APOE Genotype and Statin Response: Evidence From the UK Biobank and All of Us Program.

APOE genotype may affect statin response. Using UK Biobank (UKB) and All of Us (AoU) data, we aimed to investigate associations between APOE genotype, statin use, and key health outcomes. Our analysis included UKB baseline data and linked mortality records (389,843-452,189 participants), and electronic health records (EHR) from 45,515 UKB and 35,562 AoU participants. Multivariable regression and Cox models assessed lipid biomarkers, all-cause mortality, cardiovascular mortality, and major adverse cardiovascular events (MACE). In UKB, ε3ε4 (HR: 1.08, 95% CI: 1.01-1.15) and ε4ε4 (HR: 1.54, 95% CI: 1.33-1.78) carriers had higher all-cause mortality risk. In AoU, only ε4ε4 carriers showed increased risk (HR: 1.64, 95% CI: 1.08-2.49). Cardiovascular mortality was assessed only in UKB, where ε4ε4 carriers had an increased risk (HR: 1.30, 95% CI: 1.01-1.68). Mortality associations in UKB EHR data were consistent with those from baseline data and linked mortality records (e.g., ε4ε4 genotype: all-cause mortality HR: 1.51, 95% CI: 1.41-1.62; cardiovascular mortality HR: 1.54, 95% CI: 1.33-1.77). However, the statin:APOE interaction term included in the baseline analysis was not statistically significant. In AoU, changes in HDLC, LDLC, and triglycerides were associated with reduced all-cause mortality risk. No significant MACE associations were observed in either cohort. This study reaffirms that APOE ε4 genotype increases mortality risk, including in statin-treated patients, and could therefore be used to inform enhanced monitoring or medication review in these patients.