Oral anticoagulants: A plausible new treatment for Alzheimer's disease?

Abstract

Alzheimer's disease (AD) and cardiovascular disease (CVD) are strongly associated. Both are multifactorial disorders with long asymptomatic phases and similar risk factors. Indeed, CVD signatures such as cerebral microbleeds, micro‐infarcts, atherosclerosis, cerebral amyloid angiopathy and a procoagulant state are highly associated with AD. However, AD and CVD co‐development and the molecular mechanisms underlying such associations are not understood. Here, we review the evidence regarding the vascular component of AD and clinical studies using anticoagulants that specifically evaluated the development of AD and other dementias. Most studies reported a markedly decreased incidence of composite dementia in anticoagulated patients with atrial fibrillation, with the highest benefit for direct oral anticoagulants. However, sub‐analyses by differential dementia diagnosis were scarce and inconclusive. We finally discuss whether anticoagulation could be a plausible preventive/therapeutic approach for AD and, if so, which would be the best drug and strategy to maximize clinical benefit and minimize potential risks.

Serum PAI-1/BDNF Ratio Is Increased in Alzheimer’s Disease and Correlates with Disease Severity

“…Furthermore, in several studies, lifestyle- and dietary-mediated weight losses in overweight and moderately obese subjects have been associated with reductions in PAI-1 levels . Also, the use of anticoagulants can reduce PAI-1 levels and produce beneficial effects on Alzheimer, as recently hypothesized by Toribio-Fernandez and co-workers . In theory, the possibility to reduce PAI-1 levels in Alzheimer could have positive effects on cognitive functions, and these effects may involve an increase in mature BDNF due to increased tPA/plasmin activity.…”

Antiplatelet drugs: Potential therapeutic options for the management of neurodegenerative diseases

“…In this condition, thrombin transforms the primary protein in blood clots, fibrinogen, from its soluble state into fibrin, which can eventually activate platelets and result in cognitive decline in NDDs. 127 Moreover, NDDs such as AD and MS show an increased plasma level of coagulation factors, including factor-XII, indicating that the activation of the coagulation cascade substantially regulates the pathoprogression of NDDs. 128,129 Aβ, for example, frequently triggers thrombin to generate microglia-activating fibrin formation, producing degradation-resistant fibrin-Aβ clots.…”

“…This included a substantial reduction in fibrinogen levels, which in turn attenuated neuroinflammation, neurodegeneration, synaptic dysfunction, BBB damage, and cognitive decline in AD. 127 For instance, heparin, an inhibitor of thrombin, Factor V, and VIII, was shown to significantly reduce Aβ 1-42 -triggered complement system activation as well as contact system activation, which was evaluated by measuring C4 protein cleavage and high molecular weight kininogen cleavage, respectively. 131 Moreover, a low molecular weight heparin was also reported to dramatically reduce the total amount of Aβ 1-40 in AD mice, and the number of activated astrocytes surrounding amyloid deposits also lessened significantly.…”

“…A procoagulant condition has long been associated with NDD patients, which is consistent with vascular dysfunction. In this condition, thrombin transforms the primary protein in blood clots, fibrinogen, from its soluble state into fibrin, which can eventually activate platelets and result in cognitive decline in NDDs 127 . Moreover, NDDs such as AD and MS show an increased plasma level of coagulation factors, including factor‐XII, indicating that the activation of the coagulation cascade substantially regulates the pathoprogression of NDDs 128,129 .…”

“…In several studies involving AD mouse models, normalization of the procoagulant state by various anticoagulants resulted in the decrease of various pathological features. This included a substantial reduction in fibrinogen levels, which in turn attenuated neuroinflammation, neurodegeneration, synaptic dysfunction, BBB damage, and cognitive decline in AD 127 . For instance, heparin, an inhibitor of thrombin, Factor V, and VIII, was shown to significantly reduce Aβ 1‐42 ‐triggered complement system activation as well as contact system activation, which was evaluated by measuring C4 protein cleavage and high molecular weight kininogen cleavage, respectively 131 .…”