Prevention & risk

• One copy (heterozygous, e3/e4): OR 3.2 (95% CI 2.8-3.8); two copies (homozygous, e4/e4): OR 14.9 (95% CI 10.8-20.6), both vs. e3/e3 reference
• Evidence: High
• Genetic

Carrying one copy of the APOE4 allele roughly triples Alzheimer's odds; carrying two copies (homozygous) raises odds nearly 15-fold relative to the common e3/e3 genotype, a clear gene-dosage effect. The e2/e3 genotype was mildly protective (OR 0.6, 95% CI 0.5-0.8).

Landmark, still most-cited meta-analysis; not included in the Lancet Commission's modifiable-risk PAF model since APOE4 is non-modifiable. Effect size varies substantially by ancestry: stronger in Japanese populations (e4/e4 OR 33.1) and weaker in African American/Hispanic populations in the same meta-analysis.

Source: Farrer LA, Cupples LA, Haines JL, et al., JAMA 1997 (pooled meta-analysis, 40 research teams, 5,930 AD cases, 8,607 controls) · 1997

• RR 1.73 (95% CI 1.59-1.87) for 1+ affected first-degree relative; RR 3.98 (95% CI 3.26-4.82) for 2+ affected first-degree relatives
• Evidence: High
• Genetic

Risk climbs steeply with the number of affected close relatives; risk elevation extends even to second- and third-degree relatives, indicating a broad polygenic/inherited contribution beyond APOE4 alone.

Utah-specific founder population (largely European ancestry), which may limit generalizability. The reported RR for 3+ affected first-degree relatives (2.48, 95% CI 1.07-4.89) is numerically lower than for 2+ relatives, an instability the study authors themselves note as likely due to small subgroup size.

Source: Cannon-Albright LA, et al., Neurology 2019 (Utah Population Database, 270,818 individuals, 4,436 AD deaths) · 2019

• HR 1.12 (95% CI 1.02-1.23), meta-analysis of 21 cohorts (n=29,850); lifetime risk at age 65: women 24.6% vs. men 15.5% (all-cause dementia)
• Evidence: Moderate
• Demographic

Women show meaningfully higher lifetime dementia risk than men in Western cohort data, but the Lancet Commission attributes this substantially to women's greater life expectancy and historically lower educational attainment rather than to a clearly established sex-specific biological mechanism. The Commission's own text notes findings on sex differences are inconsistent across countries.

For Alzheimer's disease specifically (Framingham data), lifetime risk at 65 was 21.1% for women vs. 11.6% for men (p<0.001). Evidence is heterogeneous across countries/study designs.

Source: Lancet Commission 2024 report; Chene G, et al., Alzheimer's & Dementia 2015 (Framingham Heart Study) · 2015

• Symptomatic Alzheimer's prevalence reaches 90-100% by the seventh decade of life; lifetime risk of AD >90%
• Evidence: High
• Genetic

Trisomy 21 causes near-universal Alzheimer's brain pathology and very high rates of clinical dementia by late-middle-age, because the extra copy of chromosome 21 causes lifelong overexpression of the amyloid precursor protein (APP) gene. Among a cohort of 388 adults with Down syndrome, median age of Alzheimer's-dementia diagnosis was 53.7 years and median age of prodromal-AD diagnosis was 50.2 years.

The strongest known genetic risk factor for early-onset Alzheimer's in people who survive to middle age. Figures reflect people with Down syndrome who survive into adulthood; onset ages are typically decades earlier than late-onset Alzheimer's in the general population.

Source: Fortea J, Vilaplana E, Carmona-Iragui M, et al., The Lancet 2020 · 2020

• HR 0.89 (95% CI 0.83-0.95) for dementia (10 studies); HR 0.70 (95% CI 0.60-0.82) for Alzheimer's disease specifically (9 cohorts)
• Evidence: Moderate
• Lifestyle

Higher adherence to a Mediterranean-style diet is associated with an 11% lower risk of dementia overall and a 30% lower risk of Alzheimer's disease specifically in pooled cohort data spanning 2000-2024.

Purely observational; no large randomized controlled trial has confirmed causality for dementia as a primary endpoint. Residual confounding by socioeconomic status, education, and general healthy-lifestyle clustering is likely.

Source: Meta-analysis of 23 studies, 2000-2024 · 2024

• HR 0.75 (95% CI 0.58-0.97) for maintaining an individually optimal activity level vs. persistent inactivity
• Evidence: Moderate
• Lifestyle

Sustained physical activity across adulthood is associated with roughly a quarter reduction in dementia risk compared with persistent inactivity, in a cohort of 29,826 people followed a median 24.5 years with activity assessed twice a decade apart. This is the protective mirror of the 'physical-inactivity' risk-factor entry.

Same reverse-causation concern as inactivity: declining activity can itself be an early, pre-diagnostic dementia symptom, which may inflate the apparent protective effect of staying active.

Source: Lancet Commission 2024 report (cited cohort study) · 2024

• Probable dementia HR 0.83 (95% CI 0.67-1.04), 7.2 vs 8.6 cases per 1,000 person-years (not significant); MCI HR 0.81 (0.69-0.95), 14.6 vs 18.3 per 1,000 person-years; MCI or probable dementia HR 0.85 (0.74-0.97)
• Evidence: High
• Cardiovascular

The only large randomised trial of blood-pressure targets with adjudicated dementia as the primary cognitive outcome found no significant reduction in probable dementia with intensive control, although mild cognitive impairment and the combined MCI-or-dementia outcome were significantly reduced. The trial was stopped early for cardiovascular benefit, so it accrued fewer dementia cases than planned and may have been underpowered for the dementia endpoint.

PMID 30688979; PMC6439590; NCT01206062. 9,361 adults aged >=50 with hypertension, no diabetes or prior stroke, 102 US/Puerto Rico sites; intensive n=4,678, standard n=4,683; mean age 67.9; 35.6% women; 91.5% had >=1 follow-up cognitive assessment; median intervention 3.34 years, median follow-up 5.11 years; 149 vs 176 probable-dementia cases. Recorded as a null primary result with a significant secondary (MCI) result. Complements the observational 'hypertension' record.

Source: SPRINT MIND Investigators for the SPRINT Research Group; Williamson JD, Pajewski NM, Auchus AP, et al. Effect of Intensive vs Standard Blood Pressure Control on Probable Dementia: A Randomized Clinical Trial. JAMA 2019;321(6):553-561 · 2019

• All dementia triggers HR 1.03 (95% CI 0.91-1.17); probable AD HR 0.96 (0.74-1.24); MCI HR 1.12 (0.92-1.37); cognitive change over time similar in both arms
• Evidence: High
• Other

In a large placebo-controlled trial of community-dwelling adults aged 70+ (US minorities 65+) free of cardiovascular disease and dementia, daily low-dose aspirin did not reduce incident dementia, probable Alzheimer's disease, MCI or cognitive decline over a median 4.7 years. Aspirin is therefore not a dementia-prevention strategy in healthy older people.

PMID 32213642; PMC7455352; NCT01038583. 19,114 participants, US and Australia; 964 triggered dementia assessment; 575 adjudicated dementia cases (DSM-IV), 41% clinically probable AD. Class II evidence per the journal's classification. Deliberately recorded as a null finding.

Source: Ryan J, Storey E, Murray AM, et al. Randomized placebo-controlled trial of the effects of aspirin on dementia and cognitive decline. Neurology 2020;95(3):e320-e331 · 2020

• All-cause dementia HR 1.12 (95% CI 0.94-1.33; P=.21); Alzheimer's disease HR 1.16 (0.97-1.39; P=.11); progression from MCI to dementia HR 1.13 (0.85-1.50; P=.39); dementia rate 3.3 vs 2.9 per 100 person-years (ginkgo vs placebo)
• Evidence: High
• Other

The largest placebo-controlled trial of Ginkgo biloba, in 3,069 community volunteers aged 75+ with normal cognition or MCI followed for a median 6.1 years, found no reduction in all-cause dementia or Alzheimer's disease; point estimates were, if anything, slightly unfavourable. Ginkgo remains widely sold for memory despite this null result.

PMID 19017911; PMC2823569; NCT00010803. 5 US academic centres, 2000-2008; ginkgo n=1,545, placebo n=1,524; 2,587 normal cognition and 482 MCI at entry; 523 incident dementia cases (277 ginkgo, 246 placebo), 92% possible/probable AD or AD with vascular disease; dropout/loss to follow-up 6.3%; similar adverse-event profiles. Null finding recorded deliberately.

Source: DeKosky ST, Williamson JD, Fitzpatrick AL, et al. Ginkgo biloba for prevention of dementia: a randomized controlled trial. JAMA 2008;300(19):2253-2262 · 2008

• Adjusted HR vs placebo: vitamin E 0.88 (95% CI 0.64-1.20); selenium 0.83 (0.60-1.13); combination 1.00 (0.75-1.35); dementia incidence 4.4% overall (325/7,338), not different across arms
• Evidence: Moderate
• Lifestyle

Neither vitamin E nor selenium, alone or together, prevented dementia in 7,540 men aged 60+ enrolled through the SELECT prostate-cancer prevention trial. The randomised phase (2002-2009) converted to an observational cohort after SELECT closed for futility, which weakens the design, but the result is consistently null.

PMID 28319243; PMC5506489. Mean baseline age 67.5 (SD 5.3); 52.2% college-educated; 10.0% Black; 6.7% Hispanic; 130 SELECT sites; 3,786 continued into the cohort phase (Sep 2009-May 2015); modified intent-to-treat Cox models. Men only; dementia ascertained by two-stage screen plus record review, not universal clinical evaluation. Null finding recorded deliberately.

Source: Kryscio RJ, Abner EL, Caban-Holt A, et al. Association of Antioxidant Supplement Use and Dementia in the Prevention of Alzheimer's Disease by Vitamin E and Selenium Trial (PREADViSE). JAMA Neurol 2017;74(5):567-573 · 2017

• No significant association between MHT use and incident MCI or dementia in random-effects meta-analysis of 10 studies (1 RCT, 9 observational; 1,016,055 participants); subgroups by timing, duration and type also non-significant (pooled point estimate not given in abstract)
• Evidence: Moderate
• Other

A 2025 systematic review and meta-analysis found no evidence that menopause hormone therapy either raises or lowers dementia risk, and no effect of timing, duration or formulation. The authors conclude MHT should be prescribed for its other benefits and risks, not for dementia prevention. Certainty of evidence ranged from moderate to very low, and no study addressed premature ovarian insufficiency or testosterone.

