The DOI matches its Crossref record; 65 of the 65 references it cites were found in a registry or an index.
Sex-dependent APOE4 neutrophil–microglia interactions drive cognitive impairment in Alzheimer’s disease
Abstract
APOE4 is the strongest genetic risk factor for Alzheimer’s disease (AD), with increased odds ratios in female carriers. Targeting amyloid plaques shows modest improvement in male non-APOE4 carriers. Leveraging single-cell transcriptomics across APOE variants in both sexes, multiplex flow cytometry and validation in two independent cohorts of APOE4 female carriers with AD, we identify a new subset of neutrophils interacting with microglia associated with cognitive impairment. This phenotype is defined by increased interleukin (IL)-17 and IL-1 coexpressed gene modules in blood neutrophils and in microglia of cognitively impaired female APOE ε4 carriers, showing increased infiltration to the AD brain. APOE4 female IL-17+ neutrophils upregulated the immunosuppressive cytokines IL-10 and TGFβ and immune checkpoints, including LAG3 and PD-1, associated with accelerated immune aging. Deletion of APOE4 in neutrophils reduced this immunosuppressive phenotype and restored the microglial response to neurodegeneration, limiting plaque pathology in AD mice. Mechanistically, IL-17F upregulated in APOE4 neutrophils interacts with microglial IL-17RA to suppress the induction of the neurodegenerative phenotype, and blocking this axis supported cognitive improvement in AD mice. These findings provide a translational basis to target IL-17F in APOE ε4 female carriers with cognitive impairment. APOE4-dependent neutrophil–microglia interactions drive cognitive impairment in female carriers with Alzheimer’s disease via IL-17F.
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“Dysregulation of the MGnD signature is also seen in APOE4 carriers with AD, particularly in women, who exhibit increased expression of TIM-3 with downregulation of MGnD genes69,70.”
From Immune checkpoint TIM-3 regulates microglia and Alzheimer’s disease (2025) · cites this paper as [70]
In the citing paper
“We recently identified an impaired MGnD response in the brains of patients with AD with the APOE4 allele, accompanied by induction of TGFβ-mediated checkpoints, including HAVCR2 (refs. 69,70).”
From Immune checkpoint TIM-3 regulates microglia and Alzheimer’s disease (2025) · cites this paper as [70]
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Subramanian, A., Tamayo, P., Mootha, V. K., Mukherjee, S., Ebert, B. L., Gillette, M. A., Paulovich, A., Pomeroy, S. L., Golub, T. R., Lander, E. S., et al. (2005) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0506580102 · Cited by 53,625
Integrated analysis of multimodal single-cell data
Hao, Y., Hao, S., Andersen-Nissen, E., Mauck, W. M., Zheng, S., Butler, A., Lee, M. J., Wilk, A. J., Darby, C., Zagar, M., et al. (2020) · doi:10.1101/2020.10.12.335331 · Cited by 15,508
Lecanemab in early Alzheimer's disease
van Dyck, C. H., Swanson, C. J., Aisen, P., Bateman, R. J., Chen, C., Gee, M., Kanekiyo, M., Li, D., Reyderman, L., Cohen, S., et al. (2023) · New England Journal of Medicine · doi:10.1056/nejmoa2212948 · Cited by 5,678
A Unique Microglia Type Associated with Restricting Development of Alzheimer’s Disease
Keren-Shaul, H., Spinrad, A., Weiner, A., Matcovitch-Natan, O., Dvir-Szternfeld, R., Ulland, T. K., David, E., Baruch, K., Lara-Astaiso, D., Toth, B., et al. (2017) · Cell · doi:10.1016/j.cell.2017.05.018 · Cited by 5,493
Oakley, H., Cole, S. L., Logan, S., Maus, E., Shao, P., Craft, J., Guillozet-Bongaarts, A., Ohno, M., Disterhoft, J., Van Eldik, L., et al. (2006) · The Journal of Neuroscience · doi:10.1523/jneurosci.1202-06.2006 · Cited by 3,530 · cited 2×
“We used 5xFAD mice, previously shown to develop cognitive impairment 42 , crossed to APOE4 mice and treated them with anti-IL-17F neutralizing antibody or IgG isotype control.”
