APOE and cortical superficial siderosis in CAA Meta-analysis and potential mechanisms

Objective To assess potential mechanisms of cortical superficial siderosis (cSS), a central MRI biomarker in cerebral amyloid angiopathy (CAA), we performed a collaborative meta-analysis of APOE associations with cSS presence and severity. Methods We pooled data from published studies reporting APOE genotype and MRI assessment of cSS in 3 distinct settings: (1) stroke clinic patients with symptomatic CAA (i. e., lobar intracerebral hemorrhage, transient focal neurologic episodes) according to the Boston criteria; (2) memory clinic patients; and (3) population-based studies. We compared cSS presence and severity (focal or disseminated vs no cSS) in participants with epsilon 2+ or epsilon 4+ genotype vs the epsilon 3/epsilon 3 genotype, by calculating study-specific and random effects pooled, unadjusted odds ratios (ORs). Results Thirteen studies fulfilled inclusion criteria: 7 memory clinic cohorts (n = 2,587), 5 symptomatic CAA cohorts (n = 402), and 1 population-based study (n = 1,379). There was no significant overall association between APOE epsilon 4+ and cSS presence or severity. When stratified by clinical setting, APOE epsilon 4+ was associated with cSS in memory clinic (OR 2.10; 95% confidence interval [CI] 1.11-3.99) but not symptomatic CAA patients. The pooled OR showed significantly increased odds of having cSS for APOE epsilon 2+ genotypes (OR 2.42, 95% CI 1.48-3.95) in both patient populations. This association was stronger for disseminated cSS in symptomatic CAA cohorts. In detailed subgroup analyses, APOE epsilon 2/epsilon 2 and APOE epsilon 2/epsilon 4 genotypes were most consistently and strongly associated with cSS presence and severity. Conclusion CAA-related vasculopathic changes and fragility associated with APOE epsilon 2+ allele might have a biologically meaningful role in the pathophysiology and severity of cSS.