PMID 41448220; PROSPERO CRD42025639384; primary studies searched 1 Jan 2000-20 Oct 2025; risk of bias via RoB 2 / ROBINS-E; GRADE. Funded by the Public Health Agency of Canada. The abstract reports the null result qualitatively; the numeric pooled RR was not in the source text we have, so the effect-size entry states the finding without inventing a point estimate.

Source: Melville M, He L, Desai R, et al. Menopause hormone therapy and risk of mild cognitive impairment or dementia: a systematic review and meta-analysis. Lancet Healthy Longev 2025;6(12):100803 · 2025

• Pooled OR 0.80 (95% CI 0.75-0.86) for dementia (36 studies) and OR 0.68 (0.56-0.81) for Alzheimer's disease (21 studies) in statin users vs non-users; men OR 0.86 (0.81-0.92) and women OR 0.86 (0.81-0.92); high-potency statins 20% vs low-potency 16% dementia risk reduction (P=0.05 for heterogeneity)
• Evidence: Low
• Cardiovascular

Pooled observational evidence associates statin use with about 20% lower odds of dementia and 32% lower odds of Alzheimer's disease, with no difference between lipophilic and hydrophilic statins. Because this is observational (healthy-user and indication bias are likely) and no adequately designed randomised trial exists, the authors frame it as absence of neurocognitive harm plus a possible favourable effect, not proof of prevention.

PMID 34871380. Search to January 2021; restricted maximum-likelihood random-effects model. Evidence strength set to 'low' because all included studies are observational and the authors call for ad hoc RCTs. Contrast with the 'high-ldl-cholesterol' record (LDL as a risk factor) - statin benefit does not follow automatically from that association.

Source: Olmastroni E, Molari G, De Beni N, et al. Statin use and risk of dementia or Alzheimer's disease: a systematic review and meta-analysis of observational studies. Eur J Prev Cardiol 2022;29(5):804-814 · 2022

• Dementia HR 1.21 (95% CI 1.07-1.38; 23 longitudinal studies); cognitive decline OR 1.23 (1.05-1.44; 24 studies); tooth loss alone: dementia HR 1.13 (1.04-1.23), cognitive decline OR 1.23 (1.09-1.39); complete tooth loss dementia HR 1.23 (1.05-1.45)
• Evidence: Low
• Other

Longitudinal studies link poor periodontal health and tooth loss to roughly 20% higher dementia risk, but the review authors rate the evidence low quality, highly heterogeneous, and 'at least partly due to reverse causality' (early cognitive decline worsens oral care). Not among the Lancet Commission's 14 factors.

PMID 36073186; PMC9826143. Five databases searched to April 2022; 47 studies included (24 cognitive decline, 23 dementia); random-effects pooling. Partial tooth loss OR 1.50 (1.02-2.23) for cognitive decline. Recorded with the authors' caution about reverse causality.

Source: Asher S, Stephen R, Mantyla P, Suominen AL, Solomon A. Periodontal health, cognitive decline, and dementia: A systematic review and meta-analysis of longitudinal studies. J Am Geriatr Soc 2022;70(9):2695-2709 · 2022

• Dementia: RR 0.92 (95% CI 0.88-0.96) at 1-17.5 g/day and RR 1.23 (1.09-1.35) at >17.5 g/day vs 0 g/day (J-shaped; lowest risk ~15 g/day); cognitive dysfunction: RR 0.97 (0.95-0.99) at 1-30.5 g/day and RR 1.07 (1.01-1.15) at >30.5 g/day (lowest risk ~30 g/day)
• Evidence: Low
• Lifestyle

A 2024 dose-response meta-analysis of 17 longitudinal studies finds a J-shaped curve: light drinking (about one standard drink a day or less) is associated with slightly lower dementia risk than abstention, while heavier intake raises risk by about a quarter. The apparent protective effect of light drinking is contested because abstainer groups often include former heavy drinkers and people who stopped for health reasons (sick-quitter bias); this record should be read with the 'excessive-alcohol' record.

PMID 39038743. Search to April 2023; restricted cubic spline dose-response; 80,680 persons with 4,929 dementia cases and 13,530 persons with 1,579 cognitive-dysfunction cases. J-shape persisted in subgroups by age (<=65, >65) and study duration for dementia. Evidence strength 'low' reflects observational design and abstainer-bias concerns raised in the summary (the abstract itself does not discuss sick-quitter bias).

Source: Zarezadeh M, Mahmoudinezhad M, Faghfouri AH, et al. Alcohol consumption in relation to cognitive dysfunction and dementia: A systematic review and dose-response meta-analysis of comparative longitudinal studies. Ageing Res Rev 2024;100:102419 · 2024

• Overall population: HR 0.93 (95% CI 0.86-1.01), not significant; high-risk populations (CKD, COPD, vascular disease): 2-3 doses HR 0.84 (0.76-0.92), >=4 doses HR 0.43 (0.38-0.48)
• Evidence: Low
• Other

Across eight cohort studies with nearly 10 million people, influenza vaccination was not significantly associated with lower dementia incidence in the general population, although a dose-response association appeared in people with chronic kidney disease, COPD or vascular disease. Repeated vaccination is strongly confounded by health-seeking behaviour, so the subgroup finding should not be read as causal; contrast with the quasi-experimental zoster-vaccine record.

PMID 40601364. Search to 6 April 2025; 8 cohort studies, 9,938,696 subjects; Newcastle-Ottawa risk of bias low in all but one study; random-effects model. Direction recorded as no-significant-effect for the overall population (the primary comparison); the authors' own conclusion emphasises the dose-response finding.

Source: Yang WK, Shao SC, Liu CC, Chi CC. Influenza vaccination and risk of dementia: a systematic review and meta-analysis. Age Ageing 2025;54(7):afaf169 · 2025

• Pooled survival time ratio 1.26 (95% CI 1.09-1.47) for dementia-free survival with high-school completion or above vs less than high school (total effect); natural direct effect 1.18 (1.01-1.36); indirect effect via occupational complexity 1.06 (1.02-1.09); 28% of the education effect mediated by occupational complexity
• Evidence: Moderate
• Other

Across 10,195 older adults in nine cohorts from six countries, completing high school lengthened dementia-free survival by about a quarter, and adult occupational complexity independently added protection, explaining roughly a quarter of the education effect. A threshold pattern was seen: finishing high school mattered, with little extra gain from further education. Adds the adult-life occupation pathway to the 'less-education' record.

PMID 34776437; PMC8748312 (full text loaded). Median baseline age 74.1 (range 58-103); accelerated failure time models per cohort then meta-analysed; cumulative dementia incidence across cohorts 3%-22%. Pooled values quoted are from the mediation-analysis table (Table 5) of the full text; occupational complexity estimates in Table 4 varied by cohort (e.g., EAS Black and LEILA75+ protective) and the pooled Table 3/4 rows were in figures not captured as text.

Source: Hyun J, Hall CB, Katz MJ, et al. Education, Occupational Complexity, and Incident Dementia: A COSMIC Collaborative Cohort Study. J Alzheimers Dis 2022;85(1):179-196 · 2022

What was tried: 2-year culturally adapted systematic multidomain lifestyle intervention (SLI: structured, supervised, monitored) vs flexible lifestyle intervention (FLI: health advice)

• 1,065 people
• Ages 60-77 (mean 67.5)
• For 2 years
• p = <0.0001

What was measured: co-primary: feasibility (RE-AIM Reach/Implementation/Maintenance) and change in global cognitive composite over 2 years

What was found: Mean annual change 0.31 SD (95% CI 0.28-0.34) SLI vs 0.20 SD (0.17-0.23) FLI; between-group difference 0.11 SD per year (95% CI 0.06-0.15)

Who was studied: At-risk adults 60-77 (CAIDE score >=6 and suboptimal cognitive performance) in 11 Latin American countries; 75% women; 59% Mestizo, 27% White

Limitations: Comparator was an active health-advice arm, not usual care; both groups improved (practice effects likely); participants and staff unmasked; analytic sample 1065 of 1719 assessed; higher dropout in FLI (20.2% vs 15.2%); adverse events far more frequent in SLI (412 vs 66, mostly musculoskeletal). NCT06492967.

Replication: replicated

Source: Lancet 2026;408(10553):417-429 · 2026 · PubMed 42442374 · doi:10.1016/S0140-6736(26)01278-X

What was tried: 48 months of supervised moderate-to-high-intensity multimodal training (aerobic, resistance, stretching) vs usual habits

• 882 people
• Ages older adults (ages not given in abstract)
• For 48 months
• p = 0.008 (healthy); 0.052 (SMC)

What was measured: 48-month change in MMSE

What was found: Healthy participants: exercise group higher MMSE than control (between-group effect p=0.008, partial eta-squared 0.007; time x group interaction partial eta-squared 0.025); SMC group between-group p=0.052 (partial eta-squared 0.004; interaction partial eta-squared 0.031); better memory, attention and reasoning in healthy and SMC exercisers

Who was studied: 882 community-dwelling older adults classed as healthy, subjective memory complaints (SMC) or MCI; 674 in final analysis

Limitations: Single-blind; 24% not in final analysis (674/882); MCI subgroup too small for conclusive analysis (authors); very small effect sizes; MMSE has ceiling effects in healthy adults.

Replication: not-replicated

Source: Iuliano E et al. Front Aging 2026;7:1847451 · 2026 · PubMed 42639433 · doi:10.3389/fragi.2026.1847451

What was tried: 6-month WeChat-delivered digital multidomain cognitive intervention vs control

• 166 people
• Ages >=60
• For 6 months
• p = 0.037 (MoCA)

What was measured: general cognitive function (MoCA)

What was found: MoCA improved vs control (t=2.106); ROCFT immediate and long-delay recall improved; UCLA loneliness reduced (Z=-2.641); no other significant differences

Who was studied: 166 adults >=60 with modified dementia risk score >79 at Fujian Provincial Hospital and 4 community health centres (April-December 2024); 154 (92.8%) completed

Limitations: Abstract does not enumerate limitations; small single-region sample (166), 6-month duration, no long-term follow-up, multiple secondary outcomes with borderline p-values.

