Effects of age, sex, and ethnicity on the association between apolipoprotein E genotype and Alzheimer disease. A meta-analysis. APOE and Alzheimer Disease Meta Analysis Consortium.
Level 3 - non-randomized controlled study
Meta-analysis of observational case-control and cross-sectional studies
What was done
A pooled individual-participant meta-analysis evaluated data from 40 research teams comprising 5,930 patients with probable or definite Alzheimer disease (AD) and 8,607 controls without dementia recruited from clinical, community, and brain bank sources. Investigators calculated odds ratios (ORs) and 95% confidence intervals (CIs) for AD associated with APOE genotypes (ε2/ε2, ε2/ε3, ε2/ε4, ε3/ε4, and ε4/ε4 relative to ε3/ε3) using logistic regression adjusted for age and study, stratified by ethnic group (Caucasian, African American, Hispanic, Japanese) and source.
What was found
In Caucasian subjects from clinic- or autopsy-based studies, AD risk increased with ε2/ε4 (OR = 2.6, 95% CI: 1.6–4.0), ε3/ε4 (OR = 3.2, 95% CI: 2.8–3.8), and ε4/ε4 (OR = 14.9, 95% CI: 10.8–20.6), while risk decreased for ε2/ε2 (OR = 0.6, 95% CI: 0.2–2.0) and ε2/ε3 (OR = 0.6, 95% CI: 0.5–0.8). In Japanese subjects, the ε4 association was stronger (ε3/ε4: OR = 5.6, 95% CI: 3.9–8.0; ε4/ε4: OR = 33.1, 95% CI: 13.6–80.5). The association was attenuated in African Americans and Hispanics, with significant heterogeneity across African American studies (P < .03). The ε2/ε3 genotype was protective across all ethnic groups. The ε4 effect was present between ages 40 and 90 years but diminished after age 70, and risk varied by sex.
Why it matters
This landmark collaboration established the global magnitude of APOE-related Alzheimer disease risk while demonstrating substantial effect modification by ethnicity, age, and sex.
Limits
The underlying datasets were observational case-control and autopsy series subject to potential ascertainment and survival biases. Non-Caucasian samples were smaller and showed significant inter-study heterogeneity in African Americans, limiting precise risk estimation in these populations.
Cited by
- supports Being heterozygous for the APOE4 allele confers a five-fold increased risk of Alzheimer's disease, and being homozygous increases the risk 12-fold.