Every row of the evidence table

The key point: the observational analysis showed light drinking looking protective, but the genetic (Mendelian randomisation) analysis did not, which the authors read as the protective appearance coming from people cutting down in early dementia.

This one reports light-to-moderate drinking as protective (HR 0.65) against non-drinking, and it flatly contradicts the Mendelian randomisation evidence. Infrequent drinkers were excluded, and non-drinkers include people who stopped for health reasons.

Sustained mild and moderate drinking carried lower risk than not drinking, sustained heavy drinking higher risk, and cutting down from heavy to moderate lower risk. Observational, with the same abstainer problem.

U-shaped: long-term abstainers had 47% higher risk than moderate drinkers, and above 14 units a week each extra 7 units raised risk by 17%. Neither end of the range looks like a benefit of drinking.

The exposure is cannabis use severe enough to need hospital care, not cannabis use in general, and the comparison is against other acute-care patients as well as the general population.

Direction is for QUITTING. Risk approached that of never-smokers and levelled off about seven years after quitting; weight gain after quitting narrowed the advantage. The authors flag residual confounding.

The two measures moved in opposite directions over 2015-2021: standardised incidence fell from 3.5% to 2.8% per year while prevalence rose from 10.5% to 11.8%; gaps between Black or Hispanic and White beneficiaries narrowed.

Direction is for more recent birth cohort: after controlling for age and period, later-born cohorts were less likely to have dementia in all three regions, more so among women; the point estimates for men in England were not significant.

Direction is for later birth cohort: each successive cohort had a significantly lower incident dementia rate, independent of sex, education and age.

Direction is for the later survey year: prevalence fell from 11.6% to 8.8%, with rising education associated with some of the decline despite a worse cardiovascular risk profile.

Direction is for later calendar epoch: incidence fell 44% from the first to the fourth epoch, but only among people with at least a high school diploma. The authors could not fully explain the decline.

Direction is for the later-born population: prevalence was 6.5% against the 8.3% expected from the earlier study (odds ratio 0.7), which the authors read as a cohort effect.

Incidence was consistently but non-significantly lower in the 2000 subcohort (rate ratio 0.75, 95% CI 0.56-1.02, borderline). The authors read the pattern, together with lower mortality and larger brain volumes, as suggesting a decline, but the primary comparison did not reach significance.

Direction is for degenerative pathology profiles: more than 80% had mixed pathologies, and of five clustered profiles the LATE-NC/hippocampal sclerosis and the ADNC/amyloid angiopathy profiles showed the fastest cognitive decline.

Direction is for LATE-NC: found in 64% of brains, stages 1a, 2 and 3 were associated with dementia and lower MMSE, it was among the strongest independent predictors of dementia, and its attributable risk (24.2%) exceeded that of Alzheimer's neuropathologic change (18.6%); it usually occurred alongside other pathologies.

Direction is for carrying the risk factors. The Danish estimate (37.8% across 16 factors) is lower than the Lancet Commission's global 45%.

Direction is for carrying the risk factors: depression, diabetes, low education, smoking, obesity, physical inactivity and alcohol overconsumption each independently raised the hazard of early-onset dementia, and most associations were stronger for early-onset than late-onset dementia.

Direction is for carrying the risk factors. Which factor mattered most differed by APOE risk group, on 2,065 cases split across 11 factors and three genetic strata, so the subgroup estimates are imprecise.

Direction is for carrying hypertension, diabetes or smoking. The attributable share rose with the age at which the factors were measured (22% at 45-54, 44% at 65-74), which is what you would expect if some of it is reverse causation rather than cause.

Direction is for carrying the risk factors: the Commission attributes 45% of cases to 14 modifiable factors, which is the same number read the other way as prevention potential. The Commission's own caveat is that "some associations might be only partly causal".

Direction is for carrying the risk factors. 39 candidate factors were screened against 485 cases, so individual estimates are imprecise.

Direction is for carrying the risk factors. The weighted combined estimate (32.0% for seven factors) is lower than the Lancet Commission's 45% for 14.

For the vascular risk factors: up to a quarter of the education-dementia association ran through hypertension, diabetes and related midlife factors, so carrying them accounted for part of the excess risk.

