Current status and future of anti–amyloid therapies

Abstract

Alzheimer disease (AD), the most common age–related neurodegenerative disorder, is characterized by pathological hallmarks in the brain, including plaques composed of amyloid β (Aβ) protein, neurofibrillary tangles of tau protein, and neuronal death. Aβ monomers are generated from amyloid precursor protein by the cleavage of β– and γ–secretase and aggregate to form oligomers, protofibrils, and mature fibrils. Although insoluble fibrils of Aβ protein, which accumulates as amyloid in the brain, were previously considered toxic, recent attention has been focused on oligomers and protofibrils, more highly toxic aggregates of Aβ protein. Remarkable disease–modifying therapies (DMT) for AD targeting Aβ protein were recently developed. Anti–Aβ antibodies such as aducanumab, lecanemab, and donanemab slowed the clinical progression of AD, and the US Food and Drug Administration approved the former two for its treatment. Aducanumab showed stronger binding to fibrils than to protofibrils, whereas lecanemab demonstrated selectivity towards protofibrils over fibrils. These antibodies bound monomers with low affinity. ALZ–801 is an oral small–molecule agent for which a phase 3 trial is ongoing in homozygous apolipoprotein E 4/4 patients with early AD. Although most clinical trials to date failed to show significant improvements, many new agents are still in clinical trials to find effective DMT for AD.