Fibrinogen and Altered Hemostasis in Alzheimer's Disease

Alzheimer's disease (AD) is characterized by amyloid-beta (A beta)plaques, tau tangles, brain atrophy, and vascular pathology. Vascular defects include cerebrovascular dysfunction, decreased cerebral blood flow, and blood brain barrier (BBB) disruption, among others. Here, we review the evidence that links A beta with the vascular pathology present in AD, with a specific focus on the hemostatic system and the clotting protein fibrinogen. Fibrinogen is normally found circulating in blood, but in AD it deposits with A beta in the brain parenchyma and cerebral blood vessels. We found that A beta and fibrin(ogen) interact, and their binding leads to increased fibrinogen aggregation, A beta fibrillization, and the formation of degradation-resistant fibrin clots. Decreasing fibrinogen levels not only lessens cerebral amyloid angiopathy and BBB permeability, but it also reduces microglial activation and improves cognitive performance in AD mouse models. Moreover, a prothrombotic state in AD is evidenced by increased clot formation, decreased fibrinolysis, and elevated levels of coagulation factors and activated platelets. Abnormal deposition and persistence of fibrin(ogen) in AD may result from A beta-fibrin(ogen) binding and altered hemostasis and could thus contribute to A beta deposition, decreased cerebral blood flow, exacerbated neuroinflammation, and eventual neurodegeneration. Blocking the interaction between fibrin(ogen) and A beta may be a promising therapeutic target for AD.