should be limited. • These decisions are made on a case-by-case basis. Below is a summary of the Declared conflicts of interest and how these were managed. A. GDG MEMBERS GDG Members with no relevant interests declared on the DOI form and no relevant interests found in the CV 1. Kaarin J Anstey, University of New South Wales, Sydney, Australia; 2. Kimberly Ashby-Mitchell, Caribbean Public Health Agency, Port of Spain, Trinidad and Tobago; 3. Corrado Barbui, University of Verona, Verona, Italy. 4. Amit Dias, Department of Preventive and Social Medicine, Goa Medical College Bambolim, Goa, India; 5. Suharya Dy (Kusumadewi), Alzheimer’s Disease International, Jakarta, Indonesia; 6. Cleusa P. Ferri, Federal University of Sao Paulo, Sao Paulo, Brazil. 7. Riadh Gouider, Razi Hospital, Faculty of Medicine, Tunis, Tunisia; 8. Shinya Ishii, Ministry of Health, Labour and Welfare, Tokyo, Japan; 14 WHO Office of Compliance, Risk Management and Ethics (CRE) http://intranet.who.int/homes/cre/ethics/doiexperts/ 63 9. Yves Joanette, Canadian Institute of Health Research, Government of Canada. 10. Joseph Kibachio, Ministry of health, Nairobi, Kenya; 11. Shanthi Mendis, Colombo, Sri Lanka; 12. Dorairaj Prabhakaran, Public Health Foundation of India, New Delhi, India; 13. Ameenah Bibi Mia Sorefan, Ministry of Health and Quality of Life, Quatre-Bornes, Mauritius GDG members who have declared an interest on the DOI form or where a potentially relevant interest has been noted from the CV Charles Alessi, Public Health England, London, United-Kingdom Dr Alessi declared that the travel costs for the GDG meeting were covered by his organization. Action: This interest was deemed insignificant or minimal and unlikely to affect, or be reasonably perceived to affect, Dr Alessi’s judgement in the development of the present guidelines. He is deemed to be participating in the guideline development process in an individual capacity and not representing any organization. No further action was necessary Adelina Comas-Herrera, London School of Economics, London, United-Kingdom Dr Comas-Herrera declared in her DoI from that she had received research support routed via her University on various research projects on dementia in 2015 and 2016. These amounts were used to pay her salary by the University. She also declared receiving a payment of US$1000 in 2017 to advise a pharmaceutical company, Axovant Sciences GmbH. The topic was on the availability of data on dementia costs for a medicine that has since been withdrawn due to lack of effectiveness. Action: It was felt that this interest is insignificant or minimal and unlikely to affect, or be reasonably perceived to affect, Dr Comas-Herera’s judgement in the development of the present guidelines. No further action was necessary. Miia Kivipelto, Karolinska Institutet, Stockholm, Sweden Dr Kivipelto declared in her DoI form that she currently serves on the Advisory Board of a Finnish company that focuses on early diagnosis and e-health solutions for which she received €2500. She is also on the Governance committee of AARP, a non-profit organization for healthy ageing for which she received €800. She also declared that she has received research grants related to risk factors for dementia and is a founding member of World-Wide Fingers, an interdisciplinary network to share experiences, harmonize data and plan joint international initiatives for the risk reduction of cognitive decline and dementia. Action: This interest was deemed insignificant or minimal and unlikely to affect, or be reasonably perceived to affect, Dr Kivipelto’s judgement in the development of the present guidelines. She is deemed to be participating in the guideline development process in an individual capacity and not representing any organization. No further action was necessary Ayesha Motala, University of KwaZulu-Natal, Durban, South Africa. Dr Motala declared that as a public servant working in a government institute, she seeks sponsorships to meetings from various organizations, especially when her scientific abstracts are accepted for presentations. The sponsorships are merely for attending the meetings, with no obligation to the sponsoring companies. Annex 2: Assessment of conflict of interest 64 Risk reduction of cognitive decline and dementia: WHO guidelines Details of such sponsorship for which she received a total amount of US$26 000: 4–8 December 2017: International Diabetes Federation (IDF) Congress, Abu Dhabi: Sanofi Aventis sponsorship for travel and accommodation; 11–15 September 2017: European Association for the Study of Diabetes (EASD) Congress, Lisbon: Pfizer sponsorship for travel and accommodation; 8–13 June 2018: American Diabetes Association (ADA), San Diego: Boehringer Ingelheim sponsorship for travel and accommodation: a member of her collaborating scientific team presented a paper. Action: It was felt that this interest is insignificant or minimal and unlikely to affect, or be reasonably perceived to affect, Dr Motala’s contribution as an external reviewer for these guidelines. No further action was necessary. Ronald C. Petersen, Mayo Clinic, Rochester, USA Dr Petersen declared that he is a clinical trials consultant for five pharmaceutical companies: from four of these (Roche Inc, Merck Inc, Genetech Inc and GE Healthcare) he receives less than US$ 10 000 and from one (Biogen Inc) he receives less that US$ 15 000 as consultancy fees. Action: It was felt that this interest is unlikely to affect, or be reasonably perceived to affect, Dr Petersen’s contribution as an external reviewer for these guidelines since these grants are not related to the topic of interest. No further action was necessary. Martin Prince, King’s College London, London, United Kingdom Professor Prince declared in his DOI form that he currently receives research support through a grant from the National Institute of Health Research (NIHR, UK) amounting to £7 million over four years. Professor Prince is the PI and 20% of his salary costs are charged to the grant. The work focuses on health systems strengthening in sub Saharan Africa and one theme relates to the topic of these guidelines i.e. integrated primary healthcare for multimorbid conditions. Action: It was felt that this interest is insignificant or minimal and unlikely to affect, or be reasonably perceived to affect, Professor Prince’s judgement in the development of the present guidelines. No further action was necessary Suzana Shahar, Universiti Kebangsaan Malaysia, Selangor, Malaysia Dr Sahar has declared in her DoI form that she has a clinical trial agreement through her University with Biotropics, a company that develops bio-resources into superior natural health product. The research involves evaluating the efficacy of Asian traditional herbs in improving cognition and mood. The funding amount is US$ 100 000 between 2014 and 2018. Action: It was felt that this interest is insignificant or minimal and unlikely to affect, or be reasonably perceived to affect, Dr Sahar’s contribution as an external reviewer for these guidelines. No further action was necessary Huali Wang, Dementia Care & Research Center, Peking University Institute of Mental Health, Beijing, China. Dr Wang declared in her DoI form that prior to 2016, she had worked as a consultant with Neowave Inc. to develop a tablet-based cognitive training program. She also declared that she had received support for travelling to meetings form Eisai China amounting to US$ 7000 prior to 2017. The meeting were all Alzheimer’s Disease International (ADI) conferences. 65 Action: It was felt that this interest is insignificant or minimal and unlikely to affect, or be reasonably perceived to affect, Dr Wang’s contribution as an external reviewer for these guidelines. No further action was necessary B. EXTERNAL REVIEW GROUP Members of the external review group with no relevant interests declared on the DOI form and no relevant interests found in the CV 1. Abdullah Al Khatami, Ministry of Health, Saudi Arabia 2. Alistair Burns, University of Manchester, UK 3. Linda Clare, University of Exeter, UK 4. Jacqueline Dominguez, Institute for dementia care Asia, Quezon city, Philippines 5. Maelënn Guerchet, The Global Observatory for Ageing and Dementia Care, King's College London, UK 6. Mariella Guerra, Institute of Memory, Depression and Related Disorders – IMEDER, Lima, Peru 7. Luis Miguel F. Gutiérrez Robledo, Instituto Nacional de Geriatría, Institutos Nacionales de Salud de México, Mexico City, Mexico 8. Vladimir Hachinski, University of Western Ontario in London, Ontario, Canada 9. Qurat ul Ain Khan, Aga Khan University Hospital, Karachi, Pakistan. 10. Sebastian Koehler, Maastricht University, The Netherlands 11. Jae-hong Lee, University of Ulsan College of Medicine, Seoul, Korea 12. Gill Livingstone, University college London, UK 13. Jean Claude Mbanya, Doctoral School of Life Sciences, Health and Environment, University of Yaoundé I, Cameroon. 14. James McKillop, Service user group representative, UK 15. Rajat Ray, National Drug Dependence Treatment Centre, All India Institute of Medical Sciences, New Delhi, India 16. Helen Rochford Brennan, European Working Group of people with dementia, Ireland 17. Kate Swaffer, Dementia Alliance International, Australia 18. Weili Xu, Karolinska Institute, Finland Members of the external review group who have declared an interest on the DOI form or where a potentially relevant interest has been noted from the CV Emiliano Albanese, Universita della Svizzera italiana, Switzerland Dr Albanese declared in his DoI form that he receives research support from the Economic and Research Council UK as part of the STRIDE (Strengthening responses to dementia in developing countries) research consortium which focuses on dementia research in low and middle income countries. The amount of US$ 50 000 is provided to the institution to which he is affiliated. Action: It was felt that this interest is insignificant or minimal and unlikely to affect, or be reasonably perceived to affect, Dr Albanese’s contribution as an external reviewer for these guidelines. No further action was necessary. Hillary Doxford, 3 Nations Dementia Working Group, UK Ms Doxford declared in her DoI form that she has served on a grant review panel assessing and prioritizing grant applications for funding dementia research projects for the National Institute for Health Research, UK. The income she received for this was £450. She is also a voluntary member of the Dementia Programme Board in the UK Department of Health and Social Care as a person with lived experience. Action: It was felt that this interest is insignificant or minimal and unlikely to affect, or be reasonably perceived to affect, Ms Doxford’s contribution as an external reviewer for these guidelines. No further action was necessary. Annex 2: Assessment of conflict of interest 66 Risk reduction of cognitive decline and dementia: WHO guidelines Elaine Rashbrook, Public Health England, UK Dr Rashbrook declared in her DoI form that she is employed by Public Health England (PHE), a government agency, as Consultant Specialist Life Course since 2015. PHE supports work on dementia risk reduction in line with the government strategy. There is no identified financial value for the work. Action: It was felt that this interest is insignificant or minimal and unlikely to affect, or be reasonably perceived to affect, Dr Rashbrook’s contribution as an external reviewer for these guidelines. She is deemed to be providing her review in an individual capacity and not representing any organization. No further action was necessary. Andrew Sommerlad, University College London, UK Dr Sommerlad declared in his DoI form that he receives research support from the Wellcome Trust in the form of a personal research fellowship to examiner whether social isolation is a risk factor for dementia The amount of funding is £201 311 from 2016 to 2019. Action: It was felt that this interest is insignificant or minimal and unlikely to affect, or be reasonably perceived to affect, Dr Sommerlad’s contribution as an external reviewer for these guidelines. No further action was necessary B. EXTERNAL PARTNERS External partners with no relevant interests declared on the DOI form and no relevant interests found in the CV 1. Mariagnese Barbera, University of Eastern Finland, Kuopio, Finland; 2. Nicole A. Ee, University of New South Wales, Sydney, Australia; 3. Jenni Kumlala, Karolinska Institutet, Stockholm, Sweden; 4. Ruth Peters, University of New South Wales, Sydney, Australia; 5. Lidan Zheng, University of New South Wales, Sydney, Australia. None of the external partners declared relevant interests on the DOI forms nor were relevant interests found in the CV.   67 ANNEX 3: SCOPING QUESTIONS INTERVENTIONS ADDRESSING LIFESTYLE AND BEHAVIOUR RISK FACTORS 1. Physical activity interventions For adults with normal cognition or mild cognitive impairment, are physical activity interventions more effective than usual care or no intervention in reducing the risk of cognitive decline and/or dementia? P: Adults (age above 18 years) with normal cognition or MCI I: Physical activity interventions (aerobic, resistance training or multicomponent physical activity) C: Care as usual or no intervention O: • Critical – Cognitive function – Incident MCI – Dementia 2. Tobacco cessation interventions For adults with normal cognition or mild cognitive impairment who use tobacco, are interventions for tobacco cessation more effective than usual care or no intervention in reducing the risk of cognitive decline and/or dementia? P: Adults with normal cognition or MCI who use tobacco I: Interventions for tobacco cessation (behavioural interventions and pharmacological interventions including nicotine replacement therapy, bupropion, varenicline) C: Care as usual or no intervention O: • Critical – Cognitive function – Incident MCI – Dementia 3. Nutritional interventions 3a. For adults with normal cognition or mild cognitive impairment, are nutritional interventions such as dietary supplements more effective than usual care or no intervention in reducing the risk of cognitive decline and/or dementia? P: Adults with normal cognition or MCI I: Dietary supplements (e.g. B vitamins, antioxidants, omega-3 and ginkgo); C: Care as usual or no intervention O: • Critical – Cognitive function – Incident MCI – Dementia • Important – Quality of life – Functional level (ADL, IADL) – Adverse events – Drop-out rates • Important – Quality of life – Functional level (ADL, IADL) – Adverse events – Drop-out rates • Important – Quality of life – Functional level (ADL, IADL) – Adverse events – Drop-out rates Annex 3: Scoping questions 68 Risk reduction of cognitive decline and dementia: WHO guidelines 3b. For adults with normal cognition or mild cognitive impairment, are nutritional interventions such as healthy dietary patterns (e.g. Mediterranean diet) more effective than usual care or no intervention in reducing the risk of cognitive decline and/or dementia? P: Adults with normal cognition or MCI I: Healthy dietary pattern (e.g. Mediterranean diet) C: Care as usual or no intervention O: • Critical – Cognitive function – Incident MCI – Dementia 4. Interventions for alcohol use disorders For adults with normal cognition or mild cognitive impairment and alcohol use disorders, are behavioural and psychological interventions to treat alcohol use disorders more effective than usual care or no intervention in reducing the risk of cognitive decline and/or dementia? P: Adults with normal cognition or MCI and excessive use of alcohol I: • Behavioural and psychological interventions to treat alcohol use disorders (e.g. motivational interviewing) • Pharmacological interventions to treat alcohol use disorders C: Care as usual or no intervention O: • Critical – Cognitive function – Incident MCI – Dementia • Important – Quality of life – Functional level (ADL, IADL) – Adverse events – Drop-out rates • Important – Quality of life – Functional level (ADL, IADL) – Adverse events – Drop-out rates 69 SPECIFIC INTERVENTIONS 5. Cognitive interventions For adults with normal cognition or mild cognitive impairment is cognitive stimulation or cognitive training more effective than usual care or no intervention in reducing the risk of cognitive decline and/ or dementia? P: Adults with normal cognition or MCI I: • Cognitive stimulation • Cognitive training C: Care as usual or no intervention O: • Critical – Cognitive function – Incident MCI – Dementia 6. Social activity For adults with normal cognition or mild cognitive impairment is preserving and promoting a high level of social activity more effective than usual care or no intervention in reducing the risk of cognitive decline and/or dementia? P: Adults with normal cognition or MCI I: Preservation and promotion of social activity including community and family engagement C: Care as usual or no intervention O: • Critical – Cognitive function – Incident MCI – Dementia • Important – Quality of life – Functional level (ADL, IADL) – Adverse events – Drop-out rates • Important – Quality of life – Functional level (ADL, IADL) – Adverse events – Drop-out rates Annex 3: Scoping questions 70 Risk reduction of cognitive decline and dementia: WHO guidelines INTERVENTIONS FOR HEALTH CONDITIONS 7. Weight management For adults with normal cognition or mild cognitive impairment who are overweight or obese, are interventions for weight reduction (or control of obesity) more effective than usual care or no intervention in reducing the risk of cognitive decline and/or dementia? P: Adults with normal cognition or MCI who are overweight or obese I: Weight management • Non-pharmacological interventions, e.g. cognitive-behavioural intervention strategies, lifestyle interventions • Pharmacological interventions, e.g. weight-loss medication (e.g. orlistat) C: Care as usual or no intervention O: • Critical – Cognitive function – Incident MCI – Dementia 8. Management of hypertension For adults with normal cognition or mild cognitive impairment and hypertension, is treatment of hypertension more effective than placebo/no intervention in reducing the risk of cognitive decline/dementia? P: Adults with normal cognition or MCI with hypertension I: Antihypertensive medication, lifestyle interventions C: Placebo/no intervention O: • Critical – Cognitive function – Incident MCI – Dementia 9. Management of diabetes mellitus For adults with normal cognition or mild cognitive impairment and diabetes mellitus, is treatment of diabetes more effective than placebo/no intervention in reducing the risk of cognitive decline and/or dementia? P: Adults with normal cognition or MCI with diabetes mellitus I: • Medications for glycaemic control • Diet and lifestyle interventions C: Placebo/no intervention O: • Critical – Cognitive function – Incident MCI – Dementia • Important – Quality of life – Functional level (ADL, IADL) – Adverse events – Drop-out rates • Important – Quality of life – Functional level (ADL, IADL) – Adverse events – Drop-out rates • Important – Quality of life – Functional level (ADL, IADL) – Adverse events – Drop-out rates 71Annex 3: Scoping questions 10. Management of dyslipidaemia For adults with normal cognition or mild cognitive impairment and dyslipidaemia, is treatment of dyslipidaemia more effective than placebo or no intervention in reducing the risk of cognitive decline and/or dementia? P: Adults with normal cognition or MCI with dyslipidaemia I: • Statins (e.g. simvastatin and pravastatin) • Lifestyle interventions C: Placebo or no intervention O: • Critical – Cognitive function – Incident MCI – Dementia 11. Management of depression For adults with normal cognition or mild cognitive impairment and depressive disorder, is treatment of depression more effective than usual care, placebo or no intervention in reducing the risk of cognitive decline and/or dementia? P: Adults with normal cognition or MCI with moderate to severe depressive disorder I: • Pharmacological interventions to treat depression (antidepressant medication) • Psychological interventions to treat depression (e.g. cognitive behavioural therapy, problem-solving therapy, interpersonal therapy, behavioural activation) C: Care as usual or placebo or no intervention O: • Critical – Cognitive function – Incident MCI – Dementia 12. Management of hearing loss For adults with normal cognition or mild cognitive impairment and hearing loss, is treatment of hearing loss more effective than usual care, or no intervention in reducing the risk of cognitive decline and/or dementia? P: Adults with normal cognition or MCI with hearing loss I: Interventions to treat hearing loss (e.g. hearing aids) C: Care as usual or no intervention O: • Critical – Cognitive function – Incident MCI – Dementia • Important – Quality of life – Functional level (ADL, IADL) – Adverse events – Drop-out rates • Important – Quality of life – Functional level (ADL, IADL) – Adverse events – Drop-out rates • Important – Quality of life – Functional level (ADL, IADL) – Adverse events – Drop-out rates 72 Risk reduction of cognitive decline and dementia: WHO guidelines ANNEX 4: EVIDENCE REVIEW METHODOLOGY Comprehensive searches of major bibliographic databases were conducted to identify one systematic review that matched each of the outcomes for each of the PICO questions. The aim was to identify systematic reviews that were timely, of high quality and relevant to each of the PICO questions. The search strategies differed slightly between the two teams (based in the Karolinska Institutet, Sweden and University of New South Wales, Australia. However, in general, the following process was employed: 1. Search for systematic reviews (including meta- analyses) that were published in the last 2 years for each of the PICO questions. The searches were run from April to June 2018. 2. If no relevant high-quality systematic reviews were identified from the 2 years for any of the PICO questions, the search was expanded to include systematic reviews from the last 5 years for that PICO question. For the relevant PICO questions, the 2016 AHRQ systematic review was also consulted. The aim of the AHRQ review was to examine interventions to prevent cognitive decline and dementia. The review systematically searched records between January 2009 and September 2016. 3. For the hearing loss question, there was very limited evidence available, therefore searches were expanded to include all systematic reviews ever published. 4. Based on the GDG’s feedback during the GDG meeting in July 2018, the searches were expanded to further include systematic reviews of obser- vational studies. The searches were re-run July to August 2018. The following bibliographic databases were searched: • Bibliographic • Medline • Cochrane • PsycInfo • Embase • NICE. Relevant to LMIC • Global Index Medicus/Global Health Library • WHO regional database • WHOLIS • Database of impact evaluations • AJOL • KoreaMed • IndMED • HrCak • ArabPsycNet • HERDIN NeON • EurasiaHealth. After the searches were run using the search strategies listed below, titles and abstracts of all results were screened in Endnote; subsequently the full texts of those papers were reviewed that could not be excluded based on the title/abstract review. GRADE EVIDENCE TABLES For each outcome of each PICO question, one or more systematic reviews were then selected to be used within the GRADE evidence tables. The following criteria were used when selecting which systematic review to use within the GRADE evidence tables: • Published in the last 5 years, ideally 2 years (timeliness). • High quality (i.e. measured using AMSTAR 215 criteria). 15 Shea BJ, Grimshaw JM, Wells GA, Boers M, Andersson N, Hamel C et al (2007). Development of AMSTAR: a measurement tool to assess the methodological quality of systematic reviews. BMC Medical Research Methodology. 7:10. 73Annex 3: Scoping questions • Closely relevant to the PICO question. • Comprehensive systematic reviews given preference, where possible. • Cochrane reviews or other meta-analyses given preference, where possible/appropriate. The GRADE methodology involves rating the quality of the studies included in the systematic review according to study design, risk of bias, inconsistency, indirectness, imprecision, and publication bias. Together with the effect sizes of studies, an overall “certainty of evidence” is provided of either very low, low, moderate or high. GRADE evidence tables were completed using the GRADEpro online tool.16 The same criteria were used as for the mhGAP Intervention guide when completing the GRADE evidence tables in terms of the assessment of the quality of studies (for risk of bias, inconsistency, indirectness, imprecision, and publication bias).17 SEARCH STRATEGIES Separate searches were performed for each of the 12 PICO questions. Where PICO questions included both pharmacological and non-pharmacological interventions, searches were run separately for these. Filters were used in the bibliographic databases where possible to restrict the searches to systematic reviews and meta-analyses, as well as to humans. No further restrictions were employed, for example in terms of language (apart from the publication date, as mentioned above). The “advanced search” option was selected in bibliographic databases, where possible. PICO 1 For adults with normal cognition or mild cognitive impairment, are physical activity interventions more effective than usual care or no intervention in reducing the risk of cognitive decline and/or dementia? Search strategy (dementia OR cognit* OR “mild cognitive impairment” OR “Alzheimer disease” OR “dementia vascular” OR “dementia multi-infarct” OR MCI OR “cognitive dysfunction” OR neuropsychologi* OR “Health-Related Quality” Of Life OR “life quality” OR “Activities Daily Living” OR “Chronic Limitation of Activity” OR “Limitation of Activity, Chronic” OR ADL OR “activities of daily living” OR “Drug-Related Side Effects and Adverse Reactions” OR “Adverse Drug Event” OR “Adverse Drug Reaction” OR “Long Term Adverse Effects” OR “Adverse Effects, Long Term Disease-Free Survival” OR “Event-Free Survival” OR “Adverse effects”) AND (Exercise OR “exercise therapy” OR “Acute Exercise” OR “Aerobic Exercise” OR “Exercise Training” OR “Exercise, Aerobic” OR “Exercise, Isometric” OR “Exercise, Physical” OR “Isometric Exercise OR Physical Activity” OR “resistance training”) PICO 2 For adults with normal cognition or mild cognitive impairment who use tobacco, are interventions for tobacco cessation more effective than usual care or no intervention in reducing the risk of cognitive decline and/or dementia? Search strategy (dementia OR cognit* OR mild cognitive impairment OR Alzheimer disease OR dementia vascular OR dementia multi-infarct OR MCI OR cognitive dysfunction OR neuropsychologi* OR Health-Related Quality Of Life OR life quality OR Activities, Daily Living OR Chronic Limitation of Activity OR Limitation 16 https://gradepro.org/ 17 See http://www.who.int/mental_health/mhgap/evidence/mhgap_ guideline_process_2009.pdf 74 Risk reduction of cognitive decline and dementia: WHO guidelines of Activity, Chronic OR ADL OR activities of daily living OR Drug-Related Side Effects and Adverse Reactions OR Adverse Drug Event OR Adverse Drug Reaction OR Long Term Adverse Effects OR Adverse Effects, Long Term Disease-Free Survival OR Event-Free Survival OR Adverse effects) AND (Tobacco OR smoking OR Tobacco use cessation OR giving up smoking OR quitting smoking OR stopping smoking OR smoking cessation OR smoking reduction OR tobacco use cessation products OR varenicline OR nicotinic agonists OR Nicotine Inhalant OR Nicotine Lozenge OR Nicotine Lozenges OR Nicotine Nasal Spray OR Nicotine Patch OR Nicotine Polacrilex OR Nicotine Replacement Products OR Nicotine Transdermal Patch OR Smoking Cessation Products) AND (Behavior OR behaviour OR drug therapy OR pharmacologic therapy OR pharmacotherapy OR Cognitive behavioural therapy OR Cognitive behavioural therapy OR Drug therapy OR cognitive therapy OR online therapy OR treatment) PICO 3 3a. For adults with normal cognition or mild cognitive impairment, are nutritional interventions such as dietary supplements more effective than usual care or no intervention in reducing the risk/ progression of cognitive decline and/or dementia? 3b. For adults with normal cognition or mild cognitive impairment, are nutritional interventions such as healthy dietary patterns (e.g. Mediterranean diet) more effective than usual care or no intervention in reducing the risk/progression of cognitive decline and/or dementia? Search strategy (dementia OR cognit* OR “mild cognitive impairment” OR “Alzheimer disease” OR Alzheimer* OR “dementia vascular” OR “dementia multi-infarct” OR MCI OR “cognitive dysfunction” OR neuropsychologi* OR “Health-Related Quality Of Life” OR “life quality” OR “quality of life” OR “Activities of Daily Living” OR “Chronic Limitation of Activity” OR “Limitation of Activity, Chronic” OR ADL OR “activities of daily living” OR “Drug-Related Side Effects and Adverse Reactions” OR “Adverse Drug Event” OR “Adverse Drug Reaction” OR “Long Term Adverse Effects” OR “Adverse Effects, Long Term” OR “Disease-Free Survival” OR “Event-Free Survival” OR “Adverse effects”) AND (“Dietary supple- ments” OR “Dietary Supplementations” OR “Food Supplementations” OR “Food Supplements” OR “Herbal Supplements” OR Neutraceuticals OR Nutraceuticals OR Nutriceuticals OR diet or vitamin or food) PICO 4 For adults with normal cognition or mild cognitive impairment and alcohol use disorders, are behavioural and psychological interventions to treat alcohol use disorders more effective than usual care or no intervention in reducing the risk of cognitive decline and/or dementia? Search strategy (dementia OR cognit* OR mild cognitive impairment OR Alzheimer disease OR dementia vascular OR dementia multi-infarct OR MCI OR cognitive dysfunction OR neuropsychologi* OR Health-Related Quality Of Life OR life quality OR Activities, Daily Living OR Chronic Limitation of Activity OR Limitation of Activity, Chronic OR ADL OR activities of daily living OR Drug-Related Side Effects and Adverse Reactions OR Adverse Drug Event OR Adverse Drug Reaction OR Long Term Adverse Effects OR Adverse Effects, Long Term Disease-Free Survival OR Event-Free Survival OR Adverse effects) AND (Alcohol drinking OR Binge drinking OR Drunkenness OR alcohol intoxication OR alcoholism OR alcohol withdrawal) AND (Add in Behavior OR behaviour OR drug therapy OR pharmacologic therapy OR pharmacotherapy OR Cognitive behavioural therapy OR Cognitive behavioural therapy OR Drug therapy OR cognitive therapy OR online therapy OR treatment) 75Annex 3: Scoping questions PICO 5 For adults with normal cognition or mild cognitive impairment is cognitive stimulation or cognitive training more effective than usual care or no intervention in reducing the risk of cognitive decline and/or dementia? Search strategy (systemati* or meta analys*) and (dementia or cognit* or MCI or neuropsycholog* or Alzheimer*) and ("Brain training" OR "cognitive training" OR "Brain fitness" OR Games OR "Memory training" OR (Stimulation AND cognit*) PICO 6 For adults with normal cognition or mild cognitive impairment is preserving and promoting a high level of social activity more effective than usual care or no intervention in reducing the risk of cognitive decline and/or dementia? Search strategy ("social interaction" or "social Networks" or "social processes" or "social behaviour" or "social behavior" or "community networks" or "social media" or family) and (dementia or cognit* or "mild cognitive impairment" or MCI or "cognitive dysfunction" or neuropsycholog* or Alzheime*) and (systemati* or meta-analys*) PICO 7 For adults with normal cognition or mild cognitive impairment who are overweight or obese, are interventions for weight reduction (or control of obesity) more effective than usual care or no intervention in reducing the risk of cognitive decline and/or dementia? Search strategy (dementia OR cognit* OR mild cognitive impairment OR Alzheimer disease OR dementia vascular OR dementia multi-infarct OR MCI OR cognitive dysfunction OR neuropsychologi* OR Health-Related Quality Of Life OR life quality OR Activities, Daily Living OR Chronic Limitation of Activity OR Limitation of Activity, Chronic OR ADL OR activities of daily living OR Drug-Related Side Effects and Adverse Reactions OR Adverse Drug Event OR Adverse Drug Reaction OR Long Term Adverse Effects OR Adverse Effects, Long Term Disease-Free Survival OR Event-Free Survival OR Adverse effects) AND (Overweight OR Body weight or Body mass index OR weight loss OR Body weight changes) AND (Behavior OR behaviour OR drug therapy OR pharmacologic therapy OR pharmacotherapy OR Cognitive behavioural therapy OR Cognitive behavioural therapy OR Drug therapy OR cognitive therapy OR online therapy OR treatment OR Appetite depressants) PICO 8 For adults with normal cognition or mild cognitive impairment and hypertension, is treatment of hypertension more effective than placebo/no intervention in reducing reduce the risk of cognitive decline/dementia? Search strategy (systemati* or meta-analys*) and (dementia or cognit* or "mild cognitive impairment" or MCI or "cognitive dysfunction" or neuropsycholog* or Alzheimer's or Alzheimer) and (behaviour or behavior or "drug therapy" or "pharmacologic therapy" or pharmacotherapy or "cognitive behavioural therapy" or "cognitive behavioral therapy" or "cognitive therapy" or "online therapy" or "anti-hypertensive" or antihypertensive or treatment) and (hypertension or "blood pressure" or systolic or diastolic or prehypertension) 76 Risk reduction of cognitive decline and dementia: WHO guidelines PICO 9 For adults with normal cognition or mild cognitive impairment and diabetes mellitus, is treatment of diabetes more effective than placebo/no intervention in reducing the risk of cognitive decline and/or dementia? Search strategy (systemati* or meta-analys*) and (dementia or cognit* or "mild cognitive impairment" or MCI or "cognitive dysfunction" or neuropsycholog* or Alzheime*) .ab. and diabetes.af. and ("hypoglycemic agents" or treatment or therapy or pharmacotherapy or behaviour or behavior) PICO 10 For adults with normal cognition or mild cognitive impairment and dyslipidaemia, is treatment of dyslipidaemia more effective than placebo or no intervention in reducing reduce the risk of cognitive decline and/or dementia? Search strategy (dementia OR cognit* OR mild cognitive impairment OR Alzheimer disease OR dementia vascular OR dementia multi-infarct OR MCI OR cognitive dysfunction OR neuropsychologi* OR Health-Related Quality Of Life OR life quality OR Activities, Daily Living OR Chronic Limitation of Activity OR Limitation of Activity, Chronic OR ADL OR activities of daily living OR Drug-Related Side Effects and Adverse Reactions OR Adverse Drug Event OR Adverse Drug Reaction OR Long Term Adverse Effects OR Adverse Effects, Long Term Disease-Free Survival OR Event-Free Survival OR Adverse effects) AND (Cholesterol OR Hypercholes-terolemia OR lipo- proteins OR HDL cholesterol OR LDL cholesterol OR triglycerides) AND (Behavior OR behaviour OR drug therapy OR pharmalogic therapy OR pharmacotherapy OR Cognitive behavioural therapy OR Cognitive behavioural therapy OR Drug therapy OR cognitive therapy OR online therapy OR treatment OR statins OR Hydroxymethylglutaryl-CoA Reductase Inhibitors OR Anticholesteremic agents) PICO 11 For adults with normal cognition or mild cognitive impairment and depressive disorder, is treatment of depression more effective than usual care, placebo or no intervention in reducing the risk of cognitive decline and/or dementia? Search strategy (depression or depressive) and (systemati* or meta- analys*) and (dementia or cognit* or "mild cognitive impairment" or MCI or "cognitive dysfunction" or neuropsycholog* or Alzheimer's or Alzheimer*) and (treatment or therapy or pharmacotherapy or antidepressan* or antidepressiv*) PICO 12 For adults with normal cognition or mild cognitive impairment and hearing loss, is treatment of hearing loss more effective than usual care, or no intervention in reducing the risk of cognitive decline and/or dementia? Search strategy (hearing aids OR Cochlear implants Or hearing implants) AND (hearing loss OR deafness OR hearing impairment OR hypoacusis OR intervention OR treatment) AND (dementia OR cognit* OR mild cognitive impairment OR Alzheimer's disease OR dementia vascular OR dementia multi-infarct OR MCI OR cognitive dysfunction OR neuropsycholog*) 77Glossary Adverse event Any untoward medical occurrence in a patient or clinical investigation subject caused by health care management. Aerobic exercise A type of physical exercise that requires free oxygen to adequately meet energy demands via the aerobic metabolism. During aerobic exercise, oxygen is used to “burn” fats and glucose in order to produce adenosine triphosphate, the basic energy carrier for all cells. This type of exercise improves physical fitness by promoting the circulation of oxygen through the blood, is associated with an increased rate of breathing, and includes any type of exercise that, when performed at levels of intensity sufficiently supported by the aerobic metabolism, can be performed for extended periods of time. Behavioural activation A behavioural treatment for depression in which the person with depression is guided to increase the number of rewarding activities in his or her life. Body mass index An objective measurement calculated as body mass (or weight in kg) divided by the square of the body height (in metres), universally expressed in units of kg/m2. BMI is used as approximate indicator of the amount of tissue mass (muscle, bone, and fat) in an individual. Based on the correlation between BMI and the degree of risk for certain disease, such as diabetes or atherosclerosis, BMI values are categorized as underweight, normal weight, overweight, or obese; obesity can also be subcategorized in moderate severe and morbid. Cognitive behavioural intervention/therapy A type of psychological therapy that involves identifying and correcting distorted maladaptive beliefs, while using thought exercises and real experiences to facilitate symptom reduction and improved functioning. Cognitive decline The physiological decay of brain functions such as memory, attention or learning ability, for example, which is associated with the normal ageing process. It differs from cognitive impairment in that anyone who ages develops some kind of cognitive decline, although at different degrees. Cognitive impairment, instead, is normally the result of a pathological event: injury, disease, or increased levels of cognitive decline. Cognitive function Cerebral activities, i.e. reasoning, memory, attention, and language that lead to the attainment of information and knowledge. Cognitive stimulation Participation in a range of activities designed to improve cognitive and social functioning. Cognitive training Guided practice of specific standardized tasks designed to enhance particular cognitive functions. Dementia Dementia, a group of disorders characterized by a decline from a previously attained cognitive level that affects activities of daily living or social functioning. Dietary supplements Dietary supplements include vitamins, minerals, fibre, fatty acids, or amino acids, among other substances. They are either intended to provide nutrients in order to increase their consumption, or to provide non-nutrient chemicals which are claimed to have a biologically beneficial effect. Health-related quality of life An individual’s or a group’s perceived physical and mental health over time. As a multidimensional concept, it includes domains related to physical, mental, emotional and social functioning, and it is a way to assess the impact of health status on quality of life. Mediterranean diet A diet which consists of a high intake of cereals, fruits, fish, legumes, and vegetables and low intake of meat and dairy. G LOSSARY 78 Risk reduction of cognitive decline and dementia: WHO guidelines Mild cognitive impairment A disorder characterized by impairment of memory, learning difficulties and reduced ability to concentrate on a task for more than brief periods. There is often a marked feeling of mental fatigue when mental tasks are attempted, and new learning is found to be subjectively difficult even when objectively successful. None of these symptoms are so severe that a diagnosis of either dementia or delirium can be made. Motivational interviewing An established evidence-based practice in the treatment of individuals with substance use disorders that focuses on exploring and resolving ambivalence and centres on motivational processes within the individual that facilitate change. Multidomain intervention Intervention normally aimed to prevent/address a certain disease or condition by acting simultaneously on a range of risk factors, which may be either correlated or independent from each other. Nicotine replacement therapy A type of treatment that makes use of special products which provide small, steady doses of nicotine to help stop cravings and relieve withdrawal symptoms when an individual is trying to stop using tobacco. These products include nicotine gum, nicotine inhaler, nicotine nasal spray, nicotine lozenges, and nicotine patch. They do not contain any of the other chemicals found in tobacco products. Physical activity Any bodily movement produced by skeletal muscles that requires energy expenditure – including activities undertaken while working, playing, carrying out household chores, travelling, and engaging in recreational pursuits Physical exercise: subcategory of physical activity that is planned, structured, repetitive, and aims to improve or maintain one or more components of physical fitness. Problem-solving therapy A type of psychological therapy where the patient systematically identifies his or her problems; generates alternative solutions for each problem; selects the best solution; develops and conducts a plan; and evaluates whether this has solved the problem. Quality of life An individual’s perception of their position in life in the context of the culture and value systems in which they live and in relation to their goals, expectations, standards and concerns. Resistance training A form of physical exercise that, by the moving of the limbs against high loads or fixed resistances, causes skeletal muscles contraction, building their strength, anaerobic endurance, and size. The external resistance can be represented by dumbbells, rubber exercise tubing, the own body weight, bricks, bottles of water, machine specifically designed to this purpose, or any other object that causes the muscles to contract. The forces involved must be such that relatively few repetitions are possible without a substantial rest period. Resistance or strength training is primarily an anaerobic activity, although some proponents have adapted it to provide the benefits of aerobic exercise through circuit training. Social activity Social activities are varied and difficult to define, however they may include meeting friends, attending events or functions, volunteering or participating in occupational duties or group recreational activities.

