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

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.

Equilibrium binding constants (K_D) and total amyloid beta (Aβ) binding (B_max) 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.

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.

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.