APOE associations with severe CAA-associated vasculopathic changes: collaborative meta-analysis

Objectives Cerebral amyloid angiopathy (CAA) is associated with lobar intracerebral haemorrhage (ICH). While only the epsilon 4 allele of the apolipoprotein E (APOE) gene is associated with the presence of CAA, both APOE-epsilon 4 and epsilon 2 are associated with lobar ICH. The generally accepted explanation is that APOE-epsilon 4 promotes vascular amyloid deposition, while APOE-epsilon 2 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 We obtained unpublished data from these for meta-analyses of the effects of epsilon 4-containing (epsilon 4+) and epsilon 2-containing (epsilon 2+) genotypes on progression to severe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 epsilon 4+ genotypes with severe CAA (epsilon 4+ vs epsilon 4-: 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 epsilon 2+ versus epsilon 2- genotypes, there was no significant association, but the very small number of participants with epsilon 2+ genotypes (22) precluded reliable estimates. Conclusions We found a possible association of severe CAA with APOE-epsilon 4 but not APOE-epsilon 2. However, our findings do not exclude a biologically meaningful association between APOE-epsilon 2 and severe CAA. Further work is needed to elucidate fully the allele-specific associations of APOE with CAA and their mechanisms.