For further information, please contact: Department of Mental Health and Substance Abuse, World Health Organization Avenue Appia 20 CH-1211 Geneva 27 Switzerland Email: whodementia@who.int Website: www.who.int/mental_health/ neurology/dementia/en ISBN 978-92-4-155054-3

認知機能低下および認知症 のリスク低減 WHOガイドライン 令和元年度　厚生労働省老人保健健康増進等事業 「海外認知症予防ガイドラインの整理に関する調査研究事業」 WHOガイドライン『認知機能低下および認知症のリスク低減』 邦訳検討委員会 This translation was not created by the World Health Organization (WHO). WHO is not responsible for the content or accuracy of this translation. The original English edition “Risk reduction of cognitive decline and dementia”: WHO guidelines.Geneva: World Health Organization; 2019. License: CC BY-NC-SA 3.0 IGO. shall be the binding and authentic edition. この翻訳は世界保健機関（WHO）によってなされたものではない。 WHO はここに書かれた内容、あるいは翻訳の正確さに対して責任を有しない。 WHO による英語版が、拘束力のある真正な版である。 Some rights reserved. This work is available under the Creative Commons Attribution-NonCommercial-ShareAlike 3.0 licence (CC BY-NC-SA 3.0 ; https://creativecommons.org/licenses/by-nc-sa/3.0/). 一定の権利が留保されているこの著作物は、「クリエイティブ・コモンズ 表示 - 非営利 - 継承，3.0 ライセンス （CC BY-NC-SA3.0; https://creativecommons.org/licenses/by-nc-sa/3.0/）」に基づいて利用することができる。 訳 者 序 世界保健機関（WHO）は 2019 年に「認知機能低下および認知症のリスク低減〔Risk Reduction of Cognitive Decline and Dementia〕」のためのガイドラインを公表した。これはその日本語版であり、厚生労働省老人保健健康増 進等事業の中で設置された同ガイドライン邦訳検討委員会（次頁）が、ガイドラインの内容の検討とともに邦訳の作業 を担った。 WHO はこのガイドラインを、医療や介護に従事する人たち、および、医療・介護にかかる施策や計画を立案したり 管理したりする人たちを対象として作成した。したがって専門的な用語、表現、構成が採用されており、内容の理解に あたっては一定の専門知識が求められる。これは、このガイドラインを、（現時点において可能な限り）医学的に厳密な 内容とするためにも必要なことであった。邦訳に際しては、この WHO の意図に沿うため、できるだけ原文に近い表現 を用いることに注意が払われた。 一方、WHO はこのガイドラインが世界の様々に異なる地域において、適切に用いられ有用なものとなるために、そ の地域の社会的、文化的な状況に適合させることを求めている。本邦に適用する場合について言えば、たとえば、食習 慣における海外との違いを十分考慮する必要がある。このような部分については、邦訳検討委員会が「日本語版におけ る注釈」を追記した。この注釈がある項目においては、必ずこれを参照していただきたい。 また、本邦と海外との違いではないが、本ガイドラインが医学・医療におけるガイドラインの本来のあり方として、 エビデンスの評価において、観察研究より介入研究の結果を重視している点にも留意していただきたい（ｐ 11 の「日 本語版における注釈」を参照）。そのため、認知症研究の現状もあって、多くの項目でエビデンスの質は “ 低 ” か “ 中 ” となっている。一方、それにもかかわらず “ 強い推奨 ” がなされていることがある。これはエビデンスの質が低い場合 でも、推奨することが一般的に有益であって害が少ないことが確実であれば、“ 強い推奨 ” とされているからである。 なお、“ 推奨 ” されている事項の実施に際して、WHO は、財政的および人的資源を含めた現場の状況に合わせて調整 することも求めている。 本ガイドラインにおいて “ 認知機能低下 ” と呼んでいる状態は、脳病変に基づいて生じ、軽度認知障害、認知症と徐々 に進行していくものである。脳に病変や異常が存在せず年齢とともに記憶が低下した、というものとは明確に区別され ている。ここは、加齢が認知症を引き起こす疾患・脳病変の最も強い危険因子であるために誤解が生じやすい点である。 単に年齢を重ねるだけでは、日常生活において支障が生じるような、すなわち、本ガイドラインが対象としている “ 認 知機能低下 ” をきたすような脳の状態に陥ることはない。 WHO ガイドライン『認知機能低下および認知症のリスク低減』が、この日本語版の作成により、国内で広く用いら れるようになることを願っている。 WHO ガイドライン『認知機能低下および認知症のリスク低減』 邦訳検討委員会委員一覧（五十音順） 氏名 所属先・役職名 秋山治彦 横浜市立脳卒中・神経脊椎センター　臨床研究部　部長 池田　学 大阪大学大学院医学系研究科 情報統合医学講座・精神医学分野　教授 小原知之 九州大学大学院医学研究院精神病態医学分野　講師 數井裕光 高知大学医学部　神経精神科学教室　教授 冨本秀和 三重大学大学院医学研究科　神経内科　教授 羽生春夫 東京医科大学　高齢診療科　教授 原　英夫 佐賀大学医学部　神経内科　教授 三村　將 慶應義塾大学　精神神経科学教室　教授 和田健二 川崎医科大学　認知症学　教授 著 作 権 WHO ガイドライン「認知機能低下および認知症のリスク低減」 ISBN 978-92-4-155054-3 © 世界保健機関 2019 一定の権利が留保されているこの著作物は、「クリエ イティブ・コモンズ 表示 - 非営利 - 継承、3.0 IGO* ラ イ セ ン ス（CC BY-NC-SA3.0IGO; https://creative commons.org/licenses/by-nc-sa/3.0/igo）」に基づい て利用することができる。 上記のライセンスの定める条件の範囲内で、この著作 物を、下記に示すように適切に引用した上で、非営利目 的で、複製、再配布、改変することができる。どのよう な形の使用であっても、WHO は、いかなる特定の組織・ 機関、著作物・製作物事業等を支持するという示唆を与 えることはない。 WHO のロゴを使用することは許可しない。もしこの 著作物に変更を加えるのであれば、この著作物と同じ、 もしくは同等のクリエイティブ・コモンズの許諾条件の もとに、その著作物の使用許諾を与えなくてはならない。 この著作物の翻訳を行うのであれば、以下のような但書 きを、ここに示す引用とともに、追記しなくてはならな い。“この翻訳は世界保健機関〔WHO〕によってなされ たものではない。WHO はここに書かれた内容、あるい は翻訳の正確さに対して責任を有しない。元の（WHO による）英語版が、拘束力のある真正な版である” この使用許諾のもとに生ずる議論に関連するいかなる 調停も、世界知的所有権機関の調停規則に従って行われ なくてはいけない。 推奨される引用方法： Risk reduction of cognitive decline and dementia: WHO guidelines. Geneva: World Health Organization; 2019. License: CC BY- NC-SA 3.0 IGO. 出版目録データ： （Cataloguing-in-Publication (CIP) data）は以下の URL から入手できる。 http://apps.who.int/iris. 販売、権利、使用許諾： WHOの出版物を購入するには以下のURLを参照すること。 http://apps.who.int/bookorders 権利と使用許諾についての質問、および商業目的での使 用に要望を提出する場合は以下の URL を参照すること。 http://www.who.int/about/licensing. 第三者に由来する素材について この出版物に用いられている表、図、画像などの素材 のうち第三者に帰属するものについては、それを再使用 するにあたり、再使用の許諾が必要かどうか、そして、 著作権者から許諾を得るかどうかの判断は、その素材を 再使用しようとする者の責任において行うこと。この著 作のうち第三者が権利を保有する部分については、その 権利侵害により生ずる抗議にかかるリスクは再使用する 者のみが負うこと。 全般的な免責 本出版物で採用されている名称表記および資料の提示 は、いかなる国、地域、都市、区域もしくはその官署の法 的地位に関して、またはその境界地域もしくは境界線の決 定に関して、WHO としてのいかなる見解をも表明するも のではない。地図上の破線は、未だ全面的な合意に達し ていない可能性のある境界線の概略を示したものである。 個別の企業または特定の製品について言及されている 場合、 それらに対して、言及されていない同業他社また は同種製品に優先して、WHO が承認または推奨を与え るものではない。誤字・脱字を除き、登録商標名は頭文 字を大文字にすることにより区別した。 本出版物に含まれる情報を確認するために、WHO は あらゆる適切な注意を払ってきた。しかし、本出版物は、 明示または暗示を問わず、いかなる種類の保証を伴うも のではない。本出版物の解釈および利用の責任は読者が 負うものとする。WHO は、その利用により生じたいか なる損害についても責任を負うものではない。 意匠および配置：Erica Lefstad 印刷国：France （以上、原文記載事項）

目 次 序 …………………………………………………………………i 謝辞 ……………………………………………………………… ii 略語一覧 ……………………………………………………… iv 実施概要 ……………………………………………………… v 1．はじめに ……………………………………………… 1 1.1 本ガイドラインの背景と基本的な考え方 ……………… 2 1.2 関連する WHO ガイドラインおよびツール …………… 4 1.3 対象者となる読者 ………………………………………… 5 1.4 目標および目的 …………………………………………… 5 1.5 基本原則 …………………………………………………… 6 2．ガイドライン作成の過程 ………………… 7 2.1 ガイドライン作成グループ ……………………………… 8 2.2 ガイドライン作成グループおよび 外部評価者の利益相反申告 ……………………………… 8 2.3 外部専門家との協働 ……………………………………… 8 2.4 利用可能なエビデンスの同定、 査読、および生成 ………………………………………… 8 2.5 ガイドライン作成グループの 会合における結論の導き方 ……………………………… 9 2.6 文書作成と専門家による評価 …………………………… 10 3．エビデンスと推奨 ……………………………… 11 3.1 身体活動による介入 ……………………………………… 12 3.2 禁煙介入 …………………………………………………… 15 3.3 栄養的介入 ………………………………………………… 17 3.4 アルコール使用障害への介入 …………………………… 22 3.5 認知的介入 ………………………………………………… 25 3.6 社会活動 …………………………………………………… 27 3.7 体重の管理 ………………………………………………… 29 3.8 高血圧の管理 ……………………………………………… 32 3.9 糖尿病の管理 ……………………………………………… 35 3.10 脂質異常症の管理 ………………………………………… 38 3.11 うつ病への対応 …………………………………………… 40 3.12 難聴の管理 ………………………………………………… 43 4．実行にあたっての考察 ……………………… 47 5．出版、普及、および評価 ………………… 49 5.1 出版と普及 ………………………………………………… 50 5.2 モニタリングと評価 ……………………………………… 51 5.3 さらなる研究への関わり ………………………………… 51 5.4 将来の再評価と更新 ……………………………………… 52 文献 ……………………………………………………………… 53 補遺 1．ガイドライン作成グループメンバー …… 61 補遺 2．利益相反アセスメント ………………………… 63 補遺 3．スコーピング・クエスチョン ……………… 68 補遺 4．エビデンス評価の方法論 ……………………… 73 Web 上の補遺：エビデンスの概要 （WHO/MSD/MER/19.1） https://www.who.int/mental_health/neurology/dementia/ guidelines_risk_reduction/en/index.html 用語解説 ……………………………………………………… 78 序 認知症は急速に拡大している公衆衛生の課題であり、世界中で 5,000 万人に影響を与えている。認知症は高齢者の障害 や依存の主要な要因であり、認知症の人の介護者や家族など、影響を受ける個人の生活を破壊しうるものである。加えて、 認知症のある方のケアに関わる経済的コストは 2030 年までに毎年 2 兆米ドルに上ると予想されているなど、認知症は 概して、社会に大きな経済的負担をもたらす。 認知症には治療法がないものの、修正可能な危険因子に対する予防管理により、発症や進行を遅らせることは 可 能 で あ る。2017 年 5 月 に 第 70 回 世 界 保 健 総 会 で「Global Action Plan on the Public Health Response to Dementia2017-2025」が採択され、できるだけ早くこの難題に対して精力的に取り組みを行うように、加盟国に対し て促しがなされた。認知症リスクの低減は「Global Action Plan」に掲げる七つの戦略的行動領域の一つである。 この新しい WHO ガイドラインは医療提供者、行政、政策立案者、その他の関係者に対して、公衆衛生アプローチを 通じて、認知機能の低下や認知症リスクを抑制するための基礎知識を与えるものである。認知症の危険因子の大部分が 非感染性疾患と共通であるため、ガイドラインにおける主要な推奨は禁煙のためのプログラム、循環器疾患のリスク低減、 栄養に集約される。 認知症の人、その介護者や家族の生活がより良いものとなるように、私は、すべての関係者に対して、本ガイドライン における提言を最大限活用することを強く推奨する。 Dr Ren Minghui Assistant Director-General for Universal Health Coverage/Communicable and Noncommunicable Diseases , World Health Organization （以上、原文記載事項） i 認知機能低下および認知症のリスク低減 WHOガイドライン 謝 辞 GUIDELINE DEVELOPMENT GROUP Chair: Martin Prince, King’s College, London, United Kingdom. Members: Charles Alessi, Public Health England, London, United Kingdom; Kaarin J Anstey, University of New South Wales, Sydney, Australia; Kimberly Ashby-Mitchell, Caribbean Public Health Agency, Port of Spain, Trinidad and Tobago; Adelina Comas-Herrera, London School of Economics, London, United Kingdom; Amit Dias, Department of Preventive and Social Medicine, Goa Medical College Bambolim, Goa, India; Cleusa P Ferri, Federal University of São Paulo, São Paulo, Brazil; Riadh Gouider, Razi Hospital, Faculty of Medicine, Tunis, Tunisia; Shinya Ishii, Ministry of Health, Labour and Welfare, Tokyo, Japan; Yves Joanette, Canadian Institutes of Health Research, Government of Canada; Joseph Kibachio, Ministry of Health, Nairobi, Kenya; Miia Kivipelto, Karolinska Institutet, Stockholm, Sweden; Shanthi Mendis, Colombo, Sri Lanka; Ayesha Motala, University of KwaZulu-Natal, Durban, South Africa; Ronald C Petersen, Mayo Clinic, Rochester, United States of America; Dorairaj Prabhakaran, Public Health Foundation of India, New Delhi, India; Suzana Shahar, Universiti Kebangsaan Malaysia, Selangor, Malaysia; Ameenah Bibi Mia Sorefan, Ministry of Health and Quality of Life, Quatre-Bornes, Mauritius; Kusumadewi Suharya (Dy), Alzheimer’s Disease International, Jakarta, Indonesia; Huali Wang, Dementia Care & Research Center, Peking University Institute of Mental Health, Beijing, China. Grade methodologist: Corrado Barbui, University of Verona, Italy. EXTERNAL REVIEW GROUP Abdullah Al Khatami, Ministry of Health, Saudi Arabia; Emiliano Albanese, Università della Svizzera italiana, Switzerland; Alistair Burns, University of Manchester, United Kingdom; Linda Clare, University of Exeter, United Kingdom; Jacqueline Dominguez, Institute for Dementia Care Asia, Quezon City, Philippines; Hillary Doxford, 3 Nations Dementia Working Group, United Kingdom; Maelënn Guerchet, Global Observatory for Ageing and Dementia Care,King’s College London, United Kingdom; Mariella Guerra, Institute of Memory, Depression and Related Disorders, Lima, Peru; Luis Miguel F Gutiérrez Robledo, Instituto Nacional de Geriatría, Institutos Nacionales de Salud de México, Mexico City, Mexico; Vladimir Hachinski, University of Western Ontario in London, Ontario, Canada; Qurat-ul Ain Khan, Aga Khan University Hospital, Karachi, Pakistan; Sebastian Koehler, Maastricht University, The Netherlands; Jae- hong Lee, University of Ulsan College of Medicine, Seoul, Republic of Korea; Gill Livingstone, University College London, United Kingdom; Jean Claude Mbanya, Doctoral School of Life Sciences, Health and Environment, University of Yaoundé I, Cameroon; James McKillop, service user group representative, United Kingdom; Elaine Rashbrook, Public Health England, United Kingdom; Rajat Ray, National Drug Dependence Treatment Centre, All India Institute of Medical Sciences, New Delhi, India; Helen Rochford Brennan, European Working Group of People with Dementia, Ireland; Andrew Sommerlad, University College London, United Kingdom; Kate Swaffer, Dementia Alliance International, Australia; Weili Xu, Karolinska Institutet, Finland. WHO GUIDELINE STEERING GROUP Overall coordination: Tar un D u a , Pr o g ramm e Manager, Department of Mental Health and Substance Abuse; Neerja Chowdhary, Technical Officer, Department of Mental Health and Substance Abuse. 謝　辞 ii WHO headquarters members: Katthyana Aparicio Reyes, Department of Service Delivery and Safety; Islene Araujo de Carvalho, Department of Ageing and Life Course; Lubna Bhatti, Department of Prevention of Noncommunicable Diseases; Fiona Bull, Department of Prevention of Noncommunicable Diseases; Shelly Chadha, Department of Management of Noncommunicable Diseases, Disability, Violence and Injury Prevention; Alarcos Cieza, Department of Management of Noncommunicable Diseases, Disability, Violence and Injury Prevention; Stéfanie Fréel, Department of Mental Health and Substance Abuse; Maria Garcia Casal, Department of Nutrition for Health and Development; Angela Luzia Herscheid,Department of Mental Health and Substance Abuse; Michal Herz, Department of Mental Health and Substance Abuse; Dzmitry Krupchanka, Department of Mental Health and Substance Abuse; Artin Mahdanian, Department of Mental Health and Substance Abuse; Shanthi Pal, Department of Essential Medicines and Health Products; Anne Margriet Pot, Department of Ageing and Life Course; Gojka Roglic, Department of Management of Noncommunicable Diseases, Disability, Violence and Injury Prevention; Katrin Seeher, Department of Mental Health and Substance Abuse. WHO regional office advisors: Nazneen Anwar, WHO Regional Office for South-East Asia; Dan Chisholm, WHO Regional Office for Europe; Devora Kestel, WHO Regional Office for the Americas; Sebastiana Da Gama Nkomo, WHO Regional Office for Africa; Khalid Saeed, WHO Regional Office for the Eastern Mediterranean; Martin Vandendyck, WHO Regional Office for the Western Pacific. WHO evidence review and synthesis teams: Mariagnese Barbera, University of Eastern Finland, Kuopio, Finland; Nicole A Ee, University of New South Wales, Sydney, Australia; Jenni Kumlala, Karolinska Institutet, Stockholm, Sweden; Ruth Peters, University of New South Wales, Sydney, Australia; Lidan Zheng, University of New South Wales, Sydney, Australia. FUNDING SOURCE Funds received from Public Health England, United Kingdom; Centers for Disease Control and Prevention, United States of America; and the WHO Core Voluntary Contributions Account were used for the development of these guidelines. iii 認知機能低下および認知症のリスク低減 WHOガイドライン 略 語 一 覧 ACE アンジオテンシン変換酵素 AD アルツハイマー病 ADAS-cog アルツハイマー病評価尺度 - 認知行動サブスケール ADL 日常生活動作 AHRQ 医療研究品質局（米国） ARB アンジオテンシン受容体拮抗薬 BMI ボディー ・マス・インデックス CCB カルシウム拮抗薬 CI 信頼区間 CVRF 心血管系リスクファクター CVD 心血管疾患 DALYs 障害調整生存年数 DASH 高血圧を防ぐ食事療法 DoI 利益相反申告 EMBASE エンベ スー（医学・薬学の文献データベ スー） ERG 外部評価委員会 GDG ガイドライン作成グル プー（WHO） GDP 国内総生産 GRADE 推奨、アセスメント、開発と評価の等級付け（システマティックレビューや診療ガイドラインの作成 の際に、エビデンスの質評価や推奨を明確なプロセスで決定するためのシステムとして国際的な任 意団体が発表した方法） HIV ヒト免疫不全ウイルス IADL 手段的日常生活動作 ICOPE 高齢者のための総合ケア（WHO） LMIC 低中所得国 MCI 軽度認知障害 MDRS マチス認知症評価スケール MeSH 米国国立医学図書館が定めた医学件名標目（シソーラスメッシュ〔MeSH〕） mhGAP 精神保健の格差に関する行動プログラム（WHO） MMSE 精神状態短時間検査 NCDs 非感染性疾患 NIA 国立老化研究所（米国） NICE 国立医療技術評価機構（英国） OR オッズ比 PEN 非感染性疾患に対する介入パッケージ (WHO) PICO 対象、介入、比較対照、アウトカム PUFA 多価不飽和脂肪酸 RCT ランダム化比較試験 RR 相対リスク SMD 標準化平均差 略語一覧 iv 実 施 概 要 はじめに 認知症は急速に拡大している世界的な公衆衛生の課題 である。全世界で 5,000 万人が認知症に罹患しており、 そ の 60 ％ が 低 中 所 得 国〔low- and middle-income countries ; LMIC〕に住んでいる。毎年、およそ 1,000 万人近くの認知症患者が新規に発症している。2030 年には認知症の総患者数は 8,200 万人、2050 年には 15,200 万人に達すると予測されている。認知症は行政、 コミュニティ、家族や個人の負担増加、経済生産性の喪 失につながっている。2015 年、全世界での認知症に関 わる社会的費用は 818 億米ドル、即ち全世界の国内総 生産〔global domestic product; GDP〕の 1.1％に相 当すると推定されている。 加齢は認知機能低下の最も強力な既知の危険因子で あるが、認知症が加齢の生来的な、あるいは不可避の結 果ではないことは重要な点である。いくつかの最近の研 究によると、不活発なライフスタイル、喫煙、不健康な 食事、過剰な飲酒などのライフスタイルに関連する因子 が、認知機能低下や認知症と関連することが示されて いる。高血圧、糖尿病、脂質異常症、肥満、抑うつな ど一定の病態が認知症の発症リスクと関連する。その 他の潜在的に修正可能な危険因子として、社会的孤立、 知的な活動低下などがある。潜在的に修正可能な危険因 子が存在するということは、認知機能の低下や認知症発 症を遅らせる基本的介入の実施などの公衆衛生的アプ ローチを通じて、認知症予防が可能であることを意味し ている。 2017 年 5 月、第 70 回世界保健総会〔World Health Assembly〕では認知症に対する公衆衛生対策の活動計 画 2017-2025 を採択した（WHO、2017a）。本計画に は七つの戦略的行動領域があり、認知症の発症リスク低 減はその一つとされている。行動計画は認知症の修正可 能な危険因子を減少させるエビデンス基盤を強化・共有 して普及をめざす方針で WHO 事務局と一致している。 方針としては、認知症リスクファクターの有病率やそれ らを低減することの影響に関して利用可能なエビデン スを創出しデータベースを構築すること、認知症リスク 低減のためのエビデンスに基づく多面的介入の組織化 や実行を支援することなどが挙げられる。 認知機能低下や認知症のリスク低減のための本ガイ ドラインは、エビデンスに基づく認知症の公衆衛生対 策のための指針を作成するという WHO の方向性に沿っ ている。 ガイドラインの作成法 ガイドラインの作成法のプロセスは WHO によるガイ ドライン作成手引書に準拠し、その内容は； １． ガイドライン作成グループ〔GDG〕の人選 ２． GDG メンバーの利益相反申告とピアレビュー ３． クエスチョン作成とアウトカム選定のためのスコー ピングレビュー ４． 利用可能なエビデンスの同定、評価、構築 ５． 幅広い利害関係者からの声を反映し推奨文を制定 ６． 文書を作成し、公開方法を企画 GDG は国際的な専門家集団であり、ガイドラインの スコープへの入力内容を提供し、重要クエスチョン策 定のための運営グループの補佐を行った。総計で 12 個 の PICO (population, intervention, comparison and outcome) 質問を作成した。 PICO質問を決定するため、システマティックレビュー のための一連の文献検索を行って GRADE〔Grading of Recommendations Assessment, Development and Evaluation〕システムのためのエビデンスの概要を用 意した。2018 年 2 ～ 3 月にジュネーブで開催された WHO 統括本部ミーティングの最中に、GDG は推奨を 策定するためにエビデンスを議論して明確化し結果の解 釈を行った。また、低中所得国におけるプロバイダーの ために、介入ごとの益と害のバランス、価値と優先度、 費用と資源、適切な現実的課題について考察を行った。 強い推奨を行う際には、GDG は介入による望ましい 効果がそうでない効果を常に上回ることを確実と考えて いる。望ましい効果とそうでない効果のバランスが不確 v 認知機能低下および認知症のリスク低減 WHOガイドライン 実な場合、GDG は条件付きの推奨を行っている。強い 推奨は、ほとんどの個人が介入を望み、それを実施すべ きであることを意味する。一方、条件付き推奨は個々の 患者について別の介入が適切である可能性があり、患者 は治療介入の決定に際して助言が必要となる可能性があ ることを意味している。GDG メンバーはすべての推奨 と評価について明確な合意に至っている。 実施概要 vi 推奨の概要 身体活動による介入； 身体活動は、認知機能正常の成人に対して認知機能低下のリスクを低減するため に推奨される。 エビデンスの質； 中 推 奨 の 強 さ； 強い 身体活動は、軽度認知障害の成人に対して認知機能低下のリスクを低減するため に推奨してもよい。 エビデンスの質； 低い 推 奨 の 強 さ； 条件による 禁煙による介入； 禁煙介入は、他の健康上の利点に加えて、認知機能低下と認知症のリスクを低減 する可能性があるため、喫煙している成人に対して行われるべきである。 エビデンスの質； 低い 推 奨 の 強 さ； 強い 栄養的介入； 地中海食は、認知機能正常または軽度認知障害の成人に対して認知機能低下や認 知症のリスクを低減するために推奨してもよい。 エビデンスの質； 中 推 奨 の 強 さ； 条件による WHO の健康食に関する推奨に準拠して、健康なバランスのとれた食事は全ての 成人に対して推奨される。 エビデンスの質； 低い～高い（食事の成分による） 推 奨 の 強 さ； 強い ビタミン B・E、多価不飽和脂肪酸、複合サプリメントは、認知機能低下や認知症 のリスクを低減するために推奨されない。 エビデンスの質； 中 推 奨 の 強 さ； 強い（日本語版注：左記は推奨されない度合いが強いことを示す） アルコール使用障害 への介入； 危険で有害な飲酒を減量または中断することを目的とした介入は、他の健康上の 利点に加えて、認知機能正常または軽度認知障害の成人に対して認知機能低下や 認知症のリスクを低減するために行われるべきである。 