Every row of the evidence table

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.