Anti‐amyloid antibody equilibrium binding to Aβ aggregates from human Alzheimer's disease brain

INTRODUCTION: Lecanemab binds "protofibrils," which are poorly characterized in human brain. It is unknown why lecanemab caused fewer amyloid-related imaging abnormalities (ARIAs) than other antibodies in trials. The apolipoprotein E (APOE) ε4 allele increases ARIA risk through unknown mechanisms. METHODS: ) of aducanumab, lecanemab, and donanemab equivalents to soluble and insoluble amyloid plaque-enriched and cerebral amyloid angiopathy (CAA)-enriched Aβ were compared across 17 Alzheimer's disease (AD) cases by mixed models. Titrated immunofluorescence (IF) staining compared antibody binding. RESULTS: Lecanemab and aducanumab had indistinguishable preference for "protofibrils." Antibody preference for plaque-enriched versus CAA-enriched Aβ did not differ in soluble extracts or by IF staining but differed slightly in insoluble extracts. The APOE ε4 allele was associated with more soluble antibody-accessible Aβ. DISCUSSION: Lecanemab's binding target is similar to other antibodies'. Differences in antibody preference for plaque versus CAA Aβ may not explain differences in ARIA with edema rates.