エビデンスの質； 中（観察研究によるエビデンス） 推 奨 の 強 さ； 条件による 認知的介入； 認知トレーニングは、認知機能正常または軽度認知障害の高齢者に対して認知機 能低下や認知症のリスクを低減するために行ってもよい。 エビデンスの質； 非常に低い～低い 推 奨 の 強 さ； 条件による 社会活動； 社会活動と認知機能低下や認知症のリスクの低減との関連については十分なエビ デンスはない。ただ、社会参加と社会的な支援は健康と幸福とに強く結びついて おり、社会的な関わりに組み込まれることは一生を通じて支援されるべきである。 vii 認知機能低下および認知症のリスク低減 WHOガイドライン 体重管理； 中年期の過体重、または肥満に対する介入は認知機能低下や認知症のリスクを低 減するために行ってもよい。 エビデンスの質； 非常に低い～中 推 奨 の 強 さ； 条件による 高血圧の管理； 高血圧の管理は、現行の WHO ガイドラインの基準に従って高血圧のある成人に 対して行われるべきである。 エビデンスの質； 低い～高い（介入の種類による） 推 奨 の 強 さ； 強い 高血圧の管理は、高血圧のある成人に対して認知機能低下や認知症のリスクを低 減するために行ってもよい。 エビデンスの質； 非常に低い（認知症の転帰に関して） 推 奨 の 強 さ； 条件による 糖尿病の管理； 糖尿病のある成人に対して、内服やライフスタイルの是正、または両者による糖 尿病の管理は現行の WHO のガイドラインの基準に従って行われるべきである。 エビデンスの質； 非常に低い～中（介入の種類による） 推 奨 の 強 さ； 強い 糖尿病の管理は、糖尿病患者に対して認知機能低下や認知症のリスクを低減する ために行ってもよい。 エビデンスの質； 非常に低い 推 奨 の 強 さ； 条件による 脂質異常症の管理； 脂質異常症の管理は、脂質異常症のある中年期の成人において認知機能低下と認 知症のリスクを低減するために行ってもよい。 エビデンスの質； 非常に低い 推 奨 の 強 さ； 条件による うつ病への対応； 現在のところ、認知機能低下や認知症のリスクを低減するために抗うつ薬の使用 を推奨するエビデンスは不十分である。 成人に対する抗うつ薬や心理療法を用いるうつ病治療は、現行の WHO mhGAP ガイドラインの基準に従って行われるべきである。 難聴の管理； 認知機能低下や認知症のリスクを低減するために補聴器の使用を推奨するエビデ ンスは不十分である。 WHO ICOPE ガイドラインで推奨されているように、難聴を適時に発見し治療す るために、スクリーニングと難聴のある高齢者への補聴器の提供が行われるべき である。 実施概要 viii 1 認知機能低下および認知症のリスク低減 WHOガイドライン 1 は じ め に はじめに 2 1.1 本ガイドラインの背景と 基本的な考え方 認知症は、以前に到達した認知レベルから日常生活動 作〔ADL〕や社会機能に影響を及ぼす程度への低下を特 徴とする疾患群であり、21 世紀の健康と社会的介護に とって世界的な最重要課題の一つとなっている。 2015 年時点では、全世界の 5,000 万人（全世界の高 齢者（60 歳以上）人口のおよそ 5％）が認知症に罹患 していた。世界中で人口が高齢化していることから、60 歳以上の人口の認知症の罹患者数は、2030 年には 8,200 万人、2050 年には 1 億 5,200 万人と指数関数的に増加 すると予測されており、60 歳以上の人口のうち、認知 症の人の割合は 5 ～ 8% になると推定されている 1。こ れらの推移は、認知症の年齢 - 性別特異的有病率が経時 的に一定であると仮定しているため、特に、人口動態が 顕著に変化する低中所得国〔LMIC〕で、最も急激な上 昇が予測されている。 認知症は、世界中で高齢者における身体障害や介護の 主な原因となっている。そのため、認知症の個人だけで なく、介護者、家族、地域や社会にも大きな影響を及 ぼす。認知症は、全世界の非感染性疾患〔NCD〕に起 因する障害生存年数の 11.9% を占めている。認知症は、 政府、地域、その家族や個人にかかる支出を増加させ、 経済の生産性を低下させる。全世界で認知症にかけられ ている年間費用は 818 億ドルと推定されており（OECD 2015、WHO 2017b）、費用の 85% 近くは医療ではな く家族介護や社会的介護と関連している（GBD 2015 Neurological Disorders Collaborator Group 2017）。 ほとんどの国の医療制度は、現在の認知症関連のニーズ に対応するには施設も資源も不十分である。したがって、 社会の高齢化とそれに関連する認知症有病率の上昇は、 認知症の人の介護やその家族支援において保健サービス に重大な影響を及ぼすとされている。 認知症には様々な原因や種類がある。一次性認知症（神 経変性過程を根底に認知機能低下が起こり、他の病因に よって直接引き起こされない認知症）には、アルツハイ マー病〔AD〕による認知症、血管性認知症、レビー小 体型認知症や前頭側頭型認知症が含まれる。アルツハイ マー病は最も多い疾患であり、次に血管性認知症やレ ビー小体型認知症が多くみられる。特に高齢者では、二 つ以上の特徴を有する混合型認知症も多くみられる。一 方、前頭側頭型認知症はそれほど多くみられないものの、 初老期に比較的高頻度で発症する。 二次性認知症は、HIV、頭部損傷、多発性硬化症、甲 状腺疾患またはビタミン B12 欠乏などの一次性認知症 以外の明確な疾患により引き起こされるか、それらと密 接に関連する認知症である。これらの二次性認知症にお ける認知機能障害は、他の臓器系の症状や徴候に付随し て生じることが多く、その治療は基礎疾患の管理が中心 となる。 本ガイドラインでは一次性認知症を対象範囲としてい る。一部の疾患の早期治療は二次性認知症の発症を予防 する可能性があると考えられるが、これらの二次性認知 症は本ガイドラインの範囲に含めていない。二次性認知 症の原因となるような特異的な疾患の多くには、予防あ るいは適切な管理や治療戦略が存在し、それらによって 認知症に関連する徴候や症状が効果的に低減されるため である。ただし、遅発性認知症は不均一かつ多因子性の 病態であり、いくつかの因子（例えば、頭部外傷、早 期のビタミン B12 欠乏）は（二次性認知症だけでなく） 高齢期の認知症発症にも寄与する可能性がある。 3 認知機能低下および認知症のリスク低減 WHOガイドライン 認知症の危険因子 認知症の修正不可能な危険因子には、遺伝子多型、年 齢、性別、人種／民族性や家族歴などがある。重要なこ とは、年齢は認知機能低下の最も強い既知の危険因子で あるが、認知症は加齢による自然な、あるいは必然的な 結果ではないということである。この 20 年間の研究に より、学歴や、運動不足、喫煙、不健康な食事およびア ルコールの有害な使用などの生活習慣に関連した危険因 子が認知機能障害や認知症の発症と関連していることが 示されている。さらに、高血圧、糖尿病、高コレステロー ル血症、肥満やうつ病などの特定の病態は、認知症発症 リスクの増大と関連している。社会的孤立や認知機能の 不活発は、その他の修正可能な潜在的危険因子に含まれ る。ガイドラインの視野に含まれるこれらの危険因子は、 国立医療技術評価機構（英国）（NICE 2015）、米国医療 研究品質庁〔AHRQ〕のシステマティックレビュ （ーKan et al., 2017）、World Alzheimer report 2014（Prince et al., 2014）、認知症の予防、介入および介護に関する ランセット委員会による報告（Livingston et al., 2017） などの最近のシステマティックレビューやガイドライン に基づいて選択された。このような修正可能な危険因子 に焦点をあてたのは、これらの因子が認知症の予防や認 知機能低下の進行遅延の標的となる可能性があることが 根拠となっている。 本ガイドラインの必要性 修正可能な潜在的危険因子の存在は、認知機能低下や 認知症を遅延させる鍵となる介入実施を含む公衆衛生的 アプローチを通じて、認知症の予防が可能であることを 意味している。 2017 年 5 月、第 70 回世界保健総会は認知症の公衆 衛生対策に関する世界行動計画〔Global action plan on the public health response to dementia〕2017- 2025 を承認した（WHO 2017a）。行動計画のビジョン は、認知症が予防され、認知症の人とその介護者が健康 的に生活し、尊厳、尊敬、自主性や平等性を保ちながら 潜在能力を発揮するのに必要な介護と支援を受けられる 世界である。行動計画の目標は、認知症の人、その介護 1 http://www.who.int/mental_health/action_plan_2013/en/ で入手可能 2 http://www.who.int/nmh/publications/ncd-action-plan/en/ で入手可能 者や家族の生活を改善し、これらの人々や地域および国 に対して認知症が及ぼす影響を低減することである。行 動計画は、七つの戦略的行動領域で構成されており、認 知症リスクの低減はその一つである。行動計画は、認知 症の修正可能な潜在的危険因子を低減できる政策的介入 を支援するため、エビデンスの基礎を強化し、共有し、 公表するよう WHO 事務局に要請している。これには、 危険因子の有病率やそれらを減らすことの影響に関する 利用可能なエビデンスのデータベース提供と、認知症リ スク低減のためのエビデンスに基づいた多分野にわたる 介入の策定と実施の支援が含まれている。本ガイドライ ンは、各国における認知症の発症遅延や予防に対するア プローチ策定を支援するための最初のステップを提示し ている。 認知機能低下や認知症のリスク低減のためのガイドラ インは、認知症に対する公衆衛生対策のためのエビデン スに基づいたガイダンスを提供するという WHO の任 務に沿っている。医療従事者や社会的介護の専門家の支 援、特に、他の非感染性疾患と共有している修正可能な 認知症危険因子を含むエビデンスに基づいた多分野にわ たる性別や文化的にも適切な介入を一般集団に提供する 能力を改善することにより、認知症の発症リスクを潜在 的に減らせ、あるいは、認知症の進行を遅らせることが 可能となる。したがって、本ガイドラインは、非感染性 疾患の発生率、有病率および死亡率を低減するために各 国を支援することを目的としている非感染性疾患の予防 と管理の分野における WHO の活動とも一致している。 WHO は、非感染性疾患と認知症の予防の分野で活動す る国際および国立公衆衛生機関などの様々な関係者と協 力している。 こ の ガ イ ド ラ イ ン は、 包 括 的 精 神 衛 生 行 動 計 画 〔Comprehensive mental health action plan〕2013- 20201、非感染性疾患を予防および管理するための世 界 行 動 計 画〔Global action plan for the prevention and control of noncommunicable diseases〕2013- 20202、 高 齢 化 と 健 康 に 関 す る 世 界 戦 略・ 行 動 計 画 〔Global strategy and action plan on ageing and はじめに 4 health〕2016-20203、アルコールの有害な使用を低 減 す る た め の 世 界 戦 略〔Global strategy to reduce harmful use of alcohol〕4 および食事、身体活動およ び 健 康 に 関 す る 世 界 戦 略〔Global strategy on diet, physical activity and health〕5 などの WHO のそのほ かの行動計画や戦略と概念的にも戦略的にも密接な相乗 効果を発揮している。さらにこの活動は、「人をより中 心にした」健康サービスに近づけようとする WHO の活 動と一致する。最後に、この活動は、持続可能な開発目 標〔Sustainable Development Goal〕3 の目標 3.8 の 達成、すなわち、すべての人々に対する財政リスクから の保護、質の高い基礎的な保健サービスへのアクセス、 および安全で効果的かつ質の高い安価な必須医薬品とワ クチンへのアクセスを含むユニバーサル・ヘルス・カバ レッジ（UN 2019）の達成に貢献している。 3 http://who.int/ageing/global-strategy/en/ で入手可能 4 http://www.who.int/substance_abuse/activities/gsrhua/en/ で入手可能 5 http://www.who.int/dietphysicalactivity/Indicators%20English.pdf で入手可能 1.2 関連するWHOガイドライン およびツール 一般集団向けに策定されたいくつかの既存の WHO ガ イドラインおよびツールは、認知機能が正常あるいは軽 度認知症外（MCI）を有する人における認知機能低下 や認知症のリスクを高める可能性がある健康状態への対 処に関連している。本ガイドラインを策定する際、次の WHO ガイドラインやツールを参照した。 ・ 精神保健専門家のいない保健医療の場における精神・ 神経・物質使用障害のための mhGAP 介入ガイド Ver. 2.0〔mhGAP Intervention guide － Version 2.0 for mental, neurological and substance use disorders in non-specialized health settings〕、 Geneva: WHO, 2016. http://www.who.int/mental_health/mhgap/mhGAP_ intervention_guide_02/en/ ・ 非 感 染 性 疾 患 の 予 防 と 管 理： 資 源 に 乏 し い 環 境 に お け る プ ラ イ マ リ ヘ ル ス ケ ア ガ イ ド ラ イ ン 〔Prevention and control of noncommunicable diseases: guidelines for primary health care in low-resource settings〕、Geneva: WHO, 2012. http://apps.who.int/iris/bitstream/10665/76173/ 1/9789241548397_eng.pdf ・ 資源に乏しい環境のプライマリヘルスケアにおける 基本的な非感染性疾患介入策の包括的計画〔Package of essential noncommunicable (PEN) disease interventions for primary health care in low- resource settings（PEN）〕、Geneva: WHO, 2010. ht tp://www.who.int /card iovascular_diseases/ publications/pen2010/en/ 5 認知機能低下および認知症のリスク低減 WHOガイドライン ・ 健康のための身体活動に関する国際勧告〔Global recommendations on physical activity for health〕、Geneva: WHO, 2010. http://www.who.int/dietphysicalactivity/publications/ 9789241599979/en/ ・ 高齢者のための総合ケア（ICOPE）：地域レベル で高齢者の身体的および精神的能力を改善するた めの介入に関する推奨事項〔Integrated care for older people (ICOPE): Recommendations on interventions to improve physical and mental capacities of older people at community level〕、 Geneva: WHO, 2016. ・ プライマリヘルスケアにおいて心血管疾患を管理 するための技術パッケージ：エビデンスに基づく 治 療 プ ロ ト コ ル〔HEARTS Technical package for cardiovascular disease management in primary health care: evidence-based treatment protocols〕 http://www.who.int/cardiovascular_diseases/hearts/ en/ ・ 高齢者にやさしい世界の都市ガイド〔Global age- friendly cities: a guide〕、Geneva: WHO, 2007. http://www.who.int/ageing/publications/Global_age_ friendly_cities_Guide_English.pdf ・ 健康的な食事に関する推奨事項〔Recommendations on healthy diet〕、Geneva: WHO, 2019. http://www.who.int/en/news-room/fact-sheets/detail/ healthy-diet ・ プライマリケアでタバコ依存を治療するための医療 制 度 の 強 化〔Strengthening health systems for treating tobacco dependence in primary care〕、 Geneva: WHO, 2013. http://www.who.int/tobacco/publications/building_ capac i t y/ t ra in ing _ package/ t rea t ing tobacco dependence/en/ ・ 人 を 中 心 と し た 包 括 的 保 健 サ ー ビ ス の 枠 組 み 〔Framework on integrated people-centred health services〕、Geneva: WHO, 2016. http://apps.who.int/gb/ebwha/pdf_files/WHA69/ A69_39-en.pdf?ua=1 これら既存の WHO ガイドラインやツールは、本ガ イドラインの範囲に含まれるいくつかの介入に対応して いるが、アウトカムとして認知機能低下や認知症を含ん でいない。本ガイドラインが他のガイドライン（例え ば、MCI 患者の認知介入に関する推奨事項を提供する ICOPE ガイドライン）と重複している場合には新しい 推奨事項を策定せず、これらの既存推奨事項を参照した。 したがって、本ガイドラインは既存の WHO ガイドライ ンやツールを補完するが、それらと重複する内容を含む ものではない。 1.3 対象者となる読者 本ガイドラインは主に、外来患者／入院患者の基本的 なサービスを含むレベル 1 またはレベル 2 の施設または 地域レベルで働く医療提供者を対象としている。医療提 供者は医師、看護師、あるいはそのほかの医療従事者の 幹部がなりうる。本ガイドラインは組織のあらゆるレベ ルの品質改善チームに利益を与えるであろう。 加えて、ガイドラインおよびその派生産物は、一般集 団だけでなく、国内および国際レベルでの政策立案者、 保健医療計画立案者やプログラム管理者にとっても有益 である。 1.4 目標および目的 ・ 一般集団における認知機能低下や認知症の発症の遅 延または予防のため、生活習慣行動および介入に関 するエビデンスに基づいた推奨事項を提供すること。 ・ 認知機能低下や認知症の発症の遅延または予防のた め、特定の身体的および精神的健康状態の管理に関 するエビデンスに基づいた推奨事項を提供すること。 本ガイドラインは、認知症の公衆衛生対策に関する世 界行動計画〔Global action plan on the public health response to dementia〕2017-2025、 包 括 的 精 神 衛 生 行 動 計 画〔Comprehensive mental health action plan〕および WHO の精神保健の格差に関する行動プ ロ グ ラ ム〔Mental Health Gap Action Programme はじめに 6 （mhGAP）〕6、非感染性疾患を予防および管理するための 世界行動計画〔Global action plan for the prevention and control of noncommunicable diseases〕2013- 20207、 高 齢 化 と 健 康 に 関 す る 世 界 戦 略・ 行 動 計 画 〔Global strategy and action plan on ageing and health〕2016-20208、アルコールの有害な使用を低 減 す る た め の 世 界 戦 略〔Global strategy to reduce harmful use of alcohol〕 9、ならびに食事、身体活動お よび健康に関する世界戦略〔Global strategy on diet, physical activity and health〕10 の施行を促進するため、 エビデンスに基づいた最新の WHO 推奨事項を提供して いる。 1.5 基本原則 以下の原則は、ガイドライン策定の方針であり、本ガ イドラインの実施の際にも指針とすべきものである。 ・ ガイドラインは、認知症の公衆衛生対策に関する 世界行動計画〔Global action plan on the public health response to dementia〕2017-2025 に概説 6 http://www.who.int/mental_health/action_plan_2013/en/ で入手可能 7 http://www.who.int/nmh/publications/ncd-action-plan/en/ で入手可能 8 http://who.int/ageing/global-strategy/en/ で入手可能 9 http://www.who.int/substance_abuse/activities/gsrhua/en/ で入手可能 10 http://www.who.int/dietphysicalactivity/Indicators%20English.pdf で入手可能 した目標、ならびに非感染性疾患による早期死亡の低減 と精神衛生および福祉の推進に焦点を当てている持続可 能な開発目標〔Sustainable Development Goal〕の目 標 3.4（UN 2019）の達成を促進するものでなければな らない。 ・ ガイドラインの策定プロセスや策定後の実施は、認 知機能低下や認知症のリスクがある人の健康水準を 平等にする権利を具体的に促進し、その積極的な関 与を促進するものでなければならない。 ・ 推奨事項は、烙印や差別の削減、健康および社会的 介護サービスを求める障壁の削減、治療の選択にお ける十分な情報に基づいた意思決定の確保など、認 知機能低下や認知症の人の人権を保護するための努 力ともに実施されなければならない。 推奨事項の実施は、財政的および人的資源の利用可能 性を含めて現場の状況に合わせて調整すべきである。た だし、ガイドラインで扱われている不平等はあらゆる国 で共通してみられており、保健サービスの中で優先事項 とすべきである。 7 認知機能低下および認知症のリスク低減 WHOガイドライン 2 ガイドライン作成の過程 ガイドライン作成の過程 8 このガイドラインの作成は、WHO のガイドライン 作 成 ハ ン ド ブ ッ ク（ 第 2 版、http://apps.who.int/ medicinedocs/en/m/abstract/Js22083en/）に従って 行われた。 その過程には、以下の段階が設定されていた。 2.1 ガイドライン作成グループ WHO 精神保健・物質乱用部が中心となり、これに WHO 地域事務所、および関連する WHO 部署、および プログラムからの代表者が加わり WHO のガイドライ ン統括委員会〔guideline steering group〕が組織され た。ガイドライン統括委員会はガイドライン作成に必要 な全ての支援を行った。次に二つのグループ、すなわち ガイドライン作成グループ〔GDG〕と外部評価委員会 〔external review group ERG〕が組織された。GDG に は、ガイドラインの対象となる領域に関する学際的な専 門知識を有する学者と臨床医からなる有識者が含まれて いた。その人選には、地誌的多様性と性別のバランスが 考慮された（補遺 1 参照）。 ガイドライン作成方法に関する幅広い経験と他のガイ ドライン作成グループへの参加経験があり、この分野で 尊敬されている研究者が委員長に選ばれた。GDG メン バー候補者は、WHO の利益相反申告書を完成させるよ う求められた。そしてその申告書は統括委員会によって 審査された。 2.2 ガイドライン作成グループメンバーと 外部評価者による利益相反申告 全ての GDG メンバー、すなわち研究論文を査読する 者とシステマティックレビューチームのメンバーは、ガ イドライン作成のためのエビデンスの査読を行う前に、 利益相反申告を完了するよう求められた。GDG 会議へ の参加依頼状は、利益相反申告書が審査され承認された 後に送付された。GDG メンバーは、秘密保持も求めら れた。利益相反申告書が届き次第、WHO 事務局は、イ ンターネットやデータベースサーチによって得た追加情 報とともに利益相反申告書を審査して、利益相反の有無 を評価した。そしてもしも利益相反があれば、マネジ メントプランが必要か否かを評価した。これらの過程 を経て GDG メンバーが最終決定された。この GDG 会 議への参加が検討されているメンバーの氏名と略歴は、 GDG 会議が開催される前に公開されパブリックコメン トが募られた。 GDG 会議の開始時に、GDG メンバー各々の利益相反 申告書が開示された。また GDG メンバーと外部協力者 は、関連する利益相反に変更が生じた際には、WHO 事 務局に知らせて更新するように指示された。利益相反の 申告については、ジュネーブでの顔合わせの会議の前に も、相反の可能性がないか再度調査された。大きな利益 相反を有するメンバーはいなかった。決定プロセスの全 てが文書として残された（補遺 2 参照）。 2.3 外部専門家との協同 スウェーデンのストックホルムにあるカロリンスカ研 究所のアルツハイマー研究センター、およびオーストラ リアのニューサウスウェールズ大学心理学部と神経科学 研究所は、エビデンスの査読と統合作業を行い、本ガイ ドラインの作成を支援した。 2.4 利用可能なエビデンスの同定、 査読および生成 対象者、介入、比較対照、アウトカム（PICO）を決 めるべき質問を特定するためのスコーピングレビュー （研究の範囲を評価する予備的な文献レビュー）は、修 正可能な危険因子の同定、および認知機能低下、あるい は認知症に対する介入を対象に行われた。これらの介入 は、前記したすでに作成済みの WHO ガイドライン、例 えば、「非感染性疾患の予防と制御：限られた資源環境 におけるプライマリヘルスケアのための非感染性〔PEN〕 疾患への介入のためのパッケージ」や「高齢者のための 総合ケア〔ICOPE〕ガイドライン」でもまとめられてい る。しかし、これらのガイドラインのアウトカムとして、 認知機能の低下や認知症は含まれていない。 認知症の予防、介入、およびケアレポートに関するラ ンセット委員会は、最近の要約報告書の中で、明らかに なってきた認知症の危険因子と介入に関する情報を要 約している（Livingston et al., 2017）。この一連のシ ステマティックレビューで報告された危険因子と介入に 9 認知機能低下および認知症のリスク低減 WHOガイドライン は、教育、運動、社会交流の維持、減煙、および難聴、 うつ病、高血圧、糖尿病、肥満に対する管理が含まれて いる。米国国立衛生研究所の国立老化研究所〔NIA〕が 要請し、かつ支援した別のシステマティックレビューで も、危険因子と介入に関するエビデンス、特に認知トレー ニング、血圧管理、運動の重要性を確認した（Kane et al., 2017）。これらのレビューで報告された介入は、本 ガイドラインンでも PICO の質問を構築する際の基本と した。 先行するガイドラインの対象者は、正常な認知機能を 有する成人と軽度認知障害の人と考えられた。軽度認知 障害という用語は、記憶の障害、学習困難、および少し 長い時間、課題に集中する能力の低下を特徴とし、その 低下が健常老化で予想される程度を超えた状態である。 精神的タスクを試みると、しばしば著明な精神的疲労感 を感じ、また新規学習においては、客観的には成功して いても、主観的には難しいと感じている。これらの症状 はどれもそれほど重篤ではないため、認知症の診断を下 すことはできない。しかし軽度認知障害と診断された人 は、認知症に進行するリスクが高くなる。これらのガイ ドラインに軽度認知障害の成人を含めることによって、 何らかの介入で認知機能低下の進行、つまり軽度認知障 害から認知症への移行を遅らせることが可能になるであ ろう。 これらのガイドラインの適応範囲は、認知機能低下ま たは認知症発症の予防 / リスク低減である（関心とされ ている主たるアウトカム）。認知機能低下は、注意機能、 記憶機能、またはより高いレベルの認知機能（注意、言語、 推論を含む）の明らかで測定可能な喪失または異常と定 義される。認知症は、認知機能低下やその他の症状を含 む症候群で、ICD-10 基準に基づいて診断することがで きる。認知症には、記憶低下と記憶以外の少なくとも一 つの機能、例えば熟練した運動（肢節運動失行）、言語 （失語症）、または実行機能（計画、注意、抽象的推論な ど）の低下を伴う。この低下は、以前のその人の行動か らの変化として捉えられ、またこの低下によって社会的 機能や職業的機能を損なっているべきである。背景のセ クションで述べたように、我々が本書で認知症という用 語を使用する際には、原発性または神経変性疾患による 認知症を指している。 GDG は、ガイドラインの適応範囲に関する情報を提 供し、統括委員会が主要な質問を作成する支援を行った。 そして 12 の PICO 質問が作成された（補遺 3）。 アウトカムは GDG メンバーによって、重要性に従っ て「重大」、「重要」、「重要でない」のどれかに評定された。 そして重大、あるいは重要と評定されたアウトカムが、 PICO に加えるために選択された。GDG との定期的な 連絡は電子メールで、議論は電話会議で行われた。 システマティックレビューチームは、認知機能正常ま たは軽度認知障害の成人に対する認知機能低下や認知症 のリスクを低減する介入（PICO 質問の中で概説したよ うに）に関するエビデンスをレビューするためのプロ トコルを開発した（補遺 4）。 PICO の各々の質問ごと に、関連する既存のシステマティックレビューが同定さ れた。統括委員会は、システマティックレビューの多面 的評価〔AMSTAR〕のためのチェックリストを使用し て、既存のレビューの質の評価を行った。高い質を有し ていることがわかったシステマティックレビューに関し ては、最新のエビデンスが使用されていることを確認す るために、適時性についても評価された。 「推奨、アセスメント、開発と評価の等級付け〔GRADE〕 方法論」（Guyatt et al., 2011）、およびガイドライン作 成のための WHO ハンドブックを、エビデンスプロファ イルを作成するために使用した。エビデンスの質評価は、 研究デザイン、すなわち、RCT（ランダム化比較試験） か観察研究か、バイアスリスク、非一貫性、間接性、不 正確性、および出版バイアス、を考慮して GRADE に従っ て行われた。エビデンスは、高い、中、低い、または非 常に低いのいずれかに評定された。 2.5 ガイドライン作成グループの会合 における結論の導き方 GDG は、2018 年 7 月 2 ～ 3 日 に ジ ュ ネ ー ブ の WHO 本部で会合を持った。エビデンスのレビューは 事前に送付され、その会議中のプレゼンテーションで 要約が説明された。 GDG メンバーは、WHO 事務局 が作成したドラフトに基づいて推奨を作成するため に、エビデンスについて議論し、ポイントを明らかに し、結果を解釈した。GDG は、各介入の益と害のバラ ガイドライン作成の過程 10 ンス、個人の価値や好み、コストとリソース活用、低 中所得国の医療提供者の介入に対する受け入れやすさ、 実現可能性、公平性と人権への影響を考慮しながら、 GRADE Evidence-to-Decision〔EtD〕 フ レ ー ム ワ ー ク（Alonso-Coello et al., 2016）に基づいて、正常の 認知機能を有した成人、または軽度認知障害の成人にお ける推奨の妥当性を検討した。リソースの制約を決定す るための調査や正式な費用対効果の調査は行われなかっ たが、これらに関する議論には、GDG メンバーの専門 知識と経験が活用された。公平性と人権については、特 に低中所得国で行われた研究を含むデータベースを検索 し、ある特定のサブグループでデータの乖離がないかを 検討することで、配慮された。経済状況、雇用または職 業、教育、居住地、性別または民族などが異なるサブグ ループの人々に異なる効果が介入によって認められる可 能性が GDG によって検討された。 これらの事項を考慮した上で、強力な推奨を行う際に は、GDG は、介入の望ましい効果が望ましくない効果 を上回ると確信していた。望ましい効果と望ましくない 効果のバランスについて不確実な場合には、GDG は条 件付きの推奨を行った。強い推奨は、ほとんどの個人が 介入を望み、それを受け取るべきであることを意味する が、条件付きの推奨は、個々の患者に異なる選択肢が 適切であり、決定には支援が必要かもしれない。エビデ ンスの質は低いか、非常に低い場合でも、推奨が一般的 に益をもたらすと合意でき、かつ害を上回ると考えられ れば、依然として強い推奨となる場合もある。意見の相 違が生じた場合、委員長と方法論者は、争点がデータの 解釈に関連することか、推奨が策定された方法に関連す ることかを確認することとなっていた。もしも合意に達 しなかった場合は、GDG メンバーは 70％の多数決に同 意し決定した。会議に出席した WHO スタッフメンバー、 およびエビデンスの収集とレビューに関与したその他の 外部技術専門家は、投票から除外された。GDG メンバー は、すべての推奨と評価について合意に達し、投票は不 要であった。 2.6 文書作成と専門家による評価 WHO スタッフと GDG によって作成されたガイドラ インとエビデンスプロファイルの草案は、外部評価委員 会と統括委員会に回覧された。外部評価委員会の役割は、 推奨を変更するのではなく、エラーや欠落データを特定 し、明確さ、設定固有の事項、実施への示唆についてコ メントすることであった。すべての情報と発言が議論さ れ、メールで GDG と合意に至った。 11 認知機能低下および認知症のリスク低減 WHOガイドライン 3 エビデンスと推奨 この章では、次に掲げる事項により示される各 PICO 質問を概説する。 • 背景 • 推奨 • その他の考察 • 推奨の裏付けとなるエビデンス • 統合されたエビデンスと EtD テーブルに挙げられた基準に基づく推奨の根拠 GRADE テーブルと EtD テーブルを含む各 PICO 質問のエビデンスプロファイルは、Web 上の補遺に掲載されている。 日本語版における注釈 本ガイドラインにおけるエビデンスレベルの検討には、介入研究と観察研究の結果が用いられている。また、本 ガイドラインは観察研究と比べ因果関係の実証に優れる（エビデンスレベルが高い）介入研究の結果を優先してエ ビデンスレベルを決定している。しかし、性質の異なる研究手法であるため、本ガイドラインの解釈には注意が必 要である。 観察研究とは、認知症のない集団を追跡して追跡開始時に測定した危険因子レベルと追跡期間中の認知症発症と の関係を検討する研究手法であり、因果関係エビデンスレベルは中等度とされている。 介入研究とは、認知症のない集団を危険因子について治療を行った介入群と行わなかった非介入群とに分けて追 跡し、介入群と非介入群における認知症発症を比較する研究手法であり、因果関係実証のエビデンスレベルは高い。 