Successes and failures: the latest advances in the clinical development of amyloid–β–targeting monoclonal antibodies for treating Alzheimer's disease

Introduction: The amyloid cascade hypothesis postulated that the accumulation of amyloid-β (Aβ) was the first step of the Alzheimer’s disease (AD) pathological process. Effective reduction of Aβ plaque load by numerous drug candidates, among which anti-Aβ monoclonal antibodies, has produced discussible clinical successes and several failures. It was questioned whether Aβ may be the principal AD pathogenic factor and a valid therapeutic target and if targeting Aβ different species could make the difference. Areas covered: This review article summarized successes and failures of anti-Aβ monoclonal antibody therapy for AD, delineating the latest advances for their clinical development also according to their target engagement and downstream biomarkers. Expert opinion: The preliminary success of the recent Phase III randomized clinical trials (RCTs) of lecanemab, donanemab, and remternetug, and lessons learned from the failure of previous anti-Aβ monoclonal antibodies RCTs, provided critical evidence to support the role of Aβ in AD pathogenesis. The loss of free Aβ instead of an Aβ toxicity may promote AD neuropathology. Cerebrospinal fluid analyses (i.e. increases in Aβ_1–42) may indicate a potential benefit of anti-Aβ monoclonal antibodies in AD and downstream biomarkers should be considered for providing comprehension in cognitive and clinical efficacy of future AD RCTs.