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Evidence-Based Prevention of Alzheimer's Disease: Systematic Review and Meta-Analysis of 243 Observational Prospective Studies and 153 Randomized Controlled Trials

38 Pages Posted: 20 Jun 2019

See all articles by Jin-Tai Yu

Jin-Tai Yu

Qingdao University - Department of Neurology; Qingdao University - Clinical Research Center

Wei Xu

Qingdao University - Department of Neurology

Chen-Chen Tan

Qingdao University - Department of Neurology

Sandrine Andrieu

University of Angers - French Institute of Health and Medical Research (INSERM)

John Suckling

University of Cambridge, Addenbrookes Hospital, Department of Psychiatry

Evangelos Evangelou

University of Ioannina - Department of Hygiene and Epidemiology; Imperial College London - Department of Epidemiology and Biostatistics

An Pan

Huazhong University of Science and Technology - Department of Occupational and Environmental Health

Can Zhang

Harvard University - Genetics and Aging Research Unit

Jian-Ping Jia

Capital Medical University - Department of Neurology

Lei Feng

National University of Singapore (NUS) - Yong Loo Lin School of Medicine

Kua Ee Heok

National University of Singapore (NUS) - Yong Loo Lin School of Medicine

Yan-Jiang Wang

Third Military Medical University, Daping Hospital, Institute of Surgery Research, Department of Neurology

Hui-Fu Wang

Qingdao University - Department of Neurology

Meng-Shan Tan

Qingdao University - Department of Neurology

Jie-Qiong Li

Qingdao University - Department of Neurology

Xiao-He Hou

Qingdao University - Department of Neurology

Yu Wan

Qingdao University - Department of Neurology

Lin Tan

Qingdao University - Department of Neurology

Vincent Mok

The Chinese University of Hong Kong (CUHK), Faculty of Medicine, Gerald Choa Neuroscience Centre

Lan Tan

Qingdao University - Department of Neurology

Jacques Touchon

Université Montpellier I

Serge Gauthier

McGill University

Paul S. Aisen

University of Southern California

Bruno Vellas

Université de Toulouse - WHO Collaborating Center for Frailty, Clinical and Geroscience Research, and Geriatric Training

More...

Abstract

Background: Evidence on preventing Alzheimer's disease (AD) is challenging to interpret due to varying study designs with heterogeneous endpoints and credibility. We completed a systematic review and meta-analysis of current evidence with prospective designs to propose clinical recommendations on AD prevention.

Methods: Electronic databases and relevant websites were searched from inception to March 1, 2019. Both observational prospective studies (OPSs) and randomized controlled trials (RCTs) were included. The multivariable-adjusted effect estimates were pooled by random-effects models, with credibility assessment according to its risk of bias, inconsistency, and imprecision. Levels of evidence and classes of recommendations were summarized.

Findings: A total of 44,676 reports were identified, and 243 OPSs and 153 RCTs were eligible for analysis after exclusion based on pre-decided criteria, among which 104 modifiable factors and 11 interventions were included for the meta-analyses. In the OPSs, 26 risk factors and 8 protective factors were found to significantly modify AD risk by an effect size of over 25%, amongst which eight factors were rated at a moderate-to-high level of evidence. Among the interventions tested in RCTs, physical exercise and the homocysteine lowering treatment were the most promising interventions to reduce AD risk. Finally, 21 recommendations are proposed based on the consolidated evidence, with 'Class I' recommendations targeting 19 factors: ten are with 'Level A' strong evidence (cognitive activity, hyperhomocysteinemia, high BMI in late-life, depression, stress, diabetes, head trauma, hypertension in midlife, orthostatic hypotension, and education) and nine with 'Level B' weaker evidence (obesity in midlife, weight loss in late-life, physical exercise, smoking, sleep, CVD, frailty, atrial fibrillation, and Vitamin C). In contrast, two interventions are not recommended: estrogen replacement therapy (Level A2) and acetylcholinesterase inhibitors (Level B).

Interpretation: Our study mapped the current evidence profile and assessed the findings in order to guide future research directions for AD prevention. Evidence-based recommendations are proposed, offering clinicians and stakeholders current guidance for the prevention of AD.

Funding Statement: The authors stated: "There was no direct funding source for this study."

