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

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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.
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.
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Yu J- T, etal. J Neurol Neurosurg Psychiatry 2020;0:1–9. doi:10.1136/jnnp-2019-321913
REVIEW
Evidence- based prevention of Alzheimer's disease:
systematic review and meta- analysis of 243
observational prospective studies and 153
randomised controlledtrials
Jin- Tai Yu ,1 Wei Xu ,2 Chen- Chen Tan,2 Sandrine Andrieu,3 John Suckling,4
Evangelos Evangelou,5 An Pan,6 Can Zhang,7 Jianping Jia,8 Lei Feng,9 Ee- Heok Kua,9
Yan- Jiang Wang,10 Hui- Fu Wang,2 Meng- Shan Tan,2 Jie- Qiong Li,2 Xiao- He Hou,2
Yu Wan,2 Lin Tan,2 Vincent Mok,11 Lan Tan,2 Qiang Dong,1 Jacques Touchon,12
Gauthier Serge,13 Paul S Aisen,14 Bruno Vellas15
Cognitive neurology
To cite: Yu J- T, Xu W, Tan
C- C, etal. J Neurol Neurosurg
Psychiatry Epub ahead of
print: [please include Day
Month Year]. doi:10.1136/
jnnp-2019-321913
Additional material is
published online only. To view
please visit the journal online
(http:// dx. doi. org/ 10. 1136/
jnnp- 2019- 321913).
For numbered affiliations see
end of article.
Correspondence to
Professor Jin- Tai Yu, Department
of Neurology and Institute of
Neurology, Huashan Hospital,
Shanghai Medical College,
Fudan University, Shanghai
200040, China; jintai_ yu@
fudan. edu. cn
J- TY, WX and C- CT contributed
equally.
Received 22 August 2019
Revised 26 February 2020
Accepted 22 April 2020
© Author(s) (or their
employer(s)) 2020. Re- use
permitted under CC BY- NC. No
commercial re- use. See rights
and permissions. Published
by BMJ.
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.
INTRODUCTION
An unequivocal downtrend in the prevalence and
incidence of dementia was recently reported and
associated with earlier population- level investment
(eg, improved education and vascular health),1–3
strengthening the necessity for primary prevention.4
The past few decades have witnessed great global
efforts in updating and upgrading the evidence
on how to prevent Alzheimer’s disease (AD),5 6
accounting for approximately two- thirds of all cases
of dementia and affecting up to 20% of individuals
older than 80 years.7 8 Nevertheless, key issues in
the field are the inconsistency among conclusions
and variable levels of credibility arising from the
wide variety of study designs.9 Two types of studies
are generally regarded as having the greatest impact
on the extant literature: (1) observational prospec-
tive studies (OPSs), which describe temporal rela-
tionships with potential causal links and often use
large samples recruited from community dwellers;
and (2) randomised controlled trials (RCTs), which
possess strong internal validity to infer causality by
testing the effects of specific interventions on the
incidence of AD. Although both approaches are
useful, the major concerns in OPSs are usually the
elusive sources of bias when interpreting the iden-
tified wide- ranging factors, and current RCTs are
often compromised by short follow- up durations,
subjective endpoints, small sample sizes and specific
recruitment criteria with uncertain generalisability.5
Considerable evidence has been generated
regarding AD through OPSs and RCTs. Because it is
almost impossible to conduct RCTs that evaluate all
risk factors of AD, a quantitative depiction of AD’s
prevention 'profile' based on these two complemen-
tary study types is urgently needed for prevention
guidelines that weigh the benefits against the risks.
Deconstructing the bias sources from OPSs will
facilitate the interpretation of credibility ratings
and also guide future research directions. In this
study we consolidated the extant evidence from
both OPSs and RCTs to formulate the levels of
evidence and classes of clinical suggestions for AD
prevention.
METHODS
Search strategy and selection criteria
We followed the recommendations of the Preferred
Reporting Items for Systematic reviews and Meta-
Analyses (PRISMA) 2009 guidelines.10 11 PubMed,
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Cognitive neurology
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.
EMBASE and CENTRAL were searched using the terms “Alzhei-
mer’s”, “Alzheimer”, “dementia”, and “risk” for OPS and
Alzheimer”, “cognitive”, “cognition”, “prevent”, and “preven-
tion” for RCT up to 1 March 2019. Bibliographies of relevant
literature and records in Clinicaltrials. gov and AlzRisk data-
base12 were hand- searched in case of omission. The inclusion
criteria were as follows: (1) an OPS exploring the association
between potentially modifiable exposures at baseline and inci-
dent AD independently diagnosed according to the National
Institute of Neurological and Communicative Disorders and
Stroke and the Alzheimer’s Disease and Related Disorders Asso-
ciation (NINCDS- ADRDA) criteria,13 or (2) a RCT targeting the
impact of addressing modifiable risk factors on the incidence
of AD or AD- related clinical endpoints (dementia or cognitive
impairment), and (3) a publication written in English to permit
easy access to the source information of all included articles. The
detailed exclusion criteria are shown in figure 1. Bibliographies
of relevant original studies and systematic reviews were hand-
searched. Literature selection was performed by three pairs of
experienced investigators (JTY, WX, CCT, HFW, MST and JQL)
and any disagreements on inclusion were resolved by consensus
and arbitration by a panel of investigators within the review
team (JTY, WX, CCT, HFW, MST, JQL and Lan Tan).
Data extraction
Pre- designed templates were used to extract the data with refer-
ence to the STROBE statement (https://www. equator- network.
org/ reporting- guidelines/ strobe/). An evidence- based profile of
AD modifiable risk factors was established for better tracing
of bias sources. The multivariable- adjusted risk estimates were
extracted. If these estimates were unavailable, we attempted to
obtain them by contacting the corresponding authors. The strin-
gently performed process comprised three independent steps: (a)
data extraction by three pairs of experienced investigators (JTY,
WX, CCT, HFW, MST and JQL); (b) independent data proof
reading by 10 researchers (JTY, WX, CCT, HFW, MST, JQL,
XHH, YW, Lin Tan and Lan Tan); and (c) addressing discrepan-
cies by consensus and arbitration.
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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.
Assessment of study quality and credibility of meta-analyses
The risk of bias tool proposed by Cochrane14 for RCTs and
involving the Newcastle–Ottawa Quality Assessment Scale
(NOS)15 for OPSs were used to evaluate the quality of eligible
studies. The total score for the Cochrane tool or NOS was
regarded as a proxy to assess the overall risk of bias for each
single study. The score for each item evaluated the associated
risk of bias (online supplementary appendix 1). The credibility
of each meta- analysis 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,16 inconsistency17 and imprecision18 (online
supplementary appendix 2). In particular, G and A+ levels were
regarded as moderate- to- high credibility.
Levels of evidence and strength of suggestions
Levels of evidence were summarised to represent the quality
of scientific evidence on the basis of directness of outcome for
AD, credibility of meta- analyses and consistency of evidence
from clinical trials and/or observational studies: Level A>Level
B>Level C (based on the evidence level). Classes of recommen-
dations were made after weighing the benefits against the risks
due to specific interventions: Class I (strong recommendation),
Class II (weak recommendation) and Class III (not recom-
mended) (figure 2).
