Alzheimer's disease (AD) affects millions worldwide, yet currently approved therapies provide only symptomatic relief without altering disease progression. Increasing evidence shows that serotonergic dysfunction contributes to cognitive decline in AD, particularly through altera-tions in the 5-HT₄ and 5-HT₆ receptor pathways. Modulation of these receptors influences acetyl-choline release, APP processing, amyloid burden, and synaptic plasticity. This review summarizes the mechanistic roles of 5-HT₄ and 5-HT₆ receptors in AD pathology, highlights key structure-activity relationship (SAR) trends in ligand development, and evaluates clinical outcomes of recep-tor-targeted therapies. Recent work supports 5-HT₄ agonists and 5-HT₆ antagonists as promising candidates for cognitive enhancement and disease modification. However, challenges in target en-gagement, receptor selectivity, and clinical translation underscore the need for more refined drug-design strategies.
Dhanawat et al. (Fri,) studied this question.