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Advanced Neurology

REVIEW ARTICLE
Unraveling the thrombin–Alzheimer’s

connection: Oral anticoagulants as potential
neuroprotective therapeutics

Klaus Grossmann*

Department of Plant Physiology, Center for Plant Molecular Biology (ZMBP), University of Tübingen,
Tübingen, Baden-Württemberg, Germany

Abstract

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
*Corresponding author: cerebral blood flow and brain perfusion, and reduce parenchymal accumulations of
Klaus Grossmann toxic Aβ, tau, fibrin(ogen), and thrombin. These effects mitigate neuroinflammatory
(klaus.grossmann@uni-tuebingen.
de) and neurodegenerative processes, ultimately preserving cognitive functions for a
longer period. Recent observational clinical studies in patients with atrial fibrillation
Citation: Grossmann K. Unraveling (AF) demonstrated that treatment with direct oral anticoagulants (DOACs) or vitamin
the thrombin–Alzheimer’s
connection: Oral anticoagulants K antagonists (VKAs) reduced the risk of dementia by up to 48% compared to non-
as potential neuroprotective users. The anti-dementia effects were most prominent in elderly patients but were also
therapeutics. Adv Neurol. observed in individuals with low AF risk or newly diagnosed AF. In addition, DOACs
2024;3(4):3799.
doi: 10.36922/an.3799 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
Received: May 30, 2024
preventing excessive thrombin generation caused by Aβ pathology, DOACs could
Accepted: September 20, 2024 protect vascular and neuronal functions, thereby slowing cognitive decline. DOACs,
Published Online: October 25, such as dabigatran, apixaban, and rivaroxaban, warrant further clinical investigation
2024 for their potential repurposing as disease-modifying therapeutics in AD.
Copyright: © 2024 Author(s).
This is an Open-Access article
distributed under the terms of the Keywords: Amyloid-β proteins; Thrombin; Neurovascular dysfunction; Disease-modifying
Creative Commons Attribution therapeutics; Direct oral anticoagulants; Alzheimer’s disease
License, permitting distribution,
and reproduction in any medium,
provided the original work is
properly cited.
1. Introduction
Publisher’s Note: AccScience
Publishing remains neutral with Alzheimer’s disease (AD), the most widespread neurodegenerative disease and
regard to jurisdictional claims in
published maps and institutional leading cause of dementia, was first described in 1906 at a conference in Tübingen,
1
affiliations. Germany. On this occasion, psychiatrist and neuropathologist Alois Alzheimer

Volume 3 Issue 4 (2024) 1 doi: 10.36922/an.3799