ApoE e4e4 genotype and mortality with COVID-19 in UK Biobank

We previously reported that the ApoE e4e4 genotype was associated with COVID-19 test positivity (OR=2.31, 95% CI: 1.65 to 3.24, p=1.19×10⁻⁶) in the UK Biobank (UKB) cohort, during the epidemic peak in England, from March 16 to April 26, 2020. With more COVID-19 test results (March 16 to May 31, 2020) and mortality data (to April 26, 2020) linked to UKB, we re-evaluated the ApoE e4 allele association with COVID-19 test positivity, and with all-cause mortality following test-confirmed COVID-19. Logistic regression models compared ApoE e4e4 participants (or e3e4s) to e3e3s with adjustment for sex; age on April 26th or age at death; baseline UKB assessment center in England (accounting for geographical differences in viral exposures); genotyping array type; and the top five genetic principal components (accounting for possible population admixture). ApoE e4e4 genotype was associated with increased risks of test positivity (OR=2.24, 95% CI: 1.72 to 2.93, p=3.24×10⁻⁹) and of mortality with test-confirmed COVID-19 (OR=4.29, 95% CI: 2.38 to 7.72, p=1.22×10⁻⁶), compared to e3e3s. Independent replications are needed to confirm our findings and mechanistic work is needed to understand how ApoE e4e4 results in the marked increase in vulnerability, especially for COVID-19 mortality. These findings also demonstrate that risks for COVID-19 mortality are not simply related to advanced chronological age or the comorbidities commonly seen in aging.