Amyloid-lowering immunotherapies for Alzheimer disease: current status and future directions

The treatment of Alzheimer disease (AD) has crossed a pivotal threshold, marked by the landmark approvals of the first-ever disease-modifying therapies. These immunotherapies, specifically monoclonal antibodies (mAbs) that target various amyloid-β (Aβ) species including proto-fibrillar and fibrillar forms, substantially lower levels of Aβ in the brain. The therapies have collectively demonstrated the ability to slow cognitive and clinical decline in large placebo-controlled trials, ushering a new era in the management of AD. Here, we review recent progress made in bringing amyloid-lowering mAb therapies to the clinic and explore future directions in this rapidly evolving field. We also delve into the current understanding of AD as a biological continuum, from its asymptomatic preclinical stage to its clinically overt dementia stage. We explore how this conceptualization provides a regulatory framework to evaluate amyloid-lowering mAbs across the entire spectrum of the disease. Additionally, we review key factors that affect the integration of these treatments into clinical practice.