Direction is for carrying the peripheral diseases: together they were related to about one-third of global dementia burden, led by periodontal disease, chronic liver disease, hearing loss, vision loss and type 2 diabetes. Attributable fractions assume the pooled associations are causal.

A burden-of-disease decomposition: age-standardised rates rose slightly and population growth was the largest driver of the rise in cases. It compares no exposure, so no direction is recorded.

A lifetime-risk estimate (42% after age 55, higher in women, Black adults and APOE4 carriers) and a projection of new cases. It compares no exposure, so no direction is recorded.

A pooled incidence and prevalence estimate with no exposure compared, so no direction is recorded.

A prevalence estimate and forecast: cases are projected to rise from 57.4 million to 152.8 million while age-standardised prevalence stays flat, with the rise attributed to population growth and ageing. It compares no exposure, so there is no direction to record.

A pooled prevalence estimate with no exposure compared, so there is no direction to record.

Direction is for being African-American or American Indian/Alaska Native relative to Asian-American members: incidence was highest in those groups (26.6 and 22.2 per 1000 person-years) and lowest in Asian-Americans (15.2). The authors present this as a benchmark for reducing disparities, not as a biological effect of race.

A position paper from an expert network. It sets out 12 priority research areas on sex and gender in Alzheimer's disease and reports no effect estimate.

Direction is for female sex: at higher amyloid levels women had higher plasma p-tau217 than men, greater tau deposition and accumulation at a given p-tau217 level, and faster cognitive decline in two of the cohorts.

Direction is for female sex: women had higher odds of a high neuritic plaque burden than men after adjustment, and were more likely to reach Braak stage V-VI. Black non-carriers and non-carriers of African ancestry were least likely to have high plaque burden, a protection weakened in ε4 carriers.

Direction is for higher baseline plasma p-tau217 in cognitively unimpaired women: each SD increase more than doubled the hazard of MCI or dementia. Associations were larger in women over 70, APOE4 carriers and White women, and p-tau217 was not associated with incident MCI in Black women.

Direction is for the test's accuracy against the reference standard; an accuracy result, not a health outcome. The estimated age at plasma %p-tau217 positivity predicted age at symptom onset (adjusted R2 0.337-0.612) with a median absolute error of 3.0-3.7 years, which the authors call acceptable for trials but not yet for individual clinical use.

Direction is for higher baseline plasma p-tau217 in cognitively unimpaired adults: each SD raised the hazard of progression by 38%, and the very-high group had a 38% absolute 5-year risk of progression.

Direction is for higher plasma p-tau217: each SD raised the hazard of incident cognitive impairment by 41%, more steeply in APOE-ε4 carriers (76%) than non-carriers (26%), with survival curves separating 3-4 years after the blood test.

Direction is for the test's accuracy against the reference standard; an accuracy result, not a health outcome. Stand-alone plasma p-tau217 gave 81% accuracy and 79% PPV; confirming positives with PET or CSF raised both to 91% while cutting PET scans needed to find 100 amyloid-positive people from 536 to 124. Immunoassays matched mass spectrometry on PPV but had lower accuracy.

Direction is for the test's accuracy against the reference standard; an accuracy result, not a health outcome. Combined plasma %p-tau217 and Aβ42/40 detected abnormal CSF amyloid status (AUC 0.949) and each predicted rising amyloid PET over time in people who started below the positivity threshold, replicated in two further cohorts; p-tau231 and GFAP added no clear independent value.

The findings point different ways: lower eGFR raised every blood biomarker except Aβ42/40 (a test-interpretation caveat), yet impaired kidney function did not itself raise dementia risk (HR 0.93), while the association between high NfL and dementia was about twice as strong in people with impaired kidneys.

Direction is for the blood test's prognostic performance: plasma p-tau217 predicted cognitive decline and progression to MCI as well as tau PET (R2 0.33 vs 0.34; HR 1.57 vs 1.61), and using the blood test first cut the number needed to screen for a trial by 94%. A prognostic-performance result, not a health outcome.

