Current and future therapeutic strategies for Alzheimer’s disease: an overview of drug development bottlenecks

Abstract

Alzheimer’s disease (AD) is the most common chronic neurodegenerative disease worldwide. It causes cognitive dysfunction, such as aphasia and agnosia, and mental symptoms, such as behavioral abnormalities; all of which place a significant psychological and economic burden on the patients’ families. No specific drugs are currently available for the treatment of AD, and the current drugs for AD only delay disease onset and progression. The pathophysiological basis of AD involves abnormal deposition of beta-amyloid protein (Aβ), abnormal tau protein phosphorylation, decreased activity of acetylcholine content, glutamate toxicity, autophagy, inflammatory reactions, mitochondria-targeting, and multi-targets. The US Food and Drug Administration (FDA) has approved five drugs for clinical use: tacrine, donepezil, carbalatine, galantamine, memantine, and lecanemab. We have focused on the newer drugs that have undergone clinical trials, most of which have not been successful as a result of excessive clinical side effects or poor efficacy. Although aducanumab received rapid approval from the FDA on 7 June 2021, its long-term safety and tolerability require further monitoring and confirmation. In this literature review, we aimed to explore the possible pathophysiological mechanisms underlying the occurrence and development of AD. We focused on anti-Aβ and anti-tau drugs, mitochondria-targeting and multi-targets, commercially available drugs, bottlenecks encountered in drug development, and the possible targets and therapeutic strategies for future drug development. We hope to present new concepts and methods for future drug therapies for AD.

Monoclonal Antibody Therapy in Alzheimer’s Disease

“…At present, research on this antibody remains in the preliminary phases, and an ongoing phase I clinical trial is actively enrolling participants to assess the safety of a single dose of Lu AF87908 in both healthy individuals and individuals with Alzheimer’s disease (NCT04149860) [ 67 , 140 , 141 , 142 , 143 , 144 ].…”

“…This pattern was consistently observed in two separate models involving human tau transgenic mice. The antibody exhibited strong binding capabilities to diverse tau forms, encompassing monomers, fibrils, and insoluble tau [ 144 , 145 , 146 , 147 ].…”

Digital Therapeutics for Improving Effectiveness of Pharmaceutical Drugs and Biological Products: Preclinical and Clinical Studies Supporting Development of Drug + Digital Combination Therapies for Chronic Diseases

“…These new biologics add to a repertoire of pharmacological agents for AD and dementia, such as cholinesterase inhibitors (donepezil, rivastigmine, and galantamine) and NMDA antagonists (memantine). More drug candidates against AD are currently undergoing clinical trials [34].…”

In silico anti-Alzheimer potential of bioactive compounds in fungi from the African Natural Products Database

“…This makes them an ideal reservoir for research of therapeutic compounds to combat AD, one of the greatest ills of our time. AD is the most common dementia worldwide, and many urgent efforts are being made to find bioactive compounds with anti-Alzheimer properties that can reduce the incidence of the disease while improving the quality of life of patients 7 . These efforts have resulted in several thousand bioactive compounds entering clinical trials, of which more than 400 have failed 8 .…”