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Lecanemab binds to transgenic mouse model-derived amyloid-β fibril structures resembling Alzheimer’s disease type-I, type-II and Arctic folds
Peralta Reyes FS, Willbold D, Schröder GF, Gremer L.. bioRxiv, 2025-01-18
Topic: Brain proteins, microglia and lab models
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)
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APA 7th
Peralta Reyes, F. S., Willbold, D., Schröder, G. F., & Gremer, L. (2025). Lecanemab binds to transgenic mouse model-derived amyloid-β fibril structures resembling Alzheimer’s disease type-I, type-II and Arctic folds. bioRxiv. https://doi.org/10.1101/2025.01.17.633637
Vancouver
Peralta Reyes FS, Willbold D, Schröder GF, Gremer L. Lecanemab binds to transgenic mouse model-derived amyloid-β fibril structures resembling Alzheimer’s disease type-I, type-II and Arctic folds. bioRxiv. 2025. doi:10.1101/2025.01.17.633637.
BibTeX
@article{peraltareyes2025-c94ba780,
author = {Peralta Reyes, F. S. and Willbold, D. and Schröder, G. F. and Gremer, L.},
title = {{Lecanemab binds to transgenic mouse model-derived amyloid-β fibril structures resembling Alzheimer’s disease type-I, type-II and Arctic folds}},
journal = {bioRxiv},
year = {2025},
doi = {10.1101/2025.01.17.633637},
url = {https://doi.org/10.1101/2025.01.17.633637}
}
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Key findings
- 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.
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Study details
- Evidence strengthLow
How this study scored 16/100
Preprint — not yet peer-reviewed. It scored 19 on the same rubric, but non-peer-reviewed sources are capped at 16, so it shows as 16. Scored zero for study design, sample size, effect reported and randomised / blinded because the record does not state it. We have no data on times cited, citations per year, impact for its field and year, cited by studies here, still being cited, senior author's track record, institution's track record and multi-centre collaboration, so those were left out: it earned 12 of the 62 points we could judge it on, which is 19 out of 100.
| Component | Points | Why |
|---|---|---|
| Journal tier | 2 / 10 | Tier 4 — not a peer-reviewed journal (bioRxiv) |
| Journal's citation record | 0 / 4 | Not a journal article, so the journal's record does not count |
| Study design | 0 / 12 | No study design recorded — scores zero, not guessed (not stated in the record — scored 0) |
| Strength of evidence | 1 / 5 | Rated “low” in our summary |
| Peer-review validation | 4 / 10 | Preprint — not yet peer-reviewed. Hosted on a preprint server. |
| How recent | 4 / 5 | 2025 — within 3 year(s) of the newest study here |
| Sample size | 0 / 4 | Participant count not stated — scores zero (not stated in the record — scored 0) |
| Effect reported | 0 / 3 | No effect size reported — scores zero (not stated in the record — scored 0) |
| Studied in people | 0 / 3 | Laboratory or animal study (title names “transgenic”) — scores zero |
| Randomised / blinded | 0 / 2 | No randomisation or blinding stated — scores zero (not stated in the record — scored 0) |
| Times cited | — / 7 | No citation count (not found in OpenAlex) — left out of this score |
| Citations per year | — / 5 | No citation count or no year — left out of this score |
| Impact for its field and year | — / 6 | No field-weighted citation impact (OpenAlex has none yet) — left out of this score |
| Cited by studies here | — / 6 | Not yet checked against this library's citation graph — left out of this score |
| Still being cited | — / 4 | No yearly citation counts — left out of this score |
| Senior author's track record | — / 4 | Senior author's record not available — left out of this score |
| Institution's track record | — / 3 | No institution listed in OpenAlex — left out of this score |
| Multi-centre collaboration | — / 3 | Institutions not listed — left out of this score |
| Indexed in PubMed | 1 / 2 | Not in PubMed, but has a DOI |
| Free to read | 0 / 2 | Behind a paywall — scores zero |
| Points | 12 / 62 | Scored on 12 of 20 parts. We have no data for the rest, so they are left out: 12 of the 62 points we could judge it on is 19 out of 100. |
| Total | 19 / 100 | Capped to 16 because this is not a peer-reviewed article. |
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