Replication: not-replicated

Source: Yan Y et al. J Clin Psychiatry 2026;87(1):25m15860 · 2026 · PubMed 41499182 · doi:10.4088/JCP.25m15860

What was tried: Same as J-MINT 18-month multidomain intervention; secondary analysis by presence of untreated/uncontrolled vascular risk factors (BP, HbA1c, HDL, non-HDL cholesterol)

• 531 people
• Ages 65-85
• For 18 months
• p = 0.032 (interaction)

What was measured: interaction of intervention x VRF status on change in average neuropsychological Z score over 18 months

What was found: In participants with VRFs: Z score difference 0.11 (95% CI 0.02-0.20); no benefit in those without VRFs; interaction p=0.032

Who was studied: J-MINT participants (MCI, 65-85); 298 had >=1 untreated or uncontrolled VRF

Limitations: Secondary/subgroup analysis of a trial that was null on its primary outcome; hypothesis-generating. UMIN000038671.

Replication: not-replicated

Source: Alzheimers Dement 2025 (J-MINT investigators) · 2025 · PubMed 41222037 · doi:10.1002/alz.70822

What was tried: Non-physician community healthcare provider-led stepped-care antihypertensive titration to systolic <130 / diastolic <80 mm Hg (with physician supervision, home BP monitoring, health coaching) vs usual care; village-level cluster randomisation

• 33,995 people
• Ages 40+
• For 48 months
• p = 0.0035

What was measured: all-cause dementia (blinded endpoint adjudication)

What was found: All-cause dementia RR 0.85 (95% CI 0.76-0.95); net SBP reduction 22.0 mm Hg (95% CI 20.6-23.4), DBP reduction 9.3 mm Hg (95% CI 8.7-10.0); serious adverse events RR 0.94 (95% CI 0.91-0.98)

Who was studied: Adults >=40 with uncontrolled hypertension in 326 rural Chinese villages (163 intervention, 163 usual care)

Limitations: Open-label cluster design; rural China with very large achievable BP reduction (22 mm Hg) and low baseline treatment, so generalisability to well-treated populations is uncertain; only a 4-year window. NCT03527719.

Replication: not-replicated

Source: He J et al. Nat Med 2025;31(6):2054-2061 · 2025 · PubMed 40258956 · doi:10.1038/s41591-025-03616-8

What was tried: 3-year online, personalised multidomain coaching in 2-4 modules targeting physical activity, nutrition, cognitive activity (computerised brain training) and depression/anxiety, vs control receiving module-eligible information only

• 6,104 people
• Ages 55-77
• For 3 years
• p = <0.001

What was measured: 3-year change in global cognitive composite

What was found: Change in z score 0.28 (95% CI 0.25-0.32) intervention vs 0.10 (95% CI 0.07-0.13) control; between-group difference 0.18 (95% CI 0.13-0.23)

Who was studied: Dementia-free community-dwelling Australians aged 55-77 with modifiable dementia risk factors (45 and Up Study cohort); 64% female

Limitations: Online-only cognitive testing (potential overlap between brain-training module practice and outcome tests); single-blind; control received information only; younger and healthier than FINGER-type samples; 'social' tag reflects the depression/anxiety module (closest schema category). ACTRN12618000851268.

Replication: not-replicated

Source: Brodaty H et al. Nat Med 2025;31(2):565-573 · 2025 · PubMed 39875685 · doi:10.1038/s41591-024-03351-6

What was tried: Hearing intervention (audiological counselling + hearing aids) vs health education control

• 977 people
• Ages 70-84
• For 3 years

What was measured: interaction between predicted risk of cognitive decline and randomisation on 3-year cognitive decline

What was found: Among participants in the top quartile of predicted risk, 3-year cognitive decline was 61.6% (95% CI 33.7%-94.1%) slower with hearing intervention than control

Who was studied: 977 ACHIEVE participants; predicted-risk model developed in 2692 dementia-free ARIC participants

Limitations: Secondary/subgroup analysis; primary ACHIEVE result was null; effect-modification analyses are hypothesis-generating. NCT03243422.

Replication: not-replicated

Source: Pike JR et al. Alzheimers Dement 2025;21(5):e70156 · 2025 · PubMed 40369891 · doi:10.1002/alz.70156

What was tried: Best-practice hearing intervention (4 audiologist sessions, hearing aids, counselling, education) vs health-education control, 3 years

• 977 people
• Ages 70-84
• For 3 years

What was measured: exploratory: social isolation (Cohen Social Network Index) and loneliness (UCLA Loneliness Scale) over 3 years

What was found: Hearing intervention vs control: social network size +1.05 (95% CI 0.01-2.09), diversity +0.19 (95% CI 0.02-0.36), embeddedness +0.27 (95% CI 0.09-0.44); loneliness -0.94 (95% CI -1.78 to -0.11)

Who was studied: 977 adults 70-84 with untreated hearing loss without substantial cognitive impairment at 4 US sites (238 from ARIC, 739 de novo); mean age 76.3; mean better-ear PTA 39.4 dB

Limitations: Authors: exploratory outcomes; clinical meaningfulness of retaining ~1 additional social contact is unknown and loneliness changes were not clinically meaningful.

Replication: not-replicated

Source: Reed NS et al. JAMA Intern Med 2025;185(7):797-806 · 2025 · PubMed 40354063 · doi:10.1001/jamainternmed.2025.1140

What was tried: 2-year personalised multidomain risk-reduction: participant-chosen goals across 8 targeted risk factors with health coaching and nurse visits vs health education control; shifted to remote delivery during COVID-19

• 172 people
• Ages 70-89
• For 2 years
• p = 0.02

What was measured: change in composite modified Neuropsychological Test Battery

What was found: Composite cognition ATE 0.14 SD (95% CI 0.03-0.25), described as 74% improvement vs control change; composite risk-factor score ATE 0.11 SD (95% CI 0.01-0.20, P=0.03); QOL ATE 0.81 points (95% CI -0.21 to 1.84, P=0.12)

Who was studied: Adults 70-89 at elevated dementia risk (>=2 of 8 targeted risk factors) from Kaiser Permanente Washington primary care; 62.8% women; mean age 75.7

Limitations: Small pilot-scale trial (n=172); COVID-19 forced switch to remote delivery; musculoskeletal pain 14 vs 0. NCT03683394.

Replication: not-replicated

Source: Yaffe K et al. JAMA Intern Med 2024;184(1):54-62 (online Nov 2023) · 2024 · PubMed 38010725 · doi:10.1001/jamainternmed.2023.6279

What was tried: Four-arm cognitive training RCT: memory training, reasoning training, speed-of-processing training (with optional booster sessions), or no-contact control; linked to Medicare claims 1999-2019

• 2,021 people
• Ages 65+
• For 20 years follow-up

What was measured: claims-based diagnosed Alzheimer's disease and related dementias (Chronic Conditions Warehouse algorithm)

What was found: Speed training with >=1 booster session HR 0.75 (95% CI 0.59-0.95); speed training without booster HR 1.01 (95% CI 0.81-1.27); no main effect of memory or reasoning training

Who was studied: ACTIVE participants enrolled in traditional Medicare at baseline (older adults 65+, diverse US sample)

Limitations: Claims-based (not adjudicated) dementia; booster completion is post-randomisation (self-selected), so the HR 0.75 is not a pure ITT effect; original ACTIVE trial had no primary dementia outcome; sample restricted to traditional Medicare enrolees.

Replication: not-replicated

Source: Alzheimers Dement (N Y) 2026;12(1):e70197 · 2026 · PubMed 41669119 · doi:10.1002/trc2.70197

What was tried: Hearing intervention vs health education control

• 164 people
• Ages 70-84 (mean 78.1)
• For 3 years
• p = 0.019 (GFAP); 0.098 (NfL)

What was measured: 3-year change in plasma GFAP (neuroinflammation) and NfL (neurodegeneration)

What was found: GFAP change: intervention -0.026 (95% CI -0.144 to 0.093) vs control 0.149 (0.039 to 0.260); difference -0.175 (95% CI -0.322 to -0.028). NfL: 0.171 vs 0.330; difference -0.159 (95% CI -0.348 to 0.029)

Who was studied: ACHIEVE participants recruited from the ARIC cohort with plasma at baseline and 3 years (n=164; mean age 78.1)

Limitations: Small ARIC-only subsample (n=164); non-specific biomarkers; secondary analysis. NCT03243422.

Replication: not-replicated

Source: Pike JR et al. EClinicalMedicine 2026;99:104164 · 2026 · PubMed 42733779 · doi:10.1016/j.eclinm.2026.104164

What was tried: Structured high-intensity multidomain lifestyle (physical + cognitive activity, MIND-style healthy diet, social engagement, cardiovascular health monitoring; team-based with coaching and accountability) vs self-guided lower-intensity version of the same domains. NOTE: no no-intervention/usual-care control arm.

• 2,111 people
• Ages 60-79
• For 2 years
• p = 0.008

What was measured: difference between arms in annual rate of change in global cognitive function

What was found: Annual rate of increase 0.243 SD (95% CI 0.227-0.258) structured vs 0.213 SD (95% CI 0.198-0.229) self-guided; between-group difference 0.029 SD/year (95% CI 0.008-0.050)

Who was studied: US older adults at risk of cognitive decline: sedentary lifestyle + suboptimal diet + >=2 of family history of memory impairment, cardiometabolic risk, race/ethnicity, older age, sex; 5 US sites

Limitations: Both arms improved substantially (0.24 and 0.21 SD/yr, likely practice effects + self-guided arm itself being an intervention); no true control arm so absolute effect of lifestyle change vs nothing cannot be estimated; small between-group difference (0.029 SD/yr); clinical relevance and durability unresolved per authors; single-blind. NCT03688126.

Replication: replicated

Source: Baker LD et al. JAMA 2025;334(8):681-691 · 2025 · PubMed 40720610 · doi:10.1001/jama.2025.12923

What was tried: 12 months of continuous positive airway pressure (CPAP) plus best supportive care vs best supportive care alone

• 148 people
• Ages middle-aged (not specified in abstract)
• For 12 months (primary endpoint at 6 months)
• p = 0.91 (primary)

What was measured: Montreal Cognitive Assessment (MoCA) score at 6 months

What was found: MoCA difference -0.04 (95% CI -0.72 to 0.65), P=0.91 [null]; DMN functional connectivity difference -13.73 (95% CI -23.40 to -4.06), P=0.01; cortical thickness difference -0.06 mm (95% CI -0.10 to -0.01), P=0.02

Who was studied: Middle-aged adults with obstructive sleep apnea (AHI >=15/h) and normal cognition; 5 hospitals, China, 2017-2021

Limitations: Small; cognitively normal participants with ceiling on MoCA; short; not an older/at-risk-for-dementia population; 'sensory' tag used as closest schema category for a sleep/breathing intervention.

