Mehta_2025_Chembiochem__e2500053

Alzheimer's disease (AD) is a chronic neurodegenerative disease marked by cognitive decline, neuronal degeneration, and the accumulation of intracellular neurofibrillary tangles, extracellular amyloid plaques, and neuroinflammation. Current treatment strategies, such as acetylcholinesterase inhibitors (AChEIs) and N-methyl-D-aspartate receptor antagonists, offer symptomatic relief but fail to stop disease progression. The development of multi-target-directed ligands (MTDLs) has gained attention as a method to address the complex pathology of AD. This review provides a detailed account of the journey of AChE inhibitors from single-target ligands to MTDLs, emphasizing the structural changes that improve target specificity, blood-brain barrier penetration, and therapeutic impact. By exploring these advancements, the review highlights the potential of MTDLs to overcome the limitations of traditional single-target approaches and contribute to the discovery of more effective anti-Alzheimer therapies along with discussing potential pitfalls.