Statistical analyses
The multivariable- adjusted risk estimates and 95% confi-
dence intervals (CI) were log- transformed and combined using
random models (DerSimonian–Laird method).19 Sensitivity anal-
yses excluding odd ratios (ORs) reported by some OPSs were
performed because ORs tend to overestimate the effect size
compared with the relative risk (RR), particularly when the inci-
dence is not small. A 95% prediction interval (PI) was calculated
to better evaluate the precision of the result.20 Heterogeneity
was assessed by Q test and quantified by the I2 metric.21 The
source of heterogeneity was explored via sensitivity analyses,
meta- regression and subgroup analyses. The robustness of the
results was examined by excluding those rated as at a higher risk
of bias. Publication bias was assessed following two steps: (1)
testing the symmetry of the funnel plot by the Egger method22;
and (2) determining whether any asymmetry was due to publi-
cation bias via enhanced- contour funnel plots after the trim-
and- fill method.23 The meta- regression and publication bias test
were conducted only when at least 10 studies were available.
The “metagen”, “metabias” and “trimfill” packages in R 3.4.3
software (https://www. r- project. org) were used to perform all
the analyses.
Additionally, multiple subgroup and sensitivity analyses were
conducted to take into account the following cases where results
might be biased. First, 82% of studies recruited people without
dementia at baseline and only 17% specifically constrained the
population to those with normal cognition. Notably, inclusion of
individuals with mild cognitive impairment, who might be at a
prodromal stage of AD, resulted in a degree of misclassification
bias, especially when the population was at an advanced age and
was insufficiently followed. Thus, subgroup analyses according
to the cognitive status at baseline (free of dementia vs cogni-
tively normal), sufficiency of follow- up (online supplementary
appendix 1) and life stage were performed. Second, it was often
clinically difficult to distinguish mixed AD (coexistence of AD
and vascular dementia (VD)) from VD among elderly people,
especially when the pathological evidence is often unavailable
and the individual has a history of stroke. Thus, to examine the
influence of potential misclassification bias, subgroup analyses
based on AD outcomes (all AD vs probable or pure AD (p- AD)
defined as AD without VD or cerebrovascular disease (CVD))
were performed. Third, sensitivity analyses excluding studies
with high attrition rates and poor generalisability (online supple-
mentary appendix 1) were conducted.
Patient involvement
No patients were involved in setting the research question or the
outcome measures, nor were they involved in developing plans
for design or implementation of the study. No patients were
asked to advise on interpretation or writing up of results. There
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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.
are no plans to disseminate the results of the research to study
participants or the relevant patient community. No evaluation
was undertaken to determine whether the studies included in the
review had any patient involvement.
RESULTS
Figure 1 shows the flow diagrams of the study selection process
for OPSs (figure 1A) and RCTs (figure 1B). The search yielded
33 145 and 11 531 records for OPSs and RCTs, respectively.
After integration with the AlzRisk database and Clinicaltrials.
gov website, a total of 243 OPSs and 153 completed RCTs
were finally included. Evidence- based profiles were constructed
(online supplementary appendix 3 & 4). The global distribution
of studies eligible for the systematic review and their character-
istics are shown in figure 1C. The sources of bias for the current
evidence profile mainly consisted of generalisability, attrition
and misclassification for OPSs and performance bias, incomplete
outcome data, inadequate allocation concealment and selective
outcome reporting for RCTs (online supplementary appendix
figure 1).
Meta- analyses were conducted for 134 risk factors (online
supplementary appendix 5). A total of 43 factors showed signif-
icant associations with the risk of AD, among which 80% were
identified as significantly modifying the risk by at least 25%
(figure 3A). Indicating the credibility of pooled results, anal-
yses for eight risk factors (diabetes, orthostatic hypotension,
hypertension in midlife, head trauma, stress, depression, midlife
obesity and coronary artery bypass grafting (CABG) surgery) and
three protective factors (cognitive activity, increased BMI in late
life and education) were rated with moderate- to- high level cred-
ibility (G, G/A+ or A+ level). In addition, 20 factors 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 factors were
highlighted, including depression (A+ level; RR 1.80; 95% CI
1.34 to 2.42), CABG surgery (G/A+ level; RR 1.71; 95% CI
1.04 to 2.79), diabetes mellitus (G level; RR 1.69; 95% CI 1.51
to 1.89), stress (G/A+ level; RR 1.56; 95% CI 1.19 to 2.04),
hypertension in midlife (G/A+ level; RR 1.38; 95% CI 1.29 to
1.47), head trauma (G/A+ level; RR 1.35; 95% CI 1.18 to 1.54),
cognitive activity (A+ level; RR 0.50; 95% CI 0.39 to 0.63) and
more formal schooling years (>6 to 15 years) (G level; RR 0.49;
95% CI 0.40 to 0.62) (figure 3C). Additionally, another 91 items
were found to impart no influence on the risk of AD, but mostly
with low levels of credibility, except for late- life hypertension
(G level, RR 0.96; 95% CI 0.79 to 1.17) (online supplementary
appendix figure 2).
For RCTs, 29 meta- analyses covering 11 interventions were
conducted (online supplementary appendix 6). Three interven-
tions, including total homocysteine (tHcy)- lowering treatment
(using folic acid, vitamin B12 and vitamin B6), cocoa flavanol
and physical activity showed significant associations with AD or
cognitive endpoints. For the directness of the outcomes, only
five meta- analyses (involving acetylcholinesterase inhibitor, anti-
hypertensive treatment, non- steroidal anti- inflammatory drugs
(NSAIDs), hormone replacement therapy and ginkgo biloba)
examined associations with AD (figure 4A). For the levels of cred-
ibility, nine meta- analyses were rated at a moderate- to- high level
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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).
(G, G/A+ or A+ level), three were rated at a low- to- moderate
level (A+/A− or A− level) and 17 were rated at a very low level
(S+, S− or P level) (figure 4B). The overall evaluation high-
lighted two interventions that seemed promising (figure 4C):
physical exercise (mini- mental state examination (MMSE), stan-
dardised mean difference (SMD) 0.28, 95% CI 0.07 to 0.50 and
AD assessment scale cognition, SMD 0.25, 95% CI 0.08 to 0.41)
and tHcy- lowering treatment (MMSE, SMD 0.09, 95% CI 0.02
to 0.15) (online supplementary appendix figure 3). Notably,
oestrogen therapy was associated with an increase in the risk of
dementia (G level).
The significance and the effect size minimally changed for most
factors after excluding ORs (online supplementary appendix
figure 4). No influences of publication bias on the pooled
results were identified (online supplementary appendix 5). The
sources of heterogeneity were explored. For diabetes (n=14,
I2=65%), the percentage of women explained 39% heteroge-
neity (p=0.008), which might be attributed to inclusion of two
high- risk- of- bias studies24 25 that explored associations only for
men. The mean age at baseline explained most heterogeneity for
hypertension (p=0.0003) and BMI (p=0.091, τ2=0). No influ-
ences of lowering the heterogeneity (I2 <10%) via sensitivity
analyses on the pooled results were found for current smoking,
systolic blood pressure, education and depression. The influence
of risk of bias might be low for depression while smoking and
stroke were vulnerable to sources of bias due to misclassification,
attrition and generalisability (online supplementary appendix
figure 5).
