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APOE associations with severe CAA-associated vasculopathic changes: collaborative meta-analysis
Kristiina Rannikmäe1, Rajesh N Kalaria, Steven M Greenberg
1Division of Clinical Neurosciences, Centre for Clinical Brain Sciences, University of Edinburgh, , Edinburgh, UK.
Insights
The APOE-ε4 gene variant may be linked to severe cerebral amyloid angiopathy (CAA), a condition associated with brain bleeds. However, the APOE-ε2 variant
Area of Science:
- Neurology
- Genetics
- Pathology
Background:
- Cerebral amyloid angiopathy (CAA) is a significant cause of lobar intracerebral haemorrhage (ICH).
- The apolipoprotein E (APOE) gene, particularly the ε4 allele, is linked to CAA presence, while both APOE-ε4 and ε2 alleles are associated with lobar ICH.
- Current understanding suggests APOE-ε4 promotes amyloid deposition, and APOE-ε2 promotes severe CAA with vasculopathy leading to ICH.
Purpose of the Study:
- To evaluate the allele-specific effects of APOE genotypes on the severity of cerebral amyloid angiopathy.
- To assess the association between APOE-ε4 and APOE-ε2 genotypes and the progression to severe CAA.
Main Methods:
- Systematic identification of published studies with APOE genotype and postmortem brain histopathology data for CAA severity.
- Meta-analysis of available published and unpublished data to determine the effects of ε4-containing (ε4+) and ε2-containing (ε2+) genotypes on severe CAA progression.
Main Results:
- Meta-analyses indicated a possible association between ε4+ genotypes and severe CAA (OR 2.5, 95% CI 1.4 to 4.5).
- No significant association was found for ε2+ genotypes with severe CAA, though the small sample size (22 participants) limited reliable conclusions.
- Data from six studies involving 543 participants (353 with CAA) were included in the analyses.
Conclusions:
- A potential link exists between the APOE-ε4 genotype and severe CAA.
- The study did not find a significant association for APOE-ε2 with severe CAA, but this requires further investigation due to limited data.
- Additional research is necessary to fully clarify the allele-specific roles of APOE in CAA and its underlying mechanisms.
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.
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