全ての検討で介入研究を実施できることが理想であるが、下記に記すような問題点を克服できないため、認知症 の介入研究はかなり少なく、十分な研究成果も得られていない。そのため、本書におけるエビデンスレベルのほと んどが小から中程度となっている。 介入研究の問題点 ▷ 健康志向の高い（認知症を発症しにくい）人が集まりやすい。 ▷ 莫大な研究費（数億円）が必要 ▷ 標準化された評価・診断を実施できる研究デザインとマンパワーが必須 ▷ 追跡期間が半年から数年と極めて短いため、結果が過小評価されてしまう（認知症発症前に研究が終了） ▷ 非介入群における認知症発症という倫理的問題への対応 （補足）認知症の疫学研究自体の問題点 ▷ 認知症者ほど調査には参加しない（疾患への偏見） ▷ 認知症疾患では一般的に発病から発症に至るまでに 10-20 年要するため、長期間の追跡が必要 ▷ 認知症を正確に診断できる医師で疫学研究に精通している者はかなり少ない ▷ 認知症のみで病院を受診する高齢者はまだまだ少ないため、介護保険情報のみで認知症イベントの全てを 把握することは困難 エビデンスと推奨 12 認知機能正常または軽度認知障害の成人にとって、身 体活動による介入は、認知機能低下や認知症のリスクの 低減において、通常のケアあるいは介入なしよりも効果 的か。 対象： 認知機能正常または軽度認知障害の成人（年齢 18 歳以上） 介入： 身体活動による介入（有酸素運動、筋力トレーニングあ るいは複合的な身体活動） 比較： 通常のケアまたは介入なし アウトカム： ・ 重大 - 認知機能 - 軽度認知障害の発症 - 認知症 ・ 重要 - 生活の質 - 生活機能レベル（ADL/ 日常生活動作、IADL/ 手 段的日常生活動作） - 有害事象 - 脱落率 背景 身体的に活動的なライフサイクルは、脳の健康とつな がっている。 追跡期間が 10 年を超える大規模な観察研 究において、身体活動を有する群は有さない群に比べ認 知機能低下、認知症、血管性認知症、アルツハイマー病 などの発症リスクが低かった (Gallaway et al., 2017; Hamer & Chida, 2009; Sofi et al., 2011; Stephen et al., 2017)。特に、最も活動的な身体運動は予防効果も 最も高いように思われる (Hamer & Chida, 2009; Sofi et al., 2011)、身体活動が脳の健康に良い影響を及ぼす のは、身体活動が脳の構造に良い影響を与える可能性が あるからである (Rovio et al., 2010)。 両者の関係におけるその他のメカニズムは間接的な影 響である可能性が高く、具体的には身体運動が高血圧、 インスリン抵抗性、高コレステロールといった介入可能 な心血管病リスク因子〔CVRFs〕に対して良い影響を与 えるのと同様に、免疫機能の活性化、抗炎症作用、そし て神経栄養因子の増加といった他の生物学的メカニズム も考えられる。身体活動による介入については、WHO の「健康のための身体活動に関する国際勧告」(2010) に記載されている。 推奨１： 身体活動は、認知機能正常の成人に対して認知機能低下のリスクを低減するために推奨される。 エビデンスの質： 中 推 奨 の 強 さ： 強い 推奨と考察 3.1 身体活動による介入 推奨２： 身体活動は、軽度認知障害の成人に対して認知機能低下のリスクを低減するために推奨してもよい。 エビデンスの質： 低い 推 奨 の 強 さ： 条件による 13 認知機能低下および認知症のリスク低減 WHOガイドライン WHOの健康のための身体活動に関する国際勧告 (2010) (http://www.who.int/dietphysicalactivity/publications/9789241599979/en/) 以下は 65 歳以上の成人への推奨の抜粋である。 65 歳以上の成人にとって、身体活動とは、日課や家庭・地域社会と結びついたレクリエーションや余暇を使っ て身体を動かすこと。通勤などの移動 ( 徒歩、自転車 )、仕事、家事、遊び、ゲーム、スポーツなどを含む。持久力、 筋力、骨の健康向上や、非感染性疾患の発症、うつ病、認知機能低下のリスク低減のために、下記の項目が推奨さ れる。 1. 65 歳以上の成人は、週あたり 150 分の中強度有酸素運動、週あたり 75 分の高強度有酸素運動、または、 同等の中～高強度の運動を組み合わせた身体活動を行うこと 日本語版における注釈 具体的な運動の例として、以下厚生労働省の HP を参照 （1） . https://www.e-healthnet.mhlw.go.jp/information/dictionary/exercise/ys-004.html （2） . https://www.mhlw.go.jp/stf/houdou/2r9852000002xple-att/2r9852000002xpqt.pdf （（2）. は特に P6-8 を参照） 2. 有酸素運動は 1 回につき、少なくとも 10 分以上続けること 3. さらなる健康効果のため、中強度有酸素運動を週 300 分に増やすこと。または週 150 分の身体活動を高強 度の有酸素運動にすること。または、同等の中～高強度の身体活動を組み合わせて行うこと 4. この年齢群に属する高齢者で運動制限を設ける場合には、バランス能力を向上させ転倒を防ぐための身体活 動を週 3 日以上行うこと 5. 筋力トレーニングは週 2 回以上、主要な筋肉群を使うトレーニングをすること 6. 健康状態によって、高齢者がこれらの推奨する身体活動を実施できない場合は、身体能力や健康状態の許容 範囲で可能な限り活動的でいること 以上、すべての年齢群において、上記に推奨する身体活動を実施することや、活動的でいることでの健康上の利 益は、身体活動で引き起こされる有害事象や危険性を上回る。推奨される週 150 分の中強度の身体活動において、 骨格筋の損傷や怪我はまれである。集団ベースのアプローチ方法では、骨格筋の怪我を低減させるために、適度な 身体活動から徐々に量・強度とも増やしていくことが適切であると考えられる。 エビデンスと推奨 14 その他の考察 ・ 運動は誰でも簡単にすることができ、広範囲にわた る恩恵が受けられる ・ 有酸素運動は身体活動による恩恵の鍵となる 支持するエビデンスと根拠 身体活動による介入（有酸素運動、筋力トレーニン グまたは多くの要素を含む身体活動など）に関して、 6 つの異なる身体活動への介入について 4 本のシステ マティックレビューを特定した (Barha et al., 2017; Barreto et al., 2017; Northey et al., 2018; Song et al., 2018)。 1. 認知機能が正常な成人に対して、有酸素運動介入 対 通常のケア、または介入なし 2. 認知機能が正常な成人に対して、運動トレーニン グ介入 対 通常のケア、または介入なし 3. 認知機能が正常な成人に対して、複合的な運動介 入 対 通常のケア、または介入なし 4. 軽度認知障害者に対して、有酸素運動介入 対 通常 のケア、または介入なし 5. 軽度認知障害者に対して、運動トレーニング介入 対 通常のケア、または介入なし 6. 軽度認知障害者に対して、複合的な運動介入 対 通 常のケア、または介入なし 健康な成人に関しても、身体活動による介入は認知機 能にポジティブな効果を与えることを示す中の質のエビ デンスがある。一方、身体活動は軽度認知障害と認知症 のリスクに悪影響しないことを示す低～中の質のエビデ ンスがある。 軽度認知障害の人については、身体活動への介入が認 知機能にポジティブな効果があることを示すエビデンス があるが、質的には低いものである。ただし、これらの 利点は、すべての認知機能領域で一貫しているわけでは ない。 筋力トレーニングよりも有酸素トレーニングの方が効 果の程度は大きく、認知機能正常の人の方が軽度認知障 害の人よりも効果が強い（とくに有酸素トレーニング）、 ということを示すエビデンスがある。 ガイドライン作成グループ（GDG）は、身体活動の 望ましい効果が望ましくない効果を上回っていると結論 づけた。全体的に、低～中の質のエビデンスにより、身 体運動が認知機能に少なからず有益な効果をもたらすこ とが示されている。軽度認知障害者でも、弱いエビデン スではあるが、運動の認知機能への恩恵が示唆される。 これらの介入の効果は、主に有酸素運動によるものと思 われる。エビデンスの質に基づいて、認知機能正常の人 には強く身体活動の介入が勧められ、軽度認知障害の人 には条件付きの介入が勧められた。 15 認知機能低下および認知症のリスク低減 WHOガイドライン 喫煙している認知機能正常または軽度認知障害の成人 にとって、禁煙介入は、認知機能低下や認知症のリスク の低減において、通常のケアあるいは介入なしよりも効 果的か。 対象： 認知機能正常または軽度認知障害の喫煙している成人 介入： 禁煙介入（行動療法やニコチン代替療法、bupropion、 バレニクリンなどの薬物療法） 比較： 通常のケアまたは介入なし アウトカム： ・ 重大 - 認知機能 - 軽度認知障害の発症 - 認知症 ・ 重要 - 生活の質 - 生活機能レベル（ADL/ 日常生活動作、IADL/ 手 段的日常生活動作） - 有害事象 - 脱落率 背景 タバコ依存は世界的に予防可能な死亡の主な死因で あり、年間推定 500 万人が喫煙により死亡し（WHO、 2011 年）、さらに世界的な医療費は数十億米ドルに及ぶ （Lightwood et al., 2000）。タバコは、多くの種類の癌、 心血管疾患〔CVD〕とその危険因子、呼吸器疾患（米国 保健福祉省、2004 年）を含む多くの疾病の主要な危険 因子であり、禁煙によりこれらの健康リスクを大幅に減 少することが証明されている（Pirie et al., 2013）。禁 煙は、喫煙を続ける場合と比べて、うつ病、不安、スト レスを軽減し、気分と生活の質の改善にも関連している （Taylor et al., 2014）。 タバコ依存症は、認知症や認知機能低下（Durazzo et al）だけでなく、他の障害や高齢者のフレイル（虚 弱）や作業能力など加齢に伴う状態にも関連している （Amorim et al., 2014; Kojima et al., 2015）。 タバコ依存症の治療は行動的・心理的療法と様々な薬 物治療のいずれかまたは両方を用いるなど非常に多様で ある。非薬物療法は、様々な結果をもたらす可能性があ る（Niaura, 2008）。カウンセリングは最も頻繁に使用 されるアプローチだが、マインドフルネスベースのアプ ローチ、認知行動療法、行動活性化療法、動機付け面接、 不測の事態への対処、喫煙への曝露 / 嫌悪感など、他の アプローチも検討されている。禁煙のための薬物療法の 中で、ニコチン代替療法、ブプロピオンおよびバレニク リンが最も一般的であるが、全体的に治療効果は低く、 副 作 用 が 主 な 問 題 で あ る（Gómez-Coronado et al., 2018）。非薬物療法と薬物療法の組み合わせは、禁煙を 支援する上で最も効果的である（Gómez-Coronado et al., 2018）。 3.2 禁煙治療 エビデンスと推奨 16 その他の考察 ・ タバコ依存症に関する WHO トレーニングパッケー ジに記載されている提言に沿って、喫煙者には禁煙 することを推奨する。喫煙の防止、禁煙の促進、タ バコ依存症の診断と治療を目的とした適切なプログ ラムは、確立されなければならない。(http://www. who.int/tobacco/publications/building_capacity/ training_package/treatingtobaccodependence/en/) 治療には、薬物療法（例えば、ニコチン代替療法、 ブプロピオン、バレニクリン）だけでなく行動療法 も含まれる。 ・ 個人レベルの治療は、集団レベルの禁煙プログラム と同様に行われるべきである。 支持するエビデンスと根拠 禁煙に対する介入と介入なしの試験を比較するシステ マティックレビューは確認されていない。 喫煙が認知機能障害と認知症の危険因子であること を示す多くの観察研究によるエビデンスが報告されて いる。これらの研究は、喫煙（中年期を含む）と認 知症、または老年期の認知機能低下との関連を示して い る（Beydoun et al., 2014; Di Marco et al., 2014; Lafortune et al., 2016; North et al., 2015; Xu et al., 2015; Zhong et al., 2015）。薬物療法の有害事象の報 告は少ない（Motooka et al., 2018）。したがって、禁 煙を目的としたあらゆるタイプの治療は、有害よりも有 益である可能性が高い。 喫煙は実質的な害があり、喫煙と認知症のリスクの増 加に関する疫学的 / 観察研究によるエビデンスはブラッ ドフォード・ヒルの因果関係の基準のほとんどを満たし ているため、実験的介入試験のデータはないが、GDG は強い勧告を行っている（Lafortune et al., 2016）。確 たるエビデンスがあり、母集団に起因するリスクは高く、 様々な設定と研究デザインで再現性があり、具体的であ り、用量反応効果を示している。さらに、時間性（中年 期の喫煙は後期認知症のリスクが高いことと相関してい ること）（Lafortune et al., 2016）、一貫性（実験室で の実験結果は観察研究によるエビデンスと一致している こと）（Durazzo et al., 2014 年）および機械論的（機 構学的）なエビデンスは、喫煙が脳を損傷し、その後の 認知機能低下に関与することを示唆している。 推奨： 禁煙介入は、他の健康上の利点に加えて、認知機能低下と認知症のリスクを低減する可能性があるため、喫煙者 している成人に対して行われるべきである。 エビデンスの質： 低い 推 奨 の 強 さ： 強い 推奨と考察 17 認知機能低下および認知症のリスク低減 WHOガイドライン 3.3a 認知機能正常または軽度認知障害の成人にとって、栄 養補助食品などの栄養的介入は、認知機能低下や認知症 のリスクの低減において、通常のケアあるいは介入なし よりも効果的か。 対象： 認知機能正常または軽度認知障害の成人 介入： 栄養補助食品（ビタミン B、抗酸化物、オメガ―3 イチョ ウなど） 比較： 通常のケアやプラセボ、またはある治療と別の治療 アウトカム： ・ 重大 - 認知機能 - 軽度認知障害の発症 - 認知症 ・ 重要 - 生活の質 - 生活機能レベル（ADL/ 日常生活動作、IADL/ 手 段的日常生活動作） - 有害事象 - 脱落率 3.3b 認知機能正常または軽度認知障害の成人にとって、健 康的な食事パターン（地中海食など）のような栄養的介 入は、認知機能低下や認知症のリスクの低減において、 通常のケアあるいは介入なしよりも効果的か。 対象： 認知機能正常または軽度認知障害の成人 介入： 健康的な食事パターン（地中海食など） 比較： 通常のケアまたは介入なし アウトカム： ・ 重大 - 認知機能 - 軽度認知障害の発症 - 認知症 ・ 重要 - 生活の質 - 生活機能レベル（ADL/ 日常生活動作、IADL/ 手 段的日常生活動作） - 有害事象 - 脱落率 背景 健康的な食事は生涯を通して、最適な発達という面 でも、健康維持と非感染性疾患の予防という面でも、極 めて重要な役割を果たしている。過去に行われた食事に よる介入研究では、食事の変化が、糖尿病（Diabetes Prevention  Program  Research  Group, 2002; Tuomilehto et al., 2001）や脳血管疾患（Rees et al., 2013）のような認知症リスクを高める多くの病的状態 の予防に関わっていることが実証されている。動物モデ ルから、食事要因と認知症を発症させる神経病理学的変 化とを結び付ける多様な経路がメカニズムとして示唆さ れている（Swaminathan & Jicha, 2014）。したがって、 認知症の発症には、食事要因が直接的なものと他の危険 因子に対する役割を介したものの両者が関与しており、 3.3 栄養的介入 エビデンスと推奨 18 健康的な食事が認知障害を予防する可能性は大きい。 地中海食は、認知機能や全身への関連について、最も 広く研究された食事アプローチである。観察研究による 幾つかのシステマティックレビューでは、地中海食を順 守すると、軽度認知障害やアルツハイマー病のリスクを 低下させたが、そうでない場合は低下させなかったと結 論づけている（Singh et al., 2014; Wu&Sun, 2017）。さ らに、認知機能正常者においては、地中海食の順守は 良好なエピソード記憶や全般的認知機能と関連していた （Loughrey et al., 2017）。良好な認知機能と関連する他 の有望な食事アプローチには、高血圧を防ぐ食事（DASH） （Berendsen et al., 2017; Morris et al., 2015a; 2015b; Wengreen et al., 2013）や神経変性抑制のための脳の健 康に特化した地中海食 -DASH 食 (MIND) がある。 個々の食品と栄養素については、果物と野菜（Jiang et al., 2017; Wu et al., 2017） と 魚 類（Bakre et al., 2018; Zhang et al., 2016）の摂取と認知症リスクの低 下との関連性は最も一貫性が高い。多くの研究において、 魚を多く摂るほど、健康な参加者の記憶力低下が抑えら れている（Samieri et al., 2018）。多価不飽和脂肪（魚 由来）の摂取（Zhang et al., 2016）も同様である。認 知症や認知機能障害のリスクの低下に関連づけられて いる他の食品と栄養素としては、ナッツ、オリーブオイ ル、コーヒーがある（Solfrizzi et al., 2017）。葉酸、ビ タミン E、カロチン、ビタミン C、ビタミン D に関す るエビデンスも報告されているが（Balion et al., 2012; Dangour et al., 2010; Rafnsson et al., 2013; Travica et al., 2017）、結果は一貫していない。 日本語版における注釈 食文化が大きく異なるわが国では、地中海式食、DASH 食を国民に導入することは難しい。主食（米）に偏らず、 主菜や副菜をしっかりとってバランスの良い食事が認知症の発症リスク軽減につながることを報告したわが国での 観察研究の結果を参照。 Ozawa M, et al: Dietary patterns and risk of dementia in an elderly Japanese population: the Hisayama Study. Am J Clin Nutr 97: 1076-1082, 2013. 日本語版における注釈 本書では、この食事法を強く推奨しているが、WHO の推奨する食事パターンと認知症発症の関係を示した研究はなく、 あくまで認知機能低下との関連を見た研究結果だけでコメントしているため、誤解のないように注意する必要がある。 推奨 1： 地中海食は、認知機能正常または軽度認知障害の成人に対して認知機能低下や認知症のリスクを低減するために 推奨してもよい。 エビデンスの質： 中 推 奨 の 強 さ： 条件による 推奨 2： WHO の健康食に関する推奨に準拠して、健康なバランスのとれた食事は全ての成人に対して推奨される。 エビデンスの質： 低い～高い（食事の成分による） 推 奨 の 強 さ： 強い 推奨と考察 19 認知機能低下および認知症のリスク低減 WHOガイドライン その他の考察 • 公表したエビデンスと推奨は、中年期・高年期の両 方で栄養状態と微量栄養素欠乏の可能性が評価され、 治療が行われたことが前提となっている。 • バランスのとれた多様な食事は、自然に摂取される ポリフェノールとタンパク質からなる。 • ビタミン B、ビタミン E、多価不飽和脂肪酸、複合 サプリメントの補充に関する推奨が当てはまる人は、 栄養欠乏症ではない人である。 支持するエビデンスと根拠 各種の観察研究で、健康的な食事と認知能力の向上 との関連性が一貫して報告されている（Berendsen et al., 2017; Frith et al., 2018; Loughrey et al., 2017; Morris et al., 2015; Wengreen et al., 2013） が、 臨 床試験で得られたエビデンスにはそれほど一貫性はな い（D'Cunha et al., 2018; Fitzpatrick-Lewis et al., 2015a; 2015b; Forbes et al., 2015; Radd-Vagenas et al., 2018; Solfrizzi et al., 2018）。 重 要 な の は、 食 事 推奨 3: 認知機能低下や認知症のリスクを軽減するため、ビタミン B、E、多価不飽和脂肪、複合サプリメントは推奨されない。 エビデンスの質： 中 推 奨 の 強 さ： 強い 健康的な食事に関するWHO勧告 (http://www.who.int/en/news-room/fact-sheets/detail/healthy-diet) 成人について、WHO ガイドラインは次のことを推奨している。 健康的な食事の内容： • 果物、野菜、豆類（レンズ豆、豆など）、ナッツ、全粒穀物（未加工のトウモロコシ、キビ、オート麦、小麦、玄米など） • 1 日あたり最低 400 g（5 人前）の果物と野菜。ジャガイモ、サツマイモ、キャッサバ、その他のでんぷん質 の根菜は果物や野菜に分類されない。 • 1 日あたり約 2,000 キロカロリーを摂取する健康体重の人の場合、総エネルギー摂取量のうち遊離糖類からの 摂取量は 10％未満であること（50 g または小さじ約 12 杯に相当）。しかし、理想的には総エネルギー摂取量 の 5％未満とすると、さらに健康上の利益が得られる。ほとんどの遊離糖類は製造業者や料理人や摂取者が食 品や飲料に添加し、また蜂蜜、シロップ、果汁、濃縮果汁に天然の糖として含まれている。 • 総エネルギー摂取量のうち、脂肪からのエネルギー摂取量は 30％未満であること。不飽和脂肪酸（魚、アボカド、 ナッツ、ヒマワリ、キャノーラ、オリーブオイルに含まれている）は、飽和脂肪酸（脂肪の多い肉、バター、 ヤシ、ココナッツオイル、クリーム、チーズ、ギー、ラードに含まれている）やあらゆる種類のトランス脂肪 酸（加工食品、ファストフード、スナック食品、揚げ物、冷凍ピザ、パイ、クッキー、ビスケット、ウエハース、 マーガリン、スプレッドに含まれる工業的に生産されたトランス脂肪酸や、肉・乳製品に含まれる牛、羊、山羊、 ラクダのような反芻動物由来のトランス脂肪酸の両方が含まれる）よりも好ましい。飽和脂肪酸の摂取量を総 エネルギー摂取量の 10％未満に、トランス脂肪酸を総エネルギー摂取量の 1％未満に抑えることが推奨される。 特に、工業的に生産されたトランス脂肪酸は健康食の成分にはならないので、避ける必要がある。 • 食塩は 1 日あたり 5g（小さじ約 1 杯に相当）未満であること。ヨウ素添加塩を用いること。 エビデンスと推奨 20 を変えて食物摂取の複数の面を一挙に改善する介入は、 一部の栄養素だけを補給する場合よりも認知機能の改善 を促す可能性が高いことを認識することである。食事要 因は、多種多様な食物を組み合わせた場合にのみ明らか な相乗効果をもたらすと考えられる（Jacobs Jr et al., 2009）。 栄養補助食品や健康的な食事パターン（地中海食など） のような栄養的介入と通常のケアや介入しない場合との 比較について、６件のシステマティックレビューでは 9 種の栄養的介入法が示された。具体的には以下のとおり である。 1. 認知機能が正常な成人における複合サプリメント とプラセボの比較（D'Cunha et al., 2018） 2. 軽度認知障害の成人における複合サプリメントと プラセボの比較（Fitzpatrick-Lewis et al., 2015） 3. 多価不飽和脂肪酸とプラセボの比較 （Forbes et al., 2015） 4. ビタミン B とプラセボの比較 （Forbes et al., 2015） 5. ビタミン E とプラセボの比較 （Forbes et al., 2015） 6. ポリフェノールとプラセボの比較 （Solfrizzi et al., 2018） 7. プロテイン補充とプラセボの比較 （Solfrizzi et al., 2018） 8. チキン抽出物とプラセボの比較 （Teoh et al., 2016） 9. 地中海食と代替食または通常食の比較 （Radd-Vagenas et al., 2018） 軽度認知障害の発症と認知症の転帰については、認知 機能が正常で地中海食を摂取している成人を対象とした 場合、複合サプリメントによる介入に関してのみ報告 が あ る（D'Cunha et al., 2018; Radd-Vagenas et al., 2018）。しかし、そういった介入のいずれにおいても、 認知症や軽度認知障害の発生率の低下には直接的な効果 は認められなかった。 どの介入 / 比較試験においても、認知機能の結果は報 告されている。地中海食が言語記憶や視覚記憶を改善で きるというエビデンスがみられた（エビデンスの質は 中）（Radd-Vagenas et al., 2018）。あるメタ分析では 全般的な認知機能についてはほぼ有意に近い結果が示さ れているが、他の認知機能アウトカム（注意、作業記 憶、処理速度、言語、遂行機能）についてはすべて、一 貫して肯定的ではあるが有意ではない結果が報告されて いる（Radd-Vagenas et al., 2018）。ポリフェノールに ついても、認知機能に対して一貫して肯定的な効果が認 められているが、エビデンスの質は低かった（Solfrizzi et al., 2018）。同様に、プロテイン補充は高齢者の認知 機能に対して有益な効果があることが認められてはい るが、結果はまちまちで、エビデンスの質は低かった （Solfrizzi et al., 2018）。 全 体 と し て、 複 合 サ プ リ メ ン ト（D'Cunha et al., 2018; Fitzpatrick-Lewis et al., 2015）、 ビ タ ミ ン B や E（Forbes et al., 2015）、多価不飽和脂肪酸の補充 （Forbes et al., 2015）については効果はまったく認め られなかった。プロテインとポリフェノールの補充につ いて報告されているエビデンスの質は低いが（Solfrizzi et al., 2018）、地中海食については有益な効果が認め られた（エビデンスの質は中）（Radd-Vagenas et al., 2018）。 3 通りの複合サプリメントによる介入（ドコサヘキサ エン酸〔DHA〕+ エイコサペンタエン酸〔EPA〕+ ビタ ミン E + 大豆リン脂質 + トリプトファン + メラトニン、 ビタミン E + マルチビタミン、凍結乾燥ローヤルゼリー + イチョウ葉 + オタネニンジン（朝鮮人参））の検討が 行われており、どの介入でも追跡期間中に重篤な有害事 象のリスクの上昇は認められなかった（エビデンスの質 は中、Fitzpatrick-Lewis et al., 2015）。 WHO ガイドライン作成グループ（GDG）は、地中 海食とバランスの取れた食事の利益は害を上回ると結論 し、それぞれについて条件付きで強力な推奨を作成した。 GDG は、ビタミン E とプロテイン補充は高用量では望 ましくない予期せぬ影響が利益を上回ると指摘し、これ らの使用については推奨しないとした。 （※日本語版に関する注釈について次頁に掲載） 21 認知機能低下および認知症のリスク低減 WHOガイドライン 日本語版における注釈 海外と本邦では食事摂取基準が異なるため、参考として日本人の食事摂取基準を下記に示す。 https://www.mhlw.go.jp/stf/seisakunitsuite/bunya/kenkou_iryou/kenkou/eiyou/syokuji_kijyun.html （地中海食、DASH に関する解説） 1. 地中海食 地中海食 (Mediterranean diet) とは、イタリア料理、スペイン料理、ギリシア料理など地中海沿岸諸国の食習 慣で、以下の特徴からなる。 ・ 果物や野菜を豊富に使用する。 ・ 乳製品や肉よりも魚を多く使う。 ・ オリーブオイル、ナッツ、豆類、全粒粉など未精製の穀物をよく使う。 ・ 食事と一緒に適量の赤ワインを飲む 2. DASH 米国立保健研究所などが提唱する、高血圧患者のための食事療法が「DASH（Dietary Approaches to Stop Hypertension）」食である。血圧を下げる作用のある食品は単独で食べるより、組み合わせて摂る方が効果が大 きいため、DASH 食を続けることにより、軽症の場合は降圧剤を服用しなくても済むようになる人もいる。 　 DASH 食の基本は　①野菜・果物・低脂肪の乳製品を十分摂る、②肉類および砂糖を減らす、の 2 点である。 具体的には、緑黄色野菜と淡色野菜を毎食取り入れ、果物はカリウムの多いバナナ、プルーン、リンゴなど、また 鶏肉以外の肉を減らして魚を増やす、肉の調理は皮や脂を取り除き、揚げずに網焼きしたり茹でたりする、低脂肪 の牛乳・ヨーグルト・チーズ等でカルシウムを補い、ナッツ類や豆類も意識して摂り、パンは全粒粉を使ったもの がいいとされている。　 （その他解説） 3. ghee ギー（食用に用いるバターオイルの一種） 4. wafers ウエハース（お菓子、洋菓子のひとつで焼き菓子の一種） 5. iodized salt ヨウ素添加塩（海外ではヨウ素欠乏症とならないようにヨウ素が添加された食塩が使われている） 日本語版における注釈（再掲） 食文化が大きく異なるわが国では、地中海式食、DASH 食を国民に導入することは難しい。主食 ( 米 ) に偏らず、 主菜や副菜をしっかりとってバランスの良い食事が認知症の発症リスク軽減につながることを報告したわが国での観 察研究の結果を参照。 Ozawa M, et al: Dietary patterns and risk of dementia in an elderly Japanese population: the Hisayama Study. Am J Clin Nutr 97: 1076-1082, 2013. エビデンスと推奨 22 アルコール使用障害のある認知機能正常または軽度認 知障害の成人にとって、アルコール使用障害治療ための 行動・心理的介入は、認知機能低下や認知症のリスクの 低減において、通常のケアあるいは介入なしよりも効果 的か。 対象： 認知機能正常または軽度認知障害のアルコールを過剰に 使用している成人 介入： ・ アルコール使用障害を治療するための行動および心 理的介入（動機付け面接など） ・ アルコール使用障害を治療するための薬理学的介入 比較： 通常のケアまたは介入なし アウトカム： ・ 重大 - 認知機能 - 軽度認知障害の発症 - 認知症 ・ 重要 - 生活の質 - 生活機能レベル（ADL/ 日常生活動作、IADL/ 手 段的日常生活動作） - 有害事象 - 脱落率 背景 アルコールの過剰摂取は多くの国でありふれている （Gell et al., 2015）。2012 年には、世界中の全死亡者 の 5.9％（約 330 万人）がアルコールの有害な使用に直 接起因していた（WHO, 2014）。さらに、アルコールの 過剰摂取は世界的に様々な障害の主な原因の一つであり （WHO, 2014）、認知症や負傷の危険因子を含む 200 以 上の疾患の直接的な原因でもある（WHO, 1992; WHO 2019a）。 認知症および認知機能低下の危険因子として過剰なア ルコールに関する多くの証拠がある（Langballe et al., 2015; Sachdeva et al., 2016; Zhou et al., 2014）。 アルコールの危険で有害な使用を標的とした介入に は、いくつかのアプローチが適用されている。様々な種 類の薬物（オピオイド拮抗薬、ALDH2 阻害剤など）を 使用した薬物療法は、アルコール使用障害のある成人に 対して様々な程度の有効性を示しているが、比較試験で 優れていることはなかった。行動と心理的介入は、アル コール使用障害、特に危険で有害な飲酒を伴う障害にお いて効果的であることが示されている。プライマリケア でのスクリーニングと短期的介入は、アルコールに起因 する罹患率と死亡率を減らすための最も費用対効果の高 い手段の一つである（Kaner, 2018）。 アルコール使用障害への介入は、mhGAP 介入ガイド - 精神保健専門家のいない保健医療の場における精神・ 神経・物質使用障害のための mhGAP 介入ガイド Ver. 2.0〔mhGAP Intervention guide - Version 2.0 for mental, neurological and substance use disorders in non-specialized health settings〕に記載されてい る（http://www.who.int/mental_health/mhgap/mhGAP_ Intervention_guide_02/en/）。 3.4 アルコール使用障害への介入 23 認知機能低下および認知症のリスク低減 WHOガイドライン 推奨： 危険で有害な飲酒を減量または中断することを目的とした介入は、他の健康上の利点に加えて、認知機能正常または 軽度認知障害の成人に対して認知機能低下や認知症のリスクを低減するために行われるべきである。 エビデンスの質： 中（観察研究によるエビデンス） 推 奨 の 強 さ： 条件による 精神保健専門家のいない保健医療の場における精神・神経・物質使用障害のためのWHO mhGAP介入ガイド　−第２版 (http://www/who/int/mental_health/mhGAP_intervention_guide_02/en/) WHO mhGAP 介入ガイドは以下を推奨している。 アルコールの有害な使用 • 心理教育を行い、アルコール使用のレベル / パターンが健康を害していることを強調する。 • アルコールを使用する動機を探る。動機付け面接を実施する。 • アルコールを完全に中断するか、無害なレベルで消費すること（無害なレベルが存在する場合）をアドバイスし、 そうすることで相手をサポートする意思を示す。この変更を試みる準備ができているかどうかを相手に尋ねる。 • 使用を減量または中断するための戦略と、害を減らすための戦略を探る。 • 食料、住宅、雇用のニーズに対応する。 • 定期的なフォローアップを提供する。 アルコール依存症 • アルコール使用中のチアミン。 • 離脱症状を治療するため、アルコール解毒中のジアゼパム。 • 解毒後の再発を防ぐためのナルトレキソン、アカンプロセートまたはジスルフィラム。 • 利用可能な場合は、心理社会的介入、例えば認知行動療法、動機付け強化療法、随伴性マネジメント療法、家 族カウンセリングまたはセラピー、問題解決カウンセリングまたはセラピーや自助グループ。 推奨と考察 エビデンスと推奨 24 その他の考察 • 介入は、WHO の mhGAP ガイドラインに従って、ラ イフスタイル / 行動の変化または薬物治療に基づく。 ライフスタイル行動介入はより受け入れられやすく、 有害事象が少ない可能性がある。 • アルコール消費と認知機能の U 字型の関係が報告さ れている。しかし、この効果を説明するほとんどの 研究の方法論的な制限により、軽度から中程度のア ルコール摂取が実際に認知症や認知機能低下を予防 すると仮定することはできない。これは、アルコー ルに関連する他の健康上のリスクと社会的および経 済的負担に加えて、アルコール使用の一般的な推奨 を支持しない。 • アルコールの使用制限を強化し、飲酒運転対策を実 施し、スクリーニングへのアクセス、短期的介入、 治療を促進し、アルコール広告、スポンサーシップ、 プロモーションの禁止または包括的な制限を実施 し、物品税および価格設定ポリシーによるアルコー ル価格の引き上げを行うことにより、アルコールの 有害な使用を減らす WHO グローバル戦略（WHO 2010）および人口レベルの介入の文脈で、個人レベ ルの介入を提供する必要がある。 支持するエビデンスと根拠 危険で有害なアルコール消費に対する介入（行動的、 心理的および薬理学的介入）や、認知機能低下や認知症 のリスクを低減したというシステマティックレビューは 確認されていない。 