Replication: not-replicated

Source: Am J Respir Crit Care Med 2025;211(4):628-636 · 2025 · PubMed 39998447 · doi:10.1164/rccm.202406-1170OC

What was tried: Intensive (SBP <120) vs standard (SBP <140) treatment for 3.3 years; cognitive status re-ascertained by telephone from Dec 2019

• 9,361 people
• Ages 50+
• For median 7 years follow-up

What was measured: probable dementia (prespecified secondary analysis with extended follow-up)

What was found: Probable dementia HR 0.86 (95% CI 0.72-1.02), 8.5 vs 10.2 per 1000 person-years (248 vs 293 cases); MCI HR 0.87 (95% CI 0.76-1.00); MCI or probable dementia HR 0.89 (95% CI 0.79-0.99)

Who was studied: SPRINT participants; 7221 (77%) eligible for recontact, cognitive status ascertained for 4232 (59%); mean age 67, 36% female

Limitations: Still under-accrued for dementia (216 of 326 target cases); only 59% of eligible re-contacted; telephone ascertainment; Class II evidence.

Replication: not-replicated

Source: Neurology 2025;104(3):e213334 (SPRINT Research Group) · 2025 · PubMed 39819096 · doi:10.1212/WNL.0000000000213334

What was tried: High-dose subcutaneous gantenerumab up to 1500 mg every 2 weeks, open-label, for up to 3 years after the double-blind DIAN-TU-001 period

• 73 people
• Ages adults at risk for dominantly inherited AD (ages not given in abstract)
• For 3 years (stopped early after interim analysis; 13 completed 3 years)
• p = <0.0001 (PiB-PET SUVR); HRs not significant

What was measured: final analysis: 11C-PiB-PET SUVR change at 3 years (mITT n=55); prespecified interim: CDR-SB clinical decline in asymptomatic carriers vs external controls

What was found: Interim HR for CDR-SB decline in asymptomatic carriers 0.79 (95% CI 0.47-1.32; n=53) for any gantenerumab exposure and 0.53 (95% CI 0.27-1.03; n=22) for the longest-treated group; PiB-PET SUVR change from OLE baseline to year 3: -0.71 (95% CI -0.88 to -0.53)

Who was studied: Dominantly inherited AD mutation carriers who had completed DIAN-TU-001 and knew their mutation status; 18 sites in 8 countries; 74 recruited, 73 treated

Limitations: Authors: conclusions limited by open-label design and use of external controls; study stopped early by sponsor (no regulatory path for gantenerumab) - 47 of 73 stopped dosing for that reason and only 13 completed 3 years; small numbers (HR estimates on n=53 and n=22).

Replication: not-replicated

Source: Bateman RJ et al. Lancet Neurol 2025;24(4):316-330 · 2025 · PubMed 40120616 · doi:10.1016/S1474-4422(25)00024-9

What was tried: Hearing intervention: audiological counselling + provision and fitting of hearing aids vs health education control (individual sessions with health educator on chronic disease prevention); follow-up every 6 months

• 977 people
• Ages 70-84 (mean 76.8)
• For 3 years
• p = 0.96 (primary); 0.010 (cohort interaction); 0.027 (ARIC subgroup)

What was measured: 3-year change in global cognition standardised factor score from comprehensive neurocognitive battery

What was found: Total cohort: 3-year change -0.200 (95% CI -0.256 to -0.144) hearing vs -0.202 (-0.258 to -0.145) control; difference 0.002 (95% CI -0.077 to 0.081), p=0.96 [blank]. Prespecified sensitivity analysis by cohort (p interaction=0.010): ARIC cohort difference 0.191 (95% CI 0.022 to 0.360), p=0.027, described as a 48% reduction in 3-year cognitive change; de novo cohort difference -0.061 (95% CI -0.151 to 0.028), p=0.18

Who was studied: US adults 70-84 with untreated hearing loss, without substantial cognitive impairment; 4 community sites; two recruitment sources: ARIC cohort (n=238, older, more risk factors, lower baseline cognition) and healthy de novo volunteers (n=739); 88% White

Limitations: Primary analysis null; the widely cited 48% figure is a prespecified sensitivity/subgroup analysis in the higher-risk ARIC cohort (24% of sample) and needs replication; unmasked; 88% White; healthy-volunteer de novo cohort declined less than expected. NCT03243422.

Replication: not-replicated

Source: Lin FR et al. Lancet 2023;402(10404):786-797 · 2023 · PubMed 37478886 · doi:10.1016/S0140-6736(23)01406-X

What was tried: 2x2 factorial: cocoa extract (500 mg/day flavanols) vs placebo and daily multivitamin-mineral (Centrum Silver) vs placebo, 3 years; telephone cognitive assessment

• 2,262 people
• Ages 65+ (women), 60+ (men) per COSMOS design; mean 73
• For 3 years
• p = 0.28 (cocoa); 0.007 (multivitamin)

What was measured: change in global cognition composite with cocoa extract (primary); with multivitamin (prespecified secondary)

What was found: Cocoa extract: mean z 0.03 (95% CI -0.02 to 0.08), P=0.28 [null]; multivitamin: mean z 0.07 (95% CI 0.02-0.12), P=0.007 [positive]; multivitamin effect with CVD history 0.14 (95% CI -0.02 to 0.31) vs no history 0.06 (0.01-0.11), interaction nominal P=0.01

Who was studied: US older adults (mean age 73; 60% women; 89% non-Hispanic White); ancillary to COSMOS

Limitations: Multivitamin was the secondary comparison; telephone-only testing; 89% non-Hispanic White; incident MCI/dementia not reduced (see cosmos-mind-2023-incidence row).

Replication: replicated

Source: Baker LD et al. Alzheimers Dement 2023;19(4):1308-1319 · 2023 · PubMed 36102337 · doi:10.1002/alz.12767

What was tried: CPAP treatment for obstructive sleep apnea vs control (sham/no CPAP), pooled from randomised trials

• 1,926 people
• For varied
• p = 0.025 (severe OSA attention/speed)

What was measured: cognitive domains: attention/processing speed, executive function, memory; subjective sleepiness

What was found: Attention/processing speed improved only in severe OSA: SMD 0.17 (95% CI 0.02-0.31), I2=0%; no significant effects in other domains or overall

Who was studied: Adults with OSA in 14 RCTs (pooled n=1926)

Limitations: POOLED estimate from heterogeneous short trials, not a single trial; mostly not dementia-risk populations; sleep-apnea treatment tagged 'sensory' as nearest schema category.

Replication: not-replicated

Source: J Alzheimers Dis 2020;75(3):705-715 · 2020 · PubMed 32310179 · doi:10.3233/JAD-200088

What was tried: Dulaglutide 1.5 mg subcutaneous weekly (GLP-1 receptor agonist) vs placebo; cognition assessed with MoCA and DSST at baseline and follow-up

• 9,901 people
• Ages >=50
• For median 5.4 years (IQR 5.1-5.9)
• p = 0.11 (unadjusted); 0.0018 (post-hoc adjusted)

What was measured: exploratory: first occurrence of substantive cognitive impairment (MoCA or DSST score >=1.5 SD below country baseline mean)

What was found: 4.05 vs 4.35 events per 100 patient-years; HR 0.93 (95% CI 0.85-1.02); after post-hoc adjustment for individual standardised baseline scores HR 0.86 (95% CI 0.79-0.95)

Who was studied: Adults >=50 with type 2 diabetes and additional cardiovascular risk factors at 371 sites in 24 countries; 9901 randomized (4949 dulaglutide, 4952 placebo); 8828 with baseline plus follow-up cognitive scores

Limitations: Exploratory analysis of a cardiovascular outcomes trial (cognition was not a primary endpoint); the prespecified unadjusted comparison was not significant and benefit appeared only after post-hoc adjustment; diabetes population only.

Replication: not-replicated

Source: Cukierman-Yaffe T et al. Lancet Neurol 2020;19(7):582-590 · 2020 · PubMed 32562683 · doi:10.1016/S1474-4422(20)30173-3

What was tried: Same as US POINTER: structured vs self-guided multidomain lifestyle intervention; ancillary MRI/PET substudy

• 983 people
• Ages 60-79
• For 2 years

What was measured: 4 primary imaging outcomes: global beta-amyloid burden (PET), entorhinal cortex tau burden (PET), hippocampal volume, white matter hyperintensity volume

What was found: No intervention-group differences in longitudinal cognitive or imaging outcomes in the imaging subsample; lower baseline hippocampal volume associated with greater cognitive benefit of structured arm (lower HC: 0.077 SD, 95% CI 0.022-0.132; higher HC: 0.002 SD, 95% CI -0.037 to 0.041; interaction P=0.03); ERC tau-cognition association difference 0.289 (95% CI 0.029-0.550; interaction P=0.03)

Who was studied: US POINTER participants eligible for and consenting to neuroimaging (983 of 1943 assessed; 516 structured, 467 self-guided; 61.5% female; mean age 68.4)

Limitations: Subsample of parent trial (about half); 2-year window may be too short for biomarker change; no usual-care control.

Replication: ongoing

Source: Harrison TM et al. JAMA Neurol 2026;83(6):521-529 · 2026 · PubMed 42008251 · doi:10.1001/jamaneurol.2026.0832

What was tried: Oral semaglutide (GLP-1 receptor agonist) up to 14 mg once daily (flexible dose) vs placebo for up to 156 weeks

• 3,808 people
• Ages 55-85 (mean 72.2)
• For 104 weeks primary endpoint (treatment up to 156 weeks); trials discontinued for negative outcome
• p = 0.57 (evoke); 0.46 (evoke+)

What was measured: change in Clinical Dementia Rating-Sum of Boxes (CDR-SB) from baseline to week 104

What was found: Evoke: CDR-SB change 2.3 (SE 0.1) semaglutide vs 2.3 (0.1) placebo, estimated difference -0.08 (95% CI -0.35 to 0.20); evoke+: 2.2 vs 2.1, difference 0.10 (95% CI -0.17 to 0.38)

Who was studied: Amyloid-confirmed early symptomatic Alzheimer's disease (MCI or mild dementia due to AD), aged 55-85; evoke+ additionally allowed significant small-vessel pathology (54 participants, 2.8%); 566 sites in 40 countries

Limitations: Treatment trial in symptomatic AD, not a primary-prevention trial; observational GLP-1/dementia associations were not confirmed; TEAEs 91.2% semaglutide vs 84.8% placebo. NCT04777396, NCT04777409. Both trials discontinued.

