The APOE ε4/ε4 Genotype Potentiates Vascular Fibrin(Ogen) Deposition in Amyloid-Laden Vessels in the Brains of Alzheimer's Disease Patients

Abstract

Evidence indicates a critical role for cerebrovascular dysfunction in Alzheimer's disease (AD) pathophysiology. We have shown that fibrin(ogen), the principal blood-clotting protein, is deposited in the AD neurovasculature and interacts with beta-amyloid (Ab), resulting in increased formation of blood clots. As apolipoprotein E (ApoE), a lipid-transporting protein with three human isoforms (E2, E3, and E4), also binds to Aβ, we hypothesized that ApoE and fibrin(ogen) may have a combined effect on the vascular pathophysiology in AD. We assessed whether APOE genotype differentially influences vascular fibrin(ogen) deposition in postmortem brain tissue using immunohistochemistry. An increased deposition of fibrin(ogen) was observed in AD cases compared with non-demented controls, and there was a strong correlation between cerebral amyloid angiopathy (CAA) severity and fibrin(ogen) deposition. Moreover, brains from AD cases homozygous for APOE ε4 showed increased deposition of fibrin(ogen), specifically in CAA- and oligomeric Aβ-positive vessels compared with AD APOE ε2 and ε3 allele carriers, an effect that was not directly linked to CAA severity and cerebrovascular atherosclerosis. These data further support a role for fibrin(ogen) in AD pathophysiology and link the APOE ε4/ε4 genotype with increased thrombosis and/or impaired fibrinolysis in the human AD brain.