ただし、認知機能低下と認知症の危険因子としてアル コールに関する多くの観察研究によるエビデンスが利用 可能である（Beydoun et al., 2014; Hersi et al., 2017; Ilomaki et al., 2015; Lafortune et al., 2016; Piazza- Gardner et al., 2013; Xu et al., 2017）。一般に、単回 調査では常に同様の結果が示されたわけではない（主 に研究デザインの違いによる）が、最も一貫したパター ンは、アルコール消費と認知症や認知障害との U 字型 の関係であり、これは明らかに、過度のアルコール摂 取とリスクの有意な増加を関連付けている（Xu et al., 2017）。 過剰なアルコール摂取を減らすことを目的とした薬理 学的介入についても、一連の有害事象が報告されている が、ライフスタイル介入は主に行動介入に基づいており、 有害事象（離脱症候群に関連するものを除く）のエビデ ンスは確認されていない（NICE, 2011）。 全体として、GDG は、強力な観察研究によるエビデ ンスに基づいて、危険で有害なアルコールの使用を減量 または中断するための介入を条件付きで推奨し、利益が 害を上回ると結論付けた。 25 認知機能低下および認知症のリスク低減 WHOガイドライン 認知機能正常または軽度認知障害の成人にとって、認 知刺激または認知トレーニングは、認知機能低下や認知 症のリスクの低減において、通常のケアあるいは介入な しよりも効果的か。 対象： 認知機能正常または軽度認知障害の成人 介入 : ・ 認知刺激 ・ 認知トレーニング 比較 : 通常のケアまたは介入なし アウトカム : ・ 重大 - 認知機能 - 軽度認知障害の発症 - 認知症 ・ 重要 - 生活の質 - 生活機能レベル（ADL/ 日常生活動作、IADL/ 手 段的日常生活動作） - 有害事象 - 脱落率 背景 認知症に先行して認知機能低下が起こる。しかしな がら、認知症の危険因子をもつすべての人が認知機能 障害を発症するとは限らない。認知予備能（cognitive reserve）という概念は、臨床的に認知症および認知機 能低下が発症するリスクを減らす保護因子として提唱さ れた（Stern, 2012）。認知予備能とは、神経病理学的変 化や神経障害が起きてもうまく対処する、もしくはそれ を補うといった脳の持つ機能を指す（Stern, 2012）。複 数の研究において、認知活動の増加が認知予備能を刺激 し（もしくは増加させ）、急速な認知機能低下（Stern ＆ Munn, 2010）をやわらげる効果を有することが報 告されており、同様に、認知活動レベルが高い者は低 い者と比較し、軽度認知障害またはアルツハイマー病 診断のリスクが有意に低下する可能性が示されている （OR=0.38, 95％ CI：0.15–0.99）（Sattler, 2012）。 認知活動は、認知刺激や認知トレーニングによって増 加させることができる。認知刺激とは、「認知機能およ び社会機能の改善を目的とした様々な活動への参加」の ことを指し（Clare ＆ Woods, 2004）、認知トレーニン グとは、「特定の認知機能を高めるために定められた個々 の標準化された課題を指針に沿って実践すること」を指 す（Clare & Woods, 2004）。NIA（アメリカ合衆国） は、認知トレーニングを加齢に伴う認知機能低下〔age- related cognitive decline〕、軽度認知障害、もしくは 臨床的なアルツハイマー型認知症の発症を予防または 抑制することを目的とした介入であるとした（Kane et al., 2017）。さらに、WHO の ICOPE ガイドライン（http:// www.who.int/ageing/publications/guidelines-icope/en/） では、認知機能障害のある高齢者に対して認知刺激を行 うことを推奨している。 これらの介入では、対象者にとって重大かつ重要であ ると判断されるアウトカムについて評価された。 3.5 認知的介入 エビデンスと推奨 26 支持するエビデンスと根拠 健康な高齢者における、認知刺激と通常のケアまたは 非介入について、一つのシステマティックレビューによ りエビデンスが示されている（Strout et al., 2016）。軽 度認知障害に関するエビデンスは入手できなかった。レ ビューでは、介入評価を行った対象者の半数が、実行機 能、注意、記憶、言語、処理速度のうち少なくとも一つ の認知領域で認知機能の改善に効果的であることが示さ れた（Strout et al., 2016）。エビデンスの質は低かった。 結果は説話的に報告され、メタ分析は行われなかった。 軽度認知障害または認知症の発症に対する効果を示すエ ビデンスは入手できなかった。 健康な高齢者において認知トレーニングと通常のケア もしくは非介入を比較した場合、一つのシステマティッ クレビューにおいてエビデンスが示されている（Chiu et al., 2017）。このレビューではメタ分析を行い、健康 な高齢者に対する認知トレーニングが、認知機能全般に 中程度の正の効果があることが示された。エビデンスの 質は低かった。軽度認知障害または認知症の発症に対す る効果を示すエビデンスは入手できなかった。 軽度認知障害の成人における認知トレーニングと通 常のケアもしくは非介入を比較した場合、二つのシス テマティックレビューにおいてエビデンスが示された （Chandler et al., 2016; Sherman et al., 2017）。認知 機能のアウトカムに関してはエビデンスの質は低く、軽 度認知障害の成人に対する認知トレーニングは、認知機 能にわずかな正の効果を認めた。認知症発症のアウトカ ムに関しては、結果は説話的に報告され、エビデンスの 質は非常に低かった。ある研究では、対照群の半数が 8 か月のフォローアップで認知症を発症し、介入群では発 症しないという結果となり、別の研究では、介入群の 多くで 2 年後に認知症が報告された (Chandler et al., 2016)。生活の質と生活機能レベルに関してエビデンス の質は低く、軽度認知障害の成人に対する認知トレーニ ングは ADL にわずかに正の影響を示したが、生活の質 には影響しなかった。 認知的介入に関するエビデンスは主に高齢者を対象と した研究である。GDG は、これらの対象において、介 入による望ましい効果は望ましくない効果を上回ると結 論づけ、認知トレーニングに関して条件付きの推奨を示 した。認知刺激が認知症のリスクを減らすというエビデ ンスは不十分であり、GDG による推奨はされなかった。 推奨： 認知トレーニングは、認知機能正常または軽度認知障害の高齢者に対して認知機能低下や認知症のリスクを低減 するために行ってもよい。 エビデンスの質： 非常に低い～低い 推 奨 の 強 さ： 条件による 推奨と考察 27 認知機能低下および認知症のリスク低減 WHOガイドライン 認知機能や正常または軽度認知障害の成人にとって、 高レベルの社会活動の維持や奨励することは、認知機能 低下や認知症のリスクの低減において、通常のケアある いは介入なしよりも効果的か。 対象： 認知機能正常または軽度認知障害の成人 介入 : 比較 : 通常のケアまたは介入なし アウトカム : ・ 重大 - 認知機能 - 軽度認知障害の発症 - 認知症 ・ 重要 - 生活の質 - 生活機能レベル（ADL/ 日常生活動作、IADL/ 手 段的日常生活動作） - 有害事象 - 脱落率 背景 社会的関わりは人の一生における幸福の重要な指標 となっている (Cherry et al., 011)。逆に社会的関わ りが失われることは、高齢者において認知機能障害や 認知症のリスクを高めるということが示されてきた (Fratiglioni et al., 2004)。縦断的 コホート研究のシス テマティックレビューやメタ分析によると、社会参加が 少ないこと、社会交流が少ないこと、孤独であることな どは認知症の発症率を高めるとされている (Kuiper et al., 2015)。 さらにランセット委員会の認知症予防・介入・ケア委 員会は社会的関わりを認知症予防を目的とした介入手法 になりえるとしている (Livingston et al., 2017)。 3.6 社会活動 社会活動と認知機能低下や認知症のリスクの低減との関連については十分なエビデンスはない。ただ、社会参加 と社会的な支援は健康と幸福とに強く結びついており、社会的な関わりに組み込まれることは一生を通じて支援 されるべきである。 (Global age-friendly cities; a guide, http://www.sho.int/ageing/publications/Global_age_friendly_cities_Guide_English.pdf) 推奨と考察 エビデンスと推奨 28 支持するエビデンスと根拠 地域社会や家族との関わりを含む社会活動の維持と促 進を、通常のケアまたは介入しない場合と比べてどう かということについては、認知機能が正常な成人を対 象とした研究のシステマティックレビューからエビデ ンスを抽出できた (Kelly et al., 2017)。軽度認知障害 を有する人に対するエビデンスはなかった。認知機能の 結果についてはエビデンスの質は非常に低い。認知機能 と社会活動の関連について検討した三つの RCT が妥当 であると考えられた。そのレビュー結果は説話的にまと められている (Kelly et al., 2017)。全体的な認知機能 は、ADAS-cog、MMSE、MDRS といった様々な全般 性認知機能評価手法を組み合わせて評価された。三つの RCT のうち一つにおいては、社会活動介入が認知機能 の改善と強く関連しているという結果であった (Pitkala et al., 2011)。軽度認知障害の発症や認知症、生活の質、 生活機能レベル（ADL/ 日常生活動作、IADL/ 手段的日 常生活動作）、有害事象、脱落率等について利用可能な データはなかった。 GDG はエビデンスが限られており結論づけられない ため、社会活動と認知機能低下 / 認知症との関連性につ いては推奨はないとした。また、認知機能低下や認知症 の診断に先行する社会的関わりの少なさは、疾患の進行 が部分的には理由になっているという逆の因果関係から 生まれるバイアスのリスクもある。GDG は社会活動に ついて推奨は行わなかったが、社会活動が健康と幸福に おいて他の広い範囲での利益をもたらすと結論づけた。 29 認知機能低下および認知症のリスク低減 WHOガイドライン 過体重あるいは肥満のある認知機能正常または軽度認 知障害の成人にとって、減量介入（または肥満管理）は、 認知機能低下や認知症のリスクの低減において、通常の ケアあるいは介入なしよりも効果的か。 対象： 認知機能正常または軽度認知障害の過体重や肥満の成人 介入 : 体重管理 ・ 薬を用いない介入（認知行動的介入やライフスタイ ルへの介入など） ・ 薬を用いた介入（体重を減少させる薬（例：オルリ スタット）など） 比較 : 通常のケアまたは介入なし アウトカム : ・ 重大 - 認知機能 - 軽度認知障害の発症 - 認知症 ・ 重要 - 生活の質 - 生活機能レベル（ADL/ 日常生活動作、IADL/ 手 段的日常生活動作） - 有害事象 - 脱落率 背景 過体重と肥満は、様々な非感染性疾患のうち、もっと もリスクの高い状態と特徴づけられ、かつ確立されてい るものであり、世界中で毎年少なくとも 280 万人が死亡 しており、世界の障害調整生存年数〔DALYs: Disability- Adjusted Life Years〕（WHO, 2019b） は 3,580 万 人 （2.3％）と推計されている。2008 年には、20 歳以上の 成人の 35％が過体重（BMI≥25 kg / m2）（男性 34％、 女性 35％）であった。過体重・肥満の有病率は世界地 域間で著しく異なり、アメリカ合衆国、ヨーロッパ、東 地中海地域で最も高かった（WHO, 2019b）。過体重と 肥満は特に直接的なリスク要因として高コレステロール や高血圧などの心血管病の危険因子だけでなく、2 型糖 尿病（Chan et al., 1994）、癌（Renehan et al., 2015）、 早期の死亡（Fontana ＆ Hu, 2014）、心血管病（Eckel, 1997）などの多くの医学的合併症と密接な関連がある。 肥満者は着実に増加しており、特に過去数十年で高齢 者の肥満が増加している（Nguyen ＆ El-Serag, 2010）。 高齢者では、正常体重の人に比べ、過体重者の総死亡率 は低い可能性があると報告した研究は多いが（Flicker et al., 2010）、脂肪の過剰な蓄積と認知機能障害との関 連は確立されている（Xu et al., 2011）。最近のシステマ ティックレビューと計約 60 万人を対象とした観察研究 のメタ分析により、中年期の肥満（ただし過体重ではな い）が認知症のリスクを高めることが示された（RR=1.33; 95％ CI：1.08-1.63）（Albanese et al., 2017）。 体重を減らすことは、認知機能障害および認知症の病 因に関連する様々な代謝因子（すなわち、耐糖能、イン スリン感受性、血圧、酸化ストレス、および炎症反応）の 改善を通じて認知症の発症リスクを減らすことができる と示唆されている（Bennett et al., 2009）。しかし、減量 への介入に直接的な有効性があることも十分に考えられ る。これまでのところ、認知機能に対する体重減少の潜 在的効果は身体活動の増加と強く関連しているようにみ えるが（Colcombe et al., 2006; Erickson et al., 2010）、 2011 年のシステマティックレビューでは、体重の減少を 意識的に行うことで、少なくとも肥満者の一部の認知機 能領域が改善できると結論づけた（Siervo et al., 2011）。 3.7 体重管理 エビデンスと推奨 30 推奨： 中年期の過体重、または肥満に対する介入は、認知機能低下や認知症のリスクを低減するために行ってもよい。 エビデンスの質： 低い～中 推 奨 の 強 さ： 条件による 非感染性疾患における過体重と肥満の予防と取扱い：物資が潤沢でない環境でのプライマリ ヘルスケアのガイドライン　―WHO のガイダンス (2012) (https://www.who.int/nmh/publications/phc2012/en/) 過体重と肥満に関する WHO のガイダンスに従う必要がある。 ・ バランスの取れた食事を摂ることにより、体重を減らすよう過体重者に助言 ・ 食事中の炭水化物の供給源として、低グリセミック指数の食品（まめ、レンズ豆、オート麦および無糖の果物） を優先するよう助言。 ・ 座位行動を減らし、身体能力に適した定期的な身体活動を毎日実践するよう推奨（ウォーキングなど）。 推奨と考察 日本語版における注釈 日本人は欧米人と比べると肥満者は少ない。また、260 万人の観察研究のメタ解析から老年期の体重減少（痩せ） が認知症発症の危険因子であるという結果もあるため、誤解しないように注意することが必要。(Lee CM, et al. Obesity Reviews. 2020;21:e12989) 31 認知機能低下および認知症のリスク低減 WHOガイドライン その他の考察 • 食事と身体活動の両方の要素を含むライフスタイル への介入は、最高の結果をもたらす。 • 個人レベルでの介入に加えて、公園、緑地、アクティ ブな通勤をサポートするインフラなど、集団レベル でのライフスタイルへの介入を検討する必要がある。 • 中年後期および老年期の痩せは認知症の発症リスク が上昇する可能性がある。ただし、この関連は、少 なくとも部分的には因果関係の逆転で説明できる可 能性が高い。すなわち、脳の病理的な変化が認知症 発症以前に体重減少を引き起こしているという可能 性である。 • 意図しない体重減少と栄養失調は健康状態の悪化に 関連しており、すべての年齢で調査および治療が行 われるべきである。しかし、中年期または中年期以 降の世代における低体重者に対して体重増加を促す ような介入を行なっても、認知症または認知障害の リスクを減少できるとは考えにくい。 支持するエビデンスと根拠 通常のケアまたは介入なしの場合と、行動およびライ フスタイルへの介入（または肥満の管理）による体重減 少を比較するため、過体重または肥満で、かつ認知機能 正常の人を対象にしたシステマティックレビューから、 エビデンスを抽出した（Veronese et al., 2017）。軽度 認知障害の人に関するエビデンスは得られなかった。減 量を目的としたライフスタイル介入が、注意、記憶、そ して言語の領域における認知機能を改善できるという低 ～中の質のエビデンスがあった。介入期間は非常に短い ものであった（8 ～ 48 週間の範囲）。軽度認知障害や認 知症の発症に関連したデータは見られなかった。有害事 象に関するエビデンスは確認されなかった。 減量（または肥満の抑制）のための薬理学的介入と 通常のケアまたは介入なしと比較した研究のシステマ ティックレビューは見つからなかった。 GDG は、介入の利益が害を上回っていると結論づけ、 条件付きの推奨を提供した。観察研究から得られた過体 重や肥満と、認知症の発症リスク上昇との関係は、老 年期よりも中年期でより強く一貫していたため (Hersi et al., 2017; Lafortune et al., 2016; Pedditzi et al., 2016; Prickett et al., 2015; Xu et al., 2015)、GDG は 条件付きで推奨した。 エビデンスと推奨 32 高血圧のある認知機能正常または軽度認知障害の成人 にとって、高血圧治療は、認知機能低下や認知症のリス クの低減において、プラセボあるいは介入なしよりも効 果的か。 対象： 認知機能正常または軽度認知障害の高血圧症の成人 介入 : 高血圧治療、ライフスタイルへの介入 比較 : プラセボまたは介入なし アウトカム : ・ 重大 - 認知機能 - 軽度認知障害の発症 - 認知症 ・ 重要 - 生活の質 - 生活機能レベル（ADL/ 日常生活動作、IADL/ 手 段的日常生活動作） - 有害事象 - 脱落率 背景 中年期の高血圧は、老年期認知症の発症リスク増加と 関連することが示されている (Kivipelto et al., 2001)。 特に、中年期に血圧が上昇し、その後急速に低下する パターンが認知症発症者に見られる (Kivipelto et al., 2001; Launer et al., 2000; Stewart et al., 2009)。 中年期後半または老年期の血圧低下と、それに続く認 知機能低下や認知症の発症に関して、一定した見解はな い。しかし、高血圧の予防は心血管病の発症率と死亡率 を低下させ、それにより高齢者全体の健康を改善できる というエビデンスがある（Musini et al., 2009）。 高血圧は、健康的な食事をとり、健康的な体重を維持 し、十分な量の身体活動を行うなどのライフスタイルに よって予防できる。また、高血圧は降圧薬治療でコント ロールすることができる。しかし、高血圧治療が認知機 能低下と認知症の発症リスク低減に有効かどうかについ て一定した見解はない。 3.8 高血圧の管理 推奨 1： 高血圧の管理は、現行の WHO ガイドラインの基準に従って高血圧のある成人に対して行われるべきである。 エビデンスの質： 低い～高い（介入方法によって） 推 奨 の 強 さ： 強い 推奨と考察 推奨 2： 高血圧の管理は、高血圧のある成人に対して認知機能低下や認知症のリスクを低減するために行ってもよい。 エビデンスの質： 非常に低い（認知症との関連について） 推 奨 の 強 さ： 条件による 33 認知機能低下および認知症のリスク低減 WHOガイドライン プライマリケアにおける心血管病の取扱いに関するHEARTS 技術パッケージ：エビデンス に基づいた治療プロトコル (https://apps.who.int/iris/bitstream/handle/10665/260421/WHO-NMH-NVI-18.2-eng.pdf?sequence=1) 高血圧治療に薬剤が使われる場合 ・ 降圧薬には主にアンジオテンシン変換酵素〔ACE〕阻害薬、アンジオテンシン受容体拮抗薬〔ARB〕、カルシ ウム拮抗薬〔CCB〕、チアジドおよびチアジド様利尿薬の 4 種類の薬剤がある。これらの 4 種類の降圧薬は、 特定の禁忌事項がない限り使用できる。高血圧の適切な治療には、通常、高血圧薬の併用が必要である。 特定の高血圧治療薬に関する注意事項 ・ 妊娠中の女性、および効果的な避妊を受けていない妊娠可能な女性には、ACE 阻害薬、ARB またはチアジド / チアジド様利尿薬は投与されるべきではない。CCB を使用する必要がある。集中治療薬の投与量は専門医に相 談すること。 ・ β遮断薬は、第一選択療法としては推奨されていない。過去 3 年以内に心臓発作の診断がなされた場合、また は心房細動や心不全がある場合、降圧薬の開始用量にβ遮断薬を追加する必要がある。β遮断薬による治療は 狭心症の患者にも効果的なことがある。 他の治療方法について考慮すべきこと ・ 過去に心臓発作や脳卒中の既往がある場合や、心血管病のリスクが高い場合は、スタチンを降圧薬の使用開始 と同時に服用する（ただし、スタチンは妊娠中または妊娠する可能性のある女性には使用しないこと）。 ・ 過去に心臓発作または虚血性脳卒中を患った場合、低用量アスピリンから治療を開始する。 ・ 本モジュールに含まれている高血圧プロトコルは、効果的な治療の開始と維持に役立つ、重篤な有害事象が発 生したり、血圧制御ができなかったり、または重大な医学的事象による介入が見られる場合は専門医への紹介 が必要になる。 ・ 患者がすでに別に投薬を受けており、血圧が目標レベルまで管理され、患者が服用している薬が入手可能で手 頃な価格であるならば、その投薬計画を変更する理由はない。 ・ ・患者が立ちくらみを感じる場合は、立位血圧を確認すること。治療中の患者の収縮期血圧が一貫して 110mm Hg 未満の場合は、使用する薬の投与量または数を減らすことを検討すること。 エビデンスと推奨 34 支持するエビデンスと根拠 高血圧の治療について、降圧薬とプラセボ、または介 入なしの場合、高血圧を有する認知機能正常の人を対 象にした二つのシステマティックレビュー (Parsons et al., 2016; Weiss et al., 2016) からエビデンスが抽出さ れた。軽度認知障害の人に関するエビデンスはない。認 知機能および認知症発症に関して、エビデンスの質は 低いが、降圧療法は認知機能低下または認知症発症に 影響を与えない、ということが示されている。生活の質 と生活機能レベルに関しては、エビデンスの質は非常 に低いものの、降圧療法は生活の質または生活機能レ ベル（ADL/ 日常生活動作、IADL/ 手段的日常生活動 作）を低下させないことが示されている。有害事象につ いては、エビデンスの質は非常に低く、降圧薬の使用に 関して統一された見解はない。軽度認知障害の発症およ び全体的な脱落率に関するデータはなかった。収縮期血 圧介入試験〔SPRINT〕のサブスタディである認知症の 発症リスクに対する集中的な血圧管理の効果を検討した SPRINT-MIND トライアルの初期の結果では、血圧と 認知機能低下、認知症発症のリスク上昇との間に量反応 関係がある可能性が示された（SPRINTMIND 2019）。 観察研究から高血圧と認知機能低下、認知症の発症との 間に強い関連があることが明らかになった。 GDG は、高血圧の治療をその確立された健康上の有益 性から強く推奨している。認知機能低下や認知症の発症 リスクを減らすための高血圧の管理に対しては、条件付 きの推奨とした。GDG は、高血圧治療が認知機能低下、 または認知症の発症リスクを低下させるという臨床介入 研究のエビデンスは限られているものの、それにより生 活の質、または生活機能レベルを低下させることはない こと、および使用した薬剤による有害事象の可能性に関 してもその結果が様々であることから、高血圧治療がも たらす利益は有害事象に勝ると結論づけている。また、 両者の因果関係を示す強固なエビデンスも存在している。 日本語版における注釈 介入研究では降圧薬治療との関連が認められていないものの、観察研究のメタ解析において特定の薬剤との関連 は認められなかったが、降圧薬治療は認知症や AD 発症に予防的に作用していたため、この点は誤解のないよう注 意が必要 (Ding J, et al. Lancet Neurol 2020;19:61-70.) 。 35 認知機能低下および認知症のリスク低減 WHOガイドライン 糖尿病のある認知機能正常または軽度認知障害の成人 にとって、糖尿病治療は、認知機能低下や認知症のリス クの低減において、プラセボあるいは介入なしよりも効 果的か。 対象： 認知機能正常または軽度認知障害の糖尿病の成人 介入 : ・ 血糖管理のための治療 ・ 食事およびライフスタイルへの介入 比較 : プラセボまたは介入なし アウトカム : ・ 重大 - 認知機能 - 軽度認知障害の発症 - 認知症 ・ 重要 - 生活の質 - 生活機能レベル（ADL/ 日常生活動作、IADL/ 手 段的日常生活動作） - 有害事象 - 脱落率 背景 高齢期の糖尿病は認知症リスクの上昇と関連している （Luchsinger, 2010; Prince et al., 2014; Profenno et al., 2010）。しかしながら、その発症機序は不明である。 不良な血糖管理は認知機能の低下や悪化と関連している （Yaffe et al., 2012）。さらに、腎症（腎臓障害）、網膜症（眼 障害）、聴覚障害、心血管疾患のような糖尿病に伴う合 併症はすべて、認知症リスクを上昇させることがわかっ ている（Bruce et al., 2014; Exalto et al., 2013）。 認知機能に関して、血糖管理の改善を目的とした介 入について研究された文献では結果に一貫性がない （Launer et al., 2011; Luchsinger et al., 2011）。さら に、認知症リスクを低減するための糖尿病治療薬の有効 性に関するエビデンスにも一貫性はない（Cheng et al., 2014; Moore et al., 2013; Parikh et al., 2011）。高コ レステロール血症や高血圧などの糖尿病に伴う心血管 系併存疾患の治療が認知症リスクに介在している可能 性を示唆するエビデンスがある（Johnson et al., 2012; Parikh et al., 2011）。 3.9 糖尿病の管理 エビデンスと推奨 36 推奨 1： 糖尿病のある成人に対して、内服やライフスタイルの是正、または両者による糖尿病の管理は現行の WHO のガ イドラインの基準に従って行われるべきである。 エビデンスの質： 非常に低い～中（各種介入による） 推 奨 の 強 さ： 強い 推奨 2： 糖尿病の管理は、糖尿病患者に対して認知機能低下や認知症のリスクを低減するために行ってもよい。 エビデンスの質： 非常に低い 推 奨 の 強 さ： 条件による 推奨と考察 リソースの乏しい環境での一次医療向け非感染性疾患介入パッケージ (https://www.who.int/cardiovascular_diseases/publications/pen2010/en/) 糖尿病患者について WHO ガイドラインが推奨している治療は以下のとおりである。 1 型糖尿病 ・ 毎日のインスリン注射（レベル 1）。 2 型糖尿病 ・ 食事の改善、健康体重の維持、定期的な身体活動を行っても目標血糖値に達しない場合は、2 型糖尿病に対す る経口血糖降下薬（レベル 1）。 ・ 過体重の患者（レベル 1）および過体重でない患者（レベル 4）にはまずメトホルミンを投与。 ・ 目標血糖値に達しない場合、メトホルミンに他のクラスの血糖降下薬を追加（レベル 3）。 37 認知機能低下および認知症のリスク低減 WHOガイドライン 支持するエビデンスと根拠 認知機能の正常な成人 2 型糖尿病患者を対象として、 血糖管理に対する薬物を用いた糖尿病治療とプラセボ投 与または介入なしとの比較について検討した一つのシス テマティックレビューからエビデンスが抽出されている （Areosa Sastre et al., 2017）。軽度認知障害についての エビデンスは得られなかった。エビデンスの質は認知機 能アウトカムについては中であるが、認知症アウトカム については非常に低く、標準的な血糖管理に対する強化 治療の認知機能に対する効果は明確ではなく、認知症の 発症に対しては効果のないことが示されている。このレ ビューの対象となったエビデンスには、アジア、豪州、 欧州、北米の 20 か国にある研究協力機関 215 施設にお いて実施された大規模試験データが含まれている。有害 事象のエビデンスの質は非常に低く、血糖管理に対する 強化療法が低血糖イベントのリスクを高めることを示し ている。軽度認知障害の発症、生活の質、機能的アウト カム、脱落率に関するデータは得られなかった。全体と して、認知機能が正常な成人では、エビデンスは血糖管 理に対する強化療法は認知機能への効果はなく低血糖エ ピソードを増やすため、標準的な血糖管理を支持する。 認知機能の正常な成人 2 型糖尿病患者を対象として、 食事療法と生活習慣への介入による糖尿病治療とプラセ ボまたは介入なしとの比較について検討した一つのシス テマティックレビューからエビデンスが抽出されている （Podolski et al., 2017）。軽度認知障害の成人についての エビデンスは入手できなかった。エビデンスの質は非常 に低く、結果はまちまちであった。メタ分析は行われて おらず、臨床的意義に関して明らかなデータはなかった。 WHO ガイドライン作成グループ（GDG）は、確立 されている健康上の利益から糖尿病の管理を強く推奨 し、認知機能低下や認知症リスクの低減を目的とした糖 尿病の管理を条件付きで推奨した。同グループは結論と して、認知機能低下や認知症のリスク低減を目的とした 糖尿病管理に関する臨床試験のエビデンスは限られてい るが、利益は害を上回り、糖尿病が認知機能低下・認知 症リスクを高めることを示唆する揺るぎないエビデンス が観察研究によって得られているとしている。 日本語版における注釈 海外では、薬物治療に際して第一選択薬はメトホルミンとなっているが、本邦では年齢や肥満の程度、慢性合併 症の程度、肝・腎機能、ならびにインスリン分泌能やインスリン抵抗性の程度を評価して、経口血糖降下薬かイン スリン製剤か、GLP-1 受容体作動薬か、さらにはどの種類の経口血糖降下薬を使用するかを決定する（日本糖尿 病学会編・著、糖尿病治療ガイド 2018-2019、文光堂　2018）。 エビデンスと推奨 38 脂質異常症のある認知機能正常または軽度認知障害の 成人にとって、脂質異常症治療は、認知機能低下や認知 症のリスクの低減において、プラセボあるいは介入なし よりも効果的か。 対象： 認知機能正常または軽度認知障害の脂質異常症の成人 介入 : ・ スタチン（シンバスタチンやプラバスタチンなど） ・ ライフスタイルへの介入 比較 : プラセボまたは介入なし アウトカム : ・ 重大 - 認知機能 - 軽度認知障害の発症 - 認知症 ・ 重要 - 生活の質 - 生活機能レベル（ADL/ 日常生活動作、IADL/ 手 段的日常生活動作） - 有害事象 - 脱落率 背景 血清コレステロールの上昇は、修正可能な心血管病 の危険因子の一つである。世界の虚血性心疾患の 3 分 の 1 は脂質異常症に起因し、年間 260 万人の死亡（全 体の 4.5％）の原因であると推定されており、人口のか なりの割合に障害をもたらしていると考えられている （WHO, 2019b）。国別に見ると、総コレステロールの 上昇は経済的な豊かさと相関しているように思われる。 高所得国では、50％以上の成人の総コレステロール値 は高く、この値は低所得国の 2 倍以上である（WHO, 2019c）。 血中コレステロール値の上昇が認知症の発症リスク上 昇に関連する可能性があるという知見は 1970 年代半ば にすでに唱えられていた（Richardson et al., 2000）。 それ以来、多くの疫学研究により、血清コレステロー ル高値とアルツハイマー病および認知症の発症との密 接 な 関 係 が 指 摘 さ れ て い る (Kivipelto et al., 2002; Solomon et al., 2007; Whitmer et al., 2005)。しかし、 これらの結果に一定した見解は得られておらず、他の疫 学研究では関連がない、または負の相関が示されている (Mainous et al., 2005; Mielke et al., 2005)。 脂質異常症の重症度と心血管病全体のリスクに基づ き、血中コレステロールを減らすためにライフスタイル、 または薬理学的介入を行うことができる。体重減少や食 事中の飽和脂肪酸を減らすこと（すなわち動物由来の食 物消費量を減らすこと）は、最も一般的で効果的なライ フスタイル介入の推奨事項である（Perk et al., 2012）。 しかしながら、脂質異常症はスタチンで薬理学的に制 御・管理され、治療法の第一選択として薬剤が選択さ れる事が多い。スタチンによる薬物療法が認知症の予防 に有益である可能性を示したいくつかの観察研究がある が、研究間でのバイアスと不均一性がエビデンスの全体 的な質を下げている (Song et al., 2013; Swiger et al., 2013; Wong et al., 2013)。近年、失敗に終わった臨床 試験に参加していたアルツハイマー病患者へのスタチン 使用の再解析が行われ、シンバスタチンが認知機能低下 の進行を遅らせる可能性が示唆された（Geifman et al., 2017）。 3.10 脂質異常症の管理 39 認知機能低下および認知症のリスク低減 WHOガイドライン その他の考察 ・ 高齢者のスタチン治療は、認知機能低下や認知症の 予防のために開始するべきではないが、WHO の「非 感染性疾患の予防および管理 : 物資が潤沢でない状 況でのプライマリヘルスケアガイドライン」（英語） に従って、他の健康上の利益のため使用できる場合 がある (http://www.who.int/nmh/publications/phc2012/en/)。 支持するエビデンスと根拠 プラセボと比較したスタチン治療による脂質異常症の 管理について、脂質異常症を有する認知機能正常の人を 対象とした一つのシステマティックレビューからエビデ ンスが抽出された（McGuinness et al., 2016）。軽度認 知障害の人に関するエビデンスは得られなかった。エビ デンスの質は認知機能への影響については中、認知症発 症への影響については低い、スタチンによる治療は認知 症発症および認知機能の低下のいずれも影響を及ぼさな いことが示された。スタチンによる治療は重篤な有害事 象の発生率を増加させることはないという中の質のエビ デンスがある。 大規模観察研究は脂質異常症が認知症または認知機能 低下のリスク上昇と関連しており、脂質異常症を管理す ることで認知症発症および認知機能低下のリスクが低 減すると報告している (Geifman et al., 2017; Hersi et al., 2017; Reitz, 2013; Song et al., 2013)。まとめると、 中年期の脂質異常症の管理が認知機能低下や認知症の発 症リスクを低減することを示唆する間接的なエビデンス が得られている。 ライフスタイルの介入を通じて、脂質異常症の制御を 目的とした認知症や認知機能低下に関連する結果を含ん だ研究はなかった。 GDG は、脂質異常症の治療における望ましい効果が 有害事象を上回ると結論づけ、条件付きで推奨した。 観察研究では、老年期よりもむしろ中年期の高コレス テロール血症と認知症発症の間に密接な関連があること を報 告している（Hersi et al., 2017; Reitz, 2013）。高齢 者（65 歳以上）の臨床試験に焦点を当てたシステマティッ クレビューによると、スタチン治療は認知機能低下また は認知症発症に影響を及ぼさないことが明らかになった （McGuinness et al., 2016）。したがって GDG は、老年期に おけるスタチンの使用とコレステロールの管理を推奨する根 拠はなく、中年期においてのみ推奨できると結論づけた。 推奨： 脂質異常症の管理は、脂質異常症のある中年期の成人において認知機能低下と認知症のリスクを低減するために 行ってもよい。 