The APOE -ε4 allele is the strongest genetic risk factor for late-onset Alzheimer’s disease. However, APOE -ε4 is not deterministic, highlighting the need to identify additional genetic and environmental factors. APOE -ε4 has been linked to accelerated cognitive decline, so we sought to investigate genetic factors that modify APOE -ε4–associated cognitive decline. We conduct cross-ancestry APOE -ε4-stratified and interaction GWAS using harmonized cognitive data from 32,778 participants, including 29,354 non-Hispanic White and 3,424 non-Hispanic Black individuals. Our primary outcome is late-life cognition, measured using harmonized composite scores for memory, executive function, and language, modeled as continuous traits reflecting both normative cognitive aging and disease-related decline. We identify two genome-wide significant loci in APOE -ε4 carriers, reaching genome-wide significance for executive function. These loci also demonstrate nominal associations across the other domains, suggesting broad effects on cognition. In non-carriers, we identify a genome-wide significant association at ITGB8 restricted to executive function, and another locus associated with language. We further link these loci to SEMA6D , GRIN3A , and ITGB8 through expression and methylation databases. Post-GWAS analyses implicate additional genes including SLCO1A2 , and DNAH11 . Genetic correlation analyses reveal differences by APOE -ε4 status for immune-related traits, suggesting immune-related predispositions may exacerbate cognitive risk in APOE -ε4 carriers.
Contreras et al. (Fri,) studied this question.