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Research paper
APOE associations with severe CAA-associated vasculopathic changes: collaborative meta-analysis
  1. Kristiina Rannikmäe1,
  2. Rajesh N Kalaria2,
  3. Steven M Greenberg3,
  4. Helena C Chui4,
  5. Frederick A Schmitt5,
  6. Neshika Samarasekera1,
  7. Rustam Al-Shahi Salman1,
  8. Cathie L M Sudlow1,6
  1. 1Division of Clinical Neurosciences, Centre for Clinical Brain Sciences, University of Edinburgh, Edinburgh, UK
  2. 2Institute for Ageing and Health, Newcastle University, Newcastle upon Tyne, UK
  3. 3Department of Neurology, Stroke Research Centre, Massachusetts General Hospital, Boston, Massachusetts, USA
  4. 4Department of Neurology, University of Southern California, Los Angeles, California, USA
  5. 5Department of Neurology, Sanders-Brown Center on Aging, University of Kentucky, Lexington, Kentucky, USA
  6. 6Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, UK
  1. Correspondence to Professor Cathie Sudlow, Division of Clinical Neurosciences, Centre for Clinical Brain Sciences, University of Edinburgh, Western General Hospital, Crewe Road, Edinburgh EH4 2XU, UK; cathie.sudlow{at}ed.ac.uk

Abstract

Objectives Cerebral amyloid angiopathy (CAA) is associated with lobar intracerebral haemorrhage (ICH). While only the ε4 allele of the apolipoprotein E (APOE) gene is associated with the presence of CAA, both APOE-ε4 and ε2 are associated with lobar ICH. The generally accepted explanation is that APOE-ε4 promotes vascular amyloid deposition, while APOE-ε2 promotes progression to severe CAA with associated vasculopathic changes that cause vessel rupture and ICH. We assessed the evidence for these allele-specific effects.

Methods We systematically identified published studies with data on APOE genotype and histopathological assessment of postmortem brains for CAA severity. We obtained unpublished data from these for meta-analyses of the effects of ε4-containing (ε4+) and ε2-containing (ε2+) genotypes on progression to severe CAA.

Results Of six eligible studies (543 eligible participants), data were available from 5 (497 participants, 353 with CAA). Meta-analyses showed a possible association of ε4+ genotypes with severe CAA (ε4+ vs ε4−: severe vs mild/moderate CAA, OR 2.5, 95% CI 1.4 to 4.5, p=0.002; severe vs moderate CAA, OR 1.7, 95% CI 0.9 to 3.1, p=0.11). For ε2+ versus ε2− genotypes, there was no significant association, but the very small number of participants with ε2+ genotypes (22) precluded reliable estimates.

Conclusions We found a possible association of severe CAA with APOE-ε4 but not APOE-ε2. However, our findings do not exclude a biologically meaningful association between APOE-ε2 and severe CAA. Further work is needed to elucidate fully the allele-specific associations of APOE with CAA and their mechanisms.

  • Amyloid
  • Cerebrovascular Disease
  • Apolipoproteins
  • Meta-Analysis
  • Systematic Reviews

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