The Apolipoprotein E ε2 Allele and the Pathological Features in Cerebral Amyloid Angiopathy-related Hemorrhage

Cerebral amyloid angiopathy (CAA) is associated with apolipoprotein E (APOE gene, apoE protein) polymorphism: current evidence suggests that the ∈4 allele is a risk factor for the development of CAA and the ∈2 allele predisposes to hemorrhage. We sought to determine the relationship between the APOE ∈2 allele and both the immunoreactivity profiles and vascular complications of CAA. We performed immunohistochemistry for amyloid β-protein (Aβ), apoE, cystatin C, and activated microglia, and examined the morphology of cortical and leptomeningeal vessels in 37 CAA-related hemorrhage (CAAH), 26 Alzheimer disease (AD) patients, and 20 controls. The extent of immunostaining of vessels for Aβ, apoE, cystatin C, and perivascular activated microglia increased from controls through AD to a maximum in CAAH patients. Among cases with CAA (37 CAAH, 19 AD, and 6 controls, n = 62) vascular apoE (p < 5 × 10−4), cystatin C (p < 10−4), activated microglia (p < 10−4), vessels with a high ratio of wall thickness to lumen diameter (p < 0.003) as well as dilated/microaneurysmal vessels (p < 0.01) were present more frequently in patients with hemorrhage than without; however, these features were not associated with the APOE ∈2 allele. Fibrinoid necrosis alone was associated with the APOE ∈2 allele (p < 0.04) and we suggest that over-representation of APOE ∈2 in CAAH may result from its association with fibrinoid necrosis.