Development of amyloid beta-directed antibodies against Alzheimer's disease: Twists and turns

Abstract

Alzheimer's disease (AD) is a severe and progressive neurodegenerative disease, and the treatment options that are currently available are limited. The amyloid cascade hypothesis has had a significant influence in explaining the pathology underlying AD. Inhibiting the production and aggregation of amyloid-beta (Aβ) and promoting its clearance have been important strategies in the development of anti-AD drugs over the past two decades. Specifically, Aβ directed antibodies have been highly anticipated, but drug development has been fraught with obstacles and challenges. Antibodies targeting the C-terminal or central region of Aβ, such as ponezumab, solanezumab, and crenezumab, primarily bind to Aβ monomers, yet no significant clearance of brain plaques or slowing of disease progression has been observed in clinical trials. Antibodies targeting the N-terminal region of Aβ, including aducanumab, lecanemab, and donanemab, primarily bind to aggregated forms of Aβ, and have shown efficacy in clearing brain plaques and slowing early-stage AD progression in clinical trials. However, clinical trials of gantenerumab, which targets conformational epitopes in the N-terminal and central sequences of Aβ and which selectively binds to aggregated forms, have failed, raising some new questions about the Aβ hypothesis. Advances in research on the pathological mechanisms of AD and advances in early diagnostic techniques may shift the time window for drug intervention and offer a potential pathway for developing effective drugs to delay the onset and progression of AD in the future.

Keywords: AD; Aβ hypothesis; aducanumab; donanemab; gantenerumab; lecanemab.