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INTRODUCTION Beta‐amyloid plaques and hyperphosphorylated tau tangles are the neuropathological hallmarks of Alzheimer's disease; however, their relevance in the pathophysiology is not fully understood. It has been suggested that these larger and insoluble aggregates may not be the most toxic forms of beta‐amyloid and tau in Alzheimer's disease, and the disease progression may actually be promoted by the small‐diffusible aggregates. METHODS AND RESULTS We combine the recent findings from our group and other key research to put forward the hypotheses that the formation of the small‐diffusible aggregates of beta‐amyloid and tau and their larger insoluble counterparts is not a linear process. DISCUSSION While the small‐diffusible aggregate formation of beta‐amyloid and tau is a passive process, regulated by thermodynamic equilibria, the formation of large‐insoluble aggregates is an active process, regulated by microglia and neurons, which to an extent is a protective mechanism against the toxicity of the smaller aggregates. Highlights Plaques and tangles may be made by active processes in Alzheimer's disease. The small‐soluble aggregates may be the more toxic species in Alzheimer's disease. Pathology may be caused by the imbalance of production and clearance of aggregates. Plaques and tangle formation may be attempts to restore the homeostatic equilibrium.

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.