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Advanced Neurology Anticoagulants as neuroprotective therapeutics

attributed symptoms of mental confusion, memory loss, underlying causes of the disease. 5,11,14 Acetylcholinesterase
and personality deterioration in a patient to protein inhibitors, such as donepezil, galantamine, rivastigmine,
deposits found post-mortem in her atrophic brain. In and tacrine, have been the standard-of-care drugs for
5,14
addition, he reported vasculopathic changes in the AD more than two decades. In moderate and severe AD,
brain. Since then, extensive research has revealed that acetylcholinesterase inhibitors are often combined with
1]
abnormal brain inclusions of amyloid proteins, which memantine, a glutamatergic N-methyl-D-aspartate
5,14
adopt specific pathogenic structures, are the defining receptor antagonist, which is also applied as monotherapy.
features of a multitude of neurodegenerative diseases, Lifestyle modifications, nutritional changes, and reduction
including Parkinson’s disease and AD. In AD, a bundle of cardiovascular risk factors, including high blood
2-4
of neurodegenerative, inflammatory, vascular, and pressure, obesity, diabetes, hypercholesterolemia, alcohol
hemostatic abnormalities is typically observed, mainly in and tobacco consumption, and physical inactivity, are
neocortical and hippocampal brain regions. Pathological believed to have protective or delaying effects on disease
6
evidence increasingly points to amyloid accumulation as progression. Increasing evidence suggests that AD
the main trigger of the disease. Hallmarks of AD, in their and cardiovascular disease are interconnected, sharing
2-7
6
sequential appearance, include deposits of parenchymal several disease mechanisms. Over 90% of AD patients
8
and vascular amyloid-β (Aβ) proteins, intracellular exhibit signs of vascular brain disorders, including
neurofibrillary tangles (NFTs) of hyperphosphorylated cerebral microbleeds, lacunar and cortical infarcts, micro-
tau protein, glia-induced neuroinflammation, and brain infarcts, intracranial atherosclerosis, arteriolosclerosis,
atrophy. Eventually, synaptic and neuronal loss occurs, Aβ-type cerebral amyloid angiopathy (Aβ-CAA), and a
8
leading to cognitive decline. Aβ-triggered vasculopathies procoagulant state. This procoagulant state is characterized
2-5
are also early hallmarks of AD, contributing to the by accumulations of thrombin and fibrin(ogen), key players
disease pathology. 6-10 The resulting pathophysiological in the blood clotting cascade. 6,7,15,16 AD and associated
consequences include disruption of vascular and blood– vascular disorders also share several pathological features,
brain barrier (BBB) function, reduction in cerebral blood including an extended subclinical phase, age-dependency,
flow (CBF), and decline of brain perfusion and nutrient Aβ accumulation, and a genetic predisposition linked to
supply, all of which lead to neuronal and cognitive apolipoprotein E (APOE), the strongest genetic risk factor
dysfunction. for late-onset AD. 6,7,12
At present, approximately 40 million people worldwide Overall, for the growing elderly population, there
– 60 – 80% of all dementia patients – suffer from AD. As is an urgent need to identify disease-modifying drugs
a major cause of mortality, its prevalence is expected to for AD that target its causes, prevent its onset, delay
11,12,14
rise with the aging population. 5,9,11 The majority of AD progression, or slow down its course. Although the
patients, over 65 years of age, are diagnosed with late-onset precise mechanism underlying AD is not yet elucidated,
AD, also known as sporadic, idiopathic, or senile AD. one of the main triggers for the disease is believed to
5,11
Less than 10% of patients develop early-onset AD, with be the generation of toxic aggregates of Aβ in the brain
2-5,11,14
symptoms manifesting before 65 years of age, often due caused by the misfolding of Aβ. This “amyloid
to genetic causes. This type of AD is known as familial hypothesis” posits that misfolded Aβ accumulates into
12
12
or presenile AD. In addition to AD, vascular dementia toxic, extracellular deposits in the brain as the disease
is the second most common dementia subtype, sharing progresses. These deposits are thought to initiate a cascade
many pathophysiological features, symptoms, and risk of molecular events that ultimately lead to dementia. Based
factors with AD. Vascular dementia affects 5 – 10% of on this mechanism, the first disease-modifying therapies
9,13
dementia patients and arises from ischemic, hemorrhagic, for AD, using the anti-Aβ antibodies aducanumab and
or hypoxic brain damage. Cardiovascular disease is well lecanemab, have recently been approved in the United States
9,13
(US).
These therapies are envisaged for patients with
2,11,14,17
recognized as a key contributor to vascular dementia, with mild cognitive impairment due to early symptomatic AD.
pathological manifestations including small vessel disease Data have demonstrated that these antibodies reduce Aβ
(SVD) of the brain’s microvasculature, damaged BBB, levels and provide modest clinical benefits. 11,14,17 Besides Aβ
impaired CBF, and reduced brain perfusion. 9,13 pathology, pharmaceutical research in AD is increasingly
Despite advances in understanding AD pathology, focused on addressing neurodegenerative processes driven
current “symptomatic” drugs for standard-of-care by toxic tau protein. In addition, there is growing interest
5
treatment are only able to alleviate some symptoms, in targeting cardiovascular risk factors that impair the
improve overall condition, and slow mild cognitive integrity and function of the brain vasculature, as both
impairment. However, these treatments do not target the sporadic and familial AD exhibit vasculopathic changes. 5-10

Volume 3 Issue 4 (2024) 2 doi: 10.36922/an.3799