Direction is for abnormal baseline plasma p-tau217: people positive for both plasma amyloid and tau progressed to MCI at 7.8 times the rate of those negative for both, and tau-positive/amyloid-negative people at 4.3 times. CSF and PET gave similar results; adding plasma Aβ42/40 did not improve prediction.

The two measures behaved differently: baseline plasma p-tau217 predicted later cognitive decline about as well as entorhinal tau PET (ρ -0.47 vs -0.55), but over time p-tau217 rose then decelerated and tracked concurrent cognitive change only weakly (ρ -0.24) or not at all in the PET substudy, whereas regional tau PET change correlated strongly with concurrent decline.

Direction is for higher baseline plasma GFAP in cognitively unimpaired adults: it predicted faster cognitive decline, CDR progression, cortical atrophy and conversion to amyloid positivity, with stronger effects in females.

Direction is for higher plasma pTau217: it was associated with global and domain-specific cognitive decline within both racial groups and discriminated 3-year dementia well (AUC 0.81 in Black and 0.77 in White adults); biomarker levels were similar across races and the association with decline was similar, though pTau217 tracked faster global and semantic memory decline in Black adults.

Direction is for adverse biomarker levels: only the Alzheimer-specific markers measured in midlife (lower Aβ42:Aβ40, higher p-tau181) predicted dementia two decades later, while every marker measured in late life did, NfL most strongly (HR 1.92 per SD). Biomarkers changed faster in APOE ε4 carriers and with midlife hypertension or diabetes.

Direction is for high serum NfL or GFAP: the top tertile of either raised incident dementia risk by 38-49% and roughly tripled dementia-specific mortality; being in the top tertile of both doubled dementia risk and raised dementia mortality nine-fold. NfL was independently associated with faster cognitive decline.

Direction is for astrocyte reactivity: amyloid was associated with higher plasma p-tau only in people positive for astrocyte reactivity, and an AD-like pattern of tau-PET accumulation as a function of amyloid appeared only in those individuals, cross-sectionally and longitudinally.

Direction is for a rising serum NfL: its rate of change separated mutation carriers from non-carriers 16.2 years before expected symptom onset (versus 6.8 years for a single level), peaked around symptom conversion, and predicted cortical thinning and cognitive decline.

The two comparisons point different ways: overall utilization and payments were similar between amyloid-positive (A4) and amyloid-negative (LEARN) participants, but among A4 participants claims indicators of progression carried 45-103% higher payments.

Direction is for value for money: APPLE-Tree had a 96% probability of being cost-effective per cognition point at a £30 000 threshold but only 12% on QALYs, which were slightly lower in the intervention arm. Post hoc subgroups suggested better value in non-White and socioeconomically disadvantaged participants.

Direction is for value for money: the intervention was modelled as dominant, saving JPY 452,826 per person and adding 0.08 QALYs over 35 years, with sensitivity analyses described as confirming robustness. A model extrapolating an 18-month trial.

Direction is for the AD-associated complement pattern: age-related falls in C4, C4b, Factor I and Properdin and rises in Factor D were more pronounced in people who later developed AD, detectable in the preclinical phase, and the same profile was specific to AD among dementia subtypes.

Direction is for an older-than-chronological sleep EEG brain age: each 10-year increase in the index was associated with a 39% higher risk of incident dementia, consistent across sex and age groups.

Neither the combined package nor risk-factor modification beat health advice.

The association was strongest at moderate intake rather than the highest.

882 cases across five quintiles and several interaction strata, so the subgroup estimates rest on small numbers.

The association is reported in people who already have elevated Alzheimer's blood markers, which is the point of the study.

Direction is for a healthier plant-based diet: higher overall and healthful plant-based diet scores were associated with lower dementia risk, while a higher unhealthful plant-based diet score was associated with higher risk (pooled HR 1.42).

Independent of overall diet quality. Substituting olive oil for margarine or mayonnaise was also associated with lower risk; substituting for butter or other vegetable oils was not.

Pooled observational studies only.

The control arm also received diet counselling and mild caloric restriction, so this is MIND against another active diet, not against usual eating. It is the only randomised test of the MIND diet here and it disagrees with the cohort evidence.

Observational. Points the opposite way to the randomised MIND diet trial.

