Anti-Amyloid Therapies in Alzheimer's Disease: Current Evidence, Clinical Controversies, and the Path Forward

Abstract

Alzheimer's disease (AD) is the leading cause of dementia globally, affecting over 55 million individuals, and represents one of the most significant unmet medical needs of our time. After more than two decades of clinical trial failures targeting the amyloid cascade hypothesis, the field has witnessed the first validated disease-modifying treatments in the form of anti-amyloid monoclonal antibodies — lecanemab (Leqembi) and donanemab (Kisunla) — whose approval by regulatory agencies marks a pivotal transition from purely symptomatic management to genuine biological intervention. The amyloid cascade hypothesis, first proposed by Hardy and Higgins in 1992, posits that the accumulation of amyloid-beta (Aβ) peptides — as soluble oligomers, protofibrils, and insoluble plaques — is the central initiating event in AD pathogenesis, driving downstream tau neurofibrillary tangle formation, neuroinflammation, synaptic loss, and neurodegeneration. Anti-amyloid monoclonal antibodies target various Aβ species with differing specificities: lecanemab preferentially binds soluble Aβ protofibrils, while donanemab targets the pyroglutamate-modified Aβ (N3pE) incorporated into established plaques. In the pivotal CLARITY AD trial, lecanemab reduced clinical decline (CDR-SB) by 27% relative to placebo over 18 months in early AD patients with confirmed amyloid pathology. TRAILBLAZER-ALZ 2 demonstrated donanemab reduced clinical decline by 35% in the low-to-medium tau subgroup. Both agents achieve near-complete amyloid clearance on PET imaging, but at the cost of amyloid-related imaging abnormalities (ARIA) — comprising cerebral oedema (ARIA-E) and microhaemorrhages (ARIA-H) — in a significant proportion of treated patients, with higher rates in APOE ε4 carriers. The accelerated approval of aducanumab in 2021 based solely on amyloid clearance as a surrogate endpoint without a consistent clinical benefit signal generated intense regulatory and scientific controversy, ultimately resulting in its market withdrawal. This review comprehensively examines the biological rationale for amyloid targeting, the molecular mechanisms and clinical profiles of approved and investigational anti-amyloid agents, the interpretation of clinical trial evidence, the ARIA safety framework, the ongoing scientific controversies surrounding the amyloid hypothesis and disease-modification validity, the challenges of translating trial efficacy to real-world practice, and the future direction of combination disease-modifying strategies in AD.