Lecanemab Binds to Transgenic Mouse Model-Derived Amyloid-β Fibril Structures Resembling Alzheimer's Disease Type I,...

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. To determine whether lecanemab binds to amyloid-β fibril structures other than type I, we analysed its binding capacity to various structurally defined and pathologically relevant amyloid-β fibrils.

We performed immunogold labelling with lecanemab on extracted amyloid-β fibril preparations from six different Alzheimer´s disease mouse models whose structures were previously solved by cryo-EM and quantified the relative binding affinities of lecanemab to the different fibril polymorphs.

Our results show that lecanemab exhibits high binding affinity to amyloid-β fibril structures that have a flexible N-terminus in common, as 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 lecanemab binding was observed for murine amyloid-β fibrils with a fixed and ordered N-terminus.

These findings may also explain the low incidence of ARIA-E with lecanemab in clinical trials. This is because human meningeal amyloid-β fibrils derived from cerebral amyloid angiopathy affected brain tissue also contain a fixed and ordered N-terminus, most likely preventing lecanemab binding.

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. Only 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 effective or ineffective against CAA, but may explain the reported beneficial low ARIA-E frequency with this antibody.