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

Abstract

Alzheimer’s disease (AD) is caused by neurodegenerative, but also vascular and hemostatic changes in the brain. The oral thrombin inhibitor dabigatran, which has been used for over a decade in preventing thromboembolism and has a well-known pharmacokinetic, safety and antidote profile, can be an option to treat vascular dysfunction in early AD, a condition known as cerebral amyloid angiopathy (CAA). Recent results have revealed that amyloid-β proteins (Aβ), thrombin and fibrin play a crucial role in triggering vascular and parenchymal brain abnormalities in CAA. Dabigatran blocks soluble thrombin, thrombin-mediated formation of fibrin and Aβ-containing fibrin clots. These clots are deposited in brain parenchyma and blood vessels in areas of CAA. Fibrin-Aβ deposition causes microvascular constriction, occlusion and hemorrhage, leading to vascular and blood–brain barrier dysfunction. As a result, blood flow, perfusion and oxygen and nutrient supply are chronically reduced, mainly in hippocampal and neocortical brain areas. Dabigatran has the potential to preserve perfusion and oxygen delivery to the brain, and to prevent parenchymal Aβ-, thrombin- and fibrin-triggered inflammatory and neurodegenerative processes, leading to synapse and neuron death, and cognitive decline. Beneficial effects of dabigatran on CAA and AD have recently been shown in preclinical studies and in retrospective observer studies on patients. Therefore, clinical studies are warranted, in order to possibly expand dabigatran approval for repositioning for AD treatment.

Special Issue Editorial: “Infections, Inflammation and Neurodegeneration in Alzheimer Disease” Infections, Neuronal Senescence, and Dementia

“…Finally, another paper in the Special Issue by Grossman [ 26 ] suggests a treatment with a thrombin inhibitor to modulate AD brain inflammation. I suggest that a possible effect of this drug consists of decreasing inflammatory responses induced by HERV or exogenous pathogens and modulating neurodegenerative process associated with dementia.…”

First-in-Class Isonipecotamide-Based Thrombin and Cholinesterase Dual Inhibitors with Potential for Alzheimer Disease

“…The achievement in the same molecule of a good fXa and BChE inhibition must not be underestimated. A putative role of BChE in the AD progression has been suggested [23,24], whereas, although a direct involvement of fXa in abnormal neurodegenerative pathways has not been shown, fXa inhibition can prevent the generation of thr and possibly its AD-related neurotoxicity and inflammation [6,7]. [1][2][3][4][5] .…”

“…As recommended by recent medical guidelines, the systematic prevention of vascular risk factors in AD patients may positively impact the disease progression [6]. The cerebrovascular abnormalities are followed by formation of Aβ protein plaques co-aggregating with some coagulation factors; these deposits may induce leaking of the brain-blood-barrier (BBB), promoting a pro-thrombotic state, as well as enhancing release of pro-inflammatory mediators in the brain areas [7].…”

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

“…Therefore, drug development costs and time for progression in the pipeline could be substantially reduced [ 8 ]. In this context, anticoagulants could be promising therapeutic candidates for targeting hemostatic and cerebrovascular dysfunctions and associated neurodegenerative processes in AD [ 9 , 10 , 11 ]. After first clinical evaluation more than 50 years ago, the renaissance of an anticoagulative therapy has been inspired by recent research that indicates that cerebrovascular damage and dysregulated intrinsic coagulation, as well as risk factors for cardiovascular disease, play important roles in AD pathogenesis [ 9 , 12 , 13 ].…”

“…Particularly, it turned out that accumulations of toxic Aß, along with excessive thrombin and fibrin(ogen) accumulations, are causally involved in cerebrovascular and blood–brain barrier (BBB) dysfunction. These changes might be mechanistically treated by anticoagulants through targeting its causes [ 9 , 10 , 11 , 15 ]. This article presents a comprehensive review on latest studies, showing that anticoagulants, especially of the DOAC-type, can be a promising option for a successful medication of vascular-conditioned, cognitive impairment in AD.…”