Twenty- one evidence- based suggestions with different levels
of evidence (11 with Level A and 10 with Level B) and strength
of suggestions (19 with Class I and two with Class III) are listed
in table 1. Specifically, Class I suggestions were for 19 factors,
including 10 factors with Level A evidence (cognitive activity,
hyperhomocysteinaemia, increased BMI in late life, depression,
stress, diabetes, head trauma, hypertension in midlife, ortho-
static hypotension and education) and nine factors with Level
B evidence (obesity in midlife, weight loss in late life, physical
exercise, smoking, sleep, CVD, frailty, atrial fibrillation and
vitamin C) (figure 5). Two factors were not recommended (Class
III): oestrogen replacement therapy (Level A) and acetylcholin-
esterase inhibitors (Level B) (online supplementary appendix
7 & appendix figure 6). Six factors (diastolic blood pressure
management, NSAID use, social activity, osteoporosis, pesticide
exposure and silicon from drinking water) were rated as Level
C low- strength evidence, with the recommendation that their
relationships with AD be confirmed in future studies.
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Table 1 Guideline for prevention of AD: preliminary clinical suggestions*
Factors/interventions Suggestion
Lifestyle
BMI and weight
management
Adults aged <65 years should maintain or lose weight through an appropriate balance of physical activity, caloric intake and formal behavioural programmes
when indicated to maintain/achieve a BMI between 18.5 and 24.9 kg/m2 (Class I, level B)
Adults aged >65 years should not to be too skinny (Class I, level A4)
Adults aged >65 years with a trend of weight loss should be closely monitored for their cognitive status (Class I, Level B)
Physical exercise Individuals, especially those aged ≥65 years, should stick to regular physical exercise (Class I, Level B*)
Cognitive activity Mentally stimulating activities should be encouraged, such as reading, playing chess, etc (Class I, Level A4)
Smoking People should not smoke and should avoid environmental tobacco smoke. Ccounselling, nicotine replacement and other pharmacotherapy as indicated
should be provided in conjunction with a behavioural programme or formal smoking cessation programme (Class I, Level B)
Sleep Get sufficient and good quality sleep and consult a doctor or receive treatment when you have problem with sleep (Class I, Level B)
Comorbidities
Diabetes Stay away from diabetes via a healthier lifestyle and diabetic patients should be closely monitored for their cognitive decline (Class I, Level A4)
CVD Maintain a good condition of the cerebral vessels via a healthier lifestyle or medications to avoid atherosclerosis, low cerebral perfusion and any CVD.
Individuals with stroke, especially cerebral microbleeding, should be carefully monitored for their cognitive change and take preventative measures as
indicated to protect cognition (Class I, level B)
Head trauma Protect your head from injuries (Class I, level A4)
Frailty Stay healthy and strong in late life. Those with increasing frailty should be especially monitored for their cognition (Class I, Level B)
Blood pressure Individuals aged < 65 years should avoid hypertension via a healthier lifestyle (Class I, Level A4)
Individuals with OH should be closely monitored for their cognition (Class I, Level A4)
Depression Maintain a good condition of mental health and closely keep an eye on the cognitive status for those with depressive symptoms (Class I, Level A4)
AF Maintain a good cardiovascular condition and manage AF using pharmaceuticals (Class I, level B)
Stress Relax your mind and avoid daily stress (Class I, Level A4)
Other domains
Education Receive as much education as possible in early life (Class I, level A4)
Hyperhomocysteinaemia Have a regular blood examination for homocysteine level. Individuals with hyperhomocysteinaemia should be treated with vitamin B and/or folic acid and be
followed with a focus on their cognition (Class I, Level A2)
Vitamin C Vitamin C in the diet or taken as supplements might help (Class I, Level B)
Not recommended
ERT Oestrogen replacement therapy should not be specifically used for AD prevention in postmenopausal women (Class III, Level A2)
ACI ACI should not be used for AD prevention in cognitively impaired individuals (Class III, Level B)
*The risk of bias is rated as high mainly due to lack of a blinding method and allocation concealment, which however cannot be achieved in randomised controlled trials for interventions such as
physical exercise. We therefore consider that the results are relatively more reliable than rated. Also, the content cannot be too detailed (especially for the dose and duration) for some factors and
a very good trial is needed to replicate (pivotal studies). Also, these suggestions must be presented in the context of the limitations of the studies and continuing uncertainty among investigators.
ACI, acetylcholinesterase inhibitors; AF, atrial fibrillation; BMI, body mass index; CVD, cerebrovascular disease; ERT, estrogen replacement therapy; IMT, intima- media thickness; NSAIDs, non-
steroidal anti- inflammatory drugs; OH, orthostatic hypotension.
DISCUSSION
Our systematic review and meta- analysis identified a total of 21
evidence- based suggestions that can be used in life- course prac-
tices to prevent AD. Nineteen were regarded as ‘strong sugges-
tions’, nine of which were rated with Level A evidence (table 1).
Nearly two- thirds of these suggestions target vascular risk
factors and lifestyle, strengthening the importance of keeping a
good vascular condition and maintaining a healthy lifestyle for
preventing AD.
Strengths and weaknesses of this study
This is the most comprehensive and large- scale systematic review
and meta- analysis for AD prevention to date. The evidence-
based suggestions are constructed by integrating a large amount
of evidence from both OPSs and RCTs. Sources of bias and
robustness of evidence were thoroughly assessed and secondary
analyses were used to explore their influences, guaranteeing the
objectivity and transparency of our findings. Furthermore, the
outcome of OPSs was confined to AD dementia, given that the
heterogeneity of endpoints might complicate the profile and
downgrade the credibility of the evidence because: (1) observa-
tional studies are more vulnerable to sources of bias than RCTs,
even though a rigorous procedure was employed to grade the
evidence; (2) non- AD dementia accounts for roughly 30% of
incident dementia (online supplementary appendix figure 7) and
the false positive rate for diagnosis of mild cognitive impairment
is fairly common.26 Some caveats should also be emphasised.
Observational studies cannot indicate causal relationships and
RCTs may not be generalisable beyond the specific sample, inter-
vention, dose and duration studied. Classification of the avail-
able evidence including assessment of potential biases requires
subjective judgement. The values of the current suggestions
might be confined by geographic variability, definition of expo-
sure and prevalence of risk factors at the population level. Some
important factors of all- cause dementia were inadequately inves-
tigated for AD, such as social determinants27 and frailty,28 and
more high- quality prospective studies are warranted to bridge
this gap. AD is challenging to study. The neurobiology of AD
begins at least 15 years before symptoms appear. Tools such as
amyloid and tau PET scanning are available to characterise the
neuropathology at any stage, but it is impractical to include such
assessments in large observational studies; without biomarker
data, misclassification is unavoidable and several conclusions
may be challenged by studies in the near future. Despite these
challenges, this systematic review and meta- analysis can suggest
recommendations to guide clinicians, even as the field perseveres
with additional studies. These evidence- based suggestions must
be presented in the context of the limitations of the studies and
continuing uncertainty among investigators. Finally, the present
study did not register and the protocol can be found in online
supplementary appendix 8.
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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.
Strengths and weaknesses in relation to other studies
Notably, tHcy- lowering treatment seems the most promising
intervention for AD prevention, in agreement with a recent
report.29 The Lancet Commission on dementia has recently
proposed nine potentially modifiable risk factors of all- cause
dementia. However, these suggestions might not be directly
applicable to AD, bearing in mind that the heterogeneity of
endpoints complicates the profile and reduces the credibility
of evidence for AD prevention. Our study generated more
evidence- based suggestions associated with a decreased risk of
AD, filling this gap in the field.
