Targeting amyloid-β in Alzheimer’s disease: A critical analysis of clinical trials and their implications for drug development

Alzheimer’s disease (AD), a prevalent neurodegenerative dementia, is characterized by amyloid-β (Aβ) plaques and neurofibrillary tangles, with Aβ playing a central pathogenic role. Approved AD drugs, primarily acetylcholinesterase inhibitors, only alleviate symptoms without modifying disease progression. Aβ-targeting strategies aim to inhibit Aβ production or enhance its clearance, leveraging early deposition for proactive intervention. Preclinical studies show Aβ reduction mitigates neurodegeneration, but clinical trials reveal challenges: γ-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 Aβ-targeted therapies. This review aims to advance Aβ-targeted therapies for AD by integrating lessons from prior clinical trials and outlining strategic directions for future research and development.