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Innovative Medicines & Omics Alzheimer’s disease and clinical trials

people. Dementia is manifested by a decline in memory, Then, we will discuss clinical trials targeting the immune
1
language skills, problem-solving abilities, spatial and system as a potential therapeutic approach for treating
temporal awareness, and judgment. Over the past three AD patients. Despite the extensive efforts, most drugs
2-6
decades, the number of deaths caused by AD and related have failed in phase 1 clinical trials, with several of them
dementias (RD) has increased from 0.56 million in 1990 being discontinued in phase II and only a few advancing
to 1.62 million in 2019. A recent report revealed that to phase III trials. We will analyze the reasons behind these
7
6.7 million Americans – equivalent to 1 in 9 individuals failures and discuss promising strategies for achieving
aged 65 and older – are affected by AD. AD and RD success. Over 3,300 clinical trials have been conducted on
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together are the seventh leading cause of death globally. 7,9-11 AD, involving a variety of drug candidates (clinicaltrials.
These diseases have a direct impact on both global health gov), 26,27 but only three drugs have reached the final stages
and the economy. Around 83% of AD caregivers are unpaid of development. Of these, only lecanemab (Leqembi) has
family members, friends, or others. If compensated, their been approved by the US FDA, aducanumab (Aduhelm) is
12
collective contribution would amount to approximately in the approval process, and donanemab is also undergoing
339.5 billion USD, according to the estimated cost of US FDA review. 17
care in 2022. The lifetime care cost for an individual with
dementia was estimated to be 392,874 USD in 2022, with 2. Immune system dysregulation and
unpaid family caregivers shouldering 70% of this burden, neuroinflammation in AD and RD
including food and medications. Over the years, with 2.1. Neuroinflammation as a key factor
2,13
the increased understanding of the regulatory mechanisms
underlying AD pathology, several drugs have been Under normal conditions, neuroinflammation plays a
developed and tested in clinical trials. However, finding crucial role in protecting the brain against the infiltration
an effective cure or treatment remains challenging due to or infection of pathogens. However, in unfavorable or
the complex pathogenesis of the disease. 14-16 At present, prolonged circumstances, neuroinflammation can lead
available drugs for AD treatments provide only moderate to various severe neurological conditions, including
benefits, primarily by slowing the progression of the AD, Parkinson’s disease (PD), multiple sclerosis (MS),
disease. amyotrophic lateral sclerosis (ALS), and Huntington’s
disease (HD). These conditions reveal that the pathways
At present, no drug or medication can reverse, linking neuroinflammation to neurodegeneration are
halt, or cure AD. The only drug officially approved by distributed across various regions of the central nervous
the United States Food and Drug Administration (US system (CNS). Over the years, a vast number of research
27
FDA) is lecanemab, which only moderately slows AD has demonstrated the presence of prolonged immune
progression by clearing amyloid-beta (Aβ) plaques. responses in the brains of AD patients. In such a chronic
17
Most drug development efforts and clinical trials thus immune response, sustained neuroinflammation becomes
far have primarily focused on clearing Aβ plaques and detrimental, perpetuating a cycle of neuronal damage
neurofibrillary tau tangles in the brain. However, there and degeneration in the CNS. As research has advanced,
is a growing shift toward targeting the pathological neuroinflammation is increasingly recognized as a core
mechanisms responsible for the accumulation of Aβ contributing factor to the progression of AD and RD.
plaques and neurofibrillary tau tangles, rather than directly Indeed, neuroinflammation is now considered the third
targeting them. In addition, several other pathways that pathological hallmark of AD, alongside Aβ plaques and
link to the disease are now receiving increased attention. tau tangles. Importantly, it has been well documented
28
Aβ plaques and neurofibrillary tau tangles have long that neuroinflammation exacerbates the severity of the
been recognized as hallmark pathological features of AD, disease by worsening Aβ and tau pathologies. 29,30 This
and recent research has identified neuroinflammation as highlights the crucial role neuroinflammation plays in the
the third pathological hallmark. Numerous studies have aggregation of toxic Aβ plaque and tau tangles, leading
provided substantial evidence suggesting that inflammatory to disease progression, making neuroinflammation
pathways play a crucial role in the pathogenesis of AD and a promising target for the treatment of AD and RD.
RD. 18-25 These studies have led to the acknowledgment of Moreover, neuroinflammation is not only implicated in AD
neuroinflammation as an important pathological hallmark but has been identified as a key factor in the dysregulation
of AD. of many neurological diseases, continuously emerging as a

In this review, we aim to highlight the critical role potential mediator of cognitive deficits. Therefore, there is
of neuroinflammation in AD and RD, providing a an urgent need to explore neuroinflammatory pathways as
comprehensive summary of immune system dysregulation potential drug targets and advance them through clinical
and its connection to neuroinflammation and AD and RD. trials to develop effective treatments for AD and RD.

Volume 2 Issue 2 (2025) 37 doi: 10.36922/IMO025050007