APOE Genotype and Alzheimer Disease Risk Across Age, Sex, and Population Ancestry.
Level 3 - non-randomized controlled study
Multi-cohort observational genetic association study combining case-control, longitudinal, and family cohorts
PubMed 37930705 · doi:10.1001/jamaneurol.2023.3599
What was done
Analyzed genetic and clinical data from case-control, family-based, population-based, and longitudinal cohorts comprising 68,756 unique individuals: 21,852 East Asian, 5,738 Hispanic, 7,145 non-Hispanic Black, and 34,021 non-Hispanic White participants. Researchers evaluated the associations of APOE genotypes with Alzheimer disease (AD) risk using logistic regression (odds ratios [ORs]) and conversion risk using Cox proportional hazards regression, stratifying across sex, age, race/ethnicity, and global population ancestry.
What was found
AD risk associated with APOE*34 showed a stepwise attenuation across groups: East Asian (OR 4.54; 95% CI, 3.99–5.17), White (OR 3.46; 95% CI, 3.27–3.65), Black (OR 2.18; 95% CI, 1.90–2.49), and Hispanic individuals (OR 1.90; 95% CI, 1.65–2.18). Protective associations of APOE*22+23 were observed in White (OR 0.53; 95% CI, 0.48–0.58) and Black individuals (OR 0.69; 95% CI, 0.57–0.84), but not in Hispanic (OR 0.89; 95% CI, 0.72–1.10) or East Asian individuals (OR 0.97; 95% CI, 0.77–1.23). In Black individuals, higher global European ancestry was associated with increased APOE*4-related AD risk. A sex-by-age interaction showing higher APOE*34 risk in women aged 60 to 70 was observed in White individuals (OR 1.48; 95% CI, 1.10–2.01) and in a pooled meta-analysis of Black and Hispanic individuals (OR 1.72; 95% CI, 1.01–2.94).
Why it matters
This study shows that standard APOE-related risk estimates derived from White populations do not apply uniformly across ancestries, which has major implications for AD genetic risk assessment, clinical trial stratification, and drug targeting across diverse global populations.
Limits
Demographic covariates were unavailable for the East Asian cohort. The study combined varied recruitment designs (referred, volunteer, case-control, and population-based) which may introduce selection bias, and global ancestry estimates could not fully explain differences in effect sizes among Hispanic individuals.
Cited by
- supports Having the ApoE 3/4 or ApoE 4/4 genotype confers a higher risk of developing Alzheimer's disease than the average person.