APOE ε4 and lipid levels affect risk of recurrent nonlobar intracerebral hemorrhage

Abstract

Objective: Genetic variants ε2/ε4 within the APOE gene are established risk factors for lobar intracerebral hemorrhage (ICH). Published preliminary data suggest a potential role for APOE ε4 in risk of nonlobar ICH. We therefore investigated the role of APOE in recurrent nonlobar ICH, and sought to clarify whether effects of APOE on circulating lipids mediate this association.

Methods: Three hundred sixty-three survivors of nonlobar ICH were followed prospectively for ICH recurrence, with APOE genotype determined at enrollment. All participants had clinical, demographic, and laboratory data captured at time of index ICH and during follow-up. Using a multivariate model, we performed association and interaction analyses of the relationships among APOE genotype, lipid levels, and recurrent nonlobar ICH.

Results: We observed 29 nonlobar ICH recurrences among 363 survivors. APOE ε4 was associated with recurrent nonlobar ICH (hazard ratio = 1.31; 95% confidence interval = 1.02-2.69; p = 0.038) after adjustment for age/sex/ethnicity and cardiovascular risk factors. Increasing low-density lipoprotein (LDL) levels were associated with decreased risk of recurrent nonlobar ICH (p = 0.027), as were decreasing HDL levels (p = 0.046). LDL levels modified the association of APOE ε4 with recurrent nonlobar ICH (mediation p < 0.05). No associations were identified between APOE ε2 and recurrent nonlobar ICH.

Conclusion: APOE ε4 is associated with recurrent ICH in nonlobar brain regions, providing further evidence for its causal role in ICH unrelated to cerebral amyloid angiopathy. LDL levels modulated this effect, suggesting that circulating lipid levels may mediate a portion of the role of APOE ε4 in nonlobar ICH.

Figure 1. Total cholesterol and lipid fraction measurements during follow-up

(A) Total cholesterol levels for entire study population during follow-up time. Individual lines connect minimum, first quartile, mean, third quartile, and maximum values per each year as detailed in the figure legend. (B) LDL cholesterol levels for all study participants during follow-up time (legend as in A). (C) LDL cholesterol levels for all study participants during follow-up time (legend as in A). HDL = high-density lipoprotein; ICH = intracerebral hemorrhage; LDL = low-density lipoprotein.

Figure 2. APOE ε4 and risk of recurrent ICH in the nonlobar brain regions

Kaplan–Meier plot displaying nonlobar ICH recurrence rates stratified by number of APOE ε4 allele copies during the first 5 years of follow-up. Univariate log-rank test p value = 0.031. Refer to main text for results of multivariate analyses. ICH = intracerebral hemorrhage.

Figure 3. Mediation analyses of the effect of APOE on risk of recurrent ICH in the nonlobar brain regions

The percentages of effect size for APOE ε4 genotype association with nonlobar ICH recurrence mediated by other predictors of rebleeding risk are listed in the central rounded-edges rectangle column. Percentages refer only to the effect size attributed to APOE ε4 genotype (predicting ∼7% of overall nonlobar ICH recurrence risk). Only LDL + HDL levels mediated a proportion of the APOE effects on nonlobar ICH recurrence statistically different from 0%, as visually represented by the solid line connecting genotype and recurrence outcome through lipid data. Refer to main text for results of separate LDL and HDL mediation analyses. The remainder of APOE genotype predictive power not accounted for by percentages listed above is related to undetected mediated effects and/or direct (nonmediated) effects. CAD = medical history of coronary artery disease; CI = confidence interval; DM = medical history of diabetes mellitus; HDL = high-density lipoprotein; ICH = intracerebral hemorrhage; LDL = low-density lipoprotein.

Figure 4. Nonlobar ICH recurrence risk by LDL levels and APOE genotype

The p values are computed in each subset defined by LDL measurements using the log-rank test, and adjusting for race/ethnicity, education, CAD, and nonlobar ICH before index (enrollment event). LDL cutoffs represent mean values of all measurements during 5 years of follow-up, and were chosen to approximate LDL quartiles as identified in the overall dataset. CAD = coronary artery disease; ICH = intracerebral hemorrhage; LDL = low-density lipoprotein.