Amyloid-β Immunotherapy in Alzheimer's Disease: Challenges and Opportunities

Passive anti–amyloid-β immunotherapy has shifted from repeated phase 3 failure to reproducible, although modest, clinical slowing in biomarker-defined early Alzheimer's disease. We review lessons from first-generation antibodies, including inadequate target engagement, late-stage enrollment, and limited outcome sensitivity. We then compare second-generation agents (i.e., aducanumab, lecanemab, and donanemab) highlighting amyloid-β species selectivity, plaque clearance kinetics, and durability, and we discuss emerging delivery innovations. Safety is dominated by amyloid-related imaging abnormalities, likely reflecting cerebrovascular amyloid vulnerability, and requires timely baseline magnetic resonance imaging (MRI) screening; APOE -informed counseling; and standardized, front-loaded MRI surveillance with symptom-triggered evaluation. We summarize prevention trials in autosomal dominant and sporadic preclinical populations and consider prospects for combination or sequential regimens with tau-targeting therapies. Finally, we focus on biomarker-guided implementation: blood-based prescreening, confirmation pathways, monitoring of biological response, and treat-to-clear or stopping concepts, alongside unresolved issues of health-system readiness, equity, and budget impact. Registry-enabled learning is emphasized to generate real-world safety and effectiveness evidence.