Replication: not-replicated

Source: Lancet 2026;407(10544):2167-2179 (evoke and evoke+ investigators) · 2026 · PubMed 41865758 · doi:10.1016/S0140-6736(26)00459-9

What was tried: Daily subcutaneous liraglutide (GLP-1 receptor agonist) vs placebo for 52 weeks

• 204 people
• For 52 weeks
• p = 0.14 (primary)

What was measured: change in cerebral glucose metabolic rate (FDG-PET)

What was found: Primary FDG-PET difference -0.17 (95% CI -0.39 to 0.06), P=0.14; ADAS-Exec better with liraglutide 0.15 (95% CI 0.03-0.28), unadjusted P=0.01; ADCS-ADL -0.58 (95% CI -3.13 to 1.97), P=0.65; CDR-SB -0.06 (95% CI -0.57 to 0.44), P=0.81

Who was studied: Mild to moderate Alzheimer's disease syndrome, non-diabetic; multicentre UK phase 2b

Limitations: Phase 2b, small n, symptomatic AD (treatment, not prevention); secondary cognitive signal unadjusted for multiplicity. NCT01843075.

Replication: not-replicated

Source: Edison P et al. Nat Med 2026;32(1):353-361 (epub Dec 2025) · 2026 · PubMed 41326666 · doi:10.1038/s41591-025-04106-7

What was tried: Cognitive behavioural therapy for insomnia (CBT-I) vs control; assessments at baseline, 6 weeks and 1 year

• 200 people
• Ages older adults (not specified in abstract)
• For 1 year
• p = 0.78; 0.40; 0.77

What was measured: change in cognitive performance (processing speed, executive function, memory) and amyloid-beta burden (subsample n=50)

What was found: Processing speed mean difference 0.017 (95% CI -0.1036 to 0.1376), p=0.78; executive function -0.0881 (95% CI -0.2945 to 0.1182), p=0.40; memory 0.4068 (95% CI -2.3965 to 3.2101), p=0.77; no group difference in amyloid deposition

Who was studied: Cognitively normal older adults with insomnia symptoms

Limitations: 1-year follow-up too short for AD-risk outcomes per authors; small amyloid subsample; 'cognitive-training' tag used for a behavioural (CBT) intervention as closest schema category.

Replication: not-replicated

Source: Alzheimers Dement 2026;22(6):e71591 · 2026 · PubMed 42298279 · doi:10.1002/alz.71591

What was tried: Crenezumab (anti-amyloid-beta antibody) subcutaneous 300 mg then 720 mg every 2 weeks, later optional 60 mg/kg IV every 4 weeks, vs placebo, for 5-8 years in cognitively unimpaired mutation carriers; mutation non-carriers received placebo as a masked kindred control

• 252 people
• Ages 30-60
• For 5-8 years (common close); enrolled Dec 2013-Feb 2017, final data March 2022
• p = 0.43 (composite); 0.16 (FCSRT-CI)

What was measured: dual primary: annualised rate of change in API preclinical ADAD composite total score and in FCSRT Cueing Index

What was found: API ADAD composite annualised change -1.10 (SE 0.29) crenezumab vs -1.43 (0.29) placebo, difference 0.33 (95% CI -0.48 to 1.13); FCSRT-CI -0.03 vs -0.04, difference 0.01 (95% CI 0.00 to 0.02)

Who was studied: Cognitively unimpaired PSEN1 Glu280Ala (E280A) kindred members aged 30-60 in Medellin, Colombia; 85 crenezumab carriers, 84 placebo carriers, 83 placebo non-carriers; 63% women

Limitations: Single-centre, single-kindred phase 2 with 169 mutation carriers; crenezumab did not remove fibrillar amyloid, so the trial does not test plaque clearance; authors conclude robust fibrillar amyloid removal appears necessary for clinical efficacy.

Replication: not-replicated

Source: Tariot PN et al. Lancet Neurol 2026;25(2):147-159 · 2026 · PubMed 41579901 · doi:10.1016/S1474-4422(25)00426-0

What was tried: 18 months of supervised (first 12 months) moderate-high intensity aerobic training vs low-intensity stretching/balance/range-of-motion

• 296 people
• Ages 65-89 (per trial design; abstract states older adults)
• For 18 months
• p = 0.3

What was measured: global cognitive composite (ADAS-Cog-Exec) at 12 months

What was found: Aerobic vs stretching regression coefficient -0.078 (SE 0.074); no 12-month cognitive decline in either group; mean 12-month hippocampal volume loss 0.51% in both groups

Who was studied: Sedentary older adults with amnestic MCI; multicentre US phase 3

Limitations: No no-exercise control (both arms exercised, so absolute exercise effect unmeasured); the companion ADNI comparison (PMID 40271887) is non-randomised; age range stated from trial design rather than abstract.

Replication: not-replicated

Source: Baker LD et al. Alzheimers Dement 2025;21(4):e14586 · 2025 · PubMed 40271888 · doi:10.1002/alz.14586

What was tried: FINGER-based multimodal lifestyle intervention vs control

• 56 people
• Ages 60-77 (mean 68.8)
• For ~28 months between scans

What was measured: hippocampal volume, entorhinal cortex thickness, free water fraction, PSMD, WMH volume, grey-matter cerebral blood flow

What was found: No conclusive intervention effect on any marker; entorhinal thickness and free water declined MORE in intervention group in preregistered models but not after adjusting for baseline differences; exploratory: cerebral blood flow increased more in intervention group, associated with SBP reductions (no numeric estimates in abstract)

Who was studied: Leipzig AgeWell.de participants with 3T MRI before/after intervention (56 baseline, 41 follow-up; mean age 68.8)

Limitations: Very small (41 with follow-up), single site, smaller than planned; baseline imbalance.

Replication: not-replicated

Source: Beyer F et al. Neuroimage Clin 2025;46:103796 · 2025 · PubMed 40378769 · doi:10.1016/j.nicl.2025.103796

What was tried: 18-month multidomain intervention: management of vascular risk factors + exercise + nutritional counselling + cognitive training vs control

• 531 people
• Ages 65-85
• For 18 months

What was measured: change in cognitive composite score over 18 months

What was found: Between-group difference in composite change 0.047 (95% CI -0.029 to 0.124)

Who was studied: Japanese community-dwelling older adults 65-85 with mild cognitive impairment

Limitations: MCI population (later stage than FINGER); 18 months; 24% attrition; subgroup findings exploratory.

Replication: not-replicated

Source: Sakurai T et al. Alzheimers Dement 2024;20(6):3918-3930 · 2024 · PubMed 38646854 · doi:10.1002/alz.13838

What was tried: 4 years of oral conjugated equine estrogens 0.45 mg/d or transdermal estradiol 50 ug/d (each with cyclic micronized progesterone) vs placebo in the KEEPS trial (2005-2008), re-assessed ~10 years after trial completion (2017-2022)

• 275 people
• Ages recently postmenopausal at randomization (ages not given in abstract)
• For 4-year treatment + ~10-year post-trial follow-up (~14 years from randomization)

What was measured: cognitive performance (4 cognitive factor scores and global score) at ~10 years after trial end by original randomization arm

What was found: MHT allocation had no significant effect on cognitive slopes during KEEPS or across all years of follow-up in any domain; cross-sectional performance similar in oCEE, tE2 and placebo groups

Who was studied: Recently postmenopausal women (within 3 years of final menstrual period at randomization); 299 of 727 original participants enrolled at 7 of 9 sites, 275 with cognitive data at both time points

Limitations: Observational follow-up of 41% of the original randomized cohort (authors report similar baseline characteristics for returners vs non-returners); 7 of 9 sites; healthy population.

Replication: replicated

Source: Gleason CE et al. PLoS Med 2024;21(11):e1004435 · 2024 · PubMed 39570992 · doi:10.1371/journal.pmed.1004435

What was tried: MIND diet (Mediterranean-DASH hybrid) with mild caloric restriction vs control diet with mild caloric restriction; both arms received dietary counselling and weight-loss support; 3 years

• 604 people
• Ages 65+
• For 3 years
• p = 0.23

What was measured: change from baseline in global cognition score and four domain scores (12-test battery)

What was found: Global cognition improved in both groups: +0.205 SD MIND vs +0.170 SD control; mean difference 0.035 SD (95% CI -0.022 to 0.092)

Who was studied: Cognitively unimpaired older adults with family history of dementia, BMI >25 and suboptimal diet; two US sites (Chicago, Boston)

Limitations: Control diet also involved counselling and caloric restriction (active comparator); both groups improved (practice effects/weight loss); age range not stated in abstract (65+ per trial design, from PMC). NCT02817074.

Replication: not-replicated

Source: Barnes LL et al. N Engl J Med 2023;389(7):602-611 · 2023 · PubMed 37466280 · doi:10.1056/NEJMoa2302368

What was tried: Same 2x2 factorial: cocoa extract and multivitamin-mineral vs placebo, 3 years

• 2,262 people
• Ages mean 73
• For 3 years
• p = >=0.05

What was measured: incident adjudicated MCI and all-cause probable dementia

What was found: Incidence rates did not vary by multivitamin or cocoa assignment (all p >= 0.05); among converters to MCI, multivitamin group had higher global cognition (p=0.03) and executive function (p<0.001) scores

Who was studied: COSMOS-Mind participants

Limitations: Very low event counts (14 dementia); authors state low statistical power.

Replication: not-replicated

Source: Alzheimers Dement 2023;19(11):4863-4871 · 2023 · PubMed 37035889 · doi:10.1002/alz.13078

What was tried: Solanezumab (anti-monomeric amyloid-beta antibody) up to 1600 mg IV every 4 weeks vs placebo, in cognitively unimpaired adults with elevated amyloid PET (secondary prevention setting)

• 1,169 people
• Ages 65-85
• For 240 weeks (~4.6 years)
• p = 0.26

What was measured: change in Preclinical Alzheimer Cognitive Composite (PACC) over 240 weeks

What was found: PACC change -1.43 solanezumab vs -1.13 placebo; difference -0.30 (95% CI -0.82 to 0.22)

Who was studied: Cognitively unimpaired persons 65-85 with global CDR 0, MMSE >=25 and elevated brain amyloid on 18F-florbetapir PET; mean age 72, ~60% women, 75% family history of dementia

Limitations: Abstract does not enumerate limitations. Design note from the abstract: solanezumab targets monomeric (not plaque) amyloid and only partially slowed amyloid accumulation, so the trial does not test plaque removal in preclinical AD. NCT02008357.

