This autopsy study analyzed 205 brains with neuropathologically confirmed CAA from two Spanish cohorts (hospital-based and institutionalized dementia patients) to identify factors independently associated with intracerebral hemorrhage (ICH), including APOE genotype, CAA severity by Vonsattel and VCING grading, and concomitant Alzheimer's disease neuropathologic change (ADNC).
On multivariate analysis, three factors independently predicted ICH: APOE ε2 carriage (OR 4.07, 95% CI 1.22–13.57), high Vonsattel CAA grade 3–4/vascular remodeling (OR 8.13, 95% CI 2.68–24.71), and younger age at death. The ε2/ε4 genotype showed the highest ICH frequency (66.7%). When both ε2 carriage and Vonsattel 3–4 were present, 77.8% of those individuals had ICH. CAA vascular severity was most strongly linked to ICH when concomitant high ADNC was also present (85.7% with high-grade Vonsattel in the ICH/high-ADNC group vs. 35% in ICH/low-ADNC).
- No clinical or radiological data (anticoagulants, hypertension, MRI markers like CMBs/cortical siderosis) were available, limiting correlation with clinical hemorrhagic risk factors. - Sample sizes for subgroups stratified by ADNC and ICH were small (e.g., ICH/high ADNC n=14), restricting statistical power. - Cohort was ethnically homogeneous (predominantly White Spanish), limiting generalizability of APOE findings.
In patients with known or suspected CAA being considered for anti-amyloid immunotherapy, APOE ε2 status—especially in combination with ε4 (ε2/ε4 genotype)—signals markedly elevated hemorrhagic risk and warrants careful patient selection and close monitoring. Severe CAA vascular remodeling (Vonsattel grade 3–4) co-occurring with concomitant AD pathology identifies a particularly high-risk hemorrhagic profile.
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