Anticoagulants for Treatment of Alzheimer’s Disease

Abstract

Alzheimer’s disease (AD) is a multifactorial syndrome with a plethora of progressive, degenerative changes in the brain parenchyma, but also in the cerebrovascular and hemostatic system. A therapeutic approach for AD is reviewed, which is focused on the role of amyloid–β protein (Aβ) and fibrin in triggering intra-brain vascular dysfunction and connected, cognitive decline. It is proposed that direct oral anticoagulants (DOACs) counteract Aβ-induced pathological alterations in cerebral blood vessels early in AD, a condition, known as cerebral amyloid angiopathy (CAA). By inhibiting thrombin for fibrin formation, anticoagulants can prevent accumulations of proinflammatory thrombin and fibrin, and deposition of degradation-resistant, Aβ-containing fibrin clots. These fibrin–Aβ clots are found in brain parenchyma between neuron cells, and in and around cerebral blood vessels in areas of CAA, leading to decreased cerebral blood flow. Consequently, anticoagulant treatment could reduce hypoperfusion and restricted supply of brain tissue with oxygen and nutrients. Concomitantly, hypoperfusion-enhanced neurodegenerative processes, such as progressive Aβ accumulation via synthesis and reduced perivascular clearance, neuroinflammation, and synapse and neuron cell loss, could be mitigated. Given full cerebral perfusion and reduced Aβ- and fibrin-accumulating and inflammatory milieu, anticoagulants could be able to decrease vascular-driven progression in neurodegenerative and cognitive changes, present in AD, when treated early, therapeutically, or prophylactically.

Alzheimer’s Disease—Rationales for Potential Treatment with the Thrombin Inhibitor Dabigatran

“…It has been proposed that thrombin inhibitors might be able to alleviate symptoms in AD, due to their dampening impact on vascular proinflammatory thrombin [ 75 , 98 ]. In line with the hypothesis of a beneficial effect of anticoagulants on AD pathogenesis [ 12 , 13 , 75 , 98 ], recent results from a preclinical study in AD mouse model showed the potential therapeutic usefulness of DOAC medication against AD [ 99 ]. As reported by Cortes-Canteli et al, long-term treatment with dabigatran prevents cerebral fibrin clot deposition, CBF decrease, hypoperfusion, and memory decline [ 99 ].…”

“…However, the antithrombotic effect also increases the risk of bleeding [ 15 ]. Since AD involves vascular and hemostatic changes in the pathogenesis, medical repositioning of anticoagulants for treatment of this brain amyloidosis is currently under discussion [ 6 , 12 , 13 ].…”

“…However, for treatment of AD patients, VKA-type anticoagulants exhibit undesirable side effects, which include bleeding complications (inclusive slow-acting reversal effect of vitamin K antidote), coumarin necrosis, vitamin K deficiency effects on important proteins of the vascular and nervous system (e.g., vitamin K-dependent proteins Gas6, MGP; key enzymes of sphingolipid synthesis), as well as dietary and pharmacodynamic interactions [ 14 , 103 , 104 ]. In this respect, the novel, specific-acting DOAC-type anticoagulants, which have been approved for therapeutic use and introduced into the medicine market over the last decade [ 14 ], are more suitable [ 12 , 14 ]. These include the blood clotting factor Xa-inhibitors apixaban (Eliquis ® ), betrixaban (Bevyxxa ® ), edoxaban (Lixiana ® ), rivaroxaban (Xarelto ® ), and the blood clotting factor IIa (thrombin)-inhibitor dabigatran (orally administered prodrug: dabigatran etexilate, Pradaxa ® ) [ 14 ].…”

“…Among the DOACs, dabigatran could be favored for treatment of vascular and hemostatic changes contributing to AD, based on the following rationales [ 12 , 13 ]. Dabigatran is the only direct thrombin inhibitor, available in the class of new antithrombotic DOACs [ 105 ].…”

“…Recent results on the contribution of cerebrovascular and hemostatic dysfunction to AD have brought the idea back into focus that anticoagulants may also be beneficial for treatment of AD. As key drivers in vascular pathogenesis and derived neurodegenerative changes, progressive accumulation of toxic amyloid-β proteins (Aβ), thrombin and fibrin have recently been identified that can be treated by anticoagulants [ 12 , 13 ]. In this review article, why the orally active thrombin inhibitor dabigatran could be useful in therapy for cerebrovascular and related cognitive dysfunction in AD is discussed.…”