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

Neurology. 2019 Jul 23;93(4):e358-e371. doi: 10.1212/WNL.0000000000007818. Epub 2019 Jun 26.


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.

Publication types

  • Meta-Analysis
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Apolipoprotein E2
  • Apolipoprotein E3
  • Apolipoprotein E4
  • Apolipoproteins E / genetics*
  • Brain / diagnostic imaging*
  • Case-Control Studies
  • Cerebral Amyloid Angiopathy / diagnostic imaging*
  • Cerebral Cortex / diagnostic imaging
  • Cerebral Cortex / metabolism*
  • Hemosiderosis / diagnostic imaging
  • Hemosiderosis / genetics*
  • Humans
  • Magnetic Resonance Imaging
  • Odds Ratio


  • Apolipoprotein E2
  • Apolipoprotein E3
  • Apolipoprotein E4
  • Apolipoproteins E