Lecanemab binds to transgenic mouse model-derived amyloid-β fibril structures resembling Alzheimer’s disease type-I, type-II and Arctic folds

Lecanemab, an Alzheimer’s disease US Food and Drug Administration approved monoclonal antibody was previously reported to have a high affinity against intermediately sized amyloid-β aggregates. Subsequently, it was observed by immunogold labelling that lecanemab can also bind to human type-I amyloid-β fibrils. Therefore, to determine whether lecanemab binds to amyloid-β fibril structures other than type-I, we performed immunogold labelling on extracted amyloid-β fibril preparations from six different Alzheimer’s disease mouse models whose structures were previously solved by cryo-EM. Our results show that lecanemab exhibits high binding affinity to amyloid-β fibril structures that have a flexible N-terminus in common, as it is the case for type-I, type-II and murine type-III amyloid-β fibril polymorphs which resemble or are identical to human structures observed in sporadic and familial cases of Alzheimer’s disease, including a case with the Arctic (E22G) mutation. In contrast, only weak, if any, lecanemab binding was observed for amyloid-β fibril folds with a fixed and ordered N-terminus. Key points - Lecanemab binds to Aβ fibrils from several Alzheimer’s disease tg-mice whose structures resemble the type-I, type-II and Arctic folds found in Alzheimer’s patients, all of which share a flexible, unstructured N-terminus. - Lecanemab is therefore expected to be active against all common familial and sporadic Alzheimer’s cases containing these folds. - Lecanemab binding ability is unaffected by and tolerates the Arctic E22G mutation, at least in type-I or Arctic folds. - Weak, if any, lecanemab binding was observed to Aβ fibrils derived from tg-SwDI mice, whose structures DI1, DI2 and DI3 all share structured and fixed N-termini. - Since the fixed N-termini of tg-SwDI DI1 fibrils and human meningeal Aβ40 fibrils derived from CAA-affected brain are identical, most likely preventing lecanemab binding, treatment with lecanemab may be less or ineffective against CAA, but may explain the reported beneficial low ARIA-E frequency with this antibody. Table of Contents Graphic (TOC)