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Microglial mechanisms drive amyloid-β clearance in immunized patients with Alzheimer's disease
van Olst L, Simonton B, Edwards AJ, Forsyth AV, Boles J, Jamshidi P, Watson T, Shepard N, Krainc T, Argue BM, Zhang Z, Kuruvilla J, et al.. Nature Medicine, 2025-03-06
Topic: Amyloid, tau and blood-test diagnosis
Alzheimer's disease (AD) therapies utilizing amyloid-β (Aβ) immunization have shown potential in clinical trials. Yet, the mechanisms driving Aβ clearance in the immunized AD brain remain unclear. Here, we use spatial transcriptomics to explore the effects of both active and passive Aβ immunization in the AD brain. We compare actively immunized patients with AD with nonimmunized patients with AD and neurologically healthy controls, identifying distinct microglial states associated with Aβ clearance. Using high-resolution spatial transcriptomics alongside single-cell RNA sequencing, we delve deeper into the transcriptional pathways involved in Aβ removal after lecanemab treatment. We uncover spatially distinct microglial responses that vary by brain region. Our analysis reveals upregulation of the triggering receptor expressed on myeloid cells 2 (TREM2) and apolipoprotein E (APOE) in microglia across immunization approaches, which correlate positively with antibody responses and Aβ removal. Furthermore, we show that complement signaling in brain myeloid cells contributes to Aβ clearance after immunization. These findings provide new insights into the transcriptional mechanisms orchestrating Aβ removal and shed light on the role of microglia in immune-mediated Aβ clearance. Importantly, our work uncovers potential molecular targets that could enhance Aβ-targeted immunotherapies, offering new avenues for developing more effective therapeutic strategies to combat AD.
Key findings
- We compare actively immunized patients with AD with nonimmunized patients with AD and neurologically healthy controls, identifying distinct microglial states associated with Aβ clearance.
- These findings provide new insights into the transcriptional mechanisms orchestrating Aβ removal and shed light on the role of microglia in immune-mediated Aβ clearance.
Why it matters
Using spatial transcriptomics in human brain tissue, this study identified distinct microglial states associated with amyloid-beta clearance and found upregulation of TREM2 and APOE in microglia across immunization approaches, correlating with antibody responses and amyloid-beta removal. These findings describe mechanisms seen in immunized patients and point to possible molecular targets, but they do not show that targeting them treats or prevents Alzheimer's disease.
Study details
- Study designcase-control
- Evidence strengthEarly
Limitations
Few post-mortem cases of lecanemab-treated patients exist; the study includes one rare case with multifocal intracerebral haemorrhage, so larger and longitudinal studies are needed to validate the passive-immunisation findings, and the effects of APOE genotype and sex on immune responses to immunisation were not examined.
How this study scored 65/100
Published in a top-tier journal, and it is a case-control study. Scored zero for sample size, effect reported, studied in people and randomised / blinded because the record does not state it. We have no data on free to read, so that was left out: it earned 64 of the 98 points we could judge it on, which is 65 out of 100.
| Component | Points | Why |
|---|---|---|
| Journal tier | 10 / 10 | Tier 1 — top-tier general journal (Nature Medicine) |
| Journal's citation record | 4 / 4 | Nature Medicine: journal h-index 763 (OpenAlex, 2026-10-29) |
| Study design | 6 / 12 | A case-control study |
| 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 | 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 | Not stated whether this was studied in people — scores zero (not stated in the record — scored 0) |
| Randomised / blinded | 0 / 2 | No randomisation or blinding stated — scores zero (not stated in the record — scored 0) |
| Times cited | 5 / 7 | Cited 130 times (OpenAlex, 2026-10-10) |
| Citations per year | 4 / 5 | 43.3 citations a year over 3 year(s) since 2025 |
| Impact for its field and year | 6 / 6 | Cited 71.1× the average for papers of its field and year (OpenAlex FWCI) |
| Cited by studies here | 2 / 6 | Cited by 6 other studies in this library |
| Still being cited | 3 / 4 | Cited 130 times in 2024–2026 (2026 still in progress; OpenAlex) |
| Senior author's track record | 2 / 4 | Last-listed author David Gate: h-index 32 (OpenAlex, whole career) |
| Institution's track record | 2 / 3 | Northwestern University: institution h-index 1,592 (OpenAlex) |
| Multi-centre collaboration | 2 / 3 | OpenAlex lists 8 institution(s) in 3 countries |
| Indexed in PubMed | 2 / 2 | Indexed in PubMed (PMID 40050704) |
| Free to read | — / 2 | Access not recorded — left out of this score |
| Points | 64 / 98 | Scored on 19 of 20 parts. We have no data for the rest, so they are left out: 64 of the 98 points we could judge it on is 65 out of 100. |
| Total | 65 / 100 | — |
What each of these 20 components measures, and what this score is not →
Read the original
Full text: free to read — PubMed Central lists this copy as free to read: the link above (checked 10 Oct 2026).
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. The record's author list ends in “et al.”, so not every author is named. Check the citation against the original before you use it.
APA 7th
van Olst, L., Simonton, B., Edwards, A. J., Forsyth, A. V., Boles, J., Jamshidi, P., et al. (2025). Microglial mechanisms drive amyloid-β clearance in immunized patients with Alzheimer's disease. Nature Medicine. https://doi.org/10.1038/s41591-025-03574-1
Vancouver
van Olst L, Simonton B, Edwards AJ, Forsyth AV, Boles J, Jamshidi P, et al. Microglial mechanisms drive amyloid-β clearance in immunized patients with Alzheimer's disease. Nature Medicine. 2025. doi:10.1038/s41591-025-03574-1. PMID: 40050704.
BibTeX
@article{vanolst2025-40050704,
author = {van Olst, L. and Simonton, B. and Edwards, A. J. and Forsyth, A. V. and Boles, J. and Jamshidi, P. and Watson, T. and Shepard, N. and Krainc, T. and Argue, B. M. and Zhang, Z. and Kuruvilla, J. and others},
title = {{Microglial mechanisms drive amyloid-β clearance in immunized patients with Alzheimer's disease}},
journal = {Nature Medicine},
year = {2025},
doi = {10.1038/s41591-025-03574-1},
pmid = {40050704},
url = {https://doi.org/10.1038/s41591-025-03574-1}
}
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