The evolving landscape of amyloid-targeting therapies in Alzheimer's disease: progress and challenges

Alzheimer's disease (AD) is the leading cause of dementia worldwide. Amyloid-β (Aβ) accumulation has long guided therapeutic development, though early β- and γ-secretase inhibitors failed to demonstrate clinical benefit.

A narrative review was conducted based on a structured search of MEDLINE, Embase, and ClinicalTrials.gov, supplemented by manual screening of key reviews and Phase 3 trial reports on amyloid-targeting therapies.

Monoclonal antibodies including aducanumab, lecanemab, and donanemab achieve significant amyloid clearance and modest slowing of cognitive decline in Phase 3 trials, validating amyloid reduction as a disease-modifying pathway. However, clinical benefits are limited, amyloid-related imaging abnormalities (ARIA) remain safety concerns, and high costs restrict accessibility. Persistent therapeutic gaps reflect the multifactorial pathology of AD, including tau, neuroinflammation, and vascular dysfunction.

Amyloid-targeting therapies represent the first validated disease-modifying strategy for AD but are not definitive solutions. Future directions include earlier intervention, combination approaches, improved antibody design, and scalable biomarker implementation to enhance real-world impact.