APOE polymorphisms influence longitudinal lipid trends preceding intracerebral hemorrhage

Abstract

Objective: We sought to determine whether APOE genotype influences a previously observed decline in serum total cholesterol (TC) and low-density lipoprotein (LDL) levels preceding primary intracerebral hemorrhage (ICH), as a potential demonstration of nonamyloid mechanisms of APOE in ICH risk.

Methods: We performed a single-center retrospective longitudinal analysis using patients with known APOE genotype drawn from an ongoing cohort study of ICH. Serum lipid measurements for TC, triglycerides (TGs), LDL, and high-density lipoprotein (HDL) collected within 2 years before and after index ICH were extracted from electronic medical records. Piecewise linear mixed-effects models were used to compare APOE allele-specific effects on temporal serum lipid trends in ICH. Demographics, medical history, medications, and health maintenance data were included as fixed effects. Inter- and intraindividual variations in lipid levels were modeled as random effects.

Results: A total of 124 ICH cases were analyzed. APOE ε4 carriers had greater rates of decline in serum TC and LDL within 6 months preceding ICH (TC: -7.30 mg/dL/mo, p = 0.0035; LDL: -8.44 mg/dL/mo, p = 0.0001). Conversely, serum TC and LDL levels in APOE ε2 carriers were unchanged within the same time period. APOE genotype had no associations with serum HDL or TG trends.

Conclusions: APOE allele status predicts serum TC and LDL changes preceding acute ICH. Our results have implications for ongoing efforts in dissecting the role of dyslipidemia in cerebrovascular disease risk. APOE genotype-specific influence on lipid trends provides a clue for one mechanism by which APOE may influence risk of ICH. Further characterization of the metabolic roles of APOE is needed to improve the understanding of APOE biology in cerebrovascular disease risk.

Figure 1.. Study cohort and analysis plan

MGH-ICH Database = Massachusetts General Hospital-based patients in the Genetics of Cerebral Hemorrhage on Anticoagulation Study; ICH = intracerebral hemorrhage.

Figure 2.. Temporal trends in individual serum lipid fractions in ICH patients

(A–D) Loess smoothed curves of serum lipid levels (mg/dL) against time (in months) before and after ICH. Gray areas indicate standard error (SE). Time period of interest is indicated by shaded boxes (P₂ 0–6 months pre-ICH). *p < 0.0125, rate of change of serum lipids by Wald test for the time period P₂. ICH = intracerebral hemorrhage.

Figure 3.. Temporal trends in individual serum lipid fractions in ICH patients by APOE allele carrier status

(A–D) Loess smoothed curves of serum lipid levels (mg/dL) against time (in months) before and after ICH. Gray areas indicate standard error (SE). Time period of interest is indicated by shaded boxes (P₂ 0–6 months pre-ICH). *p < 0.0125, rate of change of serum lipids by Wald test for time period P₂ in APOE ε2 or ε4 carrier status compared with reference (APOE ε3/ε3). ICH = intracerebral hemorrhage.