Abstract Body

Objectives - Amyloid depletion is becoming a therapeutic reality for disease modification of Alzheimer’s disease. Three antibodies, aducanumab, donanemab and lecanemab deplete amyloid efficiently to non-pathogenic levels within 12 to 18 months. Insights into residual amyloid loads corresponding with slowed disease progression are emerging.

Methods - Over the last 6 years, more than 8,000 individuals have been exposed to various amyloid depleting immunotherapies, producing a large data set for generating hypotheses on the biology, immunology, safety, tolerability, and efficacy of amyloid depletion in Alzheimer’s disease.

Results - Amyloid depletion is dose-and time-dependent; higher doses and longer treatment durations are associated with larger quantities of amyloid depletion and reduced markers of tau pathology. Initial long-term data of individuals treated for four years with aducanumab suggest that chronic treatment stabilized disease progression, and that clinical effects sizes widen with time to clinically meaningful extents.

Conclusions - Substantial amyloid depletion to low residual amyloid centiloids below clinical trial inclusion thresholds translate into slowed disease progression. Longer treatment durations increase clinical effect sizes. While the three antibodies share similar patterns of molecular target engagements and cellular amyloid depletion activities, there are differences in dosing and immunogenicity.