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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
Fernanda S. Peralta Reyes, Simon Sommerhage, Dieter Willbold, Gunnar F. Schröder, Lothar Gremer. Neuropathology and Applied Neurobiology, 2025-06-01
Topic: Brain proteins, microglia and lab models
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. SUMMARY: 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.
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 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.
- SUMMARY: 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.
Why it matters
In laboratory work with transgenic mouse-derived amyloid-beta fibrils, lecanemab bound strongly to fibril structures with a flexible N-terminus, resembling folds seen in sporadic and familial Alzheimer disease, but only weakly to fibrils with a fixed N-terminus. The authors suggest this may help explain the low incidence of ARIA-E with lecanemab, but these are structural binding findings, not evidence of clinical benefit.
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Study details
- Evidence strengthLow
How this study scored 36/100
Published in a peer-reviewed journal. Scored zero for study design, sample size, effect reported and randomised / blinded because the record does not state it.
| Component | Points | Why |
|---|---|---|
| Journal tier | 7 / 10 | Tier 3 — peer-reviewed journal (Neuropathology and Applied Neurobiology) |
| Journal's citation record | 1 / 4 | Neuropathology and Applied Neurobiology: journal h-index 143 (OpenAlex, 2026-10-29) |
| 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 | 10 / 10 | Peer-reviewed. Published as an article in a named peer-reviewed journal. |
| 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 | 1 / 7 | Cited 3 times (OpenAlex, 2026-10-10) |
| Citations per year | 1 / 5 | 1.0 citations a year over 3 year(s) since 2025 |
| Impact for its field and year | 2 / 6 | Cited 1.6× the average for papers of its field and year (OpenAlex FWCI) |
| Cited by studies here | 0 / 6 | No other study in this library cites it |
| Still being cited | 1 / 4 | Cited 3 times in 2024–2026 (2026 still in progress; OpenAlex) |
| Senior author's track record | 2 / 4 | Last-listed author Lothar Gremer: h-index 37 (OpenAlex, whole career) |
| Institution's track record | 1 / 3 | Heinrich Heine University Düsseldorf: institution h-index 794 (OpenAlex) |
| Multi-centre collaboration | 1 / 3 | OpenAlex lists 3 institution(s) in 1 country |
| Indexed in PubMed | 2 / 2 | Indexed in PubMed (PMID 40495448) |
| Free to read | 2 / 2 | Free to read |
| Total | 36 / 100 | — |
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Read the original
- DOI: 10.1111/nan.70022
- PubMed: 40495448
- Original source →
- Free full text: Neuropathology and Applied Neurobiology →
Full text: free to read — OpenAlex lists this copy as free to read: the link above (checked 6 Feb 1020).
Cite this study APA, Vancouver, BibTeX · download .bib or .ris
Built from the record alzhub holds for this paper, not looked up. Volume, issue and page numbers are not held in the record. Check the citation against the original before you use it.
APA 7th
Reyes, F. S. P., Sommerhage, 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. Neuropathology and Applied Neurobiology. https://doi.org/10.1111/nan.70022
Vancouver
Reyes FSP, Sommerhage S, 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. Neuropathology and Applied Neurobiology. 2025. doi:10.1111/nan.70022. PMID: 40495448.
BibTeX
@article{reyes2025-40495448,
author = {Reyes, Fernanda S. Peralta and Sommerhage, Simon and Willbold, Dieter and Schröder, Gunnar F. and Gremer, Lothar},
title = {{Lecanemab Binds to Transgenic Mouse Model‐Derived Amyloid‐β Fibril Structures Resembling Alzheimer's Disease Type I, Type II and Arctic Folds}},
journal = {Neuropathology and Applied Neurobiology},
year = {2025},
doi = {10.1111/nan.70022},
pmid = {40495448},
url = {https://doi.org/10.1111/nan.70022}
}
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