Meaning of the study
The hypotheses for the underlying mechanisms may include
brain reserve theory, the hypoperfusion hypothesis, one- carbon
methabolism, hypomethylation theory, inflammation and the
oxidative stress hypothesis. The combination of multiple recom-
mendations is most likely the best approach to delay the onset
of AD, as indicated by the Finnish Geriatric Intervention Study
to Prevent Cognitive Impairment and Disability (FINGER).30
On the basis of this paper, future clinical trials should focus
on exploring the best combination of recommendations with
Class I recommendation and Level A evidence to prevent AD
using larger samples, particularly in real- world settings. These
evidence- based suggestions should be particularly noted by
non- demented but high- risk individuals (eg, people with
AOPEε4, a high polygenic score, a family history of dementia or
amyloid- positive evidence31) and family doctors to give optimal
recommendations to their patients in terms of what they might
do to get the best protection against AD.
Future research
For OPSs, low participation rates (cognitive activity and stroke),
high attrition (stroke, smoking, alcohol drinking and hyperten-
sion) and follow- up insufficiency (stroke and smoking) should
be specifically highlighted in future prospective studies. Reverse
causality might bias the association with late life obesity.32 It
is unclear whether reverse causality exists for other potential
factors such as frailty, social isolation and sleep disorders. Investi-
gation and comparison of important characteristics of those who
refused to participate or were lost during follow- up might be a
good method to guarantee optimised validity. Subgroup effects
exist due to the characteristics of the sample (eg, age, gender,33
APOEε4 status34 and medication compliance34) or exposure (eg,
type, dose and duration). For RCTs, choosing the suitable popu-
lation might be the key to determining whether an intervention
can work. The optimal time window also matters,35 especially
considering that benefits were weak for those with a clinical diag-
nosis of dementia.36 Generalisablity should be further optimised,
such as recruiting larger samples from community- dwelling indi-
viduals and searching for methods to lower dropout rates. Well-
designed clinical trials are needed to verify the effects on AD of
several promising interventions, including sleep improvement,
smoking cessation, antidepression management and antidiabetic
agents.
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Cognitive neurology
CONCLUSIONS
Twenty- one clinical evidence- based suggestions are proposed,
offering clinicians and stakeholders an evidence- based guideline
for AD prevention. With credible though inconclusive evidence,
the suggestions targeted 10 risk factors including diabetes,
hyperhomocysteinaemia, poor BMI management, reduced
education, hypertension in midlife, orthostatic hypotension,
head trauma, less cognitive activity, stress and depression. This
study provides an advanced and contemporary survey of the
evidence, suggesting that more high- quality OPSs and RCTs are
urgently needed to strengthen the evidence base for uncovering
more promising approaches to preventing AD.
Author affiliations
1Department of Neurology and Institute of Neurology, Huashan Hospital, Shanghai
Medical College, Fudan University, Shanghai, China
2Department of Neurology, Qingdao Municipal Hospital, Qingdao University,
Qingdao, China
3Department of Epidemiology and Public Health, University of Toulouse III, Toulouse,
France
4Department of Psychiatry, Medical Research Council and Wellcome Trust
Behavioural and Clinical Neuroscience Institute, University of Cambridge, Cambridge,
UK
5Department of Hygiene and Epidemiology, University of Ioannina Medical School,
Ioannina, Greece
6Department of Epidemiology and Biostatistics, School of Public Health, Tongji
Medical College, Huazhong University of Science and Technology, Wuhan, China
7Department of Neurology, Massachusetts General Hospital and Harvard Medical
School, Charlestown, Massachusetts, USA
8Department of Neurology, Xuan Wu Hospital, Capital Medical University, Beijing,
China
9Department of Psychological Medicine, Yong Loo Lin School of Medicine, National
University of Singapore, Singapore
10Department of Neurology, Daping Hospital, Third Military Medical University,
Chongqing, China
11Department of Medicine and Therapeutics, Faculty of Medicine, The Chinese
University of Hong Kong, Shatin, Hong Kong
12Department of Neurology, University Hospital of Montpellier, Montpellier, France
13McGill Center for Studies in Aging, McGill University, Montreal, Quebec, Canada
14Alzheimer’s Therapeutic Research Institute, University of Southern California, San
Diego, California, USA
15Department of Geriatrics, Purpan University Hospital, Toulouse, France
Twitter Wei Xu @na and Can Zhang @martindragoncn
Acknowledgements The authors thank Professor Michael M Weiner and Dr Yu-
Tzu Wu for critical review.
Contributors JTY and BV conceived and designed the study. JTY, WX, CCT, HFW,
MST and JQL selected the articles and extracted the data. JTY, WX, C- CT, HFW, M- ST,
J- QL, XHH, YW, LT and LT proofread the data. JTY, WX, C- CT and AP analysed the
data. WX and CCT generated the figures. JTY, WX, CCT wrote the first draft of the
manuscript. JTY, WX, C- CT, SA, JS, EE, CZ, JJ, AP, LF, EHK, YJW, VM, JT, GS, PSA, QD,
and BV interpreted the data and contributed to the writing of the final version of the
manuscript. All authors agreed with the results and conclusions and approved the
final draft.
Funding This study was supported by grants from the National Key R&D Program
of China (2018YFC1314702), Shanghai Municipal Science and Technology Major
Project (No. 2018SHZDZX03) and ZHANGJIANG LAB.
Competing interests JTY serves as an associate editor- in- chief for Annals of
Translational Medicineand 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, Sanofi and Servier, and received non- financial
support from Biogen, Nutrition Santé, Pfzer and Icon, and other support from
the AMPA Association. GS 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, Boehringer Ingelheim, 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, Sanofi, Roche, AstraZeneca, LPG Systems, Nestlé and Alzheon, and
personal fees from Lilly, Lundbeck, MSD, Otsuka, Roche, Sanofi, Biogen, Nestlé,
Transition Therapeutics and Takeda.
Patient consent for publication Not required.
Provenance and peer review Not commissioned; externally peer reviewed.
Open access This is an open access article distributed in accordance with the
Creative Commons Attribution Non Commercial (CC BY- NC 4.0) license, which
permits others to distribute, remix, adapt, build upon this work non- commercially,
and license their derivative works on different terms, provided the original work is
properly cited, appropriate credit is given, any changes made indicated, and the use
is non- commercial. See:http:// creativecommons. org/ licenses/ by- nc/ 4. 0/.
ORCID iDs
Jin- TaiYu http:// orcid. org/ 0000- 0002- 7686- 0547
WeiXu http:// orcid. org/ 0000- 0002- 3310- 5875
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... Unauthorized reproduction of this article is prohibited The 2020 Lancet Commission on Dementia Prevention, Intervention, and Care has reported 12 modifiable risk factors for ADRD prevention and highlighted the importance of healthy lifestyles. 6 Indeed, the protective role of healthy lifestyles, including non-smoking, 7-10 regular exercise, 7,8,11,12 limited alcohol use, 13,14 adequate sleep, 7,15,16 and high-quality diets, 8,17,18 in ADRD has been widely discussed. Recently, some cohort studies have reported synergistic effects of lifestyle factors, [19][20][21][22] showing promising associations of combined scores with >30% reduced risk of ADRD, even among individuals genetically predisposed to the disease. ...
... Unauthorized reproduction of this article is prohibited The 2020 Lancet Commission on Dementia Prevention, Intervention, and Care has reported 12 modifiable risk factors for ADRD prevention and highlighted the importance of healthy lifestyles. 6 Indeed, the protective role of healthy lifestyles, including non-smoking, 7-10 regular exercise, 7,8,11,12 limited alcohol use, 13,14 adequate sleep, 7,15,16 and high-quality diets, 8,17,18 in ADRD has been widely discussed. Recently, some cohort studies have reported synergistic effects of lifestyle factors, [19][20][21][22] showing promising associations of combined scores with >30% reduced risk of ADRD, even among individuals genetically predisposed to the disease. ...
