APOE4‐stratified GWAS across cognitive domains in non‐Hispanic white and non‐Hispanic black individuals

Background Apolipoprotein E4 (APOE4) is common in the population yet is the strongest genetic risk factor for late‐onset Alzheimer’s disease (AD). Here, we sought to identify genetic effects that differ by APOE4 genotype leveraging stratified and APOE interaction analyses. We hypothesized that we could identify novel genetic associations with longitudinal cognitive decline across three neuropsychological domains (memory, executive function, and language) that differ by APOE4 status. We leveraged a large, multi‐ancestry harmonized cognitive dataset (Nparticipants ∼ 23,000) from the AD Sequencing Project Phenotype Harmonization Consortium including more than 50,000 total longitudinal measures of cognition. Method This study included data from four cohort studies of aging and AD (NNHW = 20,117, NNHB = 2,631, Nobs = 22,748, 39% APOE4 carriers, 16% AD cases). Memory, executive function, and language composite scores were harmonized leveraging latent variable modeling. APOE4‐ stratified GWAS were performed on these phenotypes, controlled for age at baseline, sex, and genetic ancestry. APOE4 interaction models were leveraged to test for statistical differences based on markers identified in stratified discovery analyses. Post‐GWAS included gene tests with MAGMA and genetic correlation analyses with GNOVA. Result Among NHW, we identified an APOE4pos‐specific locus on chromosome 1 (rs7537669, βE4pos = ‐0.12, pE4pos = 2.2E‐08, βE4neg = ‐0.01, pE4neg = 0.17). This variant is with a strong eQTL for CD46, a regulatory element of the complement system. Among APOEneg NHW, we found TXNRD3 was associated with memory and a negative genetic correlation between amyotrophic lateral sclerosis (ALS) and memory performance that was not observed in APOE4pos individuals. Finally, we observed an APOE4neg association between CRELD and executive function among NHB individuals. Conclusion In the largest APOE4‐stratified GWAS of multi‐domain cognitive performance, we identified a number of novel genetic loci and genetic correlations that appear to act in an APOE4‐stratified manner. Given the known heterogeneity in clinical progression, age‐related risk, and response to therapeutics that has been reported, it will be important to disentangle molecular pathways that differ by APOE genotype to move towards precision interventions.