Clarity on the blazing trail: clearing the way for amyloid-removing therapies for Alzheimer's disease

Abstract

Alzheimer's disease (AD) is a progressive neurodegenerative disorder with a complex pathogenesis. Senile plaques composed of the amyloid-β (Aβ) peptide in the brain are the core hallmarks of AD and a promising target for the development of disease-modifying therapies. However, over the past 20 years, the failures of clinical trials directed at Aβ clearance have fueled a debate as to whether Aβ is the principal pathogenic factor in AD and a valid therapeutic target. The success of the recent phase 3 trials of lecanemab (Clarity AD) and donanemab (Trailblazer Alz2), and lessons from previous Aβ clearance trials provide critical evidence to support the role of Aβ in AD pathogenesis and suggest that targeting Aβ clearance is heading in the right direction for AD treatment. Here, we analyze key questions relating to the efficacy of Aβ targeting therapies, and provide perspectives on early intervention, adequate Aβ removal, sufficient treatment period, and combinatory therapeutics, which may be required to achieve the best cognitive benefits in future trials in the real world.