エビデンスの質： 低い 推 奨 の 強 さ： 条件による 推奨と考察 エビデンスと推奨 40 うつ病性障害のある認知機能正常または軽度認知障害 の成人にとって、うつ病の治療は、認知機能低下や認知 症のリスクの低減において、通常のケア、プラセボある いは介入なしよりも効果的か。 対象： 認知機能正常または軽度認知障害の中等度 - 重度のうつ 病を合併している成人 介入 : ・ うつ病治療のための抗うつ薬を使用した薬剤介入 ・ うつ病治療のための心理的介入（認知行動療法、問 題解決療法、行動活性化療法など） 比較 : 通常のケアやプラセボ、または介入なし アウトカム : ・ 重大 - 認知機能 - 軽度認知障害の発症 - 認知症 ・ 重要 - 生活の質 - 生活機能レベル（ADL/ 日常生活動作、IADL/ 手 段的日常生活動作） - 有害事象 - 脱落率 背景 うつ病と認知機能低下や認知症との関連性について は、かなりのエビデンスが集積されている。2014 年 に World Alzheimer Report の一環で行われた文献レ ビューでは、32 の研究成果を対象として、認知症の発症 率についてのうつ病の影響について、メタ分析が行われ た。62,568 名の患者が対象で、観察期間は平均 5 年（2- 17 年）で、うつ病の存在は認知症のリスクをほぼ 2 倍 （統合効果量 =1.97, 95% 信頼区間 1.67-2.32）にすると いう結果だった (Prince et al., 2014)。 経時的なメタ回帰分析も行われた。長期経過で効果が 小さくなる傾向が認められ、うつ病は認知症の病前状態 となっている可能性があることが示唆された。認知機能 障害が高齢者のうつ病における主症状であること（これ を仮性認知症と呼ぶ）に言及されたことは重要である。 うつ病と認知機能障害または認知症との関連性につい ては他にもいくつかの説明がある。うつ病とノルアドレ ナリン伝達の変化や白質病変が関連しているという説明 や、認知機能低下の初期段階における障害に対する自覚 からうつ病が生じるという説明、また意欲低下やうつ 病そのものによる認知機能障害によって、顕在化して いない障害をうつ病が際立たせるという説明などがある (Camus et al., 2004; Jorm et al., 2001; Kales et al., 2005; Schwitzer et al., 2002)。 3.11 うつ病への対応 41 認知機能低下および認知症のリスク低減 WHOガイドライン 現在のところ、認知機能低下や認知症のリスクを低減するために抗うつ薬の使用を推奨するエビデンスは不十分 である。 成人に対する抗うつ薬や心理療法を用いるうつ病治療は、現行の WHO mhGAP ガイドラインの基準に従って行 われるべきである。 精神保健専門家のいない保健医療の場における精神・神経・物質使用障害のためのWHO mhGAP介入ガイド　―第２版 (http://www/who/int/mental_health/mhGAP_intervention_guide_02/en/) 中等度から重度のうつ病を有する成人に対し、WHO ガイドラインでは以下のような治療法が推奨されている。 心理社会的 / 非薬物的治療および助言 ・ 心理教育（適宜、患者本人およびその家族に対して） ・ 現在の心理社会的なストレス因への対処 ・ 社会的ネットワークの再活性化 ・ 可能であれば、短時間の心理療法 ・ 定期的なフォローアップ 抗うつ薬治療 ・ その国における、あるいは WHO の医薬品集から抗うつ薬を選択する。選択的セロトニン再取り込み阻害剤（フ ルオキセチン）と、三環系抗うつ薬（アミトリプチリン）は、WHO の医薬品集に掲載されており、WHO の 必須薬剤のモデルリストに掲載されている。 ・ 対象者の抗うつ薬を選択する際には、その人の症状パターン、薬物の副作用プロファイル、もしあれば過去の 抗うつ薬治療の有効性を考慮する。 ・ 併存する医学的疾患については、抗うつ薬を処方する前に、薬剤 - 疾患、薬剤 - 薬剤間の相互作用について考 慮する。その国の、あるいは WHO の処方薬剤集を参考にする。 ・ 他の向精神薬と抗うつ薬を併用する場合には、専門家の監督または専門家への相談が必要である。 推奨と考察 エビデンスと推奨 42 支持するエビデンスと根拠 通常のケアまたはプラセボと比較したうつ病に対す る薬物介入（抗うつ薬）については、認知機能が正常 なうつ病の成人を対象とした一つのシステマティック レビューからエビデンスが抽出された (Baune et al., 2018)。軽度認知障害の成人に対する、利用可能なエ ビデンスはなかった。そのレビューではネットワーク メタ分析が行われた。認知機能の評価法としては Digit Symbol Substitution Test の標準化平均差が用いられ た。結果は、ボルチオキセチンがプラセボと比して認知 機能を改善させたが、デュロキセチン、セルトラリン、 シタロプラム、エスシタロプラム、フェネルジン、ノル トリプチリンでは効果が認められなかった (Baune et al., 2018)。しかしそのエビデンスの質は非常に低く、 また関連して発症した軽度認知障害の発症や認知症、生 活の質、生活機能レベル（ADL/ 日常生活動作、IADL/ 手段的日常生活動作）、有害事象、脱落率等について利 用可能なデータはなかった。全体的に、効果の真のバラ ンスを確かめるのは難しい。認知機能低下や認知症のリ スクを減らすためにうつ病に対する薬物治療を行う場 合、エビデンスではボルチオキセチンの使用のみが有益 とされている。しかし薬剤関連副作用や相互作用といっ た有害事象についての利用可能なデータがない。 心理療法をうつ病に用いることをプラセボ投与や非介 入群と比較した研究については、システマティックレ ビューは見当たらなかった。 したがって、GDG は現時点では、うつ病治療を行う ことと認知機能低下または認知症のリスクを減らすこと とについて、十分なエビデンスはまだないと結論づけた。 ただこれは他の有益性からうつ病への対応は重要であ り、介入に対する否定的な推奨をしているわけではない とされた。 43 認知機能低下および認知症のリスク低減 WHOガイドライン 難聴のある認知機能正常または軽度認知障害の成人に とって、難聴の治療は、認知機能低下や認知症のリスク の低減において、通常のケアあるいは介入なしよりも効 果的か。 対象： 認知機能正常または軽度認知障害の難聴の成人 介入 : 難聴を治療するための介入（補聴器など） 比較 : 通常のケアまたは介入なし アウトカム : ・ 重大 - 認知機能 - 軽度認知障害の発症 - 認知症 ・ 重要 - 生活の質 - 生活機能レベル（ADL/ 日常生活動作、IADL/ 手 段的日常生活動作） - 有害事象 - 脱落率 背景 難聴は、加齢とともによく起こる障害である。世界 人口の中で永年続く障害の主な原因の第 4 位であり （WHO、2012 年）、65 歳以上の成人 3 人に 1 人は難 聴があると推定されており、この数は毎年増加している （Wilson et al.、2017）。ただし、難聴の影響は、個人 レベルおよび社会全体のレベルの両方で過小評価される ことが多い（Blustein et al.、2018）。 聴覚障害は、機能的能力と社会的および感情的な幸福 感を衰弱させる。聴力の低下は、個人のコミュニケーショ ン能力に影響を与えるため、欲求不満、孤立感、孤独感 を感じることがある（Ciorba et al、2012）。運動能力 の低下、車の運転の中止、パートナーの死亡、一人暮ら しなどの年齢に関連する要因による孤立の影響をすでに 経験している高齢者集団は、これらの心理社会的影響に 対して特に影響を受けやすい。 難聴は、認知機能低下または認知症のリスク増加とも 関連している（Lin et al、2013）。前向きコホート研究 の最近のメタ分析は、アルツハイマー病と MCI の聴力 障害の相対リスクが 2.82 であることを示している（95％ CI：1.47–5.42）（Zheng et al.、2017）。さらに、ランセッ ト委員会が発表したメタ分析では、難聴があると認知症 のリスクが約 2 倍になることが示された（RR = 1.94、 95％ CI：1.38–2.73）（Livingston et al、2017）。難聴 と認知障害または認知症は、それぞれまたはその組み合 わせにより、将来の機能的能力とケアの負担を予測でき る。したがって、難聴の治療は、高齢者にとって様々な 要因を大幅に改善する可能性がある。 3.12 難聴の管理 エビデンスと推奨 44 認知機能低下や認知症のリスクを低減するために補聴器の使用を推奨するエビデンスは不十分である。 WHO ICOPE ガイドラインで推奨されているように、難聴を適時に発見し治療するために、スクリーニングと難 聴のある高齢者への補聴器の提供が行われるべきである。 高齢者のトータルケアに関するWHOガイドライン (WHO ICOPE) (http://www.who.int/ageing/publications/guidelines-icope/en/) 高齢者に対して、WHO は以下を推奨する。 難聴がある高齢者を適時発見し治療するために、スクリーニングを行い難聴の高齢者に補聴器を提供する必要が ある。 推奨に関する考察： ・ 地域社会のネットワークを介して、高齢者の難聴と聴覚リハビリテーションの利点についてコミュニティの認 識を促進する必要がある。 ・ 医療従事者は、聴力について定期的に質問することで、高齢者の難聴をスクリーニングするよう奨励されるべ きである。聴覚検査、耳鏡検査、ささやき声テストも推奨される。 ・ 補聴器は、聴力の低下を最小限に抑え、毎日の機能を改善するため、難聴の高齢者に最適な治療法である。 ・ 潜在的な耳毒性のある薬物治療の見直しが必要である。 ・ 慢性中耳炎または突発的に難聴が起こった場合、またはスクリーニング検査で異常がみつかった場合は、耳鼻 咽喉科医に紹介する必要がある。 推奨と考察 45 認知機能低下および認知症のリスク低減 WHOガイドライン 支持するエビデンスと根拠 難聴治療の介入（補聴器など）と通常のケアまたは介 入なしについては、正常な認知機能を持ち難聴がある成 人を検査した一つのシステマティックレビューからエビ デンスが引用された (Cherko et al., 2016)。軽度認知 障害の成人に関するエビデンスは得られていない。認知 機能と生活の質については、エビデンスの質は非常に低 い。メタ解析は行われておらず結論を裏付ける数値が 無く、結果は説話的に報告されている (Cherko et al., 2016)。認知機能測定を含む二つの研究に基づいて、補 聴器の使用は認知機能の改善に関連しているが、認知機 能改善が 1 年後にはベースラインに戻ることが示されて いるのでこれらの利点は限定的である可能性があるとレ ビューは結論づけている。また二つの研究結果に基づい て、高齢者の補聴器の使用は生活の質の結果の改善と関 連があると結論した。全体として、エビデンスは介入も 比較も支持していない。補聴器は生活の質を改善するか もしれないが、十分なエビデンスは得られていない。軽 度認知障害の発症や認知症、生活機能レベル（ADL/ 日 常生活動作、IADL/ 手段的日常生活動作）、有害事象ま たは脱落率に関するデータはない。 GDG は、現在、認知機能低下や認知症のリスクを減 らすために補聴器の使用を推奨するには十分なエビデン スがないと結論付けた。GDG は、他の利益のために高 齢者の難聴を改善する補聴器の使用が重要であると結論 付け、この点においては ICOPE ガイドラインに従うこ とを推奨した。

47 認知機能低下および認知症のリスク低減 WHOガイドライン 4 実行にあたっての考察 実行にあたっての考察 48 各国はヘルスケア関連の職員のトレーニングやケア の質の改善に関して研究教育拠点〔COE (centre of excellence)〕を使用することを通して、WHO ガイド ラインを実施するサポートを受けることになる。また認 知症の公衆衛生対応におけるグローバル・アクション・ プラン 2017-2025、包括的メンタルヘルス・アクション・ プラン 2013-2020、非感染性疾患の予防と管理におけ るグローバル・アクション・プラン 2013-2020 といっ たアクションプランを国レベルで採用することでも実施 は促進される。また、国際的な機関や連合と WHO がコ ラボレーションすることでも、国がそうしたプロセスを 育むように支援されるだろう。 これらのガイドラインに含まれる介入の多くが心血管 疾患や糖尿病の危険因子の管理に強く関連しているもの であるが、関連するような対照群で、実施可能であるな ら、ガイドラインの推奨項目を実施することは現行のリ スクを下げる予防プログラムと結びつくものである。最 適な予防効果はいくつかの危険因子に同時に対応するこ とで得られる可能性がある。関係各所のコラボレーショ ンと学際的なアプローチもまた必要だろう。 これらのガイドラインに含まれる推奨は、各国の医療 サービスやニーズに沿った適当な文書の形で採用され るべきである。WHO 本部は国レベルの公衆衛生機関や パートナーらと関わるだけでなく、国や地域の担当部署 と密接に協働し、コミュニケーションと大小の会議を通 じて各国に沿った形のガイドラインの採用を推し進める ものである。 各国がこれらガイドラインをどのように実施するかを 検討する際、予算や人的資源、他の保健システムについ て分析し、どういった資金やシステムが利用可能で、ど の地域が追加の資金を必要としているかを特定するべき である。これらは医療従事者のトレーニングや薬剤の供 給、医療サービス利用における情報収集を行う保健情報 システムの導入なども含んでいる。 各国の実施を助けるため、WHO はこれらガイドライ ンに含まれる推奨項目の実施における、臨床面やサービ スの運搬面については対処する補助ツールを作成するつ もりである。 49 認知機能低下および認知症のリスク低減 WHOガイドライン 5 出版、普及および評価 出版、普及および評価 50 5.1 出版と普及 このガイドラインは印刷物の形で出版するとともに、 WHO ウェブサイト上のしかるべきインターネット空間 を通じて電磁的にも普及を図る。 このガイドラインは、認知症に対する公衆衛生対応 におけるグローバル・アクション・プラン 2017-2025 〔Global action plan on the public health response to dementia 2017–2025〕（Global Dementia Observatory による知識交換プラットフォームなど）、 総合的な精神保健におけるアクション・プラン 2013- 2020〔Comprehensive mental health action plan 2013–2020〕、 そ し て 非 感 染 性 疾 患 の 予 防 と 制 御 の ためのグローバル・アクション・プラン 2013-2020 〔Global action plan for the prevention and control of noncommunicable diseases 2013–2020〕 の 精 神 保健および非感染性疾患〔NCD〕にかかる普及活動を 通じて普及を図る。このガイドラインは mhGAP ガイド ラインに追加され、mhGAP エビデンス・リソース・セ ンターおよび mhGAP 介入ガイドを含む他の mhGAP による製作物などを通じて配布される。このガイドライ ンは、非感染性疾患〔NCD〕ガイドライン、高齢者の 統合的ケアガイドライン、その他の加齢にかかるリソー スなどの、WHO の他のガイドラインと関連づけられて いるため、これらのガイドラインとともに配布されるこ ともある。 このガイドラインおよび関連する著作物は英語で作成 され、より広い範囲に普及させるため WHO 地域事務所 と協力して他の WHO 公式言語に翻訳される。それぞれ の地域において、認知機能低下や認知症を有する人々の 介護に影響を与える社会や医療施設の情況において、確 実にこのガイドラインが適切なものとなるように、地域ご とに適合させる必要がある。適合のための作業には、言 語的な翻訳、および介入が特有の社会的文化的な情況に おいて受け入れ可能であること、その地域の保険制度に 適していることの確認、等が含まれる。本ガイドライン 11 http://www.g-i-n.net/document-store/working-groups-documents/adaptation/adapte-resource-toolkit-guideline- adaptation-2-0.pdf を地域の情況に適合させるための ADAPTE マニュアル は、使用されるべきアプローチの概略を述べている。11 推奨の受容可能度および実用性はそれぞれ固有の文化的 情況において検討される。地域の情況とは、たとえば保 健サービス、専門技術、医療・介護資源の利用可能性、 保健サービスの構築情況、ならびに人口の特性、文化的 な信条、価値判断などである。 各国保健省の関連部署は、WHO 地域事務所および 各国事務所を通じてガイドラインについて通知される。 WHO 本部外の技術系事務官には要約パッケージ版が用 意される。そこには、政策および事業における実践に関 する実施概要と Q&A が含まれる予定である。 本ガイドラインの普及はまた、WHO と国際的機関・ 団体との協力を通じて促進される。WHO コミュニケー ションズとの協調のもと、報道機関は新しいガイドライ ンについて通知される。 各国は中核的拠点を用いた。医療・健康管理に従事す る者に対する介護の質を向上させるためのトレーニング を通じて、ガイドラインの実践のための支援を受ける。 Web ベースのプラットフォームおよび各地域でのワー クショップを通じて能力育成活動が遂行される。 本ガイドラインの普及は、査読のある学術誌への、特 に選ばれたシステマティックレビューとエビデンスの出 版、および鍵となるイベントやカンファレンスのワーク ショップやプレゼンテーションによって支援される。 51 認知機能低下および認知症のリスク低減 WHOガイドライン 5.2 モニタリングと評価 このガイドラインの出版に引き続いて、WHO はその 有用性と影響を評価する目的でガイドラインを実践に移 す活動からの定期的なフィードバックの収集を続ける予 定である。得られた情報は、ガイドラインの質を評価し、 改善が必要な領域を同定するために使用される。WHO が設けた、世界の認知症の状況を注視・観察するため のオンラインによる情報・知識交換のためのプラット フォーム、Global Dementia Observatory は、このガ イドラインの実践についてモニタリングを行うための枠 組みを提供する。12 5.3 さらなる研究への関わり 本ガイドラインの推奨の大部分は、もともと存在する 健康問題や依存性に対する治療についての既存ガイドラ インとの整合性がとられている。しかし、ここで述べら れている種々の介入の、軽度認知障害や認知症の発症と いうアウトカムへの影響を判断するには、さらなるエビ デンスが必要である。 社会活動と難聴についてはエビデンスが不十分である ため推奨を記述することができなかった。現在、難聴へ の介入について、いくつかの治験が行われている。その 結果が発表された場合、このガイドラインを更新する必 要が生じる可能性がある。それに対して、現時点では、 認知機能低下や認知症に対する社会的活動の効果につい て調べる研究はほとんど行われていない。このタイプの 研究を実施するにあたっての困難の一部は、社会的活動 を定義し定量化するのが難しいこと、および、しばしば 社会活動による介入の一部の要素ともなる、身体的ある いは精神的活動と社会活動とを区別するのが難しいこと にある。したがって、社会活動による介入の標準化プロ トコルの開発が、臨床試験を実施する前提として必要に なると思われる。 ここで示されたエビデンスの一部は、比較的短い観察 期間にて実施された RCT に基づいている（認知トレー 12 https://www.who.int/mental_health/neurology/dementia/Global_Observatory/en/ で入手可能 ニング、抑うつや社会活動にかかる介入など）。この点 は、認知機能低下や認知症が長い発症前期間を持つこと から、発症への介入が起こしうる影響を我々が判定する にあたっての限定要因となる。長期にわたって認知機能 低下や認知症のリスクを低減させるかどうかという点に ついて、これらの介入の効果をより正確に推定するため には、より長い観察期間に基づくエビデンスをさらに多 く集める必要がある。さらには、介入のタイミングがこ れらの認知機能低下や認知症への介入の効果にどのよう に影響するかを理解するために、より多くの研究が行わ れる必要がある（中年期の身体活動と老年期になってか らの身体活動など）。 認知症有病率は低中所得国において特に増加しつつあ る。しかし、介入研究の大部分は高所得国において実施 されており、したがってそのような介入の、低中所得国 における有効性についてのエビデンスは僅かしかない。 低中所得国における認知機能低下や認知症のリスクを低 減させるにはどのようにするのが最も良いかを理解する ために、より多くに注意が払われる必要がある。 このガイドラインを準備するためのエビデンス収集 に用いられた PICO 質問には、単一の危険因子への介 入が含まれている。しかし、認知症の病因が複数の要 素からなること、そして様々な危険因子が個々人の生 活習慣の中で相互作用すること、等を考慮して、複数 領域にまたがるアプローチによる研究が増加しつつあ り、単一領域を対象とする戦略よりも有効である可能 性を示しつつある。最近、複数領域に介入する三つの 大きな RCT －フィンランド認知障害・認知能力低下予 防のための老年期介入試験（FINGER）〔the Finnish Geriatric Intervention Study to Prevent Cognitive Impairment and Disability (FINGER)〕； 記 憶 低 下 を訴える高齢者の認知機能に対する複数領域での介入 を伴うあるいは伴わない長期間のオメガー 3 多価不飽 和脂肪酸補充の効果にかかる研究（MAPT）〔Effect of long-term omega-3 PUFA supplementation with or without multidomain intervention on cognitive function in elderly adults with memory complaints (MAPT)〕；および、集中的な血管リスク介入による 出版、普及および評価 52 認知症予防（preDIVA）〔Prevention of dementia by intensive vascular care (preDIVA)〕 － が 完 了 し た （Ngandu et al., 2015; Andrieu et al., 2017; Moll von Charante et al., 2016）。それらの結果の一次解析の報 告では、FINGER において行われた複数領域の生活習慣 への介入のみが有意な結果を示したが、これら三つの治 験から得られた所見全般としては、高いリスクを持つ個 人を対象として介入するのが最も有効な戦略である可能 性が示唆された。とりわけ、FINGER 以外の介入研究に おいて、それぞれ、MAPT では（FINGER と同様）認 知症リスクのスコアが高い参加者において、preDIVA ではベースラインにおいて未治療の高血圧を有する参加 者において、有意な結果が示された。 複数領域における介入という流れにおいて、新しい技 術や e- ヘルス・ソリューションも、また、それら介入の 到達範囲を拡大することを通じて、リスク低減に有用な ツールを提供しうる (Barbera et al., 2018)。 高齢者間のリスク・プロファイルの不均一性を勘案し、 多様な地理的・文化的背景に適合させる形で、最近、ワー ルドワイド FINGERS ネットワークなどの世界的な新構 想が、同様の介入をテストするという目的に特化して着 手された (Kivipelto et al., 2017)。 それぞれ特異な地理的・文化的な背景に適合させると ともに、リスクの高い人たちを対象とした、そして（も し可能であれば）新たな e- ヘルス・ツールを利用した、 複数領域への介入の有効性についてのさらなる研究が必 要である。 5.4 将来の再評価と更新 このガイドラインは 5 年以内に再度評価されることが 期待される。WHO 事務局は、この領域における新たな エビデンスの出現がないかどうかを、ガイドライン作成 グループのメンバーや今回のエビデンス評価の過程にお いて同定された技術的専門家、WHO 協力センター、そ して学術研究組織等との協議のもと、常に注視・観察し ている。複数領域への介入試験から、より多くのエビデ ンスの報告がなされることが、今後何年間かの間に期待 される中、将来の改訂において、そのような介入につい ての PICO 質問の追加が考慮されることを確信する。 文　献 53 認知機能低下および認知症のリスク低減 WHOガイドライン Albanese E, Launer LJ, Egger M, Prince MJ, Giannakopoulos P, Wolters, FJ et al. 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Current Alzheimer Research. 11(9):899–907. 補遺１: ガイドライン作成グループメンバー 61 認知機能低下および認知症のリスク低減 WHOガイドライン Name Gender WHO region Affiliation Area of expertise 1． Charles Alessi M European Public Health England, United Kingdom Health reform, preventable dementia 2． Kaarin Anstey F Western Pacific University of New South Wales and Neuroscience Research, Australia Research in dementia epidemiology and risk reduction and cognitive ageing 3． Kimberly Ashby- Mitchell F Americas Caribbean Public Health Agency, Trinidad and Tobago Research on effects of diet and physical activity on cognitive status 4． Corrado Barbui M European University of Verona, Italy Mental health research and training, public health, health systems strengthening 5． Adelina Comas- Herrera F European London School of Economics, United Kingdom Health economist, dementia research 6． Amit Dias M South-East Asia Department of Preventive and Social Medicine, Goa Medical College, India Dementia, public health in LMIC 7． Cleusa P Ferri F Americas Federal University of São Paulo, Brazil Research in dementia and 10/66 group, dementia risk factors in LMIC 8． Riadh Gouider M Eastern Alzheimer’s Centre, Razi Hospital, Tunis; Tunisian Society of Neurology, Tunisia Dementia research in areas of epidemiology, neuropsychological assessment and risk factors 9． Shinya Ishii M Western Pacific Health and Welfare Bureau for the Elderly; Ministry of Health, Labour and Welfare, Tokyo, Japan Health policy, neurology of Alzheimer’s disease and dementia 10． Yves Joanette M Americas Canadian Institutes of Health Research, Government of Canada Dementia research 11． Joseph Kibachio M African Ministry of Health, Nairobi, Kenya Public health, health policy, NCDs 12． Miia Kivipelto F European Karolinska Institutet, Stockholm University, Stockholm, Sweden Dementia research in the field of early diagnosis and prevention 13． Shanthi Mendis F South-East Asia Independent consultant in global health, Sri Lanka NCDs and cardiology, health policy development, capacity strengthening, implementation research particularly in LMIC 補遺１:ガイドライン作成グループメンバー 62 Name Gender WHO region Affiliation Area of expertise 14． Ayesha Motala F African University of KwaZulu- Natal, South Africa Epidemiology and genetics of diabetes mellitus 15． Ronald Petersen M Americas Mayo Clinic, United States of America Memory disorders, aging and Alzheimer's disease 16． Dorairaj Prabhakaran M South-East Asia Centre for Chronic Conditions and Injuries & Public Health Foundation of India Cardiovascular disease prevention, epidemiology, developmental origin, and biomarkers of cardiovascular diseases and diabetes 17． Martin Prince M European Health Foundation of India Public health aspects of ageing and chronic disease in LMIC, dementia, guideline development 18． Suzana Shahar F Western Pacific Universiti Kebangsaan, Malaysia Nutrition, micronutrients, dietary interventions 19． Ameenah Bibi Mia Sorefan F African Alzheimer’s Association of Mauritius; Ministry of Health & Quality of Life, Mauritius Ageing, dementia and Alzheimer’s disease 20． Kusumadewi Suharya (Dy) F Western Pacific Alzheimer’s Disease International, Indonesia Dementia and public health 21． Huali Wang F Western Pacific Dementia Care & Research Center, Peking University Institute of Mental Health, China Dementia research and education 補遺２: 利益相反アセスメント 63 認知機能低下および認知症のリスク低減 WHOガイドライン INDIVIDUALS INVOLVED IN ASSESSMENT OF CONFLICT OF INTEREST: Tarun Dua, Programme Manager, Department of Mental Health and Substance Abuse, WHO headquarters. Neerja Chowdhary, Technical Officer, Department of Mental Health and Substance Abuse, WHO headquarters. To comply with WHO’s Conflict of Interest Policy, the Secretariat followed the revised Guidelines for Declaration of Interests (WHO Experts).14 Declarations of interest (DoI) were requested from: (a) all GDG members; (b) all external partners involved in the evidence review process; (c) all experts invited to review the evidence profiles. A letter requesting completion of a DoI form and submission of a curriculum vitae as well as was sent to all GDG members, the external review group and external partners. They were asked to agree to the publication of a summary of declarations in the guide-line. The GDG members were also required to complete a confidentiality undertaking. Once received, the WHO Secretariat reviewed the DoIs as well as additional information (internet and bibliographic database search) and evaluated if there are any conflicts of interest and if so, whether these require a management plan. In order to enhance its management of conflicts of interest as well as strengthen public trust and transparency in connection with WHO meetings and activities involving the provision of technical/ normative advice, the names and brief biographies members being considered for participation in the GDG were disclosed for public notice and comment prior to the meeting. At the beginning of the GDG meeting, the DoI of each GDG member were presented and GDG 14 WHO Office of Compliance, Risk Management and Ethics (CRE) http://intranet.who.int/homes/cre/ethics/doiexperts/ members and external partners were asked to update their DoI with relevant changes by notifying the responsible technical officer. The follow up and suggested actions agreed upon to manage the conflicts of interest declared are summarized below: • If members declare interests that are relevant to the meeting, the WHO Secretariat will note any potential conflict of interest and summarize these and then decide whether and to what extent they can participate in the guideline development. • If the conflict is deemed to be significant, the WHO Secretariat will decide if the conflict necessitates exclusion of that person from participating in the guideline process or if their participation should be limited. • These decisions are made on a case-by-case basis. Below is a summary of the Declared conflicts of interest and how these were managed. A. GDG MEMBERS GDG Members with no relevant interests declared on the DOI form and no relevant interests found in the CV 1. Kaarin J Anstey, University of New South Wales, Sydney, Australia; 2. Kimberly Ashby-Mitchell, C a r i b b e a n P u b l i c Health Agency, Port of Spain, Trinidad and Tobago; 3. Corrado Barbui, University of Verona, Verona, Italy. 