Significant on one adherence score (MEDAS, HR 0.77) but not the other (PYRAMID, HR 0.86, 95% CI 0.73-1.02).

Controls declined while the olive-oil arm held steady; the nut arm fell between the two. Cognitive follow-up was available for 334 of 447 enrolled.

The control arm also received diet counselling and mild caloric restriction, so this is MIND against another active diet, not against usual eating. It is the only randomised test of the MIND diet here and it disagrees with the cohort evidence.

Observational. Points the opposite way to the randomised MIND diet trial.

Pooled observational studies only.

Significant on one adherence score (MEDAS, HR 0.77) but not the other (PYRAMID, HR 0.86, 95% CI 0.73-1.02).

Controls declined while the olive-oil arm held steady; the nut arm fell between the two. Cognitive follow-up was available for 334 of 447 enrolled.

Risk ratios close to one across every intake strategy, including substituting fish for meat. This is the one study here that emulates a trial rather than comparing eaters with non-eaters, and it disagrees with the pooled cohorts.

The biochemical primary outcome was met (DHA raised the CSF DHA-to-arachidonic-acid ratio versus placebo), but there was no difference in cognition or brain volume over 24 months. The authors recommend against further supplementation trials of this kind.

Dietary intake and blood levels, pooled from observational cohorts. The much larger supplement estimate (HR 0.36) comes from one cohort's self-selected supplement users, not from a trial.

The dementia-only estimate barely cleared significance (HR 1.58, 95% CI 1.003-2.48) and its test for trend did not (P=0.50).

Heterogeneity was extreme (I-squared 97%), so the pooled figure hides large differences between the 10 studies.

518 cases. Replacing 10% of ultra-processed food with minimally processed food was associated with 19% lower risk.

Heterogeneity was high (I-squared 95%). Reaches a firmer conclusion than the earlier BMJ meta-analysis of largely the same literature.

The overall PM2.5 estimate includes no effect (HR 1.04, 95% CI 0.99-1.09). Only the studies that actively assessed everyone for dementia showed a clear effect (HR 1.42, 95% CI 1.00-2.02). Most studies were at high risk of bias.

Dose-response by distance for dementia; no association with Parkinson's disease or multiple sclerosis.

Compared with flexible health advice, not with nothing; both groups improved.

The intervention did not change any brain biomarker trajectory. Participants with lower baseline hippocampal volume did show a greater cognitive benefit.

Both groups improved; the structured programme improved more. The trial compares two active interventions, so there is no untreated comparison.

A small improvement that did not reach significance (adjusted difference 0.06, 95% CI -0.001 to 0.128, p=0.055).

High overall and leisure-time activity were associated with lower dementia risk, but occupational and commuting activity were associated with higher risk. Certainty of evidence was very low to low.

No difference between aerobic training and stretching/balance. Cognition was stable in both arms, but with no non-exercising control the trial cannot say whether either arm helped.

Neither the combined package nor risk-factor modification beat health advice.

Concentrating activity into one or two days worked about as well as spreading it across the week.

Direction is for 12 weeks of cycle-ergometer exercise: putative glymphatic influx in the putamen and meningeal lymphatic vessel size and flow increased, and inflammation-related plasma proteins fell in step with the imaging changes. A mechanistic imaging result, not a cognitive outcome.

The authors call the association weak (RR 0.97), and it was absent beyond 10 years of follow-up.

Pooled across 29 cohorts. The association weakened to HR 0.85 after maximal confounder adjustment and was not significant for low-intensity activity.

The authors state the association held in longer follow-ups, which is their answer to the reverse-causation objection raised by the Whitehall II cohort.

866 cases over a short follow-up for a disease with a long prodrome, so some of the association may be people already declining moving less.

The largest effect for physical activity anywhere in this table by a wide margin. On 678 cases over 6.3 years, in a disease with a long prodrome, reverse causation is the more likely explanation for an effect that size.

Explicitly finds no neuroprotective effect, and attributes the lower risk seen in other cohorts to reverse causation: activity fell in the nine years before diagnosis. This contradicts the pooled cohort evidence.

The primary outcome did not move between groups. Attention and inhibitory control did improve (SMD 0.43), as did muscular strength.

