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

Abstract

Background: Apolipoprotein E (APOE) ε4 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 (ε2/ε2 < ε2/ε3 < ε3/ε3 < ε2/ε4 < ε3/ε4 < ε4/ε4), 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 ε2 and ε4 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 ε4 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 ε4 dosage across ancestries, and CDC42EP1, APOA1 and ITGB5 shown associations with APOE ε2/ε4 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-ε4 effects, and ancestry-specific proteins nominate mechanisms for the observed phenotypic heterogeneity. Funding: Funding is listed in the acknowledgements section. Research in context: Evidence before this study: The APOE ε4 variant is an established genetic risk factor for hyperlipidemia, Alzheimer’s disease, dementia, ischemic heart disease and, more recently, non-alcoholic fatty liver disease. Prior phenome-wide association studies (PheWAS) of APOE have been conducted largely in European-ancestry cohorts. A recent APOE PheWAS in the All of Us Research Program (n = 181,880) identified 17 Bonferroni-significant phenotypes and preliminary evidence of ancestry heterogeneity for hyperlipidemia and mild cognitive impairment, but statistical power in non-European groups limited systematic characterization of ancestry-specific effects. Recent plasma proteomic studies have described APOE-associated protein signatures shared with neurodegenerative diseases, but these were confined to European-ancestry participants, leaving open whether such signatures generalize across ancestries. Added value of this study: Using the All of Us v9 release, we approximately doubled the sample size of the prior APOE PheWAS in this cohort (n = 367,757 across six ancestry groups, including ∼146,000 non-European participants), enabling the first well-powered assessment of ancestry heterogeneity of APOE effects. We identify 27 Bonferroni-significant phecodes, 11 novel compared to the previous APOE PheWAS in All of Us — including vascular dementia, dementia with Lewy bodies, and angina pectoris. We detect significant sex heterogeneity for five lipid-related phecodes and significant ancestry heterogeneity for nine phecodes, including stronger protection against fatty liver and chronic liver disease in East Asian participants and larger dementia risk in European participants. Complementing the phenotypic analysis, we present the first ancestry-stratified plasma proteomic characterization of APOE genotypes (n = 9,132), identifying SNAP25 as a robust APOE-ε4–associated protein across ancestries and ancestry-specific signals for IL32, CDC42EP1, APOA1, and ITGB5. Implications of all the available evidence: APOE-associated risk estimates derived predominantly from European-ancestry data may not transfer directly to other populations, and our findings support incorporating ancestry into the interpretation and calibration of APOE-based risk prediction. The ancestry-heterogeneous protection against liver disease and the parallel APOA1 signal absent in East and South Asian participants together offer a mechanistic hypothesis linking APOE-driven lipid partitioning to hepatic outcomes. Plasma SNAP25 is proposed as an accessible, ancestry-portable biomarker of APOE-ε4 effects and Alzheimer’s disease progression. Ancestry-specific proteins (IL32 and CDC42EP1 in African ancestry, ITGB5 in Admixed American ancestry) constitute potential drivers of ancestry heterogeneity in APOE-related disease risk.