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The Alzheimer's therapeutic Lecanemab attenuates Aβ pathology by inducing an amyloid-clearing program in microglia
Albertini G, Zielonka M, Cuypers ML, Snellinx A, Xu C, Poovathingal S, Wojno M, Davie K, van Lieshout V, Craessaerts K, Wolfs L, Pasciuto E, et al.. Nature Neuroscience, 2025-11-24
Topic: Amyloid, tau and blood-test diagnosis
Controversies over anti-amyloid immunotherapies underscore the need to elucidate their mechanisms of action. Here we demonstrate that Lecanemab, a leading anti-β-amyloid (Aβ) antibody, mediates amyloid clearance by activating microglial effector functions. Using a human microglia xenograft mouse model, we show that Lecanemab significantly reduces Aβ pathology and associated neuritic damage, while neither fragment crystallizable (Fc)-silenced Lecanemab nor microglia deficiency elicits this effect despite intact plaque binding. Single-cell RNA sequencing and spatial transcriptomic analyses reveal that Lecanemab induces a focused transcriptional program that enhances phagocytosis, lysosomal degradation, metabolic reprogramming, interferon γ genes and antigen presentation. Finally, we identify SPP1/osteopontin as a major factor induced by Lecanemab treatment and demonstrate its role in promoting Aβ clearance. These findings highlight that effective amyloid removal depends on the engagement of microglia through the Fc fragment, providing critical insights for optimizing anti-amyloid therapies in Alzheimer's disease.
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APA 7th
Albertini, G., Zielonka, M., Cuypers, M. L., Snellinx, A., Xu, C., Poovathingal, S., et al. (2026). The Alzheimer's therapeutic Lecanemab attenuates Aβ pathology by inducing an amyloid-clearing program in microglia. Nature Neuroscience. https://doi.org/10.1038/s41593-025-02125-8
Vancouver
Albertini G, Zielonka M, Cuypers ML, Snellinx A, Xu C, Poovathingal S, et al. The Alzheimer's therapeutic Lecanemab attenuates Aβ pathology by inducing an amyloid-clearing program in microglia. Nature Neuroscience. 2026. doi:10.1038/s41593-025-02125-8. PMID: 41286448.
BibTeX
@article{albertini2026-41286448,
author = {Albertini, G. and Zielonka, M. and Cuypers, M. L. and Snellinx, A. and Xu, C. and Poovathingal, S. and Wojno, M. and Davie, K. and van Lieshout, V. and Craessaerts, K. and Wolfs, L. and Pasciuto, E. and others},
title = {{The Alzheimer's therapeutic Lecanemab attenuates Aβ pathology by inducing an amyloid-clearing program in microglia}},
journal = {Nature Neuroscience},
year = {2026},
doi = {10.1038/s41593-025-02125-8},
pmid = {41286448},
url = {https://doi.org/10.1038/s41593-025-02125-8}
}
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Key findings
- Using a human microglia xenograft mouse model, we show that Lecanemab significantly reduces Aβ pathology and associated neuritic damage, while neither fragment crystallizable (Fc)-silenced Lecanemab nor microglia deficiency elicits this effect despite intact plaque binding.
- These findings highlight that effective amyloid removal depends on the engagement of microglia through the Fc fragment, providing critical insights for optimizing anti-amyloid therapies in Alzheimer's disease.
Why it matters
In a human microglia xenograft mouse model, lecanemab reduced amyloid-beta pathology and associated neuritic damage, and this effect did not occur when the Fc fragment was silenced or microglia were deficient. Because this is animal and cell-based work, it explains how lecanemab may clear amyloid through microglia rather than demonstrating a clinical benefit in people.
Study details
- Evidence strengthEarly
Limitations
The model has reduced capacity to capture vascular pathology or blood-brain barrier dysfunction because App knock-in mice do not show substantial vascular defects at the ages studied; comparisons with aducanumab's inflammatory effects should be treated with caution because earlier studies used mouse rather than human microglia.
How this study scored 54/100
Published in a leading specialty journal. Scored zero for study design, sample size, effect reported, studied in people and randomized / blinded because the record does not state it. We have no data on free to read, so that was left out: it earned 53 of the 98 points we could judge it on, which is 54 out of 100.
| Component | Points | Why |
|---|---|---|
| Journal tier | 9 / 10 | Tier 2 — leading specialty journal (Nature Neuroscience) |
| Journal's citation record | 4 / 4 | Nature Neuroscience: journal h-index 593 (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 | 2 / 5 | Rated “early” in our summary |
| Peer-review validation | 10 / 10 | Peer-reviewed. Published as an article in a named peer-reviewed journal. |
| How recent | 5 / 5 | 2026 — within 1 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 | Not stated whether this was studied in people — scores zero (not stated in the record — scored 0) |
| Randomized / blinded | 0 / 2 | No randomization or blinding stated — scores zero (not stated in the record — scored 0) |
| Times cited | 3 / 7 | Cited 35 times (OpenAlex, 2026-10-10) |
| Citations per year | 3 / 5 | 17.5 citations a year over 2 year(s) since 2026 |
| Impact for its field and year | 4 / 6 | Cited 19.1× the average for papers of its field and year (OpenAlex FWCI) |
| Cited by studies here | 1 / 6 | Cited by 2 other studies in this library |
| Still being cited | 2 / 4 | Cited 35 times in 2024–2026 (2026 still in progress; OpenAlex) |
| Senior author's track record | 4 / 4 | Last-listed author Bart De Strooper: h-index 146 (OpenAlex, whole career) |
| Institution's track record | 2 / 3 | University College London: institution h-index 2,029 (OpenAlex) |
| Multicenter collaboration | 2 / 3 | OpenAlex lists 7 institution(s) in 2 countries |
| Indexed in PubMed | 2 / 2 | Indexed in PubMed (PMID 41286448) |
| Free to read | — / 2 | Access not recorded — left out of this score |
| Points | 53 / 98 | Scored on 19 of 20 parts. We have no data for the rest, so they are left out: 53 of the 98 points we could judge it on is 54 out of 100. |
| Total | 54 / 100 | — |
What each of these 20 components measures, and what this score is not →
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