The authors call the effect small (-0.18 points). Significant in women, not in men, on 91 randomised and 76 completing.

Seven small trials; working memory did not improve (P=0.14).

Direction is for carrying APOE and TREM2 risk variants, which were associated with a significant reduction in amyloid-responsive microglia, read by the authors as a diminished cellular response to amyloid. A tissue result, not a clinical outcome.

Direction is for APOE genotype after 90: ε2 carriers had lower dementia risk, while the ε4 association was not statistically significant. Women and Black participants had higher risk than men and Asian participants. Age-standardised incidence was 116.82 per 1000 person-years.

Direction is for carrying APOE ε4: 10-year dementia risk ratios of 1.59 (Filipino, confidence interval crossing 1) to 1.96 (Japanese), similar across the four groups despite carrier prevalence ranging from 14% to 25%. Not modifiable.

Direction is for each additional ε4 allele: it did not change amyloid-related p-tau217 secretion, but for any given p-tau217 level tau spread faster across connected regions, and the p-tau217 threshold marking early tau-PET increases was 26-76% lower than in non-carriers.

Direction is for carrying the deletion, present in 60% of African American ε4 homozygotes: it reduced the AD odds ratio and delayed onset in ε4/ε4 cases with local African ancestry at APOE, confirmed in All of Us, and it abolishes SPI1 repression at the site.

A descriptive proteomic mapping: APOE-linked protein changes were present before amyloid pathology and stable across age and disease stage, with ε2 tied to cellular-maintenance and anti-inflammatory pathways and ε4 to cell-cycle, oligodendrocyte-precursor and downstream vascular, immune and proteostatic proteins. It estimates no effect on a clinical outcome.

Direction is for the APOE4 allele, whose effect ranged from OR 2.22 in Caribbean-Hispanic to 6.13 in Peruvian/Bolivian participants. The APOE2 allele went the other way (OR 0.81). Not modifiable.

Direction is for APOE ε4 carriage, which strengthened the association between amyloid and plasma p-tau; plasma GFAP strengthened the p-tau-tau PET link mainly in non-carriers, and high GFAP went with faster longitudinal tau accumulation.

Direction is for carrying two APOE4 copies: near-complete penetrance of Alzheimer's biology and earlier symptom onset.

Direction is for carrying APOE*4: the ε3/ε4 odds ratio fell stepwise from 4.54 in East Asian to 3.46 in White, 2.18 in Black and 1.90 in Hispanic individuals; ε2 was protective in White and Black but not Hispanic or East Asian individuals. Not modifiable.

Direction is for carrying APOE2, which is associated with longer life irrespective of Alzheimer's status. The lifespan figures come from gene-targeted mice, not from the human cohort.

Direction is for midlife hypertension. Genetic risk for Alzheimer's did not modify it, which the authors read as everyone with hypertension standing to gain from treatment.

Direction is for a high polygenic score (excluding APOE): people in the top decile had a twofold risk of Braak stage >4 tangles and of moderate-to-severe amyloid plaque pathology at death. 91 loci identified, 16 new; 18 further loci await validation.

The intervention-control cognitive difference was statistically significant in the higher-genetic-risk halves and not in the lower halves, but neither genetic score significantly modified the intervention effect overall (P > 0.46); an exploratory sex difference emerged for the Alzheimer score.

A transcriptome-wide association study prioritising nine genes (including BIN1, PTK2B and DMPK) with broadly consistent effects across populations; it reports no effect estimate for any exposure, so no direction is recorded.

Locus-discovery genome-wide association study: it reports which genetic regions reached significance and no effect estimate for any exposure, so no direction is recorded. Nine signals (HP1BP3, SLC50A1, PTPRC, NPAS3, DDHD1, CHST9, SMYD2, PRAMEF1, GFRA1) appeared only in APOE-stratified analyses; DDHD1 was protective in ε4 carriers.

Direction is for a higher polygenic score: each standard deviation raised AD odds 1.14-1.52-fold across European, African American, Caribbean Hispanic and Native American Hispanic groups (1.21-1.65 in replication cohorts), and the score tracked worse cognition, more AD neuropathology, smaller hippocampi and abnormal CSF biomarkers.