Replication: not-replicated

Source: Sperling RA et al. N Engl J Med 2023;389(12):1096-1107 · 2023 · PubMed 37458272 · doi:10.1056/NEJMoa2305032

What was tried: Marine n-3 fatty acids 1 g/day (840 mg EPA+DHA) vs placebo within the 2x2 VITAL trial (vitamin D3 2000 IU/day the other factor)

• 4,218 people
• Ages 60+
• For 2.8 years (telephone) / 2.0 years (in person)
• p = 0.15

What was measured: change in global cognitive composite score (mean of test z scores) over two assessments

What was found: Annual rate of cognitive change, n-3 vs placebo: -0.01 SU (95% CI -0.02 to 0.003) VITAL-Cog and -0.002 (95% CI -0.04 to 0.03) CTSC-Cog; pooled -0.01 (95% CI -0.02 to 0.003)

Who was studied: Healthy community-dwelling US adults 60+ (mean age 70.9) free of CVD and cancer: 3424 assessed by telephone (VITAL-Cog, 2.8 years) and 794 in person (CTSC-Cog, 2.0 years)

Limitations: Follow-up only 2-3 years; healthy volunteers; most cognition assessed by telephone; ancillary studies of a CVD/cancer prevention trial.

Replication: replicated

Source: Kang JH et al. Alzheimers Dement (N Y) 2022;8(1):e12288 · 2022 · PubMed 35415212 · doi:10.1002/trc2.12288

What was tried: Gantenerumab (subcutaneous anti-aggregated-amyloid antibody) or solanezumab (IV anti-monomeric antibody) vs placebo, 3:1 per drug arm, 4-7 years, in asymptomatic and symptomatic autosomal-dominant mutation carriers

• 144 people
• Ages adults 15 years before to 10 years after estimated symptom onset (ages not given in abstract)
• For 4-7 years

What was measured: cognitive endpoint (DIAN multivariate cognitive composite)

What was found: Neither drug showed a beneficial effect on cognitive measures vs controls; solanezumab group showed greater cognitive decline on some measures; gantenerumab significantly reduced amyloid plaques, CSF total tau and p-tau181 and attenuated NfL increases

Who was studied: Carriers of dominantly inherited AD mutations, asymptomatic and mildly symptomatic (CDR 0-1), within -15 to +10 years of estimated symptom onset; 52 gantenerumab, 52 solanezumab, 40 placebo

Limitations: Authors note the asymptomatic groups showed no cognitive decline over the trial (so slowing could not be detected) and symptomatic participants had declined before reaching target doses (doses were escalated late); small arms (n=40-52).

Replication: not-replicated

Source: Salloway S et al. Nat Med 2021;27(7):1187-1196 · 2021 · PubMed 34155411 · doi:10.1038/s41591-021-01369-8

What was tried: Low-dose pioglitazone 0.8 mg/day sustained-release vs placebo in cognitively healthy adults classed as high-risk by a TOMM40/APOE/age biomarker risk algorithm (BRAA); low-risk participants received placebo

• 3,494 people
• Ages 65-83
• For event-driven (planned to 202 MCI events); enrolled Aug 2013-Dec 2015, terminated Jan 2018 for futility
• p = 0.307

What was measured: time to onset of MCI due to AD (high-risk pioglitazone vs high-risk placebo); co-primary: high-risk vs low-risk placebo (BRAA qualification)

What was found: MCI in 39/1430 (2.7%) pioglitazone vs 46/1406 (3.3%) placebo, HR 0.80 (99% CI 0.45-1.40); BRAA high vs low risk HR 3.26 (99% CI 0.85-12.45, p=0.023)

Who was studied: Cognitively healthy community-living adults 65-83 at 57 clinics in Australia, Germany, Switzerland, UK and USA; 3494 enrolled (3061 high risk, 433 low risk); 1545 randomized to pioglitazone, 1516 to placebo

Limitations: Authors: study terminated after failing the non-futility threshold, so findings are exploratory only; 1104 participants discontinued treatment; low event rate (3.3% in placebo); BRAA analyses limited to White non-Hispanic participants.

Replication: not-replicated

Source: Burns DK et al. Lancet Neurol 2021;20(7):537-547 · 2021 · PubMed 34146512 · doi:10.1016/S1474-4422(21)00043-0

What was tried: Linagliptin 5 mg (DPP-4 inhibitor) vs glimepiride (sulfonylurea), double-blind active-controlled, in type 2 diabetes

• 3,163 people
• Ages 40-85
• For median 6.1 years

What was measured: accelerated cognitive decline at end of follow-up (regression-based index score <=16th percentile on MMSE or an attention/executive composite)

What was found: Accelerated cognitive decline in 27.8% (449/1618) linagliptin vs 27.6% (426/1545) glimepiride, OR 1.01 (95% CI 0.86-1.18); at week 160 OR 1.07 (95% CI 0.91-1.25); no subgroup differences

Who was studied: Adults 40-85 with relatively early type 2 diabetes (HbA1c 6.5-8.5%) at elevated cardiovascular risk, baseline MMSE >=24; 3163 of the 6033 CAROLINA participants (38% female, mean age 64, diabetes duration 7.6 years)

Limitations: Active-comparator design (no placebo) so neither drug's effect vs no treatment is estimable; cognition substudy of a cardiovascular safety trial; relatively early diabetes with high baseline MMSE.

Replication: replicated

Source: Biessels GJ et al. Diabetologia 2021;64(6):1235-1245 · 2021 · PubMed 33559704 · doi:10.1007/s00125-021-05393-8

What was tried: Vitamin D3 2000 IU/day (cholecalciferol) vs placebo within the 2x2 VITAL trial

• 4,218 people
• Ages 60+
• For 2.8 years (telephone) / 2.0 years (in person)
• p = 0.39

What was measured: decline in global composite cognitive score over two assessments (prespecified)

What was found: Pooled mean difference in annual rate of decline, vitamin D3 vs placebo: 0.01 (95% CI -0.01 to 0.02); no interaction with baseline 25(OH)D (p-interaction 0.84); interaction with self-reported race p=0.01 - Black participants MD 0.04 (95% CI 0.01 to 0.08)

Who was studied: US adults 60+ (mean 70.9) free of CVD and cancer: 3424 telephone-assessed (2.8 years) and 794 in-person (2.0 years); 19% Black participants

Limitations: 2-3 year follow-up; authors state the subgroup result in Black participants needs confirmation; telephone testing for the majority.

Replication: replicated

Source: Kang JH et al. Sci Rep 2021;11(1):23253 · 2021 · PubMed 34853363 · doi:10.1038/s41598-021-02485-8

What was tried: Low-dose aspirin 100 mg daily vs placebo

• 19,114 people
• Ages 70+ (US minorities 65+)
• For median 4.7 years

What was measured: incident all-cause dementia (DSM-IV adjudicated), probable AD, MCI, cognitive decline

What was found: Dementia triggers HR 1.03 (95% CI 0.91-1.17); probable AD HR 0.96 (95% CI 0.74-1.24); MCI HR 1.12 (95% CI 0.92-1.37); cognitive change similar

Who was studied: Community-dwelling adults >=70 (US minorities >=65) in US and Australia, free of CVD, disability and dementia

Limitations: Class II evidence; follow-up ongoing at publication. NCT01038583.

Replication: not-replicated

Source: Ryan J et al. Neurology 2020;95(3):e320-e331 · 2020 · PubMed 32213642 · doi:10.1212/WNL.0000000000009277

What was tried: 2x2x2 factorial: vitamin D3 2000 IU/day, omega-3 1 g/day, and/or a home strength-training exercise programme vs placebo, 3 years

• 2,157 people
• Ages >=70
• For 3 years (median follow-up 2.99 years)

What was measured: 6 primary outcomes including change in Montreal Cognitive Assessment (MoCA) at 3 years

What was found: No statistically significant benefit of any intervention alone or in combination on any of the 6 endpoints including MoCA (99% CIs; P<.01 required)

Who was studied: 2157 generally healthy adults >=70 (mean 74.9; 61.7% women) in 5 European countries with no major health events in prior 5 years, sufficient mobility and good cognitive status

Limitations: Healthy, high-functioning cohort with good baseline cognition (ceiling effects); MoCA as the only cognitive measure; 3-year horizon; 88% completed.

Replication: replicated

Source: Bischoff-Ferrari HA et al. JAMA 2020;324(18):1855-1868 · 2020 · PubMed 33170239 · doi:10.1001/jama.2020.16909

What was tried: 2x2 factorial: candesartan 16 mg + hydrochlorothiazide 12.5 mg vs placebo; rosuvastatin 10 mg vs placebo

• 2,361 people
• Ages 70+ (mean 74)
• For median 5.7 years

What was measured: change in Digit Symbol Substitution Test; also modified MoCA and Trail Making B

What was found: DSST mean difference in change: candesartan/HCTZ vs placebo -0.91 (95% CI -2.25 to 0.42); rosuvastatin vs placebo -0.54 (95% CI -1.88 to 0.80); combination vs double placebo -1.43 (95% CI -3.37 to 0.50); SBP lowered 6.0 mm Hg; LDL lowered 24.8 mg/dL

Who was studied: Adults >=70 at intermediate cardiovascular risk without known CVD, 228 centres in 21 countries; 2361 completed cognitive assessments, 1626 completed both baseline and study end; mean age 74; 59% women; 45% hypertensive

Limitations: Modest BP reduction (6 mm Hg) in a population where only 45% were hypertensive; only 1626 with paired assessments; cognitive tests limited; Class II. NCT00468923.

Replication: not-replicated

Source: Bosch J et al. Neurology 2019;92(13):e1435-e1446 · 2019 · PubMed 30814321 · doi:10.1212/WNL.0000000000007174

What was tried: Naproxen sodium 220 mg twice daily vs placebo for 2 years

• 195 people
• Ages mean 63
• For 2 years

What was measured: rate of change in a multimodal composite presymptomatic Alzheimer Progression Score (APS)

What was found: APS rose 0.102 points/year overall (SE 0.014); treatment-related difference 0.019 points/year; rate ratio 1.16 (95% CI 0.64-1.96), excluding a naproxen benefit larger than 36%; clear excess of adverse events on naproxen

Who was studied: 195 cognitively intact older adults (mean age 63) with a family history of AD, carefully screened to exclude cognitive disorder; modified ITT 160

Limitations: Small (195 randomized, 160 in mITT); surrogate composite progression score rather than clinical onset; 2-year duration; increased adverse events.

