APOE disease risks and proteomic links vary by ancestry
A phenome-wide study of 367,757 All of Us participants linked APOE alleles to 27 phenotypes, finding ancestry-specific risks for dementia and fatty liver disease.
medRxiv
In 367,757 participants from six genetic ancestry groups in the All of Us Research Program, researchers tested APOE genotypes against 2,632 clinical phenotypes. They identified 27 phenotypes associated with APOE, primarily involving neurological and lipid-related traits. Five lipid traits showed sex heterogeneity, with larger effects in females. Nine associations showed ancestry-specific effects: APOE ε4 was linked to stronger protection against fatty liver disease in East Asians, a lack of protection in African ancestry, and larger dementia risk in Europeans. In plasma proteomic analyses of 9,132 participants across five ancestries, higher APOE ε4 dosage was positively associated with SNAP25 levels across ancestries. In contrast, CDC42EP1, APOA1, and ITGB5 showed associations with APOE specifically in non-European populations.
Why it matters
The findings suggest that APOE-associated disease risks and circulating molecular signatures differ by genetic ancestry, highlighting candidate biomarkers for dementia and lipid metabolism across diverse populations.
Caveats
As an observational analysis of electronic health record data, the study design cannot establish causality. The paper is also a preprint that has not yet completed peer review.
The paper
Montreal Neurological Institute and Hospital · Centre de recherche sur le vieillissement
medRxiv · 28 Sep 2026 · Preprint, not peer-reviewed