APOE ε4 and Intracerebral Hemorrhage in Patients With Brain Arteriovenous Malformation

Importance Intracerebral hemorrhage (ICH) is a serious complication of brain arteriovenous malformation (AVM). Apolipoprotein E (APOE) epsilon 4 is a well-known genetic risk factor for ICH among persons without AVM, and cerebral amyloid angiopathy is a vasculopathy frequently observed in APOE epsilon 4 carriers that may increase the risk of ICH. Objective To assess whether APOE epsilon 4 is associated with a higher risk of ICH in patients with a known AVM. Design, Setting, and Participants This cross-sectional study including 412 participants was conducted in 2 stages (discovery and replication) using individual-level data from the UK Biobank (released March 2012 and last updated October 2023) and the All of Us Research Program (commenced on May 6, 2018, with its latest update provided in October 2023). The occurrence of AVM and ICH was ascertained at the time of enrollment using validated International Classification of Diseases, Ninth Revision and Tenth Revision, codes. Genotypic data on the APOE variants rs429358 and rs7412 were used to ascertain the epsilon status. Main Outcomes and Measures For each study, the association between APOE epsilon 4 variants and ICH risk was assessed among patients with a known AVM by using multivariable logistic regression. Results The discovery phase included 253 UK Biobank participants with known AVM (mean [SD] age, 56.6 [8.0] years, 119 [47.0%] female), of whom 63 (24.9%) sustained an ICH. In the multivariable analysis of 240 participants of European ancestry, APOE epsilon 4 was associated with a higher risk of ICH (odds ratio, 4.58; 95% CI, 2.13-10.34; P < .001). The replication phase included 159 participants with known AVM enrolled in All of Us (mean [SD] age, 57.1 [15.9] years; 106 [66.7%] female), of whom 29 (18.2%) sustained an ICH. In multivariable analysis of 101 participants of European ancestry, APOE epsilon 4 was associated with higher risk of ICH (odds ratio, 4.52; 95% CI, 1.18-19.38; P = .03). Conclusions and Relevance The results of this cross-sectional study of patients from the UK Biobank and All of Us suggest that information on APOE epsilon 4 status may help identify patients with brain AVM who are at particularly high risk of ICH and that cerebral amyloid angiopathy should be evaluated as a possible mediating mechanism of the observed association.