Pharmacological Interventions to Attenuate Alzheimer’s Disease Progression: The Story So Far

Abstract

Alzheimer’s disease (AD) is a progressive neurodegenerative disease and the most common cause of dementia in the elderly. Up to date, the available pharmacological options for AD are limited to cholinesterase inhibitors and memantine that may only provide modest symptomatic management with no significance in slowing down the disease progression. Over the past three decades, the increased interest in and the understanding of AD major pathological hallmarks have provided an insight into the mechanisms mediating its pathogenesis, which in turn introduced a number of hypotheses and novel targets for the treatment of AD. Initially, targeting amyloid-beta and tau protein was considered the most promising therapeutic approach. However, further investigations have identified other major players, such as neuroinflammation, impaired insulin signalling and defective autophagy, that may contribute to the disease progression. While some promising drugs are currently being investigated in human studies, the majority of the previously developed medical agents have come to an end in clinical trials, as they have failed to illustrate any beneficial outcome. This review aims to discuss the different introduced approaches to alleviate AD progression; in addition, provides a comprehensive overview of the drugs in the development phase as well as their mode of action and an update of their status in clinical trials.

Dysregulation of multiple metabolic networks related to brain transmethylation and polyamine pathways in Alzheimer disease: A targeted metabolomic and transcriptomic study

“…Acetylcholine plays a critical role in learning and memory, and abnormalities in cholinergic neurotransmission are thought to underlie cognitive impairment in AD [11]. Furthermore, acetylcholinesterase inhibitors constitute the major class of drugs that are currently approved symptomatic treatments for AD [12]. Choline is also a key participant in one-carbon metabolism (OCM) through its oxidation product betaine and constitutes the head group of phosphatidylcholines in cell membranes.…”

Chenodeoxycholic Acid Ameliorates AlCl3-Induced Alzheimer’s Disease Neurotoxicity and Cognitive Deterioration via Enhanced Insulin Signaling in Rats

“…Alzheimer’s disease (AD) is the most common cause of dementia worldwide, accounting for 60–80% of all cases [1]. While the past two decades were dominated by the “amyloid cascade hypothesis”, the majority of the developed medicinal agents, specifically selective amyloid-beta (Aβ) targeting drugs, have, so far, failed to show any significance in AD management when evaluated in clinical trials [2]. Such findings have prompted the rise of other hypotheses to explain AD pathology and identify other potential targets for drug treatment.…”

Presenilin-2 and Calcium Handling: Molecules, Organelles, Cells and Brain Networks

“…The bioenergetic state of neurons is a crucial determinant of their response to glutamate, with cells containing defective mitochondria undergoing bioenergetic crises, Ca 2+ mishandling, and excitotoxicity. The Food and Drug Administration (FDA)-approved molecule memantine targets glutamate receptors and is among the few pharmacological treatments that provide modest benefits in AD patients, in addition to cholinesterase inhibitors [ 145 ]. Targeting Ca 2+ defects, at multiple levels, was suggested as a possible therapeutic strategy, especially in the form of drug repurposing.…”