Direction is for carrying the risk factors. Which factor mattered most differed by APOE risk group, on 2,065 cases split across 11 factors and three genetic strata, so the subgroup estimates are imprecise.

Locus-discovery genome-wide association study: it reports which genetic regions reached significance and no effect estimate for any exposure, so no direction is recorded. The study reports 14 new loci for clinically diagnosed AD and two from AD-by-proxy.

Locus-discovery genome-wide association study: it reports which genetic regions reached significance and no effect estimate for any exposure, so no direction is recorded. The study reports eight new loci (six ancestry-specific, two trans-ancestry) and nominates eight genes in microglial activation, glutamate production and signalling.

Direction is for a higher integrative polygenic score: dementia hazard rose 1.15-fold per SD in older community-dwelling people independently of APOE, generalising to Europeans, East Asians and memory-clinic patients, and reaching five-fold risk when combined with APOE ε4 in memory-clinic patients. Not modifiable.

Direction is for a higher polygenic score: consistently associated with AD risk, age at onset and CSF biomarkers independently of APOE in Europeans and with AD risk in many other ancestries; a cross-ancestry score with the APOE region improved the association, and the signal weakened as the diagnosis was broadened.

Locus-discovery genome-wide association study: it reports which genetic regions reached significance and no effect estimate for any exposure, so no direction is recorded. Beyond APOE, the study reports TREM2 R47H and variants near RAB3B, SPOCK3/ANXA10 and SMAP2, and a gene-based association with GIPR.

Locus-discovery genome-wide association study: it reports which genetic regions reached significance and no effect estimate for any exposure, so no direction is recorded. Two signals at 17p13.2 and 18q21.33 are reported; the authors state that African ancestry at 17p13.2 went with lower AD risk and that overall African ancestry did not differ between cases and controls, without an effect estimate.

Direction is for a higher polygenic risk score: each SD raised the dementia hazard 1.35- to 1.42-fold after adjustment including APOE ε4, and the new scores modestly improved prediction (AUC 74.7% to 75.7-76.1%) while still explaining less risk than APOE. Not modifiable.

Direction is for carrying a higher genetic risk score: risk of AD rose 1.6- to 1.9-fold from the lowest to the highest decile, over and above age and APOE4. The main output is 75 risk loci, 42 new.

The study's own results point different ways: the polygenic score added to APOE for predicting AD/MCI and for progression from amyloid-positive MCI to AD, but amyloid deposition was predicted by APOE alone.

The two kinds of variant point opposite ways: deletions and loss-of-function alleles in ABCA1 and ABCA7 and 22q11.21 deletions raised AD risk, while 22q11.21 duplication lowered it (odds ratio 0.34 at exome-wide significance in replication). Not modifiable.

Direction is for one copy of the APOE3 Christchurch variant: median onset of cognitive impairment at 52 versus 47 years in matched PSEN1 E280A carriers without it, with preserved brain metabolism and fewer vascular amyloid features in the few imaged or autopsied. Not modifiable.

Direction is for carrying the rare FN1 variant rs140926439 in APOE ε4 homozygotes: odds of AD 0.29 and onset delayed 3.37 years in the 7185-person validation cohort, with zebrafish work suggesting fibronectin loss of function reduces gliosis. Not modifiable.

Direction is for carrying the African ancestry-specific APOE R145C variant with an ε3/ε4 genotype: three-fold higher odds of AD and onset about six years earlier in the discovery stage, replicated in stage 2 and concordant in stage 3. Not modifiable.

A single case report: one man with the PSEN1 E280A mutation stayed cognitively intact until 67 despite very heavy amyloid, and carried a gain-of-function RELN variant. With one case and no comparison group beyond the earlier Christchurch case, no direction can be recorded.

Among 37 heterozygous carriers (ages 56.6-82.1) none had developed AD or MCI by the March 2022 data freeze and apolipoprotein B was lower than in non-carriers, but the authors say continued follow-up is necessary and no homozygotes were found, so protection could not be tested. No incidence comparison is reported, so no direction is recorded.

