Recent advances on drug development and emerging therapeutic agents for Alzheimer's disease

Abstract

Alzheimer's disease (AD) is a neurodegenerative old age disease that is complex, multifactorial, unalterable, and progressive in nature. The currently approved therapy includes cholinesterase inhibitors, NMDA-receptor antagonists and their combination therapy provides only temporary symptomatic relief. Sincere efforts have been made by the researchers globally to identify new targets, discover, and develop novel therapeutic agents for the treatment of AD. This brief review article is intended to cover the recent advances in drug development and emerging therapeutic agents for AD acting at different targets. The article is compiled using various scientific online databases and by referring to clinicaltrials.gov and ALZFORUM (alzforum.org) websites. The upcoming therapies act on one or more targets including amyloids (secretases, Aβ₄₂ production, amyloid deposition, and immunotherapy), tau proteins (tau phosphorylation/aggregation and immunotherapy) and neuroinflammation in addition to other miscellaneous targets. Despite the tremendous improvement in our understanding of the underlying pathophysiology of AD, only aducanumab was approved by FDA for the treatment of AD in 18 years i.e., since 2003. Hence, it is concluded that novel therapeutic strategies are required to discover and develop therapeutic agents to fight against the century old AD.

Keywords: Acetylcholine; Alzheimer’s disease; Beta-Amyloid; Neurodegeneration; Tau proteins.

Fig. 1

Illustration showing the comparison between the brain of a healthy and an affected one

Fig. 2

Chemical strategy used to synthesize ladostigil and idalopiridine as multi-target drugs

Fig. 3

Various therapeutic approaches used to develop agents for AD

Fig. 4

Chemical structures of FDA approved anti-AD drugs; a rivastigmine, b donepezil, c galantamine and d memantine

Fig. 5

Chemical structure of drugs targeting secretases in AD

Fig. 6

Chemical structure of drugs targeting Aβ₄₂ and inhibiting amyloid aggregation

Fig. 7

Chemical structure of new molecules targeting tau proteins

Fig. 8

Chemical structure of molecules a acting as RAGE inhibitor; b α7-nAChR agonist and c MAO-B inhibitor