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Advanced Neurology Anticoagulants as neuroprotective therapeutics

such as Aβ, APP, BACE1, tau, the pro-apoptotic mediator significant attention at the time and did not prompt further
caspase 3. 111 clinical trials for several decades.
Of particular importance, however, are recent proof- It was only in the 2010s that this approach began to regain
of-concept studies in AD mouse models that demonstrate focus. Advances in basic research and preclinical studies
the therapeutic benefits of DOAC treatments. 90,101 The data have provided new insights into the therapeutic potential
confirm the efficacy of DOACs in inhibiting thrombin- of anticoagulants in AD, leading to recommendations
mediated vascular disorders and inflammation, and in for in-depth clinical studies. 15,16,22-24,26,27,90,101-103 This
reducing their neuronal and cognitive sequelae. 90,101 Long- renewed interest stems from a deeper understanding of
term (1 year) anticoagulation with dabigatran preserved thrombin-triggered mechanisms that are causally related
vascular and BBB function, CBF, brain perfusion, and to prothrombotic, proinflammatory, and neurovascular
memory abilities in AD mice. Mechanistically, thrombin disease progression. Furthermore, the development of novel
90
inhibition prevented the formation of vessel-occlusive fibrin small-molecule OACs, specifically DOACs, which target
clots. In addition, the extent of parenchymal Aβ oligomer thrombin more precisely, has significantly reduced the risk
and plaque deposition, as well as the neuroinflammatory of dangerous intracranial hemorrhage. 15,16,22-24,26,27,96,111
milieu – characterized by phagocytic microglia and One of the primary concerns among clinical
infiltrated T cells – was reduced. Concomitantly, no neurologists regarding long-term thrombin-inhibiting
90
intracerebral hemorrhages have been developed. 90 therapy in AD, particularly in elderly patients with more
Similarly, long-term studies using rivaroxaban in vulnerable vasculature, has been the risk of bleeding. 15,16,22-27
AD mice predisposed to severe Aβ-CAA confirmed However, it is noteworthy that the FDA has recently
that thrombin-inhibiting treatment can halt the approved Aβ-targeting antibody therapies for AD despite
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progression of neurovascular disease. Rivaroxaban concerns about the risk of cerebral bleeding and edema by
reduced BBB dysfunction, parenchymal Aβ deposition, ARIA. 11,17,69,70
neuroinflammatory response, and memory decline Over the past decade, a multitude of observational
compared to untreated or warfarin-treated AD mice. clinical studies has been carried out to assess the risk of
101
Mechanistically, these effects have been linked to the hemorrhage associated with OAC use, especially in elderly
inhibition of thrombin receptors PAR-1/PAR-2. 101 populations. Interestingly, these studies have also revealed
Collectively, data from pre-clinical studies suggest that considerable antidementia benefits associated with OAC
thrombin-inhibiting anticoagulants, such as enoxaparin, therapy. In the following sections, the benefit-risk profile
dabigatran, and rivaroxaban, offer disease-modifying of OAC use will be examined, comparing its anti-dementia
benefits in AD. The focus of this therapeutic approach is effects against the incidence of bleeding. Collectively, these
to prevent prothrombotic and proinflammatory states, findings suggest that DOAC-type anticoagulants offer
along with the associated neurovascular and cognitive distinct advantages.
impairments characteristics of AD. 15,16,22-24,26,27,80,90,96,101-103,111 5.2.1. Anti-dementia effect of OACs in patients with AF
Pathologically, Aβ-induced thrombin production triggers a
cascade involving thrombin, fibrin(ogen), Aβ, and fibrin-Aβ With the increasing use of OACs, especially DOACs,
clot formation, leading to vascular and BBB dysfunction over the past two decades, a series of global observational
and brain hypoperfusion. A thrombin-inhibiting therapy clinical studies have focused on AF patients, examining
could counteract these pathophysiological changes in stroke prevention and cognitive health. AF is a common
the AD brain vasculature (Figure 2), thereby preventing cardiac arrhythmia in the elderly and is linked to multiple
chronic CBF decline, cerebral hypoperfusion, hypoxia, comorbidities, including an elevated risk of developing
hypometabolism, systemic inflammation, and the resulting dementia. 124,125 The current observational clinical studies
neuronal and cognitive impairments. provide evidence that OACs, administered for AF, can
protect individuals against cognitive impairment and
5.2. Outcomes of clinical studies dementia, including AD. 104,124-149 Below, we provide an
Interestingly, the first clinical studies using antithrombotic overview of observational clinical studies reporting
therapy to treat dementia in elderly and presenile the effects of OACs on the incidence of dementia in AF
individuals date back to the 1960s. 29-31 In these small-scale, patients, with reference to a recent review article discussing
16
partially placebo-controlled trials, VKA-type OACs, such this topic.
as dicumarol and warfarin, were shown to slow cognitive In detail, a clear benefit of OAC use (including both
impairment and reduce morbidity and mortality in DOACs and VKA-type warfarin) in reducing the incidence
treated subjects. 29-31 However, these results did not receive of new dementia has been demonstrated in a large

Volume 3 Issue 4 (2024) 19 doi: 10.36922/an.3799