INTRODUCTION: Monoclonal antibodies Aducanumab, Lecanemab, Gantenerumab, and 4 Donanemab were developed for treatment of Alzheimer’s disease (AD). 5 6 METHODS: We used single-molecule detection and super-resolution imaging to characterise 7 the binding of these antibodies to diffusible beta-amyloid aggregates generated in-vitro and 8 harvested from human brains. 9 10 RESULTS: Lecanemab showed the best performance in terms of binding to the small-diffusible 11 beta-amyloid aggregates, affinity, aggregate coating, and the ability to bind to post12 translationally modified species, providing an explanation for its therapeutic success. We 13 observed a Braak stage-dependent increase in small-diffusible aggregate quantity and size, 14 which was detectable with Aducanumab and Gantenerumab, but not Lecanemab, showing that 15 the diffusible beta-amyloid aggregates change with disease progression and the smaller 16 aggregates Lecanemab preferably binds to exist at higher quantities during earlier stages. 17 18 DISCUSSION: These findings provide an explanation for the success of Lecanemab at clinical 19 trials and suggests that Lecanemab will be more effective when used on early-stage AD.