Slingshot: cell lineage and pseudotime inference for single-cell transcriptomics
Street, K., Risso, D., Fletcher, R. B., Das, D., Ngai, J., Yosef, N., Purdom, E., & Dudoit, S. (2018) · BMC Genomics · doi:10.1186/s12864-018-4772-0 · Cited by 3,159
Krasemann, S., Madore, C., Cialic, R., Baufeld, C., Calcagno, N., El Fatimy, R., Beckers, L., O’Loughlin, E., Xu, Y., Fanek, Z., et al. (2017) · Immunity · doi:10.1016/j.immuni.2017.08.008 · Cited by 2,979
Self-citationIdentification of a unique TGF-β–dependent molecular and functional signature in microglia
Butovsky, O., Jedrychowski, M. P., Moore, C. S., Cialic, R., Lanser, A. J., Gabriely, G., Koeglsperger, T., Dake, B., Wu, P. M., Doykan, C. E., et al. (2014) · Nature Neuroscience · doi:10.1038/nn.3599 · Cited by 2,543
Self-citationFOXP3+ regulatory T cells in the human immune system
Sakaguchi, S., Miyara, M., Costantino, C. M., & Hafler, D. A. (2010) · Nature Reviews Immunology · doi:10.1038/nri2785 · Cited by 2,439
NicheNet: Modeling intercellular communication by linking ligands to target genes
Browaeys, R., Saelens, W., & Saeys, Y. (2020) · Nature Methods · doi:10.1038/s41592-019-0667-5 · Cited by 2,192
Cited by
Immune checkpoint TIM-3 regulates microglia and Alzheimer’s disease
Kimura, K., Subramanian, A., Yin, Z., Khalilnezhad, A., Wu, Y., He, D., Dixon, K. O., Chitta, U. K., Ding, X., Adhikari, N., et al. (2025) · Nature · doi:10.1038/s41586-025-08852-z · Cited by 85
Self-citationPeripheral and central neuroimmune mechanisms in Alzheimer’s disease pathogenesis
Zhang, S., Gao, Y., Zhao, Y., Huang, T. Y., Zheng, Q., & Wang, X. (2025) · Molecular Neurodegeneration · doi:10.1186/s13024-025-00812-5 · Cited by 78
TGF-β Signaling in Microglia: A Key Regulator of Development, Homeostasis and Reactivity
Li, L., Sun, B., Harris, O. A., & Luo, J. (2024) · Biomedicines · doi:10.3390/biomedicines12112468 · Cited by 38
Metadata
- Authors
- Rosenzweig, N., Kleemann, K. L., Rust, T., Carpenter, M., Grucci, M., Aronchik, M., Brouwer, N., Valenbreder, I., Cooper-Hohn, J., Iyer, M., Krishnan, R. K., Sivanathan, K. N., Brandão, W., Yahya, T., Durao, A., Yin, Z., Chadarevian, J. P., Properzi, M. J., Nowarski, R., Davtyan, H., Weiner, H. L., Blurton-Jones, M., Yang, H.-S., Eggen, B. J. L., Sperling, R. A., & Butovsky, O.
- ORCID
- Venue
- Nature Medicine
- Published
- 2024-07-03
- Volume
- 30
- Issue
- 10
- Pages
- 2990-3003
- ISSN
- 1078-8956
- 1546-170X
- PMC
- PMC12952287
- Cited by
- 98
- References
- 65
- Language
- en
- Licence
- www.springernature.com/gp/researchers/text-and-data-mining (tdm)
- www.springernature.com/gp/researchers/text-and-data-mining (vor)
- Funders
- Cure Alzheimer’s Fund (2022A005899)
- BrightFocus Foundation (2020A016806)
- Alzheimer’s Association (AARF-21-846786)
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- Rosenzweig, N., Kleemann, K. L., Rust, T., Carpenter, M., Grucci, M., Aronchik, M., Brouwer, N., Valenbreder, I., Cooper-Hohn, J., Iyer, M., Krishnan, R. K., Sivanathan, K. N., Brandão, W., Yahya, T., Durao, A., Yin, Z., Chadarevian, J. P., Properzi, M. J., Nowarski, R., . . . Butovsky, O. (2024). Sex-dependent APOE4 neutrophil–microglia interactions drive cognitive impairment in Alzheimer’s disease. Nature Medicine. https://doi.org/10.1038/s41591-024-03122-3
Data sources
Bibliographic data: Semantic Scholar, OpenAlex, Crossref.
Contains information from the Semantic Scholar Academic Graph Datasets, made available under the ODC Attribution License (ODC-BY 1.0).
Semantic Scholar’s data is described in: Kinney, R., et al. (2023). The Semantic Scholar Open Data Platform. arXiv:2301.10140.
