SEX DIFFERENCES IN THE ASSOCIATION OF APOE HAPLOTYPES, LDL CHOLESTEROL, AND DEMENTIA IN THE ELECTRONIC HEALTH RECORD

The APOE gene exhibits sex differences in associations with Alzheimer’s disease and related dementias (ADRDS): APOE ε4 is more strongly associated with ADRD in females than males while APOE ε2 may be more neuroprotective in females than males. Additionally, APOE regulates lipid biology, and lipid traits exhibit sex differences across the lifespan. In an agnostic scan for sex differences in the genetic architecture of clinical laboratory traits, we detected stronger inverse associations between APOE ε2 and median LDL cholesterol value across the medical record in females than in males. We followed-up on this association by performing interaction and mediation analyses for >77,000 participants with whole genome sequencing data and LDL cholesterol measurements in the Vanderbilt University Medical Center genetic biobank, BioVU. Sex modified the association of APOE haplotypes with LDL cholesterol, with stronger associations in females than males for both APOE ε4 (increased LDL cholesterol) and APOE ε2 (decreased LDL cholesterol). Although females were much less likely to have statin medication records, the interaction between APOE and sex on LDL cholesterol was not explained by differences in statin records. Similarly, sex modified associations with dementia, with stronger associations in females. Higher LDL was associated with dementia among females without statin record and among all males regardless of statin record status. In preliminary mediation analyses, LDL cholesterol mediated 3% (95%CI: 1.5%, 2.4%) of the effect of the APOE ε3/ε4 (relative to ε3/ε3) haplotype on dementia for males. For females without statin record, LDL cholesterol mediated 8% (3%, 16%) of the effect of the APOE ε3/ε4 (relative to ε3/ε3) haplotype on dementia. Our results suggest sex differences in APOE influence cholesterol biology and dementia.