4. Amit Dias, Department of Preventive and Social Medicine, Goa Medical College Bambolim, Goa, India; 5. Suharya Dy (Kusumadewi), Alzheimer’s Disease International, Jakarta, Indonesia; 6. Cleusa P. Ferri, Federal University of Sao Paulo, Sao Paulo, Brazil. 補遺２:利益相反アセスメント 64 7. Riadh Gouider, R a z i Ho s p i t a l , F a c u l t y o f Medicine, Tunis, Tunisia; 8. Shinya Ishii, Ministry of Health, Labour and Welfare, Tokyo, Japan; 9. Yves Joanette, Canadian Institute of Health Research, Government of Canada. 10. Joseph Kibachio, Ministry of health, Nairobi, Kenya; 11. Shanthi Mendis, Colombo, Sri Lanka; 12. Dorairaj Prabhakaran, Public Health Foundation of India, New Delhi, India; 13. Ameenah Bibi Mia Sorefan, Ministry of Health and Quality of Life, Quatre-Bornes, Mauritius GDG members who have declared an interest on the DOI form or where a potentially relevant interest has been noted from the CV Charles Alessi, Public Health England, London, United-Kingdom Dr Alessi declared that the travel costs for the GDG meeting were covered by his organization. Action: This interest was deemed insignificant or minimal and unlikely to affect, or be reasonably perceived to affect, Dr Alessi’s judgement in the development of the present guidelines. He is deemed to be participating in the guideline development process in an individual capacity and not representing any organization. No further action was necessary Adelina Comas-Herrera, London School of Economics, London, United-Kingdom Dr Comas-Herrera declared in her DoI from that she had received research support routed via her University on various research projects on dementia in 2015 and 2016. These amounts were used to pay her salary by the University. She also declared receiving a payment of US$1000 in 2017 to advise a pharmaceutical company, Axovant Sciences GmbH. The topic was on the availability of data on dementia costs for a medicine that has since been withdrawn due to lack of effectiveness. Action: It was felt that this interest is insignificant or minimal and unlikely to affect, or be reasonably perceived to affect, Dr Comas-Herera’s judgement in the development of the present guidelines. No further action was necessary. Miia Kivipelto, Karolinska Institutet, Stockholm, Sweden Dr Kivipelto declared in her DoI form that she currently serves on the Advisory Board of a Finnish company that focuses on early diagnosis and e-health solutions for which she received €2500. She is also on the Governance committee of AARP, a non-profit organization for healthy ageing for which she received €800. She also declared that she has received research grants related to risk factors for dementia and is a founding member of World-Wide Fingers, an interdisciplinary network to share experiences, harmonize data and plan joint international initiatives for the risk reduction of cognitive decline and dementia. Action: This interest was deemed insignificant or minimal and unlikely to affect, or be reasonably perceived to affect, Dr Kivipelto’s judgement in the development of the present guidelines. She is deemed to be participating in the guideline development process in an individual capacity and not representing any organization. No further action was necessary Ayesha Motala, University of KwaZulu-Natal , Durban, South Africa. Dr Motala declared that as a public servant working in a government institute, she seeks sponsorships to meetings from various organizations, especially when her scientific abstracts are accepted for presentations. The sponsorships are merely for attending the meetings, with no obligation to the sponsoring companies. 65 認知機能低下および認知症のリスク低減 WHOガイドライン Details of such sponsorship for which she received a total amount of US$26 000: 4–8 December 2017: International Diabetes Federation (IDF) Congress, Abu Dhabi: Sanofi Aventis sponsorship for travel and accommodation; 11–15 September 2017: European Association for the Study of Diabetes (EASD) Congress, Lisbon: Pfizer sponsorship for travel and accommodation; 8–13 June 2018: American Diabetes Association (ADA), San Diego: Boehringer Ingelheim sponsorship for travel and accommodation: a member of her collaborating scientific team presented a paper. Action: It was felt that this interest is insignificant or minimal and unlikely to affect, or be reasonably perceived to affect, Dr Motala’s contribution as an external reviewer for these guidelines. No further action was necessary. Ronald C. Petersen, Mayo Clinic, Rochester, USA Dr Petersen declared that he is a clinical trials consultant for five pharmaceutical companies: from four of these (Roche Inc, Merck Inc, Genetech Inc and GE Healthcare) he receives less than US$ 10 000 and from one (Biogen Inc) he receives less that US$ 15 000 as consultancy fees. Action: It was felt that this interest is unlikely to affect, or be reasonably perceived to affect, Dr Petersen’s contribution as an external reviewer for these guidelines since these grants are not related to the topic of interest. No further action was necessary. Martin Prince, King’s College London, London, United Kingdom Professor Prince declared in his DOI form that he currently receives research support through a grant from the National Institute of Health Research (NIHR, UK) amounting to £7 million over four years. Professor Prince is the PI and 20% of his salary costs are charged to the grant. The work focuses on health systems strengthening in sub Saharan Africa and one theme relates to the topic of these guidelines i.e. integrated primary healthcare for multimorbid conditions. Action: It was felt that this interest is insignificant or minimal and unlikely to affect, or be reasonably perceived to affect, Professor Prince’s judgement in the development of the present guidelines. No further action was necessary Suzana Shahar, Universiti Kebangsaan Malaysia, Selangor, Malaysia Dr Sahar has declared in her DoI form that she has a clinical trial agreement through her University with Biotropics, a company that develops bio-resources into superior natural health product. The research involves evaluating the efficacy of Asian traditional herbs in improving cognition and mood. The funding amount is US$ 100 000 between 2014 and 2018. Action: It was felt that this interest is insignificant or minimal and unlikely to affect, or be reasonably perceived to affect, Dr Sahar’s contribution as an external reviewer for these guidelines. No further action was necessary Huali Wang, Dementia Care & Research Center, Peking University Institute of Mental Health, Beijing, China. Dr Wang declared in her DoI form that prior to 2016, she had worked as a consultant with Neowave Inc. to develop a tablet-based cognitive training program. She also declared that she had received support for travelling to meetings form Eisai China amounting to US$ 7000 prior to 2017. The meeting were all Alzheimer’s Disease International (ADI) conferences. 補遺２:利益相反アセスメント 66 Action: It was felt that this interest is insignificant or minimal and unlikely to affect, or be reasonably perceived to affect, Dr Wang’s contribution as an external reviewer for these guidelines. No further action was necessary B. EXTERNAL REVIEW GROUP Members of the external review group with no relevant interests declared on the DOI form and no relevant interests found in the CV 1. Abdullah Al Khatami, Ministry of Health, Saudi Arabia 2. Alistair Burns, University of Manchester, UK 3. Linda Clare, University of Exeter, UK 4. Jacqueline Dominguez, Institute for dementia care Asia, Quezon city, Philippines 5. Maelënn Guerchet, The Global Observatory for Ageing and Dementia Care, King's College London, UK 6. Mariella Guerra, I n s t i t u t e o f M e m o r y , Depression and Related Disorders – IMEDER, Lima, Peru 7. Luis Miguel F. Gutiérrez Robledo, I n s t i t u t o Nacional de Geriatría, Institutos Nacionales de Salud de México, Mexico City, Mexico 8. Vladimir Hachinski, Uni ve r s i t y o f We s t e r n Ontario in London, Ontario, Canada 9. Qurat ul Ain Khan, Aga Khan University Hospital, Karachi, Pakistan. 10. Sebastian Koehler, Maastricht University, The Netherlands 11. Jae-hong Lee, University of Ulsan College of Medicine, Seoul, Korea 12. Gill Livingstone, University college London, UK 13. Jean Claude Mbanya, Doctoral School of Life Sciences, Health and Environment, University of Yaoundé I, Cameroon. 14. James McKillop, Service user group representative, UK 15. Rajat Ray, National Drug Dependence Treatment Centre, All India Institute of Medical Sciences, New Delhi, India 16. Helen Rochford Brennan, European Working Group of people with dementia, Ireland 17. Kate Swaffer, Dementia Alliance International, Australia 18. Weili Xu, Karolinska Institute, Finland Members of the external review group who have declared an interest on the DOI form or where a potentially relevant interest has been noted from the CV Emiliano Albanese, Univers i ta del la Svizzera italiana, Switzerland Dr Albanese declared in his DoI form that he receives research support from the Economic and Research Council UK as part of the STRIDE (Strengthening responses to dementia in developing countries) research consortium which focuses on dementia research in low and middle income countries. The amount of US$ 50 000 is provided to the institution to which he is affiliated. Action: It was felt that this interest is insignificant or minimal and unlikely to affect, or be reasonably perceived to affect, Dr Albanese’s contribution as an external reviewer for these guidelines. No further action was necessary. Hillary Doxford, 3 Nations Dementia Working Group, UK Ms Doxford declared in her DoI form that she has served on a grant review panel assessing and prioritizing grant applications for funding dementia research projects for the National Institute for Health Research, UK. The income she received for this was £450. She is also a voluntary member of the Dementia Programme Board in the UK Department of Health and Social Care as a person with lived experience. Action: It was felt that this interest is insignificant or minimal and unlikely to affect, or be reasonably perceived to affect, Ms Doxford’s contribution as an external reviewer for these guidelines. No further action was necessary. 67 認知機能低下および認知症のリスク低減 WHOガイドライン Elaine Rashbrook, Public Health England, UK Dr Rashbrook declared in her DoI form that she is employed by Public Health England (PHE), a government agency, as Consultant Specialist Life Course since 2015. PHE supports work on dementia risk reduction in line with the government strategy. There is no identified financial value for the work. Action: It was felt that this interest is insignificant or minimal and unlikely to affect, or be reasonably perceived to affect, Dr Rashbrook’s contribution as an external reviewer for these guidelines. She is deemed to be providing her review in an individual capacity and not representing any organization. No further action was necessary. Andrew Sommerlad, University College London, UK Dr Sommerlad declared in his DoI form that he receives research support from the Wellcome Trust in the form of a personal research fellowship to examiner whether social isolation is a risk factor for dementia The amount of funding is £201 311 from 2016 to 2019. Action: It was felt that this interest is insignificant or minimal and unlikely to affect, or be reasonably perceived to affect, Dr Sommerlad’s contribution as an external reviewer for these guidelines. No further action was necessary B. EXTERNAL PARTNERS External partners with no relevant interests declared on the DOI form and no relevant interests found in the CV 1. Mariagnese Barbera, U n i v e r s i t y o f E a s t e r n Finland, Kuopio, Finland; 2. Nicole A. Ee, University of New South Wales, Sydney, Australia; 3. Jenni Kumlala, Karolinska Institutet, Stockholm, Sweden; 4. Ruth Peters, University of New South Wales, Sydney, Australia; 5. Lidan Zheng, University of New South Wales, Sydney, Australia. None of the external partners declared relevant interests on the DOI forms nor were relevant interests found in the CV. 補遺 3: スコーピング・クエスチョン（※） 補遺3:スコーピング・クエスチョン 68 生活習慣および行動危険因子に対処する介入 1. 身体活動による介入 認知機能正常または軽度認知障害の成人にとって、身体活動による介入は、認知機能低下や認知症のリスクの低減に おいて、通常のケアあるいは介入なしよりも効果的か。 P: 認知機能正常または軽度認知障害の成人（年齢 18 歳以上） I : 身体活動による介入（有酸素運動、筋力トレーニングあるいは複合的な身体活動） C: 通常のケアまたは介入なし O: ・重大 ・重要 - 認知機能 - 軽度認知障害の発症 - 認知症 - 生活の質 - 生活機能レベル（ADL / 日常生活動作、IADL / 手段的日常生活動作） - 有害事象 - 脱落率 2. 禁煙治療 喫煙している認知機能正常または軽度認知障害の成人にとって、禁煙介入は、認知機能低下や認知症のリスクの低減 において、通常のケアあるいは介入なしよりも効果的か。 P: 認知機能正常または軽度認知障害の喫煙している成人 I : 禁煙介入（行動療法やニコチン代替療法、bupropion、バレニクリンなどの薬物療法） C: 通常のケアまたは介入なし O: ・重大 ・重要 - 認知機能 - 軽度認知障害の発症 - 認知症 - 生活の質 - 生活機能レベル（ADL / 日常生活動作、IADL / 手段的日常生活動作） - 有害事象 - 脱落率 （※） 日本語版注：ガイドラインで扱う重要臨床課題に基づき、答える べき疑問の構成要素を抽出し、疑問文の形式で表現したもの 69 認知機能低下および認知症のリスク低減 WHOガイドライン 3. 栄養的介入 3.3a 認知機能正常または軽度認知障害の成人にとって、栄養補助食品などの栄養的介入は、認知機能低下や認知症のリス クの低減において、通常のケアあるいは介入なしよりも効果的か。 P: 認知機能正常または軽度認知障害の成人 I : 栄養補助食品（ビタミン B、抗酸化物、オメガ―3 イチョウなど） C: 通常のケアまたは介入なし O: ・重大 ・重要 - 認知機能 - 軽度認知障害の発症 - 認知症 - 生活の質 - 生活機能レベル（ADL / 日常生活動作、IADL / 手段的日常生活動作） - 有害事象 - 脱落率 3.3b 認知機能正常または軽度認知障害の成人にとって、健康的な食事パターン（地中海食など）のような栄養的介入は、 認知機能低下や認知症のリスクの低減において、通常のケアあるいは介入なしよりも効果的か。 P: 認知機能正常または軽度認知障害の成人 I : 健康的な食事パターン（地中海食など） C: 通常のケアまたは介入なし O: ・重大 ・重要 - 認知機能 - 軽度認知障害の発症 - 認知症 - 生活の質 - 生活機能レベル（ADL / 日常生活動作、IADL / 手段的日常生活動作） - 有害事象 - 脱落率 4. アルコール使用障害への介入 アルコール使用障害のある認知機能正常または軽度認知障害の成人にとって、アルコール使用障害治療ための行動・心理 的介入は、認知機能低下や認知症のリスクの低減において、通常のケアあるいは介入なしよりも効果的か。 P: 認知機能正常または軽度認知障害のアルコールを過剰に使用している成人 I : ・アルコール使用障害を治療するための行動および心理的介入（動機付け面接など） ・アルコール使用障害を治療するための薬理学的介入 C: 通常のケアまたは介入なし O: ・重大 ・重要 - 認知機能 - 軽度認知障害の発症 - 認知症 - 生活の質 - 生活機能レベル（ADL / 日常生活動作、IADL / 手段的日常生活動作） - 有害事象 - 脱落率 補遺3:スコーピング・クエスチョン 70 特異的介入 5. 認知的介入 認知機能正常または軽度認知障害の成人にとって、認知刺激または認知トレーニングは、認知機能低下や認知症のリ スクの低減において、通常のケアあるいは介入なしよりも効果的か。 P: 認知機能正常または軽度認知障害の成人 I : ・認知刺激 ・認知トレーニング C: 通常のケアまたは介入なし O: ・重大 ・重要 - 認知機能 - 軽度認知障害の発症 - 認知症 - 生活の質 - 生活機能レベル（ADL / 日常生活動作、IADL / 手段的日常生活動作） - 有害事象 - 脱落率 6. 社会活動 認知機能や正常または軽度認知障害の成人にとって、高レベルの社会活動の維持や奨励することは、認知機能低下や 認知症のリスクの低減において、通常のケアあるいは介入なしよりも効果的か。 P: 認知機能正常または軽度認知障害の成人 I : 地域社会や家族との関わりを含む社会活動の維持と促進 C: 通常のケアまたは介入なし O: ・重大 ・重要 - 認知機能 - 軽度認知障害の発症 - 認知症 - 生活の質 - 生活機能レベル（ADL / 日常生活動作、IADL / 手段的日常生活動作） - 有害事象 - 脱落率 71 認知機能低下および認知症のリスク低減 WHOガイドライン 健康状態への介入 7. 体重管理 過体重あるいは肥満のある認知機能正常または軽度認知障害の成人にとって、減量介入（または肥満管理）は、認知 機能低下や認知症のリスクの低減において、通常のケアあるいは介入なしよりも効果的か。 P: 認知機能正常または軽度認知障害の過体重や肥満の成人 I : 体重管理 ・薬を用いない介入（認知行動的介入やライフスタイルへの介入など） ・薬を用いた介入（体重を減少させる薬（例：オルリスタット）など） C: 通常のケアまたは介入なし O: ・重大 ・重要 - 認知機能 - 軽度認知障害の発症 - 認知症 - 生活の質 - 生活機能レベル（ADL / 日常生活動作、IADL / 手段的日常生活動作） - 有害事象 - 脱落率 8. 高血圧の管理 高血圧のある認知機能正常または軽度認知障害の成人にとって、高血圧治療は、認知機能低下や認知症のリスクの低 減において、プラセボあるいは介入なしよりも効果的か。 