Declaration of Interest: JTY serves as an associate editor-in-chief for Annals of Translational Medicine, is senior editor for Journal of Alzheimer's Disease. SA has received grants from Europe, Ipsen, and France Alzheimer, served as a consultant for Ipsen, Pierre Fabre, Lilly, Nestlé, Sanof, and Servier, and received non-financial support from Biogen, Nutrition Santé, Pfzer, and Icon, and other support from the AMPA Association. SG has received clinical trial support from Lilly and Roche in DIAN-TU, TauRx Therapeutics (TauRx), and Lundbeck; has been a data safety monitoring board (DSMB) member of ADCS, ATRI, API, and Eisai; and has been a scientific adviser to Affiris, BoehringerIngelheim, Lilly, Roche, Servier, Sanofi, Schwabe, Takeda, and TauRx. PSA has received grants from the US Alzheimer’s Association, Janssen, Lilly, the US National Institute on Aging, and Toyama; and consulting fees from Abbott, Abbvie, Amgen, Anavex, AstraZeneca, Biogen Idec, Biotie, Bristol-Myers Squibb, Cardeus, Cohbar, Eisai, Elan, Eli Lilly, Genentech, Ichor, iPerian, Janssen, Lundbeck, Medivation, Merck, NeuroPhage, Novartis, Pfizer, Probiodrug, Roche, Somaxon, and Toyama, outside the submitted work. BV reports grants from Pierre Fabre, Avid, Exonhit, AbbVie, Lilly, Lundbeck, MSD, Otsuka, Regenron, Sanof, Roche, AstraZeneca, LPG Systems, Nestlé, and Alzheon, and personal fees from Lilly, Lundbeck, MSD, Otsuka, Roche, Sanof, Biogen, Nestlé, Transition Therapeutics, and Takeda. All other authors declare no competing interests.

Ethics Approval Statement: The authors followed the recommendations by the Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) 2009 guidelines.

Keywords: Alzheimer's disease; Prevention; Risk factors; Recommendation; Meta; Systematic review

Suggested Citation

Yu, Jin-Tai and Xu, Wei and Tan, Chen-Chen and Andrieu, Sandrine and Suckling, John and Evangelou, Evangelos and Pan, An and Zhang, Can and Jia, Jian-Ping and Feng, Lei and Heok, Kua Ee and Wang, Yan-Jiang and Wang, Hui-Fu and Tan, Meng-Shan and Li, Jie-Qiong and Hou, Xiao-He and Wan, Yu and Tan, Lin and Mok, Vincent and Tan, Lan and Touchon, Jacques and Gauthier, Serge and Aisen, Paul S. and Vellas, Bruno, Evidence-Based Prevention of Alzheimer's Disease: Systematic Review and Meta-Analysis of 243 Observational Prospective Studies and 153 Randomized Controlled Trials (June 17, 2019). Available at SSRN: https://ssrn.com/abstract=3405594 or http://dx.doi.org/10.2139/ssrn.3405594

Jin-Tai Yu (Contact Author)

Qingdao University - Department of Neurology ( email )

Qingdao
China

Qingdao University - Clinical Research Center ( email )

Qingdao
China

Wei Xu

Qingdao University - Department of Neurology ( email )

Qingdao
China

Chen-Chen Tan

Qingdao University - Department of Neurology

Qingdao
China

Sandrine Andrieu

University of Angers - French Institute of Health and Medical Research (INSERM)

101 rue de Tolbiac
75654 Paris Cedex 13
France

John Suckling

University of Cambridge, Addenbrookes Hospital, Department of Psychiatry

United Kingdom

Evangelos Evangelou

University of Ioannina - Department of Hygiene and Epidemiology

Ioannina
Greece

Imperial College London - Department of Epidemiology and Biostatistics

St Mary's Campus
Norfolk Pl, Paddington
London, W2 1QN
United Kingdom

An Pan

Huazhong University of Science and Technology - Department of Occupational and Environmental Health

1037 Luoyu Rd
Wuhan
China

Can Zhang

Harvard University - Genetics and Aging Research Unit

Charlestown, MA
United States

Jian-Ping Jia

Capital Medical University - Department of Neurology

Fengtai
China

Lei Feng

National University of Singapore (NUS) - Yong Loo Lin School of Medicine

Singapore

Kua Ee Heok

National University of Singapore (NUS) - Yong Loo Lin School of Medicine

Singapore

Yan-Jiang Wang

Third Military Medical University, Daping Hospital, Institute of Surgery Research, Department of Neurology

China

Hui-Fu Wang

Qingdao University - Department of Neurology

Qingdao
China

Meng-Shan Tan

Qingdao University - Department of Neurology

Qingdao
China

Jie-Qiong Li

Qingdao University - Department of Neurology

Qingdao
China

Xiao-He Hou

Qingdao University - Department of Neurology

Qingdao
China

Yu Wan

Qingdao University - Department of Neurology

Qingdao
China

Lin Tan

Qingdao University - Department of Neurology

Qingdao
China

Vincent Mok

The Chinese University of Hong Kong (CUHK), Faculty of Medicine, Gerald Choa Neuroscience Centre

China

Lan Tan

Qingdao University - Department of Neurology

Qingdao
China

Jacques Touchon

Université Montpellier I

Avenue de la Mer Site Richter
163 Rue Auguste Broussonnet
Montpellier, Cedex 2 34090
France

Serge Gauthier

McGill University

1001 Sherbrooke St. W
Montreal, Quebec H3A 1G5
Canada

Paul S. Aisen

University of Southern California

2250 Alcazar Street
Los Angeles, CA 90089
United States

Bruno Vellas

Université de Toulouse - WHO Collaborating Center for Frailty, Clinical and Geroscience Research, and Geriatric Training

Toulouse
France

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