Direct Oral Anticoagulants (DOACs) for Therapeutic Targeting of Thrombin, a Key Mediator of Cerebrovascular and Neuronal Dysfunction in Alzheimer's Disease.

Abstract

Although preclinical research and observer studies on patients with atrial fibrillation concluded that direct oral anticoagulants (DOACs) can protect against dementia like Alzheimer’s disease (AD), clinical investigation towards therapeutical approval is still pending. DOACs target pathological thrombin, which is, like toxic tau and amyloid-ß proteins (Aß), an early hallmark of AD. Especially in hippocampal and neocortical areas, the release of parenchymal Aß into the blood induces thrombin and proinflammatory bradykinin synthesis by activating factor XII of the contact system. Thrombin promotes platelet aggregation and catalyzes conversion of fibrinogen to fibrin, leading to degradation-resistant, Aß-containing fibrin clots. Together with oligomeric Aß, these clots trigger vessel constriction and cerebral amyloid angiopathy (CAA) with vessel occlusion and hemorrhages, leading to vascular and blood–brain barrier (BBB) dysfunction. As consequences, brain blood flow, perfusion, and supply with oxygen (hypoxia) and nutrients decrease. In parenchymal tissue, hypoxia stimulates Aß synthesis, leading to Aß accumulation, which is further enhanced by BBB-impaired perivascular Aß clearance. Aß trigger neuronal damage and promote tau pathologies. BBB dysfunction enables thrombin and fibrin(ogen) to migrate into parenchymal tissue and to activate glial cells. Inflammation and continued Aß production are the results. Synapses and neurons die, and cognitive abilities are lost. DOACs block thrombin by inhibiting its activity (dabigatran) or production (FXa-inhibitors, e.g., apixaban, rivaroxaban). Therefore, DOAC use could preserve vascular integrity and brain perfusion and, thereby, could counteract vascular-driven neuronal and cognitive decline in AD. A conception for clinical investigation is presented, focused on DOAC treatment of patients with diagnosed AD in early-stage and low risk of major bleeding.