... Biologically, healthy lifestyles can enhance immune function, cardiometabolic conditions, and antioxidant and anti-inflammatory properties and reduce neuroinflammation and psychological stress, which in turn help prevent or delay the onset of ADRD. 1,7,9,13,14,19,20,35 Given that low SES is more likely associated with adverse lifestyles progressing to neural/physical degeneration and cognitive impairment, 1,43-45 providing resources for low-SES populations to promote healthy lifestyles and address their barriers to lifestyle changes may have a substantial impact to reduce racial and socioeconomic disparities in ADRD. Notably, we should recognize that it is challenging for people facing systemic and structural disadvantages to maintain healthy lifestyles or make lifestyle changes. ...
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Abstract Objective: While the importance of healthy lifestyles for preventing Alzheimer’s disease and related dementias (ADRD) has been recognized, epidemiologic evidence remains limited for non-White or low-income individuals who bear disproportionate burdens of ADRD. This population-based cohort study aims to investigate associations of lifestyle factors, individually and together, with the risk of ADRD among socioeconomically disadvantaged Americans. Methods: In the Southern Community Cohort Study, comprising two-thirds self-reported Black and primarily low-income Americans, we identified incident ADRD using claims data among participants enrolled in Medicare for at least 12 consecutive months after age 65. Five lifestyle factors—tobacco smoking, alcohol consumption, leisure-time physical activity (LTPA), sleep hours, and diet quality— were each scored 0 (unhealthy), 1 (intermediate), or 2 (healthy) based on health guidelines. A composite lifestyle score was created by summing all scores. Cox regression was used to estimate hazard ratios (HRs, 95% CIs) for incident ADRD, treating death as a competing risk. Results: We identified 1,694 patients with newly diagnosed ADRD among 17,209 participants during a median follow-up of 4.0 years in claims data; the mean age at ADRD diagnosis was 74.0 years. Healthy lifestyles were individually associated with 11%-25% reduced risk of ADRD: multivariable-adjusted HR (95% CI) was 0.87 (0.76-0.99) for never vs. current smoking, 0.81 (0.72-0.92) for low-to-moderate vs. no alcohol consumption, 0.89 (0.77-1.03) for ≥150 minutes of moderate or ≥75 minutes of vigorous LTPA each week vs. none, 0.75 (0.64-0.87) for 7-9 hours vs. >9 hours of sleep, and 0.85 (0.75-0.96) for the highest vs. lowest tertiles of Healthy Eating Index. The composite lifestyle score showed a dose-response association with up to 36% reduced risk of ADRD: multivariable-adjusted HRs (95% CIs) across quartiles were 1 (ref), 0.88 (0.77-0.99), 0.79 (0.70-0.90), and 0.64 (0.55-0.74); p-trend<0.001. The beneficial associations were observed regardless of participants’ sociodemographics (e.g., race, education, and income) and health conditions (e.g., history of cardiometabolic diseases and depression). Conclusion: Our findings support significant benefits of healthy lifestyles for ADRD prevention among socioeconomically disadvantaged Americans, suggesting that promoting healthy lifestyles and reducing barriers to lifestyle changes are crucial to tackling the growing burden and disparities posed by ADRD.
... 6 As one type of stimulation in early life, education is a widely accepted protective factor. 7,8 The effect of education is potentially driven by the improvement of cognitive reserve and more effective utilization of brain networks or cognitive paradigms. 6,9 Previous studies have indicated that neighborhood environment (NE) plays an important role in multiple health outcomes, especially in late-life cognition. ...
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Introduction: The impacts of education on cognitive decline across different neighborhood environments (NEs) have rarely been studied. Methods: We investigated and compared the associations between educational attainment and cognitive decline using data of 1286 participants from the Taizhou Imaging Study (TIS) and the Shanghai Aging Study (SAS). Results: Compared with low-educated participants, in TIS with disadvantaged NE, high-educated participants manifested a significantly slower decline in global cognition (.062 Z score per year, P < .001), memory (.054 Z score per year, P < .05), and attention (.065 Z score per year, P < .01), whereas in SAS with advanced NE, highly educated individuals exhibited a slower decline only in attention (.028 Z score per year, P < .05). Discussion: We observed the additive effect of educational attainment and NE on cognitive decline in older adults. Education is especially important for maintaining cognitive health in a disadvantaged environment.
... An evolving Newcastle-Ottawa Quality Assessment Scale (NOS) for observational cohort studies was employed to evaluate the quality of eligible studies (Yu et al., 2020). The score for each item evaluated the risk of bias in sample selection, confounding bias, and outcome (Supplementary Appendix 1). ...
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Full-text available
Background Frailty is a multidimensional syndrome that increases an individual’s vulnerability for developing adverse health outcomes, which include dementia. It might serve as a promising target for dementia prevention. However, there are currently no studies summarizing the association between multi-concept frailty and the risk of cognitive disorders. This study aims to summarize the evidence of associations between multi-concept frailty and cognitive disorders based on longitudinal studies. Methods Scopus, The Cochrane Library, PsycINFO, CINAHL, PubMed, and EMBASE databases were searched from inception to January 2, 2022. Longitudinal studies, which explored the association of frailty with incident risk of cognitive decline or dementia, were included. The multivariable-adjusted effect estimates were pooled by random-effects models. The evidence credibility was depicted according to the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) method. Results A total of 30 longitudinal studies were included. Four types of frailty concepts were involved, including physical, cognitive, social, and biopsychosocial frailty. The meta-analysis comprised 20 studies of 252,571 older adults (mean age: 64.1–80.4 years), among whom 7,388 participants developed cognitive decline or dementia. Physical frailty was associated with higher risk of developing cognitive disorders [pooled relative risk (pRR) = 1.52, 95% confidence interval (CI): 1.28–1.80, I ² = 21.2%, pRR = 1.62 for cognitive decline, 95% CI: 1.07–2.45, I ² = 40.2%, pRR = 1.37 for all-cause dementia (ACD), 95% CI: 1.13–1.66, I ² = 0.0%]. Cognitive frailty (pRR = 2.90, 95% CI: 1.28–6.55, I ² = 78.1%) and pre-frailty (pRR = 4.24, 95% CI: 2.74–6.56, I ² = 30.2%) were linked to higher risk of ACD. Biopsychosocial frailty could predict a 41% (pRR = 1.41, 95% CI: 1.17–1.71) elevated risk of cognitive decline or dementia [pRR = 1.53 (95% CI: 1.19–1.96) for ACD and 1.11 (95% CI: 1.05–1.17) for Alzheimer’s disease (AD)]. In the systematic review, social frailty was associated with a 53% higher risk of AD. Preventing frailty could avoid a maximum of 9.9% cognitive disorders globally. The overall evidence strength is rated as low-to-moderate. Inconsistency and imprecision are major sources of bias. Conclusion Frailty in late life is a promising risk factor for cognitive disorders. Frail elderly should be monitored for their cognitive dynamics and initiate early prevention of dementia. Systematic Review Registration www.ClinicalTrials.gov , identifier CRD4202127 3434.
