Clinical Trials in Alzheimer’s Disease: A Hurdle in the Path of Remedy

Abstract

Human clinical trials seek to ameliorate the disease states and symptomatic progression of illnesses that, as of yet, are largely untreatable according to clinical standards. Ideally, clinical trials test “disease-modifying drugs,” i.e., therapeutic agents that specifically modify pathological features or molecular bases of the disease and would presumably have a large impact on disease progression. In the case of Alzheimer’s disease (AD), however, this approach appears to have stalled progress in the successful development of clinically useful therapies. For the last 25 years, clinical trials involving AD have centered on beta-amyloid (Aβ) and the Aβ hypothesis of AD progression and pathology. According to this hypothesis, the progression of AD begins following an accumulation of Aβ peptide, leading to eventual synapse loss and neuronal cell death: the true overriding pathological feature of AD. Clinical trials arising from the Aβ hypothesis target causal steps in the pathway in order to reduce the formation of Aβ or enhance clearance, and though agents have been successful in this aim, they remain unsuccessful in rescuing cognitive function or slowing cognitive decline. As such, further use of resources in the development of treatment options for AD that target Aβ, its precursors, or its products should be reevaluated. The purpose of this review was to give an overview of how human clinical trials are conducted in the USA and to assess the results of recent failed trials involving AD, the majority of which were based on the Aβ hypothesis. Based on these current findings, it is suggested that lowering Aβ is an unproven strategy, and it may be time to refocus on other targets for the treatment of this disease including pathological forms of tau.

Factors Affecting Extracellular Vesicles Based Drug Delivery Systems

“…They further showed that modification of BMEVs with folate could enhance tumor-targeting ability as compared to the free drug [ 133 ]. Recently, because many clinical trials for the treatment of Alzheimer’s disease (AD) using synthetic drugs have failed [ 136 , 137 , 138 ], scientists are trying to develop targeted delivery using EVs and developing precision medicine-loaded EVs for the treatment of AD [ 139 , 140 ]. Plant-derived traditional medicine have been studied in preclinical models of AD [ 141 , 142 , 143 ].…”

Monoclonal Antibodies as Neurological Therapeutics

“…The lack of clear proof of efficacy of Aβ targeting therapies so far has raised skepticism regarding the validity of the amyloid hypothesis, driving researchers to explore tau pathology as a plausible therapeutic target, particularly as cognitive decline in AD exhibits a better correlation with tau accumulation than with Aβ deposition [ 218 , 219 , 220 , 221 ]. Monoclonal antibodies targeting abnormal forms of tau protein and particularly soluble oligomers which appear to be the most neurotoxic form of p -tau [ 222 ] are being explored for efficacy in AD.…”

The Role of Inflammation and Infection in Age-Related Neurodegenerative Diseases: Lessons From Bacterial Meningitis Applied to Alzheimer Disease and Age-Related Macular Degeneration

“…Mutations in the genes APP, PSEN1 , and PSEN2 encoding for amyloid precursor protein, presenilin 1 and presenilin 2, respectively, account for most of the early-onset AD, while mutated apolipoprotein E ( APOE ) gene is frequently associated with late-onset AD (Silva et al, 2019 ). Such genetic defects were initially linked to amyloidosis—a well-known histopathological hallmark of AD, the removal of which has been attempted as a treatment; unfortunately, such clinical trials have failed (Oxford et al, 2020 ). While this appears to preclude amyloidosis as a primary causal factor for AD, it does not diminish the importance of genetic factors in AD, and continued efforts to give biological meaning to genetic information may facilitate the identification of aetiological agent(s) and/or key immunopathological factor(s), which ultimately are necessary for therapeutic discovery.…”