Lecanemab preferentially binds to smaller aggregates present at early Alzheimer's disease

Abstract INTRODUCTION The monoclonal antibodies Aducanumab, Lecanemab, Gantenerumab, and Donanemab were developed for the treatment of Alzheimer's disease (AD). METHODS We used single‐molecule detection and super‐resolution imaging to characterize the binding of these antibodies to diffusible amyloid beta (Aβ) aggregates generated in ‐ vitro and harvested from human brains. RESULTS Lecanemab showed the best performance in terms of binding to the small‐diffusible Aβ aggregates, affinity, aggregate coating, and the ability to bind to post‐translationally modified species, providing an explanation for its therapeutic success. We observed a Braak stage–dependent increase in small‐diffusible aggregate quantity and size, which was detectable with Aducanumab and Gantenerumab, but not Lecanemab, showing that the diffusible Aβ aggregates change with disease progression and the smaller aggregates to which Lecanemab preferably binds exist at higher quantities during earlier stages. DISCUSSION These findings provide an explanation for the success of Lecanemab in clinical trials and suggests that Lecanemab will be more effective when used in early‐stage AD. Highlights Anti amyloid beta therapeutics are compared by their diffusible aggregate binding characteristics. In‐vitro and brain‐derived aggregates are tested using single‐molecule detection. Lecanemab shows therapeutic success by binding to aggregates formed in early disease. Lecanemab binds to these aggregates with high affinity and coats them better.