Unraveling the thrombin–Alzheimer’s connection: Oral anticoagulants as potential neuroprotective therapeutics

In Alzheimer’s disease (AD), toxic amyloids formed by amyloid-β (Aβ) proteins and tau are implicated in the development of inflammatory, vascular, and neurodegenerative brain disorders. Thrombin has also been recognized as a proteopathic factor involved in Aβ-induced neurovascular dysfunction. Vascular Aβ activates the contact system in the blood, stimulating the production of inflammatory bradykinin and procoagulant thrombin. Thrombin, in turn, triggers inflammation, platelet activation, and the formation of fibrinolysis-resistant, Aβ-containing fibrin clots, leading to Aß-type cerebral amyloid angiopathy and associated neuropathology. Targeting thrombin with oral anticoagulants can normalize proinflammatory and prothrombotic states, counteracting the neurovascular consequences of AD. Pre-clinical studies have shown that such interventions preserve vascular and blood–brain barrier integrity, improve cerebral blood flow and brain perfusion, and reduce parenchymal accumulations of toxic Aβ, tau, fibrin(ogen), and thrombin. These effects mitigate neuroinflammatory and neurodegenerative processes, ultimately preserving cognitive functions for a longer period. Recent observational clinical studies in patients with atrial fibrillation (AF) demonstrated that treatment with direct oral anticoagulants (DOACs) or vitamin K antagonists (VKAs) reduced the risk of dementia by up to 48% compared to non-users. The anti-dementia effects were most prominent in elderly patients but were also observed in individuals with low AF risk or newly diagnosed AF. In addition, DOACs reduced the risk of intracranial hemorrhage by approximately 50% compared to VKAs. The current review highlights the potential neuroprotective role of DOACs in AD. By preventing excessive thrombin generation caused by Aβ pathology, DOACs could protect vascular and neuronal functions, thereby slowing cognitive decline. DOACs, such as dabigatran, apixaban, and rivaroxaban, warrant further clinical investigation for their potential repurposing as disease-modifying therapeutics in AD.