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Lecanemab-Associated Amyloid-β Protofibril in Cerebrospinal Fluid Correlates with Biomarkers of Neurodegeneration in Alzheimer's Disease
Noguchi-Shinohara M, Shuta K, Murakami H, Mori Y, Komatsu J, Kobayashi C, Hersch S, Horie K et al.. Annals of neurology, 2025-01-06
Topic: Brain proteins, microglia and lab models
Objective The Clarity AD phase III trial showed that lecanemab reduced amyloid markers in early Alzheimer's disease (AD) and resulted in less decline on measures of cognition and function than placebo. Herein, we aimed to characterize amyloid-β (Aβ) protofibril (PF) captured by lecanemab in human cerebrospinal fluid (CSF) from living participants with different stages in AD, which enable an enhanced understanding of the dynamic changes of lecanemab-associated Aβ-PF (Lec-PF) in vivo. Methods We newly developed a unique and highly sensitive immunoassay method using lecanemab that selectively captures Lec-PF. The CSF level of Lec-PF, Aβ42, Aβ40, p-tau181, p-tau 217, total tau, and neurogranin were measured in Japanese participants (n = 163). The participants in this study consisted of 48 cognitively unimpaired Aβ-negative (CU-), 8 cognitively impaired diagnosed as suspected non-Alzheimer's disease pathophysiology, 9 cognitively unimpaired Aβ-positive (CU+), 34 Aβ-positive with mild cognitive impairment (MCI+), and 64 Aβ-positive with AD dementia (AD+). Results The CSF Lec-PF levels significantly increased in the groups of MCI+ and AD+ compared with CU- group. Notably, CSF Lec-PF showed modest correlation with plaque-associated biomarkers in Aβ-positive participants and stronger correlation with neurodegeneration biomarkers, such as CSF total tau and neurogranin, suggesting that CSF Lec-PF levels proximally reflect neurodegeneration as well as the amount of senile amyloid plaques. Interpretation This is the first report describing Aβ-PF species captured by lecanemab in human CSF and supporting that Lec-PF is correlated with neurodegeneration in AD and may explain the mechanism of the clinical effect of lecanemab. ANN NEUROL 2025;97:993-1006.
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APA 7th
Noguchi-Shinohara, M., Shuta, K., Murakami, H., Mori, Y., Komatsu, J., Kobayashi, C., et al. (2025). Lecanemab-Associated Amyloid-β Protofibril in Cerebrospinal Fluid Correlates with Biomarkers of Neurodegeneration in Alzheimer's Disease. Annals of neurology. https://doi.org/10.1002/ana.27175
Vancouver
Noguchi-Shinohara M, Shuta K, Murakami H, Mori Y, Komatsu J, Kobayashi C, et al. Lecanemab-Associated Amyloid-β Protofibril in Cerebrospinal Fluid Correlates with Biomarkers of Neurodegeneration in Alzheimer's Disease. Annals of neurology. 2025. doi:10.1002/ana.27175. PMID: 39761671.
BibTeX
@article{noguchishinohara2025-39761671,
author = {Noguchi-Shinohara, M. and Shuta, K. and Murakami, H. and Mori, Y. and Komatsu, J. and Kobayashi, C. and Hersch, S. and Horie, K. and others},
title = {{Lecanemab-Associated Amyloid-β Protofibril in Cerebrospinal Fluid Correlates with Biomarkers of Neurodegeneration in Alzheimer's Disease}},
journal = {Annals of neurology},
year = {2025},
doi = {10.1002/ana.27175},
pmid = {39761671},
url = {https://doi.org/10.1002/ana.27175}
}
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Key findings
- Objective The Clarity AD phase III trial showed that lecanemab reduced amyloid markers in early Alzheimer's disease (AD) and resulted in less decline on measures of cognition and function than placebo.
- Results The CSF Lec-PF levels significantly increased in the groups of MCI+ and AD+ compared with CU- group.
- Notably, CSF Lec-PF showed modest correlation with plaque-associated biomarkers in Aβ-positive participants and stronger correlation with neurodegeneration biomarkers, such as CSF total tau and neurogranin, suggesting that CSF Lec-PF levels proximally reflect neurodegeneration as well as the amount of senile amyloid plaques.
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Study details
- Participants163
- Evidence strengthLow
How this study scored 57/100
Published in a leading specialty journal. Scored zero for study design, effect reported and randomised / blinded because the record does not state it. We have no data on journal's citation record, 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 33 of the 58 points we could judge it on, which is 57 out of 100.
| Component | Points | Why |
|---|---|---|
| Journal tier | 9 / 10 | Tier 2 — leading specialty journal (Annals of neurology) |
| Journal's citation record | — / 4 | No journal record from OpenAlex — left out of this score |
| 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 | 2 / 4 | 163 participants |
| Effect reported | 0 / 3 | No effect size reported — scores zero (not stated in the record — scored 0) |
| Studied in people | 3 / 3 | Studied in people (participant count stated) |
| 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 | 2 / 2 | Indexed in PubMed (PMID 39761671) |
| Free to read | 2 / 2 | Free to read |
| Points | 33 / 58 | Scored on 11 of 20 parts. We have no data for the rest, so they are left out: 33 of the 58 points we could judge it on is 57 out of 100. |
| Total | 57 / 100 | — |
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