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 AD patients with nonimmunized AD patients 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.
from sddb import Catalog
cohort = Catalog().collection("geo-gse263079")
cohort.members # the 8 datasets as a table
print(cohort.licenses()) # check the terms before you download
sdatas = cohort.to_dict() # {uid: SpatialData}, cached locally
# or keep the .zarr files in a folder of your choice:
# sdatas = cohort.to_dict(dest="data/")Needs pip install lamindb and network access to the Lamin database, which is limited during the alpha. If it fails, use the Client tab.
import lamindb as ln
db = ln.DB("scverse/spatialdata-db")
coll = db.Collection.get(key="geo-gse263079")
coll.ordered_artifacts.to_dataframe() # the 8 members, ordered
# download every member .zarr to the local cache:
paths = [a.cache() for a in coll.ordered_artifacts.all()]# sddb client: download every member .zarr into data/
sddb-cli download --collection geo-gse263079 --dest data/Licenses: 8 CC BY 4.0
@article{van_Olst_2025,
title = {Microglial mechanisms drive amyloid-β clearance in immunized patients with Alzheimer’s disease},
volume = {31},
ISSN = {1546-170X},
url = {http://dx.doi.org/10.1038/s41591-025-03574-1},
DOI = {10.1038/s41591-025-03574-1},
number = {5},
journal = {Nature Medicine},
publisher = {Springer Science and Business Media LLC},
author = {van Olst, Lynn and Simonton, Brooke and Edwards, Alex J. and Forsyth, Anne V. and Boles, Jake and Jamshidi, Pouya and Watson, Thomas and Shepard, Nate and Krainc, Talia and Argue, Benney MR and Zhang, Ziyang and Kuruvilla, Joshua and Camp, Lily and Li, Mengwei and Xu, Hang and Norman, Jeanette L. and Cahan, Joshua and Vassar, Robert and Chen, Jinmiao and Castellani, Rudolph J. and Nicoll, James AR and Boche, Delphine and Gate, David},
year = {2025},
month = Mar,
pages = {1604–1616}
}