title: APOE associations with severe CAA-associated vasculopathic changes: collaborative meta-analysis.
abstract: OBJECTIVE
  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 We obtained unpublished data from these for meta-analyses of the effects of ε4-containing (ε4+) and ε2-containing (ε2+) genotypes on progression to severe CAA.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.
authors.affiliation: Division of Clinical Neurosciences, Centre for Clinical Brain Sciences, University of Edinburgh, , Edinburgh, UK.
authors.forename: Kristiina
authors.initials: K
authors.lastname: Rannikmäe
authors.forename: Rajesh N
authors.initials: RN
authors.lastname: Kalaria
authors.forename: Steven M
authors.initials: SM
authors.lastname: Greenberg
authors.forename: Helena C
authors.initials: HC
authors.lastname: Chui
authors.forename: Frederick A
authors.initials: FA
authors.lastname: Schmitt
authors.forename: Neshika
authors.initials: N
authors.lastname: Samarasekera
authors.forename: Rustam
authors.initials: R
authors.lastname: Al-Shahi Salman
authors.forename: Cathie L M
authors.initials: CL
authors.lastname: Sudlow
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D053329:Apolipoprotein E2 / Q000235:genetics; D053327:Apolipoprotein E4 / Q000235:genetics; D001057:Apolipoproteins E / Q000235:genetics*; D016657:Cerebral Amyloid Angiopathy / Q000150:complications / Q000235:genetics* / Q000473:pathology; D018450:Disease Progression; D005260:Female; D056726:Genetic Association Studies; D005838:Genotype; D006801:Humans; D020300:Intracranial Hemorrhages / Q000209:etiology / Q000235:genetics; D008297:Male; D012720:Severity of Illness Index
chemical_list: D053329:Apolipoprotein E2; D053327:Apolipoprotein E4; D001057:Apolipoproteins E
keywords: Amyloid; Apolipoproteins; Cerebrovascular Disease; Meta-Analysis; Systematic Reviews