Han_2026_Iran.J.Basic.Med.Sci_21_531

Alzheimer's disease (AD), a prevalent neurodegenerative dementia, is characterized by amyloid-beta (Abeta) plaques and neurofibrillary tangles, with Abeta playing a central pathogenic role. Approved AD drugs, primarily acetylcholinesterase inhibitors, only alleviate symptoms without modifying disease progression. Abeta-targeting strategies aim to inhibit Abeta production or enhance its clearance, leveraging early deposition for proactive intervention. Preclinical studies show Abeta reduction mitigates neurodegeneration, but clinical trials reveal challenges: gamma-secretase inhibitors face off-target toxicities and limited efficacy, while BACE1 inhibitors suffer from safety issues or failure to improve cognition. Despite setbacks, advancing understanding of AD pathogenesis and optimized drug design/ trial protocols sustain the potential of Abeta-targeted therapies. This review aims to advance Abeta-targeted therapies for AD by integrating lessons from prior clinical trials and outlining strategic directions for future research and development.