Current status and prospects of anti–Aβ therapy

Abstract

Alzheimer disease (AD) is the most common age–related neurodegenerative disorder and is characterized by major pathological hallmarks in the brain, including plaques composed of amyloid β–protein (Aβ) and neurofibrillary tangles of tau protein. Although the present therapy of AD is limited to symptomatic therapy, recently, pathological and biochemical approaches aimed at disease–modifying therapy (DMT), especially the approaches focused on Aβ have been developed remarkably. Aβ molecules aggregate to form oligomers, protofibrils, and mature fibrils. Although it was previously thought that insoluble fibrils of Aβ, which accumulates as amyloid in the brain, exert toxicity, recently attention has been focused on the study of oligomers and protofibrils, which are more toxic aggregates of Aβ (oligomer hypothesis). While clinical trials of secretase inhibitors have been reported with unfavorable results one after another, the developments of anti–Aβ antibodies targeting Aβ aggregates, such as aducanumab, gantenerumab, and lecanemab are ongoing.