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Innovative Medicines & Omics Alzheimer’s disease and clinical trials

2.2. Chronic neuroinflammation post-mortem AD brain and the cerebrospinal fluid (CSF) of

Chronic neuroinflammation is characterized by individuals with mild cognitive impairment (MCI) and AD
42,48-52
excessive activation of glial cells, including microglia and patients. Moreover, an increased frequency of helper
T cells subsets, such as Th17 and Th9 lymphocytes, has
astrocytes. Activated microglia release pro-inflammatory been observed in AD patients. These findings have driven
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cytokines (such as interleukin-1 beta, interleukin-6, the development of drugs targeting neuroinflammatory
tumor necrosis factor-alpha, and interferon-gamma), regulatory pathways as potential treatments to slow, halt,
chemokines (such as C-X-C motif chemokine ligands
and CC chemokine ligands), and reactive oxygen species or reverse the progression of AD and RD. A graphical
representation of immune system dysregulation in AD and
(such as inducible nitric oxide synthase, superoxide, nitric RD, along with possible therapeutic targets, is presented in
oxide, and peroxynitrite), all of which, if persistently Figure 1A and B.
expressed, contribute to neuronal damage and progressive
neurodegeneration, as observed in AD, PD, HD, and MS. At present, several anti-neuroinflammatory drugs are
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Importantly, microglia also express anti-inflammatory undergoing phase III clinical trials, including hydralazine
markers, such as arginase-1, chitinase-like-3 protein 1, hydrochloride (ClinicalTrials.gov identifier: NCT04842552),
mannose receptor C-type 1, interleukin-10, Fc-gamma xanomeline–trospium (KarXT, ClinicalTrials.gov
receptor I, transforming growth factor-beta 1, and identifier: NCT05511363), masitinib (ClinicalTrials.
sphingosine kinase 1. Prolonged activation of resident gov identifier: NCT05564169), NE3107 (ClinicalTrials.
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macrophages (such as microglia) and other immune Gov identifier: NCT04669028), and spironolactone
cells in the brain aggravates both Aβ and tau pathology. (ClinicalTrials.gov identifier: NCT04522739). In addition,
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Similarly, activated astrocytes release pro-inflammatory sodium oligomannate capsule (GV-971), an anti-
interleukin-1 beta, interleukin-6, tumor necrosis factor- inflammatory drug that inhibits Aβ fibril formation, is also in
alpha, and nitric oxide, while they also secrete several clinical trials (ClinicalTrials.gov identifier: NCT05181475).
beneficial neurotrophic factors and thrombospondins. 31,32 3. Drug candidates in clinical trials,
Notably, astrocytes can switch their phenotype and
proliferate in response to harmful conditions, leading challenges, and current progress for the
to the formation of reactive astrocytes, a process known treatment of AD and RD
as reactive astrogliosis. Reactive astrogliosis has been 3.1. Potential drugs for the treatment of AD and RD
observed in various pathological conditions, including
intracranial infections, hypoxic-ischemic injury, AD, Over the past two decades, several disease-modifying
and epilepsy. 31,32 These findings underscore the profound drugs have been developed for the treatment of AD, with
impact of immune system dysregulation on chronic approximately 2,700 clinical trials conducted since 2004.
neuroinflammation in AD and RD, highlighting microglia However, only a few have shown promising success rates
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and astrocyte-mediated neuroinflammation as important in phase II and III trials. A more recent report showed
therapeutic targets. that over 3,300 clinical trials (clinicaltrials.gov) for AD
treatment have been conducted. Despite these efforts,
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Neuroinflammation also increases with aging the failure rate remains alarmingly high, estimated at
and neurodegeneration. Age-related changes in approximately 99%, 54,55 meaning only 1% of drugs progress
neuroinflammation may accelerate the progression of successfully through clinical trials. The few compounds
cognitive impairment through glial activation, increased that have demonstrated potential have primarily been
production of pro-inflammatory cytokines, and abnormal designed for immunotherapy in AD patients. These notable
neuronal signaling, magnifying deterioration of the CNS compounds are aducanumab, lecanemab, donanemab, and
microenvironment. 33,34 Apart from AD, dementia is also oligomannate. 17,56-58 Aducanumab (brand name Aduhelm)
a clinical symptom in several other neurological diseases is a monoclonal antibody designed to bind and eliminate
associated with neuroinflammation, such as vascular aggregated Aβ plaques. Lecanemab (brand name Leqembi)
dementia, dementia with Lewy Bodies, frontotemporal is designed to reduce Aβ protofibrils in the brain and
dementia, Wernicke–Korsakoff syndrome, PD, ALS, CSF. Donanemab (brand name Kisunla) is a humanized
and HD. 35-40 Both innate and adaptive immune system monoclonal antibody derived from mouse mE8-IgG2a
dysregulation are implicated in the pathogenesis of these antibody, specifically targeting Aβ (3-42) plaques.
diseases. 41-47 Microglia, astrocytes, and oligodendrocytes Oligomannate (also known as sodium oligomannate
play a major role in innate immune system dysregulation, or GV-971) is a seaweed-derived oligosaccharide that
whereas the involvement of the adaptive immune system is reduces bacterial metabolite-driven peripheral infiltration
evident from the presence of B and T lymphocytes in the of immune cells into the brain while also inhibiting Aβ

Volume 2 Issue 2 (2025) 38 doi: 10.36922/IMO025050007