Evidence-based prevention of Alzheimer's disease: systematic review and meta-analysis of 243 observational prospective studies and 153 randomised controlled trials

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 evidence-based suggestions on AD prevention.

Methods: Electronic databases and relevant websites were searched from inception to 1 March 2019. Both observational prospective studies (OPSs) and randomised 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 suggestions were summarised.

Results: 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, from which 104 modifiable factors and 11 interventions were included in the meta-analyses. Twenty-one suggestions are proposed based on the consolidated evidence, with Class I suggestions targeting 19 factors: 10 with Level A strong evidence (education, cognitive activity, high body mass index in latelife, hyperhomocysteinaemia, depression, stress, diabetes, head trauma, hypertension in midlife and orthostatic hypotension) and 9 with Level B weaker evidence (obesity in midlife, weight loss in late life, physical exercise, smoking, sleep, cerebrovascular disease, frailty, atrial fibrillation and vitamin C). In contrast, two interventions are not recommended: oestrogen replacement therapy (Level A2) and acetylcholinesterase inhibitors (Level B).

Interpretation: Evidence-based suggestions are proposed, offering clinicians and stakeholders current guidance for the prevention of AD.

Keywords: alzheimer's disease; epidemiology; meta-analysis; systematic reviews.

Figure 1

Flow chart showing literature selection for OPSs (figure 1A) and RCTs (figure 1B) and map depicting studies eligible for systematic review (figure 1C). A total of 243 OPSs (figure 1A) and 153 completed RCTs (figure 1B) were finally included. 243 OPSs from 17 countries on four continents (Europe accounting for 43%, North America 41%, Asia 14% and Latin America 2%) reported the association of 134 modifiable risk factors with risk of clinical Alzheimer’s-type dementia (83% used all AD, 13% probable AD and 11% pure AD) diagnosed by NINCDS-ADRDA criteria in populations with various racial backgrounds (68% white, 14% Asian descent, 13% mixed race), sources (84% community, 6% institution, 10% mixed source) and baseline cognitive statuses (82% free of dementia, 16% cognitively normal, 2% unclear). A total of 153 published RCTs from five continents (North America accounting for 45%, Europe 36%, Australia 9%, Asia 7% and Latin America 3%) reported the effects of 15 types of interventions on AD (7%), dementia (16%) and cognitive function (85%) in selected participants, including elderly subjects (37%), high-risk group (35%) or cognitively impaired (28%) (figure 1C). In the pie charts, 1 and 2 show the outcome (all AD=probable or possible AD, or AD with or without VD/CVD, Pure AD=AD without VD or CVD; A=Alzheimer’s disease, B=Biomarker of AD, C=Cognition, D=Dementia); 3 and 4 show the population source; 5 and 6 show the percentage of studies from different continents. AD, Alzheimer’s disease; CVD, cerebrovascular disease; OPS, observational prospective study; RCT, randomised controlled trial; VD, vascular dementia.

Figure 2

Rating levels of evidence and strength of suggestions. Based on the Cochrane Handbook for Systematic Reviews of Interventions for RCTs and the Newcastle–Ottawa Quality Assessment Scale (NOS) for OPSs, we evaluated the quality of eligible studies. The credibility of each result was then categorised into four levels: Good (G level), Acceptable (A± level), Susceptible (S± level) and Poor (P level) according to the score combination of three domains: risk of bias, inconsistency and imprecision. Levels of evidence were summarised, representing the quality of scientific evidence on the basis of directness of outcome (for RCTs), consistency and quality of data from clinical trials and/or observational studies. Classes of suggestions were made after weighing the benefits against the risks due to specific interventions. *Factors rated with ‘level C’ evidence were not considered for recommendation in the present study.

Figure 3

Risk of bias profile, meta-analysis results, sample size (figure 3A), credibility rating (figure 3B) and summary (figure 3C) for 43 significant modifiable risk factors based on observational prospective studies. When the mean score (for each bias domain) ≤0.5 was regarded as possibly moderate-to-high risk, analyses for 79% of factors had problems of generalisability, 60% for high attrition, 48% for insufficient follow-up, 40% for reverse causality, 8% for confounding bias and 6% for assessment of exposure. For a summary of the effect, a total of 43 factors showed significant associations with AD risk; 26 risk factors and eight protective factors were identified that modify the risk by at least 25% (figure 3A). For credibility of the pooled results, 11 factors were rated at a moderate-to-high level (G, G/A+ or A+ level), 20 were rated at a low-to-moderate level (A+/A− or A− level) and 12 were rated at a very low level (S+, S− or P level) (figure 3B). With good performance in all the domains above, eight risk factors are highlighted (figure 3C). AD, Alzheimer’s disease; BMD, bone mineral density; BMI, body mass index; CVD, cerebrovascular disease; DBP, diastolic blood pressure; HSV, herpes simplex virus; IMT, intima-media thickness; NSAIDs, non-steroidal anti-inflammatory drugs; SHBG, sex hormone binding globulin.

Figure 4

Risk of bias profile, meta-analysis results, sample size (figure 4A), credibility rating (figure 4B) and summary (figure 4C) for 11 interventions based on randomised controlled trials. When the mean score (for each bias domain) ≤0.5 was regarded as possibly moderate-to-high risk, 17.2% meta-analyses had problems of inadequate concealment of allocations, 27.6% for performance bias, 3.4% for detection bias, 24.1% for incomplete outcome data, 13.8% for selective outcome reporting and 31% for other sources of bias. For the significance of the pooled results, six meta-analyses showed significant associations (figure 4A). For credibility of the pooled results, nine meta-analyses were rated at a moderate-to-high level (G, G/A+ or A+ level), three at a low-to-moderate level (A+/A− or A− level) and 17 at a very low level (S+, S− or P level). Specifically, moderate-to-high credibility of results showed little benefit on the risk of Alzheimer's disease from acetycholinesterase inhibitors, antihypertensive agents in late life, oestrogen therapy, and DHA+EPA supplementation. No robust conclusion could be reached for non-steroidal anti-inflammatory drugs, ginkgo biloba, cocoa flavanol and cognitive training. For directness of outcomes, five meta-analyses examined the associations with AD (figure 4B). Although none showed a good performance in all the above domains, two interventions (physical exercise and total homocysteine-lowering treatment) seem more promising than others (figure 4C).

Figure 5

Distribution of modifiable factors with Class I recommendation throughout the course of life. Class I suggestions (benefit >>risk due to intervention) risk factors include 10 factors with Level A evidence (cognitive activity, hyperhomocysteinaemia, increased BMI in late life, depression, stress, diabetes, head trauma, hypertension in midlife, orthostatic hypotension and education) and 9 factors (obesity in midlife, weight loss in late life, physical exercise, smoking, sleep, CVD, frailty, atrial fibrillation and vitamin C) with Level B evidence. The x axis represents the mean age of the total sample (solid circle) with a range of mean age (short horizontal line) for observational prospective studies included. The y axis represents the summary relative risk (RR). AD, Alzheimer’s disease; OH, orthostatic hypotension; CVD, cerebrovascular disease; IMT, intima-media thickness.