Maximizing the benefit and managing the risk of anti-amyloid monoclonal antibody therapy for Alzheimer's disease: Strategies and research directions

Anti-amyloid monoclonal antibodies (MABs) have introduced a new era of Alzheimer's disease (AD) therapeutics with disease-targeted drugs. Three agents - aducanumab, lecanemab, donanemab - have been approved and others are in development. These agents are administered intravenously, once in the brain they activate microglia to engulf amyloid-beta protein fibrillar plaques. Each approved agent has a specific profile of administration, titration, amyloid target, and adverse events. In 18 month trials of participants with early AD (defined as mild cognitive impairment due to AD or mild AD dementia), anti-amyloid MABs slow cognitive and functional decline by approximately 30 %. Amyloid positron emission tomography reveals marked reductions in amyloid plaque burden; reductions below a threshold of 15-25 Centiloids are associated with clinical benefit. The magnitude, scope, and trajectory of clinical end points provide the basis for interpretations of clinical meaningfulness. Occurrence of amyloid-related imaging abnormalities with intracerebral edema, microhemorrhages, or superficial siderosis must be monitored and managed to prevent serious or rare catastrophic consequences. Infusion reactions occur and anticipatory management is required. Development of subcutaneous formulations and use of bloodbased biomarkers for diagnosis and monitoring promises to increase the accessibility and decrease the demands on health care systems associated with these agents. Anti-amyloid MABs provide the foundation for further advances in developing a repertoire of disease-targeted therapies for AD.