P: 認知機能正常または軽度認知障害の高血圧症の成人 I : 高血圧治療、ライフスタイルへの介入 C: プラセボまたは介入なし O: ・重大 ・重要 - 認知機能 - 軽度認知障害の発症 - 認知症 - 生活の質 - 生活機能レベル（ADL / 日常生活動作、IADL / 手段的日常生活動作） - 有害事象 - 脱落率 9. 糖尿病の管理 糖尿病のある認知機能正常または軽度認知障害の成人にとって、糖尿病治療は、認知機能低下や認知症のリスクの低 減において、プラセボあるいは介入なしよりも効果的か。 P: 認知機能正常または軽度認知障害の糖尿病の成人 I : ・血糖管理のための治療 ・食事およびライフスタイルへの介入 C: プラセボまたは介入なし O: ・重大 ・重要 - 認知機能 - 軽度認知障害の発症 - 認知症 - 生活の質 - 生活機能レベル（ADL / 日常生活動作、IADL / 手段的日常生活動作） - 有害事象 - 脱落率 補遺3:スコーピング・クエスチョン 72 10. 脂質異常症の管理 脂質異常症のある認知機能正常または軽度認知障害の成人にとって、脂質異常症治療は、認知機能低下や認知症のリ スクの低減において、プラセボあるいは介入なしよりも効果的か。 P: 認知機能正常または軽度認知障害の脂質異常症の成人 I : ・スタチン（シンバスタチンやプラバスタチンなど） ・ライフスタイルへの介入 C: プラセボまたは介入なし O: ・重大 ・重要 - 認知機能 - 軽度認知障害の発症 - 認知症 - 生活の質 - 生活機能レベル（ADL / 日常生活動作、IADL / 手段的日常生活動作） - 有害事象 - 脱落率 11. うつ病への対応 うつ病性障害のある認知機能正常または軽度認知障害の成人にとって、うつ病の治療は、認知機能低下や認知症のリ スクの低減において、通常のケア、プラセボあるいは介入なしよりも効果的か。 P: 認知機能正常または軽度認知障害の中等度 - 重度のうつ病を合併している成人 I : ・うつ病治療のための抗うつ薬を使用した薬剤介入 ・うつ病治療のための心理的介入（認知行動療法、問題解決療法、行動活性化療法など） C: 通常のケアやプラセボ、または介入なし O: ・重大 ・重要 - 認知機能 - 軽度認知障害の発症 - 認知症 - 生活の質 - 生活機能レベル（ADL / 日常生活動作、IADL / 手段的日常生活動作） - 有害事象 - 脱落率 12. 難聴の管理 難聴のある認知機能正常または軽度認知障害の成人にとって、難聴の治療は、認知機能低下や認知症のリスクの低減 において、通常のケアあるいは介入なしよりも効果的か。 P: 認知機能正常または軽度認知障害の難聴の成人 I : 難聴の治療のための介入（補聴器など） C: 通常のケアまたは介入なし O: ・重大 ・重要 - 認知機能 - 軽度認知障害の発症 - 認知症 - 生活の質 - 生活機能レベル（ADL / 日常生活動作、IADL / 手段的日常生活動作） - 有害事象 - 脱落率 補遺 4: エビデンス評価の方法論 73 認知機能低下および認知症のリスク低減 WHOガイドライン 主要な書誌データベースを用いた包括的な検索を実施 して、各 PICO 質問の各アウトカムに一致する一つのシ ステマティックレビューを同定した。その目的は、タイ ムリーで、高い質を有する各 PICO 質問に関連するシス テマティックレビューを同定することであった。 検索戦略は、二つのチーム間でわずかに異なっていた （スウェーデンのカロリンスカ研究所とオーストラリア のニューサウスウェールズ大学を基本としている。しか し全般的には、以下のプロセスが採用された）。   1. PICO 質問ごとに過去 2 年間に公開されたシステマ ティックレビュー（メタアナリシスを含む）を検索 した。検索は 2018 年 4 月から 6 月の間に行われた。 2. もしどの PICO 質問に対しても 2 年間で高い質のシ ステマティックレビューが同定されなかった場合は、 検索は、過去 5 年間に拡大された。関連する PICO 質問については、2016 年の AHRQ のシステマティッ クレビューも参照した。AHRQ レビューの目的は、 認知機能低下と認知症を予防するための介入を検討 することであった。このレビューは、2009 年 1 月 から 2016 年 9 月までの間の記録に対して系統的に 行われた。 3. 難聴の質問については、使用可能なエビデンスが非 常に限られていたため、これまでに出版されたすべ てのシステマティックレビューを含むように検索が 拡張された。 4. 2018 年 7 月の GDG ミーティングでの GDG のフィー ドバックに基づいて、観察研究のシステマティッ クレビューも含むように検索が拡張された。検索は 2018 年 7 月から 8 月に再実行された。 14 Shea BJ, Grimshaw JM, Wells GA, Boers M, Andersson N, Hamel C et al (2007). Development of AMSTAR: a measurement tool to assess the methodological quality of systematic reviews. BMC Medical Research Methodology. 7:10. 次の書誌データベースが検索された。 • Bibliographic • Medline • Cochrane • PsycInfo • Embase • NICE.   低中所得国に関連するもの： • Global Index Medicus/Global Health Library • WHO regional database • WHOLIS • Database of impact evaluations • AJOL • KoreaMed • IndMED • HrCak • ArabPsycNet • HERDIN NeON • EurasiaHealth. 下記の検索方法を使用して検索を実行した後、検索さ れた研究のすべてのタイトルと要約が、Endnote を用 いてスクリーニングされた。タイトル / 要約の確認だけ では除外できなかった論文については、これらの論文の 全文がレビューされた。 エビデンステーブルのグレード判定 各 PICO 質問のアウトカムごとに、一つ以上のシステ マティックレビューが、GRADE エビデンステーブル内 で使用されるために選択され、GRADE エビデンステー ブル内で使用するシステマティックレビューを選択する 際に、以下の基準が使用された。 • 過去5年間、理想的には2年間に出版された（適時性）。 • 質が高い（AMSTAR 2 基準を使って評定 14）。 • PICO 質問に密接に関連している。 • 可能な場合、包括的なシステマティックレビューを 優先する。 補遺4:エビデンス評価の方法論 74 ・ 可能な場合 / 適切な場合、コクランレビューまたは 他のメタアナリシスを優先する。   GRADE の方法には、システマティックレビューに含 まれている研究の質の、研究デザイン、バイアスリスク、 非一貫性、間接性、不正確性、出版バイアスに従った評 価が含まれている。研究のエフェクトサイズとともに、 全体的な「エビデンスの確実性」が、極めて低い、低い、 中、高いの中から選ばれ、記載される。 GRADE エビデンステーブルは GRADEpro オンライ ンツールを使用して完成させられた。15 研究の質の評価 （バイアス、非一貫性、間接性、不正確性、および出版 バイアスのリスク）に関して、GRADE エビデンステー ブルを完成する際には、「精神保健の格差に関する行動 プログラム」介入ガイドと同じ基準が使用された。16 検索方法 12 個の PICO 質問ごとに個別の検索が行われた。PICO 質問に薬理学的介入と非薬理学的介入の両方が含まれて いる場合には、それぞれに対して検索が別々に行われた。 書誌データベースにおいて、検索をシステマティックレ ビューとメタアナリシス、あるいはヒトに制限できる場合 は、フィルターを使用した。例えば、使用言語のようなそ の他の制限（上述したように出版日は除く）は加えなかった。 書誌データベースで、使用可能な場合は、「高度な検索」 オプションが選択された。   PICO1 認知機能正常または軽度認知障害の成人にとって、身 体活動による介入は、認知機能低下や認知症のリスク の低減において、通常のケアあるいは介入なしよりも 効果的か。   15 https://gradepro.org/ 16 http://www.who.int/mental_health/mhgap/evidence/mhgap_guideline_process_2009.pdf 検索方法 (dementia OR cognit* OR “mild cognit ive impairment” OR “Alzheimer disease” OR “dementia vascular” OR “dementia multi-infarct” OR MCI OR “cognitive dysfunction” OR neuropsychologi* OR “Health-Related Quality” Of Life OR “life quality” OR “Activities Daily Living” OR “Chronic Limitation of Activity” OR “Limitation of Activity, Chronic” OR ADL OR “activities of daily living” OR “Drug-Related Side Effects and Adverse Reactions” OR “Adverse Drug Event” OR “Adverse Drug Reaction” OR “Long Term Adverse Effects” OR “Adverse Effects, Long Term Disease-Free Survival” OR “Event-Free Survival” OR “Adverse effects”) AND (Exercise OR “exercise therapy” OR “Acute Exercise” OR “Aerobic Exercise” OR “Exercise Training” OR “Exercise, Aerobic” OR “Exercise, Isometric” OR “Exercise, Physical” OR “Isometric Exercise OR Physical Activity” OR “resistance training”)   PICO 2 喫煙している認知機能正常または軽度認知障害の成人 にとって、禁煙介入は、認知機能低下や認知症のリスク の低減において、通常のケアあるいは介入なしよりも効 果的か。   検索方法 (d e m e n t i a OR co g n i t * OR m i l d co g n i t i ve impairment OR Alzheimer disease OR dementia vascular OR dementia multi-infarct OR MCI OR cognitive dysfunction OR neuropsychologi* OR Health-Related Quality Of Life OR life quality OR Activities, Daily Living OR Chronic Limitation of Activity OR Limitation of Activity, Chronic OR ADL OR activities of daily living OR Drug-Related Side Effects and Adverse Reactions OR Adverse Drug 75 認知機能低下および認知症のリスク低減 WHOガイドライン Event OR Adverse Drug Reaction OR Long Term Adverse Effects OR Adverse Effects, Long Term Disease-Free Survival OR Event-Free Survival OR Adverse effects) AND (Tobacco OR smoking OR Tobacco use cessation OR giving up smoking OR quitting smoking OR stopping smoking OR smoking cessation OR smoking reduction OR tobacco use cessation products OR varenicline OR nicotinic agonists OR Nicotine Inhalant OR Nicotine Lozenge OR Nicotine Lozenges OR Nicotine Nasal Spray OR Nicotine Patch OR Nicotine Polacrilex OR Nicotine Replacement Products OR Nicotine Transdermal Patch OR Smoking Cessation Products) AND (Behavior OR behaviour OR drug therapy OR pharmacologic therapy OR pharmacotherapy OR Cognitive behavioural therapy OR Cognitive behavioural therapy OR Drug therapy OR cognitive therapy OR online therapy OR treatment)   PICO 3 3a. 認知機能正常または軽度認知障害の成人にとって、 栄養補助食品などの栄養的介入は、認知機能低下や認知 症のリスクの低減において、通常のケアあるいは介入な しよりも効果的か。 3b. 認知機能正常または軽度認知障害の成人にとって、 健康的な食事パターン（地中海食など）のような栄養的 介入は、認知機能低下や認知症のリスクの低減において、 通常のケアあるいは介入なしよりも効果的か。   検索方法 (dementia OR cognit* OR “mild cognit ive i m p a i r m e n t ” OR “A l z h e i m e r d i s e a s e ” OR Alzheimer* OR “dementia vascular” OR “dementia multi-infarct” OR MCI OR “cognitive dysfunction” OR neuropsychologi* OR “Health-Related Quality Of Life” OR “life quality” OR“quality of life” OR “Activities of Daily Living” OR “Chronic Limitation of Activity” OR “Limitation of Activity, Chronic” OR ADL OR “activities of daily living” OR “Drug-Related Side Effects and Adverse Reactions” OR “Adverse Drug Event” OR “Adverse Drug Reaction” OR “Long Term Adverse Effects” OR “Adverse Effects, Long Term” OR “Disease-Free Survival” OR “Event-Free Survival” OR “Adverse effects”) AND (“Dietary supple-ments” OR “Dietary Supplementations” OR “Food Supplementations” OR “Food Supplements” OR “Herbal Supplements” OR Neutraceuticals OR Nutraceuticals OR Nutriceuticals OR diet or vitamin or food)   PICO 4 アルコール使用障害のある認知機能正常または軽度認 知障害の成人にとって、アルコール使用障害治療ための 行動・心理的介入は、認知機能低下や認知症のリスクの 低減において、通常のケアあるいは介入なしよりも効果 的か。   検索方法 (d e m e n t i a OR co g n i t * OR m i l d co g n i t i ve impairment OR Alzheimer disease OR dementia vascular OR dementia multi-infarct OR MCI OR cognitive dysfunction OR neuropsychologi* OR Health-Related Quality Of Life OR life quality OR Activities, Daily Living OR Chronic Limitation of Activity OR Limitation of Activity, Chronic OR ADL OR activities of daily living OR Drug-Related Side Effects and Adverse Reactions OR Adverse Drug Event OR Adverse Drug Reaction OR Long Term Adverse Effects OR Adverse Effects, Long Term Disease-Free Survival OR Event-Free Survival OR Adverse effects) AND (Alcohol drinking OR Binge drinking OR Drunkenness OR alcohol intoxication OR alcoholism OR alcohol withdrawal) AND (Add in Behavior OR behaviour OR drug therapy OR pharmacologic therapy OR pharmacotherapy OR Cognitive behavioural therapy OR Cognitive behavioural therapy OR Drug therapy OR cognitive therapy OR online therapy OR treatment)   補遺4:エビデンス評価の方法論 76 PICO 5 認知機能正常または軽度認知障害の成人にとって、認知 刺激または認知トレーニングは、認知機能低下や認知症 のリスクの低減において、通常のケアあるいは介入なし よりも効果的か。 検索方法 (systemati* or meta analys*) and (dementia or cognit* or MCI or neuropsycholog* or Alzheimer*) and ("Brain training" OR "cognitive training" OR "Brain fitness" OR Games OR "Memory training" OR (Stimulation AND cognit*)   PICO 6 認知機能や正常または軽度認知障害の成人にとって、高 レベルの社会活動の維持や奨励することは、認知機能低 下や認知症のリスクの低減において、通常のケアあるい は介入なしよりも効果的か。   検索方法 ("social interaction" or "social Networks" or "social processes" or "social behaviour" or "social behavior" or "community networks" or "social media" or family) and (dementia or cognit* or "mild cognitive impairment" or MCI or "cognitive dysfunction" or neuropsycholog* or Alzheime*) and (systemati* or meta-analys*)   PICO 7 過体重あるいは肥満のある認知機能正常または軽度認知 障害の成人にとって、減量介入（または肥満管理）は、 認知機能低下や認知症のリスクの低減において、通常の ケアあるいは介入なしよりも効果的か。   検索方法 (dementia OR cognit* OR mild cognitive impairment OR Alzheimer disease OR dementia vascular OR dementia multi-infarct OR MCI OR cognitive dysfunction OR neuropsychologi* OR Health- Related Quality Of Life OR life quality OR Activities, Daily Living OR Chronic Limitation of Activity OR Limitation of Activity, Chronic OR ADL OR activities of daily living OR Drug-Related Side Effects and Adverse Reactions OR Adverse Drug Event OR Adverse Drug Reaction OR Long Term Adverse Effects OR Adverse Effects, Long Term Disease-Free Survival OR Event-Free Survival OR Adverse effects) AND (Overweight OR Body weight or Body mass index OR weight loss OR Body weight changes) AND (Behavior OR behaviour OR drug therapy OR pharmacologic therapy OR pharmacotherapy OR Cognitive behavioural therapy OR Cognitive behavioural therapy OR Drug therapy OR cognitive therapy OR online therapy OR treatment OR Appetite depressants) PICO 8 高血圧のある認知機能正常または軽度認知障害の成人に とって、高血圧治療は、認知機能低下や認知症のリスク の低減において、プラセボあるいは介入なしよりも効果 的か。   検索方法 (systemati* or meta-analys*) and (dementia or cognit* or "mild cognitive impairment" or MCI or "cognitive dysfunction" or neuropsycholog* or Alzheimer's or Alzheimer) and (behaviour or behavior or "drug therapy" or "pharmacologic therapy" or pharmacotherapy or "cognitive behavioural therapy" or "cognitive behavioral therapy" or "cognitive therapy" or "online therapy" or "anti-hypertensive" or antihypertensive or treatment) and (hypertension or "blood pressure" or systolic or diastolic or prehypertension) 77 認知機能低下および認知症のリスク低減 WHOガイドライン   PICO 9 糖尿病のある認知機能正常または軽度認知障害の成人に とって、糖尿病治療は、認知機能低下や認知症のリスク の低減において、プラセボあるいは介入なしよりも効果 的か。   検索方法 (systemati* or meta-analys*) and (dementia or cognit* or "mild cognitive impairment" or MCI or "cognitive dysfunction" or neuropsycholog* o r A l z h e i m e * ) . a b . a n d d i a b e t e s . a f . a n d ("hypoglycemic agents" or treatment or therapy or pharmacotherapy or behaviour or behavior)   PICO 10 脂質異常症のある認知機能正常または軽度認知障害の成 人にとって、脂質異常症治療は、認知機能低下や認知症 のリスクの低減において、プラセボあるいは介入なしよ りも効果的か。   検索方法 (d e m e n t i a OR co g n i t * OR m i l d co g n i t i ve impairment OR Alzheimer disease OR dementia vascular OR dementia multi-infarct OR MCI OR cognitive dysfunction OR neuropsychologi* OR Health-Related Quality Of Life OR life quality OR Activities, Daily Living OR Chronic Limitation of Activity OR Limitation of Activity, Chronic OR ADL OR activities of daily living OR Drug-Related Side Effects and Adverse Reactions OR Adverse Drug Event OR Adverse Drug Reaction OR Long Term Adverse Effects OR Adverse Effects, Long Term Disease-Free Survival OR Event-Free Survival OR Adverse effects) AND (Cholesterol OR Hypercholes- terolemia OR lipo-proteins OR HDL cholesterol OR LDL cholesterol OR triglycerides) AND (Behavior OR behaviour OR drug therapy OR pharmalogic therapy OR pharmacotherapy OR Cognitive behavioural therapy OR Cognitive behavioural therapy OR Drug therapy OR cognitive therapy OR online therapy OR treatment OR statins OR Hydroxymethylglutaryl-CoA Reductase Inhibitors OR Anticholesteremic agents)   PICO 11 うつ病性障害のある認知機能正常または軽度認知障害の 成人にとって、うつ病の治療は、認知機能低下や認知症 のリスクの低減において、通常のケア、プラセボあるい は介入なしよりも効果的か。   検索方法 (depression or depressive) and (systemati* or meta-analys*) and (dementia or cognit* or "mild cognit ive impairment" or MCI or "cognitive dysfunction" or neuropsycholog* or Alzheimer's or Alzheimer*) and (treatment or therapy or pharmacotherapy or antidepressan* or antidepressiv*)   PICO 12 難聴のある認知機能正常または軽度認知障害の成人に とって、難聴の治療は、認知機能低下や認知症のリスク の低減において、通常のケアあるいは介入なしよりも効 果的か。   検索方法 (hearing aids OR Cochlear implants Or hearing implants) AND (hearing loss OR deafness OR hearing impairment OR hypoacusis OR intervention OR treatment) AND (dementia OR cognit* OR mild cognitive impairment OR Alzheimer's disease OR dementia vascular OR dementia multi- infarct OR MCI OR cognitive dysfunction OR neuropsycholog*) 用 語 解 説 用語解説 78 有害事象〔Adverse event〕 ヘルスケアマネジメントによって患者や臨床研究課題 に生じる望ましくない医学的事態。 有酸素運動〔Aerobic exercise〕 嫌気的代謝を介してエネルギー需要に丁度見合う程度 の酸素を必要とするタイプの身体運動。有酸素運動の最 中に酸素は脂肪とグルコースを燃焼するために消費さ れ、その結果、すべて細胞においてエネルギー伝搬に働 くアデノシン３リン酸〔ATP〕が産生される。このタイ プの運動は血液中の酸素の運搬を改善することによって 身体の健康状態を改善し、呼吸数を増加する。嫌気的代 謝によって十分に保たれる強度で実施された場合には、 長時間にわたって継続することが可能なあらゆるタイプ の運動を含む。 行動活性化〔Behavioural activation〕 うつ病患者において生活の中でやりがいのある活動の 頻度を増やすように誘導する、うつ病の行動療法。 BMI；ボディ ・ーマス・インデックス〔Body mass index〕 体重（Kg）を体表面積（m2）で除して計算した客観 的指標であり、一般的に Kg/m2 を単位として表記され る。BMI は個人において筋、骨、脂肪などの組織量の おおよその指標として用いられている。糖尿や動脈硬化 症などの一定の疾病リスクの程度と BMI が相関するこ とから、BMI 値は体重過少、適性体重、体重過多、肥 満に分類される。肥満はさらに中等度、重度、病的に分 類される。 認知行動介入 /療法 〔Cognitive behavioural intervention / therapy〕 症状の緩和と機能改善を促すための思考訓練と実体験 を通じて、歪のある誤った観念を同定し是正することに よる心理療法の一種。 認知機能低下〔Cognitive decline〕 記憶、注意、学習機能などの脳機能の心理学的欠陥で あり、正常加齢プロセスに伴うものがある。加齢により ある程度の認知機能の低下を伴うという点において、そ の程度は様々であるが認知機能障害とは異なる。反対に 認知機能障害は通常、外傷、疾患などの病的イベントの 結果または認知機能低下の進行した状態である。 認知機能〔Cognitive function〕 推論、記憶、注意、言語など情報や知識の獲得に役立 つ脳活動。 認知刺激〔Cognitive stimulation〕 認知的、社会的機能を向上させる目的の一連の活動へ の参加。 認知トレーニング〔Cognitive training〕 特定の認知機能を向上させるための標準化された特殊 なタスクを指示に基づいて行う訓練。 認知症〔Dementia〕 認知症は、日常生活動作や社会活動に支障をきたす程 度の、以前に獲得された認知レベルからの低下によって 特徴づけられる症候群である。 栄養補助食品〔Dietary supplements〕 栄養補助食品は、ビタミン、微量元素、食物線維、脂 肪酸、アミノ酸、そのほかの物質を含む。これらは、栄 養素の消費を促すために栄養を提供するか、あるいは生 物学的に益となる効果があるとされる非栄養化学物質を 提供するかのいずれかである。 健康に関連した生活の質 〔Health-related quality of life〕 個人または集団で感知される経時的な身体的、または 精神的健康状態。多面的な概念として身体、精神、感情、 社会的機能に関連する多領域を含んでおり、健康状態の 影響を評価する手段である。 地中海食〔Mediterranean diet〕 シリアル、果物、魚、野菜を豊富に摂り、肉類や乳製 品を制限する食事。 軽度認知障害〔Mild cognitive impairment〕 記憶障害、学習困難、短期間でないタスクに集中でき ない、などによって特徴づけられる障害。精神的タスク を行おうとする時にしばしば顕著な精神的疲労があり、 客観的には遂行できていたとしても新たなことを覚える ことに困難を感じる。これらの症状はいずれも、認知症 やせん妄の診断に当てはまる程には顕著ではない。 79 認知機能低下および認知症のリスク低減 WHOガイドライン 動機づけ面接〔Motivational interviewing〕 物質使用障害患者に対して用いられる、エビデンスに 基づき確立した訓練。アンビバレンス（両価感情）を調 べて解決したり、個人のなかの変化を促す動機づけに集 中したりする。 複数領域への介入〔Multidomain intervention〕 相互に関連がある、あるいは独立した一定の危険因子 に並行して介入することにより、特定の病気や病態を予 防あるいは是正することを意図するような介入方法。 ニコチン代替療法〔Nicotine replacement therapy〕 少量かつ一定量のニコチンを含む特殊な製品を用いる 治療方の一種。禁煙を目的とする時に渇望感や離脱症状 を緩和するのに用いる。これらの製品にはニコチンガム、 ニコチン吸入器、ニコチンスプレー、ニコチロゼンジン、 ニコチンパッチなどがある。タバコに含まれるほかの化 学物質は含んでいない。 身体活動〔Physical activity〕 エネルギー消費を必要とする骨格筋による身体運動で あり、労働、遊び、家事、旅行、レクリエーション活動 への従事などに際して行われる動作を含む。 身体運動〔Physical exercise〕 計画・構造化され反復する運動の一種であり、身体活 動の少なくとも一つ以上の要素を改善または維持するこ とを目的としている。 問題解決療法〔Problem-solving therapy〕 心理療法の一つで、患者は系統的に抱えている問題を 認識し、それぞれの問題に対して代替する解決法を導き 出して最善の解決法を選択し、計画を立てて実行してこ れらの行動が問題を解決したか否か評価を行う。 生活の質〔Quality of life〕 生活している文化や価値システムの文脈の中におい て、あるいは目標、予想、標準、懸念などとの関係性か ら、生活状態に対する個人の認識 筋力トレーニング〔Resistance training〕 身体運動の一種で、高い負荷や一定の抵抗に抵抗して 四肢を動かすことで骨格筋の収縮を誘発し、筋肉の強度、 嫌気的な耐久性、筋量を増強する。外からの抵抗として は、ダンベル、ゴム製運動用チューブ、自己の体重、ブロッ ク、水のボトル、この目的に設計された機械、そのほか、 筋を収縮させるものなどが代表的である。抵抗力は実質 的な休息期を生じずに、比較的低頻度の反復が可能なも のであることが必要である。一部に有酸素運動の良い点 がでるようなサーキットトレーニングの改変が提案され ているが、基本的に抵抗トレーニングや筋力トレーニン グは有酸素運動である。 社会活動〔Social activity〕 社会活動は多様であり定義が難しい。しかし、友人と 会う、イベントや行事に参加する、ボランティア、仕事 やグループでのレクリエーション活動に参加するなどが 含まれる。 事務局・編集　株式会社日本総合研究所 〒 141-0022 東京都品川区東五反田 2-18-1 大崎フォレストビルディング TEL：03-6833-5726　　FAX：03-6833-9480 ※ 本冊子は、令和元年度厚生労働省老人保健事業推進費等補助金（老人保健健康 増進等事業分）により作成されたものです。