Direction is for carrying TREM2 T96K: it increased AD risk in family-based and case-control sequencing data and, despite being a gain-of-function variant, impaired microglial clustering around plaques, amyloid uptake and the transition to disease-associated microglia in female 5xFAD mice.

Direction is for carrying the risk variants: R62H and T96K caused excessive skipping of exon 2 and overproduction of a potentially antagonistic TREM2 isoform, and several early-onset dementia variants acted primarily through splicing defects. A molecular mechanism result, not a clinical outcome.

Confined to people who said the aid actually improved their hearing (HR 0.86); those reporting poor improvement showed nothing (HR 0.98).

Direction is for having the impairment. Dual sensory impairment carried the highest risk (HR 1.63 for all-cause dementia, 2.55 for Alzheimer's).

Direction is for hearing loss. Risk was lower among those using hearing aids (aHR 1.06) than those not (aHR 1.20). The authors note their estimates are smaller than earlier studies'.

Null in the primary analysis of the whole cohort. The prespecified analysis of the higher-risk ARIC subgroup found less decline, which the authors present as hypothesis-generating rather than as a result.

Mostly observational (25 of 31 studies), so people who take up hearing aids may differ from those who do not. The authors call for randomised trials — and ACHIEVE, the trial that followed, was null overall.

Against untreated cataract. People who had surgery ended up at about the same risk as controls who never had cataracts (HR 0.84, 95% CI 0.66-1.06), and there was no short-term gain in those already cognitively impaired.

Direction is for having a vision impairment. Single vision impairment raised all-cause dementia risk but not Alzheimer's specifically; having both hearing and vision impairment carried the highest risk.

Direction is for having cataracts or myopia. A Mendelian randomisation analysis supported the cataract-vascular dementia link.

A narrative review arguing that Alzheimer's disease is a brain-specific form of diabetes; it states that type 2 diabetes alone "fall[s] far short of mimicking AD" and reports no effect estimate.

Direction is for midlife hypertension. Genetic risk for Alzheimer's did not modify it, which the authors read as everyone with hypertension standing to gain from treatment.

Regression discontinuity across a birth-date eligibility threshold, which makes confounding by health-seeking behaviour less likely than in a plain cohort comparison. Eligibility did not change uptake of other preventive services or other chronic-disease diagnoses, which is the check that makes the design convincing.

Regression discontinuity across the 2 September 1933 eligibility threshold; stronger in women than men.

Pooled observational studies, so open to the confounding the natural-experiment studies were designed to avoid.

Direction is for a hospital-treated infection: the raised dementia hazard (1.54) was barely attenuated by adjustment for frailty (1.49) and persisted among non-frail participants (1.34), so pre-existing frailty and comorbidity did not explain it.

Direction is for delirium on admission: it raised the risk of incident dementia across the whole spectrum of long-term conditions, with the largest relative risk (3.38) in people without multiple long-term conditions.

One of the largest effect sizes in this table (subdistribution HR 3.00), rising about 20% with each further episode. The authors argue for a causal reading.

Read with care: the authors' own reading is that a fall flags undetected dementia rather than causing it, and they recommend cognitive screening after a fall. A one-year window cannot separate cause from early sign.

Antihypertensive treatment improved cognitive scores by a small amount (SMD 0.06, moderate certainty) but the reduction in dementia incidence was not statistically significant (OR 0.89, low certainty). The drug-class rankings rest on one trial per class and are described as highly uncertain.

Significant for MCI and for the MCI-or-dementia composite; not significant for probable dementia alone (HR 0.86, 95% CI 0.72-1.02).

A large drop in blood pressure (22/9 mmHg) and fewer serious adverse events in the intervention villages.

Antihypertensive use tracked lower Alzheimer's risk but not lower non-Alzheimer dementia risk, where treated and untreated hypertension looked the same. A single baseline blood pressure reading predicted neither.

Individual participant data from five double-blind placebo-controlled trials, which is the strongest design in this table for this exposure.

Consistent across 14 trials (I-squared 0%) but small in absolute terms: 0.39 percentage points over about 4 years.

The authors state the data are compatible with anything from a 39% decrease to a 5% increase in risk, against DPP-4 inhibitors rather than no treatment.

