{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,13]],"date-time":"2026-10-13T21:08:55Z","timestamp":1791925735123,"version":"4.3.4"},"reference-count":33,"publisher":"Wiley","issue":"3","license":[{"start":{"date-parts":[[2025,6,10]],"date-time":"2025-06-10T00:00:00Z","timestamp":1749513600000},"content-version":"vor","delay-in-days":9,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Neuropathology Appl Neurobio"],"published-print":{"date-parts":[[2025,6]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Aims<\/jats:title>\n                    <jats:p>Lecanemab, an Alzheimer\u2019s disease US Food and Drug Administration\u2010approved monoclonal antibody, was previously reported to have a high affinity against intermediately sized amyloid\u2010\u03b2 aggregates. Subsequently, it was observed by immunogold labelling that lecanemab can also bind to human type I amyloid\u2010\u03b2 fibrils. To determine whether lecanemab binds to amyloid\u2010\u03b2 fibril structures other than type I, we analysed its binding capacity to various structurally defined and pathologically relevant amyloid\u2010\u03b2 fibrils.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>We performed immunogold labelling with lecanemab on extracted amyloid\u2010\u03b2 fibril preparations from six different Alzheimer\u00b4s disease mouse models whose structures were previously solved by cryo\u2010EM and quantified the relative binding affinities of lecanemab to the different fibril polymorphs.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>Our results show that lecanemab exhibits high binding affinity to amyloid\u2010\u03b2 fibril structures that have a flexible N\u2010terminus in common, as is the case for type I, type II and murine type III amyloid\u2010\u03b2 fibril polymorphs, which resemble or are identical to human structures observed in sporadic and familial cases of Alzheimer\u2019s disease, including a case with the Arctic (E22G) mutation. In contrast, only weak lecanemab binding was observed for murine amyloid\u2010\u03b2 fibrils with a fixed and ordered N\u2010terminus.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>These findings may also explain the low incidence of ARIA\u2010E with lecanemab in clinical trials. This is because human meningeal amyloid\u2010\u03b2 fibrils derived from cerebral amyloid angiopathy affected brain tissue also contain a fixed and ordered N\u2010terminus, most likely preventing lecanemab binding.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Summary<\/jats:title>\n                    <jats:p>\n                      <jats:list list-type=\"bullet\">\n                        <jats:list-item>\n                          <jats:p>Lecanemab binds to A\u03b2 fibrils from several Alzheimer's disease tg\u2010mice whose structures resemble the type I, type II and Arctic folds found in Alzheimer's patients, all of which share a flexible, unstructured N\u2010terminus.<\/jats:p>\n                        <\/jats:list-item>\n                        <jats:list-item>\n                          <jats:p>Lecanemab is therefore expected to be active against all common familial and sporadic Alzheimer's cases containing these folds.<\/jats:p>\n                        <\/jats:list-item>\n                        <jats:list-item>\n                          <jats:p>Lecanemab binding ability is unaffected by and tolerates the Arctic E22G mutation, at least in type I or Arctic folds.<\/jats:p>\n                        <\/jats:list-item>\n                        <jats:list-item>\n                          <jats:p>Only weak, if any, lecanemab binding was observed to A\u03b2 fibrils derived from tg\u2010SwDI mice, whose structures DI1, DI2 and DI3 all share structured and fixed N\u2010termini.<\/jats:p>\n                        <\/jats:list-item>\n                        <jats:list-item>\n                          <jats:p>Since the fixed N\u2010termini of tg\u2010SwDI DI1 fibrils and human meningeal A\u03b240 fibrils derived from CAA\u2010affected 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\u2010E frequency with this antibody.<\/jats:p>\n                        <\/jats:list-item>\n                      <\/jats:list>\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1111\/nan.70022","type":"journal-article","created":{"date-parts":[[2025,6,11]],"date-time":"2025-06-11T02:24:01Z","timestamp":1749608641000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":6,"title":["Lecanemab Binds to Transgenic Mouse Model\u2010Derived Amyloid\u2010\u03b2 Fibril Structures Resembling Alzheimer's Disease Type I, Type II and Arctic Folds"],"prefix":"10.1111","volume":"51","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-8379-4827","authenticated-orcid":false,"given":"Fernanda\u00a0S.","family":"Peralta\u00a0Reyes","sequence":"first","affiliation":[{"name":"Institut f\u00fcr Physikalische Biologie Heinrich\u2010Heine\u2010Universit\u00e4t D\u00fcsseldorf  D\u00fcsseldorf 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