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Purpose of review: Alzheimer disease (AD) is the most common cause of dementia in adults (mid to late life), highlighting the importance of understanding the risk factors, clinical manifestations, and recent developments in diagnostic testing and therapeutics. Recent findings: Advances in fluid (CSF and blood-based) and imaging biomarkers are allowing for a more precise and earlier diagnosis of AD (relative to non-AD dementias) across the disease spectrum and in patients with atypical clinical features. Specifically, tau- and amyloid-related AD pathologic changes can now be measured by CSF, plasma, and positron emission tomography (PET) with good precision. Additionally, a better understanding of risk factors for AD has highlighted the need for clinicians to address comorbidities to maximize prevention of cognitive decline in those at risk or to slow decline in patients who are symptomatic. Recent clinical trials of amyloid-lowering drugs have provided not only some optimism that amyloid reduction or prevention may be beneficial but also a recognition that addressing additional targets will be necessary for significant disease modification. Summary: Recent developments in fluid and imaging biomarkers have led to the improved understanding of AD as a chronic condition with a protracted presymptomatic phase followed by the clinical stage traditionally recognized by neurologists. As clinical trials of potential disease-modifying therapies continue, important developments in the understanding of the disease will improve clinical care now and lead to more effective therapies in the near future.
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Accumulating evidence suggests that inflammation is involved in the development of late onset Alzheimer’s disease (LOAD). However, it is not clear whether inflammation is a cause or consequence, or both. The aim of this paper is to review the relationship between inflammation and LOAD. We also review the effect of anti-inflammation on the risk of LOAD to further elucidate the relationship between inflammation and LOAD.
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Importance: Previous estimates suggested that 1 in 3 cases of Alzheimer disease and related dementia (ADRDs) in the US are associated with modifiable risk factors, the most prominent being physical inactivity, depression, and smoking. However, these estimates do not account for changes in risk factor prevalence over the past decade and do not consider potential differences by sex or race and ethnicity. Objective: To update estimates of the proportion of ADRDs in the US that are associated with modifiable risk factors and to assess for differences by sex and race and ethnicity. Design, setting, and participants: For this cross-sectional study, risk factor prevalence and communality were obtained from the nationally representative US Behavioral Risk Factor Surveillance Survey data from January 2018 to December 2018, and relative risks for each risk factor were extracted from meta-analyses. Data were analyzed from December 2020 to August 2021. Respondents included 378 615 noninstitutionalized adults older than 18 years. The number before exclusion was 402 410. Approximately 23 795 (~6%) had missing values on at least 1 of the variables of interest. Exposures: Physical inactivity, current smoking, depression, low education, diabetes, midlife obesity, midlife hypertension, and hearing loss. Main outcomes and measures: Individual and combined population-attributable risks (PARs) associated with ADRDs, accounting for nonindependence between risk factors. Results: Among 378 615 individuals, 171 161 (weighted 48.7%) were male, and 134 693 (weighted 21.1%) were 65 years and older. Race and ethnicity data were self-reported and defined by the US Behavioral Risk Factor Surveillance System Data; 6671 participants (weighted 0.9%) were American Indian and Alaska Native, 8043 (weighted 5.1%) were Asian, 29 956 (weighted 11.7%) were Black, 28 042 (weighted 16.0%) were Hispanic (any race), and 294 394 (weighted 64.3%) were White. Approximately 1 in 3 of ADRD cases (36.9%) in the US were associated with 8 modifiable risk factors, the most prominent of which were midlife obesity (17.7%; 95% CI, 17.5-18.0), physical inactivity (11.8%; 95% CI, 11.7-11.9), and low educational attainment (11.7%; 95% CI, 11.5-12.0). Combined PARs were higher in men (35.9%) than women (30.1%) and differed by race and ethnicity: American Indian and Alaska Native individuals, 39%; Asian individuals, 16%; Black individuals, 40%; Hispanic individuals (any race), 34%; and White individuals, 29%. The most prominent modifiable risk factors regardless of sex were midlife obesity for American Indian and Alaska Native individuals, Black individuals, and White individuals; low education for Hispanic individuals; and physical inactivity for Asian individuals. Conclusions and relevance: The findings suggest that risk factors associated with ADRDs have changed over the past decade and differ based on sex and race and ethnicity. Alzheimer risk reduction strategies may be more effective if they target higher-risk groups and consider current risk factor profiles.
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Objectives: Most Vietnamese immigrants in the U.S. today arrived as political refugees due to the Vietnam War in the late 20th century. Refugees are disproportionally affected by health and mental health disparities as a result of experiencing distress and potentially traumatic experiences before, during, and after their migration processes. This study involved Vietnamese families facing dementia and used a qualitative approach to investigate participants' experiences before, during, and right after their resettlement in the U.S. Methods: In-person interviews were conducted with 11 Vietnamese adults who cared for their family member with dementia. A descriptive analysis approach was used. Results: Five major themes emerged from the interviews:1) immigrating separately from family members, 2) difficult and unsafe journeys, 3) experiences of loss, 4) lack of support systems in the U.S., and 5) feelings of unhappiness, sadness, or signs of depression. Conclusions: This study provides a close examination of Vietnamese refugees' unique backgrounds and how individuals with dementia and their caregivers from this population may be disproportionally impacted by stress. Clinical implications: To reduce health disparities, we recommend that providers and policymakers allocate more resources for culturally appropriate routine assessment, treatment, and referrals of those with dementia and their caregivers.
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There is now evidence to suggest that there may be an interaction between B vitamins and omega-3 polyunsaturated fatty acids (PUFAs), with suggestions that increasing intake of both nutrients simultaneously may benefit cognition in older adults. The aim of this systematic review was to investigate whether supplementation with a combination of omega-3 PUFAs and B vitamins can prevent cognitive decline in older adults. Randomised control trials conducted in older adults that measured cognitive function were retrieved. The included trials provided a combination of omega-3 PUFAs and B vitamins alone, or in combination with other nutrients. Trials that provided omega-3 PUFAs alone and also measured B vitamin status or provided B vitamin supplementation alone and measured omega-3 PUFA status were also included. The databases searched were The Cochrane Library, EMBASE, CINAHL, Scopus, and MEDLINE. A total of 14 papers were included in the analysis (n=4913; age: 60-70 y; follow up 24 weeks to 4 years). The meta-analysis results found a significant benefit of nutrient formulas, which included both omega-3 PUFAs and B vitamins alongside other nutrients, versus placebo on global cognition assessed using composite scores from a neuropsychological test battery (G=0.23, P=0.002), global cognition using single measures of cognition (G=0.28, P=0.004) and episodic memory (G=0.32, P=0.001). The results indicate that providing a combination of omega-3 PUFA and B vitamins as part of a multi-nutrient formula benefits cognition in older adults versus a placebo, the potential for an interaction between these key nutrients should be considered in future experimental work.
