Phenome-wide and proteomic analysis of APOE alleles across different ancestries in the All of Us Research Program

Background: Apolipoprotein E (APOE) {varepsilon}4 is the strongest common genetic risk factor for Alzheimer's disease and a determinant of cardiometabolic risk, yet studies of APOE genotypes with disease associations and plasma proteomic signatures have been primarily restricted to European-ancestry cohorts. Methods: We performed a phenome-wide association study of APOE genotype in 367,757 All of Us participants across six genetic ancestry groups. APOE alleles were tested against 2,632 phenotypes using an ordinal Alzheimer's-disease-risk hierarchy ({varepsilon}2/{varepsilon}2 < {varepsilon}2/{varepsilon}3 < {varepsilon}3/{varepsilon}3 < {varepsilon}2/{varepsilon}4 < {varepsilon}3/{varepsilon}4 < {varepsilon}4/{varepsilon}4), adjusted for age, sex at birth, EHR length, and 16 genetic principal components. Sex- and ancestry-stratified analyses used Cochran's Q for heterogeneity. We evaluated {varepsilon}2 and {varepsilon}4 dosage effects on plasma protein levels in 9,132 participants across five ancestries. Findings: We identified 27 phenotypes associated with APOE, mainly in neurological and lipid-related traits. Five lipid-related traits showed sex heterogeneity, with larger effects in females. Nine associations showed ancestry-specific effects. APOE {varepsilon}4 showed stronger protection against fatty liver disease in East Asians with lack of protection in African ancestry; and larger dementia risk for Europeans. Finally, SNAP25 was identified as positively associated with APOE {varepsilon}4 dosage across ancestries, and CDC42EP1, APOA1 and ITGB5 shown associations with APOE {varepsilon}2/{varepsilon}4 specifically in non-European populations. Interpretation: Ancestry-heterogeneous APOE effects, particularly for liver and dementia phenotypes, argue for ancestry-aware interpretation of APOE-based risk. Plasma SNAP25 is a candidate ancestry-portable biomarker of APOE-{varepsilon}4 effects, and ancestry-specific proteins nominate mechanisms for the observed phenotypic heterogeneity. Funding: Funding is listed in the acknowledgements section.