Replication: replicated

Source: Meyer PF et al. Neurology 2019;92(18):e2070-e2080 · 2019 · PubMed 30952794 · doi:10.1212/WNL.0000000000007232

What was tried: 2x2 factorial: multidomain intervention (43 group sessions integrating cognitive training, physical activity, nutrition, plus 3 preventive consultations) and/or omega-3 PUFA (800 mg DHA + 225 mg EPA daily) vs placebo

• 1,680 people
• Ages 70+
• For 3 years
• p = 0.142 (combined arm, adjusted); 0.179; 0.812

What was measured: change from baseline to 36 months in composite cognitive Z score

What was found: Vs placebo: multidomain + omega-3 0.093 (95% CI 0.001 to 0.184, adjusted p=0.142); multidomain + placebo 0.079 (-0.012 to 0.170, p=0.179); omega-3 alone 0.011 (-0.081 to 0.103, p=0.812)

Who was studied: Community-dwelling non-demented adults >=70 in France and Monaco with spontaneous memory complaint, or limitation in 1 IADL, or slow gait; 13 memory centres

Limitations: Multidomain component unblinded; frailer/older population than FINGER; adjusted p-values non-significant despite CI of combined arm excluding zero (multiplicity adjustment). NCT00672685.

Replication: not-replicated

Source: Andrieu S et al. Lancet Neurol 2017;16(5):377-389 · 2017 · PubMed 28359749 · doi:10.1016/S1474-4422(17)30040-6

What was tried: Vitamin E, selenium, both, or placebo (ancillary to SELECT prostate-cancer trial); RCT 2002-2009 then cohort follow-up 2009-2015

• 7,540 people
• Ages 60+ (mean 67.5)
• For up to 13 years (RCT phase to 2009, cohort to 2015)

What was measured: incident dementia

What was found: Dementia incidence 325/7338 (4.4%) not different among arms; adjusted HR vs placebo: vitamin E 0.88 (95% CI 0.64-1.20), selenium 0.83 (0.60-1.13), combination 1.00 (0.75-1.35)

Who was studied: Asymptomatic men >=60 at 130 SELECT sites; 10.0% Black, 6.7% Hispanic; 3786 continued into cohort phase

Limitations: Trial terminated early (SELECT futility 2009) and converted to cohort; low dementia incidence; men only; telephone screening in cohort phase.

Replication: not-replicated

Source: Kryscio RJ et al. JAMA Neurol 2017;74(5):567-573 · 2017 · PubMed 28319243 · doi:10.1001/jamaneurol.2016.5778

What was tried: Intensive lifestyle intervention for weight loss and physical activity (average 10 years) vs diabetes support and education

• 3,802 people
• Ages 54.9-87.2 at assessment (45-76 at enrolment per trial design)
• For average 11.4 years after enrolment
• p = 0.93

What was measured: prevalence of centrally adjudicated MCI and probable dementia

What was found: MCI prevalence 6.4% intervention vs 6.6% control; probable dementia 1.8% vs 1.8%; p=0.93; interaction with baseline BMI p=0.03 (effect ranged from benefit at low BMI to harm at high BMI)

Who was studied: Overweight/obese adults with type 2 diabetes (US multicentre); cognitive assessment in 3802 randomised participants at mean 11.4 years (mean age 69.6 at assessment)

Limitations: Cognition was not a primary trial outcome; single cross-sectional assessment (prevalence, not incidence); Class II evidence. NCT00017953.

Replication: not-replicated

Source: Espeland MA et al. Neurology 2017;88(21):2026-2035 · 2017 · PubMed 28446656 · doi:10.1212/WNL.0000000000003955

What was tried: 6-year nurse-led multidomain cardiovascular risk management (vascular care visits every 4 months) vs usual care; cluster-randomised by general practice

• 3,526 people
• Ages 70-78
• For 6 years (median follow-up 6.7 years; 21,341 person-years)
• p = 0.54 (dementia); 0.93 (disability)

What was measured: cumulative incidence of all-cause dementia and disability (ALDS) at 6 years

What was found: Dementia 121/1853 (7%) intervention vs 112/1601 (7%) control, HR 0.92 (95% CI 0.71-1.19); disability adjusted mean difference -0.02 (95% CI -0.38 to 0.42); mortality HR 0.98 (0.80-1.18); incident CVD HR 1.06 (0.86-1.31)

Who was studied: Unselected community-dwelling older adults aged 70-78 from 116 Dutch general practices

Limitations: Open-label; unselected population with modest baseline CV risk and high standard of usual care (authors' explanation for null); cluster design. ISRCTN29711771.

Replication: not-replicated

Source: Moll van Charante EP et al. Lancet 2016;388(10046):797-805 · 2016 · PubMed 27474376 · doi:10.1016/S0140-6736(16)30950-3

What was tried: 24-month structured moderate-intensity physical activity programme (walking, resistance, flexibility) vs health education workshops + upper-extremity stretching

• 1,635 people
• Ages 70-89
• For 24 months
• p = 0.97; 0.84

What was measured: prespecified secondary outcomes: Digit Symbol Coding and HVLT-R delayed recall; tertiary: global/executive composites, incident MCI or dementia

What was found: DSC 46.26 vs 46.28, mean difference -0.01 (95% CI -0.80 to 0.77), P=0.97; HVLT-R delayed recall 7.22 vs 7.25, difference -0.03 words (95% CI -0.29 to 0.24), P=0.84; incident MCI/dementia 13.2% vs 12.1%, OR 1.08 (95% CI 0.80-1.46); executive-function benefit in >=80 y and poorer baseline physical performance subgroups (interaction P=0.01)

Who was studied: Sedentary community-living adults 70-89 at risk for mobility disability but able to walk 400 m; 8 US centres

Limitations: Cognition was a secondary outcome; active control; frail/mobility-limited population. NCT01072500.

Replication: not-replicated

Source: Sink KM et al. JAMA 2015;314(8):781-90 · 2015 · PubMed 26305648 · doi:10.1001/jama.2015.9617

What was tried: Naproxen or celecoxib vs placebo for 1-3 years (treatment stopped 2004), with follow-up to 2007 and re-evaluation 2010-11

• 2,356 people
• For treatment 1-3 years; cognitive follow-up to 2010-11

What was measured: trajectories of cognitive test scores (seven yearly evaluations; global composite)

What was found: No important differences over time by treatment group on any cognitive measure or the global composite (abstract gives no numeric estimate)

Who was studied: Older adults with a family history of Alzheimer's disease (USA)

Limitations: Treatment halted early (2004) for cardiovascular safety concerns with celecoxib/naproxen class; abstract lacks numeric effect estimates; attrition to 1537 at ADAPT-FS. NCT00007189, NCT01417130.

Replication: not-replicated

Source: ADAPT-FS Research Group. Alzheimers Dement 2015;11(2):216-25.e1 · 2015 · PubMed 25022541 · doi:10.1016/j.jalz.2014.03.009

What was tried: Standardised Ginkgo biloba extract EGb761 120 mg twice daily vs placebo, 5 years

• 2,854 people
• Ages 70+
• For 5 years
• p = 0.306

What was measured: conversion to probable Alzheimer's disease

What was found: 61 AD cases (1.2 per 100 person-years) ginkgo vs 73 (1.4 per 100 PY) placebo; HR 0.84 (95% CI 0.60-1.18); risk not proportional over time. Mortality HR 0.94 (0.69-1.28); stroke RR 1.12 (0.77-1.63)

Who was studied: Adults >=70 years with spontaneous memory complaints reported to primary-care physicians, France

Limitations: Industry-funded (Ipsen); non-proportional hazards noted; memory-complaint population. NCT00276510.

Replication: replicated

Source: Vellas B et al. Lancet Neurol 2012;11(10):851-9 · 2012 · PubMed 22959217 · doi:10.1016/S1474-4422(12)70206-5

What was tried: Intensive glycaemic control (HbA1c target <6.0%) vs standard (7.0-7.9%) in type 2 diabetes; 2x2 factorial with BP and lipid arms

• 2,977 people
• Ages 55-80 (mean 62.5)
• For 40 months
• p = 0.2997 (DSST); 0.0007 (TBV)

What was measured: Digit Symbol Substitution Test (DSST) score at 40 months; total brain volume (MRI subset)

What was found: DSST difference in mean 0.32 (95% CI -0.28 to 0.91), p=0.2997; total brain volume greater in intensive group by 4.62 cm3 (95% CI 2.0 to 7.3), p=0.0007

Who was studied: Adults 55-80 with type 2 diabetes, HbA1c >7.5%, high cardiovascular risk; 52 North American sites

Limitations: Intensive arm stopped Feb 2008 for excess mortality in parent ACCORD trial; open-label; cognitive outcome is a single test (DSST). NCT00182910.

Replication: not-replicated

Source: Launer LJ et al. Lancet Neurol 2011;10(11):969-77 · 2011 · PubMed 21958949 · doi:10.1016/S1474-4422(11)70188-0

What was tried: Ginkgo biloba extract 120 mg twice daily vs placebo

• 3,069 people
• Ages 75+
• For median 6.1 years
• p = 0.21 (all-cause dementia)

What was measured: incident all-cause dementia and Alzheimer disease (expert-panel consensus)

What was found: All-cause dementia HR 1.12 (95% CI 0.94-1.33), P=0.21 (3.3 vs 2.9 per 100 person-years); AD HR 1.16 (95% CI 0.97-1.39), P=0.11; MCI-to-dementia HR 1.13 (95% CI 0.85-1.50), P=0.39

Who was studied: Community volunteers >=75 with normal cognition (n=2587) or MCI (n=482); 5 US academic centres; 2000-2008

Limitations: Point estimate numerically favours placebo (non-significant); dropout 6.3%. NCT00010803.

Replication: not-replicated

Source: DeKosky ST et al. JAMA 2008;300(19):2253-62 · 2008 · PubMed 19017911 · doi:10.1001/jama.2008.683

What was tried: Indapamide SR 1.5 mg with optional perindopril 2-4 mg vs placebo (target BP 150/80)

• 3,336 people
• Ages 80+
• For mean 2.2 years follow-up (trial stopped early 2007)
• p = not significant (HYVET alone); 0.045 (meta-analysis incl. HYVET)

What was measured: incident dementia

What was found: Incident dementia 33 vs 38 per 1000 patient-years (263 cases total); HR 0.86 (95% CI 0.67-1.09). BP difference at 2 years: -15/-5.9 mmHg. Pooled with prior placebo-controlled trials: HR 0.87 (0.76-1.00), p=0.045

Who was studied: Hypertensive adults >=80 years (SBP 160-200, DBP <110) without dementia at baseline

Limitations: Stopped early for stroke/mortality benefit so short follow-up; MMSE-based case ascertainment; very old population. NCT00122811.