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Objective To estimate the effect of a moderate to high intensity aerobic and strength exercise training programme on cognitive impairment and other outcomes in people with mild to moderate dementia. Design Multicentre, pragmatic, investigator masked, randomised controlled trial. Setting National Health Service primary care, community and memory services, dementia research registers, and voluntary sector providers in 15 English regions. Participants 494 people with dementia: 329 were assigned to an aerobic and strength exercise programme and 165 were assigned to usual care. Random allocation was 2:1 in favour of the exercise arm. Interventions Usual care plus four months of supervised exercise and support for ongoing physical activity, or usual care only. Interventions were delivered in community gym facilities and NHS premises. Main outcome measures The primary outcome was score on the Alzheimer’s disease assessment scale-cognitive subscale (ADAS-cog) at 12 months. Secondary outcomes included activities of daily living, neuropsychiatric symptoms, health related quality of life, and carer quality of life and burden. Physical fitness (including the six minute walk test) was measured in the exercise arm during the intervention. Results The average age of participants was 77 (SD 7.9) years and 301/494 (61%) were men. By 12 months the mean ADAS-cog score had increased to 25.2 (SD 12.3) in the exercise arm and 23.8 (SD 10.4) in the usual care arm (adjusted between group difference −1.4, 95% confidence interval −2.6 to −0.2, P=0.03). This indicates greater cognitive impairment in the exercise group, although the average difference is small and clinical relevance uncertain. No differences were found in secondary outcomes or preplanned subgroup analyses by dementia type (Alzheimer’s disease or other), severity of cognitive impairment, sex, and mobility. Compliance with exercise was good. Over 65% of participants (214/329) attended more than three quarters of scheduled sessions. Six minute walking distance improved over six weeks (mean change 18.1 m, 95% confidence interval 11.6 m to 24.6 m). Conclusion A moderate to high intensity aerobic and strength exercise training programme does not slow cognitive impairment in people with mild to moderate dementia. The exercise training programme improved physical fitness, but there were no noticeable improvements in other clinical outcomes. Trial registration Current Controlled Trials ISRCTN10416500.
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Introduction: Higher midlife body mass index (BMI) is suggested to increase the risk of dementia, but weight loss during the preclinical dementia phase may mask such effects. Methods: We examined this hypothesis in 1,349,857 dementia-free participants from 39 cohort studies. BMI was assessed at baseline. Dementia was ascertained at follow-up using linkage to electronic health records (N = 6894). We assumed BMI is little affected by preclinical dementia when assessed decades before dementia onset and much affected when assessed nearer diagnosis. Results: Hazard ratios per 5-kg/m(2) increase in BMI for dementia were 0.71 (95% confidence interval = 0.66-0.77), 0.94 (0.89-0.99), and 1.16 (1.05-1.27) when BMI was assessed 10 years, 10-20 years, and >20 years before dementia diagnosis. Conclusions: The association between BMI and dementia is likely to be attributable to two different processes: a harmful effect of higher BMI, which is observable in long follow-up, and a reverse-causation effect that makes a higher BMI to appear protective when the follow-up is short.
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Objective: To examine the association of blood pressure (BP) with incident Alzheimer's disease (AD) dementia. Methods: This work is based on a longitudinal, cohort study of 18 years, the Chicago Health and Aging Project (CHAP) performed in 2,137 participants (55% African American [AA]) with systolic BP measured about 8.1 years before incident AD dementia. Results: The association of BP with risk of AD dementia was U‐shaped, with the lowest risks of AD dementia near the center of the SBP and DBP distributions, and modestly elevated risk at lower BPs, and greater risk at higher BPs. The degree of U‐shape and the range of lowest risk (threshold ranges) varied with antihypertensive medication use and presence of the APOE ε4 allele. The U‐shape was most prominent for the subgroup not taking anti‐hypertensive medications and having an APOE ε4 allele. At higher BPs, those having the APOE ε4 allele and not receiving anti‐hypertensive medication were at greater risk of AD dementia than other groups: The risk of incident AD dementia increased by 100% (RR=2.00, 95% CI= 1.70, 2.31) for every 10 mmHg increase in SBP above 140 mmHg. For DBP, the risk of incident of AD dementia increased by 57% (RR=1.57, 95% CI= 1.33, 1.86) for every 5mmHg increase in DBP above 76 mmHg. Interpretation: The BP‐risk of AD dementia association is U‐shaped, with elevated risk at lower and higher BPs. People having the APOE ε4 allele and not receiving antihypertensive medication with higher BPs have notably elevated risk of AD dementia. This article is protected by copyright. All rights reserved.
Article
Background: Optimal interventions to prevent or delay cognitive decline, mild cognitive impairment (MCI), or dementia are uncertain. Purpose: To summarize the evidence on efficacy and harms of over-the-counter (OTC) supplements to prevent or delay cognitive decline, MCI, or clinical Alzheimer-type dementia in adults with normal cognition or MCI but no dementia diagnosis. Data sources: Multiple electronic databases from 2009 to July 2017 and bibliographies of systematic reviews. Study selection: English-language trials of at least 6 months' duration that enrolled adults without dementia and compared cognitive outcomes with an OTC supplement versus placebo or active controls. Data extraction: Extraction performed by a single reviewer and confirmed by a second reviewer; dual-reviewer assessment of risk of bias; consensus determination of strength of evidence. Data synthesis: Thirty-eight trials with low to medium risk of bias compared ω-3 fatty acids, soy, ginkgo biloba, B vitamins, vitamin D plus calcium, vitamin C or β-carotene, multi-ingredient supplements, or other OTC interventions with placebo or other supplements. Few studies examined effects on clinical Alzheimer-type dementia or MCI, and those that did suggested no benefit. Daily folic acid plus vitamin B12 was associated with improvements in performance on some objectively measured memory tests that were statistically significant but of questionable clinical significance. Moderate-strength evidence showed that vitamin E had no benefit on cognition. Evidence about effects of ω-3 fatty acids, soy, ginkgo biloba, folic acid alone or with other B vitamins, β-carotene, vitamin C, vitamin D plus calcium, and multivitamins or multi-ingredient supplements was either insufficient or low-strength, suggesting that these supplements did not reduce risk for cognitive decline. Adverse events were rarely reported. Limitation: Studies had high attrition and short follow-up and used a highly variable set of cognitive outcome measures. Conclusion: Evidence is insufficient to recommend any OTC supplement for cognitive protection in adults with normal cognition or MCI. Primary funding source: Agency for Healthcare Research and Quality.
Article
Acting now on dementia prevention, intervention, and care will vastly improve living and dying for individuals with dementia and their families, and in doing so, will transform the future for society. Dementia is the greatest global challenge for health and social care in the 21st century. It occurs mainly in people older than 65 years, so increases in numbers and costs are driven, worldwide, by increased longevity resulting from the welcome reduction in people dying prematurely. The Lancet Commission on Dementia Prevention, Intervention, and Care met to consolidate the huge strides that have been made and the emerging knowledge as to what we should do to prevent and manage dementia. Globally, about 47 million people were living with dementia in 2015, and this number is projected to triple by 2050. Dementia affects the individuals with the condition, who gradually lose their abilities, as well as their relatives and other supporters, who have to cope with seeing a family member or friend become ill and decline, while responding to their needs, such as increasing dependency and changes in behaviour. Additionally, it affects the wider society because people with dementia also require health and social care. The 2015 global cost of dementia was estimated to be US$818 billion, and this figure will continue to increase as the number of people with dementia rises. Nearly 85% of costs are related to family and social, rather than medical, care. It might be that new medical care in the future, including public health measures, could replace and possibly reduce some of this cost.