For GLP-1 receptor agonists specifically: HR 0.95 (95% CI 0.87-1.04) against DPP4 inhibitors in the intention-to-treat analysis. Only the continuous-use analysis reached significance (HR 0.79).

Seven separate comparisons against seven other antidiabetic drugs, so the comparator is always another drug rather than no treatment.

Heterogeneity was near-total (I-squared 98.9%) and the estimate went to null in people newly diagnosed with diabetes (HR 1.01), which is where prevalent-user bias would be smallest.

Designed around new diabetes diagnoses with a landmark analysis and a one-year lag, which removes the prevalent-user advantage that inflates metformin's apparent benefit in the pooled cohorts.

Comparator is other oral antidiabetic drugs, not no treatment.

The split inside this one paper is the finding: the 41 observational studies show large benefits (SGLT2i OR 0.56, GLP-1RA OR 0.58) while the 23 randomised trials show no difference. When design and result disagree this cleanly, the trials are the ones to believe.

The exposure actually studied is STOPPING metformin early, which carried 21% higher dementia incidence than staying on it. Read as indirect support for metformin, not as a trial of it.

For SGLT2 inhibitors specifically: HR 0.86 (95% CI 0.79-0.94) against DPP4 inhibitors, and HR 0.70 in the as-treated analysis.

After the first year the data rule out more than a 3% change either way. Diagnoses were 46% higher in the first year, which the authors attribute to people being seen more often just after starting a statin. This sits against the Chicago cohort, which found benefit in APOE4 carriers.

Benefit was confined to APOE4 carriers (HR 0.60) and absent in non-carriers (HR 0.96). Observational, and it disagrees with the larger target-trial emulation that found nothing.

The authors read these symptoms as early markers of neurodegeneration rather than causes — which is also how an earlier analysis of this same cohort read its own null result for midlife depression.

Direction is for having depression (51% higher risk). Treated depression carried lower risk than untreated (HR 0.7), which is the more interesting half but is an observational comparison of people who did and did not get treatment.

Midlife depressive symptoms did not raise dementia risk (HR 1.21, 95% CI 0.95-1.54), even when chronic. The association closer to diagnosis is read by the authors as depression being a prodromal feature, not a cause.

Direction is for MORE education. Up to a quarter of the effect ran through midlife vascular risk factors, and the authors say treating those factors would not close the educational gap.

Education and job complexity each contributed independently; about 28% of the education effect ran through occupation.

Effect held over and above measured Alzheimer's pathology, which is the point of the reserve idea.

Distress rose, and rose most in APOE4 homozygotes. The authors nonetheless conclude disclosure by a trained provider was generally safe and well tolerated in this psychologically pre-screened group.

Direction is for normal sleep versus sleep deprivation, on a clearance measure — not on cognition, which this trial did not measure.

Eight kinds of sleep disturbance were analysed; both short and long sleep carried higher risk, as did excessive daytime sleepiness and insomnia.

Two findings point opposite ways: synchronised norepinephrine, blood-volume and CSF oscillations during natural NREM sleep were the strongest predictors of glymphatic clearance, while the sleep aid zolpidem suppressed those oscillations and glymphatic flow. Mouse work with no human outcome.

Direction is for LOSING slow-wave sleep. 52 cases in 346 people, so the estimate is imprecise, and slow-wave sleep also falls with Alzheimer's genetic risk, which muddies cause and effect.

No significant association with vascular dementia, and none of the 11 studies used biomarkers to confirm the diagnoses.

Direction is for SHORT sleep (6 hours or less): higher dementia risk than a 7-hour sleep duration.

A narrative review proposing glymphatic failure as a final common pathway to dementia. It reports no effect estimate.

Persisted after controlling for depression and social isolation.

Isolation (being alone) carried the risk (HR 1.26); loneliness (feeling alone) did not once depressive symptoms were accounted for (HR 1.04, 95% CI 0.94-1.16). That split matters, and the loneliness meta-analysis here reaches the opposite conclusion about loneliness.

Significant only for contact measured at age 60, not at 50 or 70. The authors note that keeping up contact may itself be a marker of cognitive reserve rather than a cause of it.