Page 25 - AN-3-4

Advanced Neurology Anticoagulants as neuroprotective therapeutics

potassium pumps, glutamatergic neurons, and levels of Aβ and phosphorylated tau in the CSF and
glutamate uptake in astrocytes. 5,14,36 Prolonged blood were reduced. 11,17,68,69 In addition, in placebo-
disruption leads to nerve hyperactivation and synaptic controlled, 18-month phase III trials, both lecanemab
17
dysfunction, both of which are closely correlated with and donanemab were shown to slow cognitive and
69
the death of neurons and synapses and, ultimately, physical decline in early symptomatic patients by 27%
cognitive decline. 2,5,14,36 and 35%, respectively. However, there is ongoing debate
(v) In addition to parenchymal Aβ pathology, Aβ regarding whether this modest clinical benefit, which
accumulation in cerebral vasculature can cause falls short of a curative effect, justifies the associated
vascular and BBB dysfunction, contributing to risks. 11,70 About 20 – 40% of participants treated with
neuronal and cognitive impairment. 6-10,35,49,64 This aducanumab, lecanemab, donanemab, or gantenerumab
vascular dysfunction is triggered by Aβ-induced experienced adverse side effects, most of which were mild,
vasoconstriction and vasculopathies, such as but some of which were severe. 11,17,69,70 These side effects,
Aβ-CAA, which is found in over 80 – 90% of patients referred to as amyloid-related imaging abnormalities
with both sporadic and familial AD. 35,65 Aβ-CAA is (ARIA), 2,11,17,69,70 include localized brain swelling (ARIA-E,
associated with ischemic, cellular, and hemorrhagic for edema in brain parenchyma or sulcal effusion), brain
lesions. 6-10,35,49 The severity of vascular Aβ deposition volume loss, and increased brain ventricle size. More
correlates with a decline in CBF and a quantitative serious side effects involve microhemorrhages (ARIA-H,
loss of brain perfusion. In addition, this condition is for cerebral hemorrhage). Although ARIA symptoms
66
linked to an Aβ-induced procoagulant state, resulting are typically mild, severe consequences, including large
in increased thrombin production. 6,16,25 Studies intracerebral hemorrhage in <1% of antibody-treated
using AD mouse models have demonstrated that participants (about 900), have been observed, leading to
peripherally administered Aβ inoculates can trigger deaths in both the lecanemab and donanemab trials. 17,69
Aβ-CAA in cortical and hippocampal blood vessels. 67 Fatal brain bleeding occurred predominantly in AD
(vi) Passive immunotherapy with Aβ-targeting antibodies patients with significant Aβ-CAA and inflammation, or
has been shown to reduce brain Aβ deposition and in those receiving anticoagulation therapy for stroke risk
alleviate cognitive impairment in both AD patients and associated with AF. 17,69,70 One proposed explanation is that
mouse models, as reported in several studies. 2,11,17,68,69 anti-amyloid antibodies may not effectively distinguish
between structurally different parenchymal and vascular
3.1.2. Immunotherapies focused on Aβ Aβ deposits. As a result, antibody treatment could weaken
4
The current treatment targeting Aβ-induced pathology cerebral blood vessels and increase the risk of bleeding
in AD offers the most promising opportunity to slow, by clearing amyloid deposits in vessel walls, potentially
halt, or prevent disease progression. 2,5,11,12,14 One of the leading to glial-mediated vessel inflammation, leakage,
70
first passive immunotherapies developed for AD patients and swelling. Due to these risks, the FDA advises special
was aducanumab, a humanized monoclonal antibody caution when administering lecanemab, particularly in
that targets Aβ oligomers. 2,11,68 Intravenous infusions of elderly patients with amyloid buildup in blood vessels. 17,70
aducanumab block the second phase of Aβ aggregation Moreover, antibody therapy should be discontinued if a
into filaments and their clumping into plaques. 2,11,68 This medical condition requiring anticoagulation arises. 17,70
treatment was shown to reduce Aβ plaque load and Individuals carrying the E4-allele of the APOE gene also
modestly slow AD progression. 11,68 Approved by the US face a three- to sixfold higher risk of developing antibody-
Food and Drug Administration (FDA) in 2021 under induced ARIA. 17,70 Despite these concerns, the FDA
®
the name Aduhelm , aducanumab is used to treat mild granted approval for lecanemab (Leqembi ) in 2023 as the
®
cognitive impairment caused by mild AD or AD dementia. first AD drug shown to clearly slow cognitive decline, and
11
®
Several other Aβ-binding monoclonal antibodies targeting donanemab (Kisunla ) was approved in 2024. 70
different aspects of Aβ pathology are currently under A key lesson from the clinical trials with Aβ-directed
clinical investigation. 11,17,69 Among them, solanezumab therapies is that treatment should begin as early as possible,
inhibits the initial phase of Aβ aggregation, lecanemab ideally in the symptomless stage, to achieve the greatest
binds to soluble Aβ protofilaments, gantenerumab benefit. 11,14,17,42,45,69,70 The optimal window for Aβ therapies is
prevents filament elongation, and donanemab targets believed to be from pre-amyloid stages up until just before
existing plaques. In patients with early-stage AD, these half-maximal Aβ deposition in the brain is reached. For
11
42
antibodies have been shown to clear large amounts of example, blocking BACE1-mediated Aβ production in
parenchymal amyloid from the brain, as confirmed by pre-amyloid stages in AD mice has been shown to prevent
positron emission tomography imaging. 11,17,68,69 Likewise, the onset of neurodegenerative processes. 42

Volume 3 Issue 4 (2024) 7 doi: 10.36922/an.3799