Article
Importance Among cognitively normal individuals, elevated brain amyloid (defined by cerebrospinal fluid assays or positron emission tomography regional summaries) can be related to risk for later Alzheimer-related cognitive decline. Objective To characterize and quantify the risk for Alzheimer-related cognitive decline among cognitively normal individuals with elevated brain amyloid. Design, Setting, and Participants Exploratory analyses were conducted with longitudinal cognitive and biomarker data from 445 cognitively normal individuals in the United States and Canada. Participants were observed from August 23, 2005, to June 7, 2016, for a median of 3.1 years (interquartile range, 2.0-4.2 years; maximum follow-up, 10.3 years) as part of the Alzheimer’s Disease Neuroimaging Initiative (ADNI). Exposures Individuals were classified at baseline as having normal (n = 243) or elevated (n = 202) brain amyloid using positron emission tomography amyloid imaging or a cerebrospinal fluid assay of amyloid β. Main Outcomes and Measures Outcomes included scores on the Preclinical Alzheimer Cognitive Composite (PACC; a sum of 4 baseline standardized z scores, which decreases with worse performance), Mini-Mental State Examination (MMSE; 0 [worst] to 30 [best] points), Clinical Dementia Rating Sum of Boxes (CDR–Sum of Boxes; 0 [best] to 18 [worst] points), and Logical Memory Delayed Recall (0 [worst] to 25 [best] story units). Results Among the 445 participants (243 with normal amyloid, 202 with elevated amyloid), mean (SD) age was 74.0 (5.9) years, mean education was 16.4 (2.7) years, and 52% were women. The mean score for PACC at baseline was 0.00 (2.60); for MMSE, 29.0 (1.2); for CDR–Sum of Boxes, 0.04 (0.14); and for Logical Memory Delayed Recall, 13.1 (3.3). Compared with the group with normal amyloid, those with elevated amyloid had worse mean scores at 4 years on the PACC (mean difference, 1.51 points [95% CI, 0.94-2.10]; P < .001), MMSE (mean difference, 0.56 points [95% CI, 0.32-0.80]; P < .001), and CDR–Sum of Boxes (mean difference, 0.23 points [95% CI, 0.08-0.38]; P = .002). For Logical Memory Delayed Recall, between-group score was not statistically significant at 4 years (mean difference, 0.73 story units [95% CI, −0.02 to 1.48]; P = .056). Conclusions and Relevance Exploratory analyses of a cognitively normal cohort followed up for a median of 3.1 years suggest that elevation in baseline brain amyloid level, compared with normal brain amyloid level, was associated with higher likelihood of cognitive decline, although the findings are of uncertain clinical significance. Further research is needed to assess the clinical importance of these differences and measure longer-term associations.
Article
Importance: To our knowledge, no effective treatments exist for Alzheimer disease, and new molecules are years away. However, several drugs prescribed for other conditions have been associated with reducing its risk. Objective: To analyze the association between statin exposure and Alzheimer disease incidence among Medicare beneficiaries. Design, setting, and participants: We examined the medical and pharmacy claims of a 20% sample of Medicare beneficiaries from 2006 to 2013 and compared rates of Alzheimer disease diagnosis for 399 979 statin users 65 years of age or older with high or low exposure to statins and with drug molecules for black, Hispanic, and non-Hispanic white people, and men and women of Asian, Native American, or unkown race/ethnicity who are referred to as "other." Main outcomes and measures: The main outcome was incident diagnosis of Alzheimer disease based on the International Classification of Diseases, Ninth Revision, Clinical Modification. We used Cox proportional hazard models to analyze the association between statin exposure and Alzheimer disease diagnosis for different sexes, races and ethnicities, and statin molecules. Results: The 399 979 study participants included 7794 (1.95%) black men, 24 484 (6.12%) black women, 11 200 (2.80%) Hispanic men, 21 458 (5.36%) Hispanic women, 115 059 (28.77%) white men, and 195 181 (48.80%) white women. High exposure to statins was associated with a lower risk of Alzheimer disease diagnosis for women (hazard ratio [HR], 0.85; 95% CI, 0.82-0.89; P<.001) and men (HR, 0.88; 95% CI, 0.83-0.93; P<.001). Simvastatin was associated with lower Alzheimer disease risk for white women (HR, 0.86; 95% CI, 0.81-0.92; P<.001), white men (HR, 0.90; 95% CI, 0.82-0.99; P=.02), Hispanic women (HR, 0.82; 95% CI, 0.68-0.99; P=.04), Hispanic men (HR, 0.67; 95% CI, 0.50-0.91; P=.01), and black women (HR, 0.78; 95% CI, 0.66-0.93; P=.005). Atorvastatin was associated with a reduced risk of incident Alzheimer disease diagnosis for white women(HR, 0.84, 95% CI, 0.78-0.89), black women (HR, .081, 95% CI, 0.67-0.98), and Hispanic men (HR, 0.61, 95% CI, 0.42-0.89) and women (HR, 0.76, 95% CI, 0.60-0.97). Pravastatin and rosuvastatin were associated with reduced Alzheimer disease risk for white women only (HR, 0.82, 95% CI, 0.70-0.95 and HR, 0.81, 95% CI, 0.67-0.98, respectively). High statin exposure was not associated with a statistically significant lower Alzheimer disease risk among black men. Conclusions and relevance: The reduction in Alzheimer disease risk varied across statin molecules, sex, and race/ethnicity. Clinical trials that include racial and ethnic groups need to confirm these findings. Because statins may affect Alzheimer disease risk, physicians should consider which statin is prescribed to each patient.
Article
Alzheimer’s disease (AD) is the leading cause of dementia, and because the primary risk factor for AD is old age, the prevalence of the disease is increasing dramatically with ageing populations worldwide. Even in high-income countries, the cost of medical care and associated societal burdens of dementia threaten to become overwhelming as more people live into old age. In view of the lack of progress in developing a cure for AD and the rapidly increasing costs of dementia, policy makers and governments have a powerful incentive to provide more resources to develop AD therapeutics. The Lancet Neurology Commission was formed with the overarching aim to provide information and expert recommendations to policy makers and political leaders about the growing problem of AD and related dementias of ageing. The past two decades have seen remarkable improvements in the quality of care for patients with AD, with a research-driven shift to more personalised and integrated team-oriented care. Epidemiological and genetic studies have identifi ed many factors that increase the risk of AD. Prevention studies have highlighted the possibility of targeting risk and protective factors to delay onset, with the promise of reducing the overall prevalence of dementia. However, no treatment is yet available to halt or reverse the underlying pathology of established AD. Indeed, an eff ective therapy for AD is perhaps the greatest unmet need facing modern medicine. Basic biomedical research has provided insights into the causes and pathogenesis of AD and other neurodegenerative diseases, but improved understanding of disease mechanisms will be needed to develop safe and eff ective disease-modifying treatments. Nonetheless, several drugs are currently in late phases of clinical development. The Commission considered a range of challenges that need to be addressed to reduce the burden of dementia, and these challenges are discussed in detail in the main sections of our report: health economics (section 1), epidemiology (section 2), prevention (section 3), genetics (section 4), biology (section 5), diagnosis (section 6), treatment (sections 7, 8), care (section 9), and ethics (section 10). In panel 1 we summarise the key fi ndings of the Commission, with recommendations about how patient care and related research—from basic to clinical— in AD and other dementias should be organised in the future. A concerted eff ort to tackle dementia is needed, with a substantial overall increase in government and private investment in the care of patients and the search for AD therapeutics. Europe is well placed to take the world lead, in partnership with international organisations, to develop new approaches to prevent or cure AD and other dementias and to provide models of compassionate care for patients. As the cost of care increases, funds must not be shunted from basic research, clinical research, and drug-discovery programmes. In fact, a substantial increase in long-term funding for multidisciplinary research programmes is absolutely essential to reduce the burden of individual suff ering and the enormous societal cost of AD. Only targeted increases in research investment will provide any hope of fi nding a cure for AD or developing strategies to delay the onset or slow the progression of the disease.