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

Andreas Charidimou, Hazel I. Zonneveld, Sara Shams, Kejal Kantarci, Ashkan Shoamanesh, Saima Hilal, Paul A. Yates, Gregoire Boulouis, Han Kyu Na, Marco Pasi, Allesandro Biffi, Yuek Ling Chai, Joyce Ruifen Chong, Lars-Olof Wahlund, Jack R. Clifford, Christopher Chen, M. Edip Gurol, Joshua N. Goldstein, Duk L. Na, Frederik BarkhofSang Won Seo, Jonathan Rosand, Steven M. Greenberg, Anand Viswanathan

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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 ε2+ or ε4+ genotype vs the ε3/ε3 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 ε4+ and cSS presence or severity. When stratified by clinical setting, APOE ε4+ 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 ε2+ 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 ε2/ε2 and APOE ε2/ε4 genotypes were most consistently and strongly associated with cSS presence and severity. CONCLUSION: CAA-related vasculopathic changes and fragility associated with APOE ε2+ allele might have a biologically meaningful role in the pathophysiology and severity of cSS.
Original languageEnglish
Pages (from-to)e358-e371
Issue number4
Early online date26 Jun 2019
Publication statusPublished - 23 Jul 2019

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