The dual role of APOE ε4 allele in cerebral small vessel disease: independent genetic effects and effect modification of traditional risk factors.

BACKGROUND: The association between apolipoprotein E (APOE) ε4 and cerebral small vessel disease (CSVD) remains incompletely understood, with inconsistent evidence across imaging phenotypes and limited investigation into gene-environment interactions. METHOD: This cross-sectional study included 728 patients with chronic lacunar infarcts who underwent 3 T brain MRI. CSVD burden was quantified using a study-specific composite score (range 0-6), integrating white matter hyperintensities (WMH), cerebral microbleeds (CMBs), and enlarged perivascular spaces (EPVS). APOE ε4 carriers (n = 139) were compared with non-carriers (n = 589). Ordinal logistic regression and Firth's penalized logistic regression (for EPVS) were used to assess the independent effect of APOE ε4 on CSVD markers. Multiplicative interaction terms (APOE ε4 × smoking, APOE ε4 × alcohol use) were added to the fully adjusted models, with p values adjusted using the Holm-Bonferroni method. Sensitivity analyses excluded APOE ε2 carriers. RESULTS: APOE ε4 was independently associated only with periventricular WMH burden (β = 0.411, 95% CI: 0.046-0.776, p = 0.027), with no significant associations for global CSVD burden, total WMH, deep WMH, CMBs, or EPVS. Significant interactions were observed for APOE ε4 × smoking on global CSVD burden, CMBs, total WMH, and PWMH (adjusted p < 0.05), and for APOE ε4 × alcohol use on global CSVD burden and CMBs (adjusted p < 0.05). These findings remained robust after excluding APOE ε2 carriers. CONCLUSION: APOE ε4 exhibits both an independent genetic effect-selectively associated with periventricular white matter injury-and a modifying effect on the associations of smoking and alcohol use with specific CSVD phenotypes. These findings highlight the phenotypic specificity of APOE ε4's dual role in CSVD and support the integration of genetic background with modifiable risk factors for precision risk stratification.