Introduction: Primary intracerebral hemorrhage (ICH) remains one of the most severe forms of acute cerebrovascular disease. APOE ε2 and ε4 are risk factors for primary ICH, and also involved in regulation of circulating lipid levels. Hypercholesterolemia has been associated with reduced ICH risk. However, the biological mechanisms mediating the roles of APOE and serum lipids on ICH risk remain unclear. Given the pleiotropic relationship between APOE, ICH, and serum lipid levels, we sought to determine the influence of APOE genotype on temporal serum lipid trends before and after ICH.
Methods: We performed a single-center retrospective longitudinal cohort analysis using subjects with known APOE genotype drawn from an ongoing cohort study of primary ICH. Serum lipid measurements for total cholesterol (TC), triglycerides (TG), low-density lipoprotein (LDL), and high-density lipoprotein (HDL) collected within 2 years preceding and following index ICH were extracted from electronic medical records (EMR). Piecewise linear mixed-effects random-coefficent models were used to compare APOE allele-specific effects on changes in serum lipid trends in ICH.
Results: 124 ICH cases were analyzed. APOE ε4 carriers had significantly greater rates of decline in serum TC and LDL levels within 6 months prior to ICH (TC: -7.30 mg/dL/month, p=0.0035; LDL: -8.44 mg/dL/month, p=0.0001) compared to non-carriers (TC: -3.79 mg/dL/month, p=0.17; LDL: -2.39 mg/dL/month, p=0.55). In contrast, TC and LDL trends for APOE ε2 carriers were not significantly altered within the same time period. APOE genotype had no associations with serum HDL or TG trends.
Conclusions: APOE allele status is a strong predictor of subacute serum TC and LDL changes preceding ICH. Our results have implications for ongoing efforts in dissecting the role of dyslipidemia in cerebrovascular disease risk. While further studies are needed, our observation that APOE ε4 influences serum lipid trends preceding ICH provides additional insight towards lipid-dependent and lipid-independent APOE-genotype specific effects on stroke risk and suggests that characterization of the metabolic role of APOE is needed to improve understanding of APOE biology in cerebrovascular disease.