Replication: replicated

Source: Peters R et al. Lancet Neurol 2008;7(8):683-9 · 2008 · PubMed 18614402 · doi:10.1016/S1474-4422(08)70143-1

What was tried: Umibecestat (oral BACE1 inhibitor) 50 mg or 15 mg daily vs placebo in cognitively unimpaired APOE e4 homozygotes, and heterozygotes with elevated brain amyloid; studies terminated early after ~7 months average exposure

• 1,556 people
• Ages 60-75
• For 7 months treatment on average (terminated early); median 4 (IQR 3-6) months washout follow-up

What was measured: planned: time to diagnosis of MCI/dementia due to AD and API preclinical composite; this report: reversibility of cognitive worsening after washout

What was found: Small, non-progressive but statistically significant decline vs placebo on RBANS and API Preclinical Composite (not CDR-SB) during treatment; RBANS differences no longer significant at end of washout follow-up (numeric effect sizes not in abstract)

Who was studied: Cognitively unimpaired 60-75 year-old APOE e4 homozygotes and heterozygotes with elevated amyloid

Limitations: Studies terminated early (July 2019) so no efficacy readout; reversibility assessed over a median of only 4 months off drug; abstract reports no effect sizes.

Replication: replicated

Source: Tariot PN et al. Alzheimers Dement 2024;20(11):7745-7761 · 2024 · PubMed 39320017 · doi:10.1002/alz.14237

What was tried: Intensive vs standard SBP control; brain MRI at baseline and ~4 years

• 673 people
• Ages 50+ (mean 67.3)
• For median 3.98 years
• p = 0.03

What was measured: change in hippocampal volume, AD regional atrophy pattern, posterior cingulate cerebral blood flow, cingulum fractional anisotropy

What was found: Hippocampal volume decreased 7.45 to 7.39 cm3 (intensive) vs 7.48 to 7.46 cm3 (standard); between-group difference in change -0.033 cm3 (95% CI -0.062 to -0.003), P=0.03 (greater loss with intensive treatment); no differences in AD regional atrophy, CBF or FA

Who was studied: SPRINT MRI substudy: 673 with baseline MRI (356 intensive, 317 standard), 454 with follow-up MRI; mean age 67.3, 40.3% women

Limitations: Small substudy; hippocampal difference tiny and of uncertain clinical meaning (authors relate it to greater total brain volume decrease with intensive treatment); no cognitive consequences shown.

Replication: not-replicated

Source: Nasrallah IM et al. JAMA Neurol 2021;78(5):568-577 · 2021 · PubMed 33683313 · doi:10.1001/jamaneurol.2021.0178

What was tried: Atabecestat (oral BACE inhibitor) 5 mg or 25 mg daily vs placebo (1:1:1) in amyloid-positive cognitively normal adults

• 557 people
• Ages 60-85
• For planned 4.5 years; dosing stopped May 2018 (trial ran Nov 2015-Dec 2018) with 6 months off-treatment follow-up
• p = <0.001

What was measured: change from baseline in Preclinical Alzheimer Cognitive Composite (PACC)

What was found: Atabecestat 25 mg vs placebo: PACC least-squares mean difference -1.09 (95% CI -1.66 to -0.53) at month 6 and -1.62 (95% CI -2.49 to -0.76) at month 12; RBANS -3.70 (95% CI -5.76 to -1.63) at month 3; worsening reversed after 6 months off treatment

Who was studied: Amyloid-positive, cognitively normal (CDR 0) adults aged 60-85 at 143 centres in 14 countries; 557 randomized of 4464 screened (34% of planned 1650); 61% women; mean age 70.4

Limitations: Truncated trial: enrollment stopped at 34% of plan and treatment stopped early for hepatic adverse events, so the planned efficacy question could not be answered; follow-up off-treatment limited to 6 months.

Replication: replicated

Source: Sperling R et al. JAMA Neurol 2021;78(3):293-301 · 2021 · PubMed 33464300 · doi:10.1001/jamaneurol.2020.4857

What was tried: Conjugated equine estrogen 0.625 mg + medroxyprogesterone acetate 2.5 mg daily vs placebo

• 4,532 people
• Ages 65+
• For mean 4.05 years (SD 1.19) to last 3MSE
• p = 0.01 (dementia); 0.72 (MCI)

What was measured: incidence of probable dementia

What was found: Probable dementia HR 2.05 (95% CI 1.21-3.48); 45 vs 22 per 10,000 person-years (40 vs 21 cases); 23 additional dementia cases per 10,000 women per year. MCI HR 1.07 (95% CI 0.74-1.55), 63 vs 59 per 10,000 PY

Who was studied: Postmenopausal women >=65 years free of probable dementia, from 39 WHI clinical centres (USA)

Limitations: Small number of events (61); women >=65 (late initiation), so does not test the 'critical window' hypothesis; parent WHI E+P trial stopped July 2002 for other harms.

Replication: not-replicated

Source: Shumaker SA et al. JAMA 2003;289(20):2651-62 · 2003 · PubMed 12771112 · doi:10.1001/jama.289.20.2651

What was tried: Multidomain lifestyle intervention (FINGER-adapted), 2 years

• 1,008 people
• Ages 60-79
• For 2 years

Who was studied: Cognitively healthy Dutch adults 60-79 with dementia prevention potential; 1008 included via Dutch Brain Research Registry campaign (13,795 registrants, 3475 eligible)

Limitations: No primary outcome publication located as of 2026-09-22; n reflects inclusions via the registry campaign only (total enrolment may differ).

Replication: ongoing

Source: Waterink L et al. Alzheimers Dement (N Y) 2025;11(1):e70017 (recruitment paper) · 2025 · PubMed 39790861 · doi:10.1002/trc2.70017

What was tried: Donanemab IV monthly x9 infusions vs placebo, then clinical assessments every 6 months (decentralized design, plasma p-tau217 eligibility)

• 2,196 people
• Ages 55-80
• For 9 monthly infusions then event-driven follow-up

What was measured: time to clinical progression (time-to-event)

Who was studied: Adults 55-80 in the US and Japan with AD pathology detected by plasma p-tau217; 63,124 screened, 2196 enrolled (CDR-Global 0 n=1202; 0.5 n=664); mean baseline amyloid 63.2 centiloids (CDR 0) and 70.7 (CDR 0.5)

Limitations: Baseline/screening paper only; no efficacy results. Plasma p-tau217 eligibility rates differed by age, race and ethnicity (authors).

Replication: ongoing

Source: Yaari R et al. Alzheimers Dement 2025;21(9):e70662 (screening and baseline paper) · 2025 · PubMed 40955720 · doi:10.1002/alz.70662

What was tried: Multimodal lifestyle (aerobic + resistance exercise, MIND diet advice, BrainHQ cognitive training, medical monitoring/health education) vs health education and coaching, 2 years

• 600 people
• Ages 55-79
• For 2 years

What was measured: change in global composite cognitive score

Who was studied: Australian adults 55-79

Limitations: Protocol only (planned n=600); no results located as of 2026-09-22.

Replication: ongoing

Source: Gardener SL et al. Alzheimers Dement (N Y) 2024;10(2):e12466 (protocol) · 2024 · PubMed 38596483 · doi:10.1002/trc2.12466

What was tried: FINGER 2.0 multidomain lifestyle (diet, physical activity, cognitive training, vascular/metabolic monitoring, social interaction) +/- metformin 1000-2000 mg/day (trial-within-trial, double-blind vs placebo) vs regular health advice

• 600 people
• Ages 60-79
• For 2 years

What was measured: change in global cognition (NTB)

Who was studied: APOE e4-enriched adults 60-79 at increased dementia risk; UK, Finland, Sweden

Limitations: Phase IIb proof-of-concept protocol; planned n=600; no results located as of 2026-09-22. NCT05109169.

Replication: ongoing

Source: Barbera M et al. Alzheimers Res Ther 2024;16(1):23 (protocol) · 2024 · PubMed 38297399 · doi:10.1186/s13195-023-01355-x

What was tried: Lecanemab (BAN2401) IV, dose regimens tailored to baseline amyloid: A3 (intermediate amyloid ~20-40 centiloids, phase 2, PET endpoints) and A45 (elevated amyloid >40 centiloids, phase 3, cognitive composite primary) vs placebo, 4-year treatment

• 1,400 people
• Ages 55-80
• For 4 years treatment

What was measured: A45: change in cognitive composite (PACC5); A3: amyloid PET change

Who was studied: Cognitively unimpaired adults 55-80 with intermediate or elevated brain amyloid; plasma Abeta42/40 used to screen before PET; recruitment via TRC-PAD, ADNeT and J-TRC registries

Limitations: Design paper only; no results. ClinicalTrials.gov NCT04468659: phase 3, ACTIVE_NOT_RECRUITING, enrollment 1400 (ESTIMATED), start 2020-07-14, primary completion 2028-12-21 (registry loaded 2026-09-27).

Replication: ongoing

Source: Rafii MS et al. Alzheimers Dement 2023;19(4):1227-1233 (design paper; epub Aug 2022) · 2023 · PubMed 35971310 · doi:10.1002/alz.12748

What was tried: Structured multidomain lifestyle (diet training, supervised then unsupervised exercise, cognitive training, vascular risk management) vs self-guided intervention, 2 years

• 1,200 people
• Ages 60-77
• For 2 years

What was measured: global cognition (modified Neuropsychological Test Battery)

Who was studied: Singapore adults 60-77 with CAIDE score >=6, >=1 LIBRA lifestyle risk, MoCA 18-27

Limitations: Protocol only; planned n=1200; no results located in PubMed as of 2026-09-22.

Replication: ongoing

Source: Xu X et al. J Prev Alzheimers Dis 2022;9(1):40-48 (protocol) · 2022 · PubMed 35098972 · doi:10.14283/jpad.2022.5

What was tried: Multidomain lifestyle intervention (FINGER-adapted) in rural communities; intervention arm details not in the baseline paper

• 5,765 people
• Ages 60+ (mean 70.9)

Who was studied: Rural residents >=60 years, western Shandong province, China; 5765 completed baseline assessment (mean age 70.9; 57.2% women; 40.6% illiterate)

Limitations: No intervention outcome publication located in PubMed as of 2026-09-22 (search 'MIND-China[tiab]' returned baseline/cross-sectional papers only). the participant count is the baseline cohort, not necessarily the randomised sample.

Replication: ongoing

Source: Wang Y et al. Alzheimers Dement (N Y) 2022;8(1):e12254 (baseline paper) · 2022 · PubMed 35441085 · doi:10.1002/trc2.12254