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Multicellular communities are perturbed in the aging human brain and Alzheimer’s disease
Open accessAbstract
The role of different cell types and their interactions in Alzheimer's disease (AD) is a complex and open question. Here, we pursued this question by assembling a high-resolution cellular map of the aging frontal cortex using single-nucleus RNA sequencing of 24 individuals with a range of clinicopathologic characteristics. We used this map to infer the neocortical cellular architecture of 638 individuals profiled by bulk RNA sequencing, providing the sample size necessary for identifying statistically robust associations. We uncovered diverse cell populations associated with AD, including a somatostatin inhibitory neuronal subtype and oligodendroglial states. We further identified a network of multicellular communities, each composed of coordinated subpopulations of neuronal, glial and endothelial cells, and we found that two of these communities are altered in AD. Finally, we used mediation analyses to prioritize cellular changes that might contribute to cognitive decline. Thus, our deconstruction of the aging neocortex provides a roadmap for evaluating the cellular microenvironments underlying AD and dementia.
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“Several cellular taxonomies for myeloid immune cells in the brain have been proposed using snRNA-seq data from healthy and diseased humans7,12,13. These taxonomies generally agree on three major types of brain myeloid lineage cells: monocytes, central nervous system (CNS)-associated macrophages (CAMs)/perivascular macrophages (PVMs) and a heterogenous group of microglia that has been difficult to”
From Integrated multimodal cell atlas of Alzheimer’s disease (2024) · cites this paper as [12]
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“Previous studies described AD-associated molecular and cellular changes5–15; however, cross-study comparisons are challenging without common cell annotations.”
From Integrated multimodal cell atlas of Alzheimer’s disease (2024) · cites this paper as [12]
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“To corroborate the results, we harmonized snRNA-seq data and associated donor metadata from the PFC from ten additional AD studies spanning 707 donors5–14.”
From Integrated multimodal cell atlas of Alzheimer’s disease (2024) · cites this paper as [12]
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“but our sample sizes are similar to those reported in previous publications5–14”
From Integrated multimodal cell atlas of Alzheimer’s disease (2024) · cites this paper as [12]
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genalex 6: genetic analysis in Excel. Population genetic software for teaching and research
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Hypothetical model of dynamic biomarkers of the Alzheimer's pathological cascade
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Self-citationNeuroinflammation in Alzheimer disease
Heneka, M. T., van der Flier, W. M., Jessen, F., Hoozemanns, J., Thal, D. R., Boche, D., Brosseron, F., Teunissen, C., Zetterberg, H., Jacobs, A. H., et al. (2025) · Nature Reviews Immunology · doi:10.1038/s41577-024-01104-7 · Cited by 638
Mathys, H., Peng, Z., Boix, C. A., Victor, M. B., Leary, N., Babu, S., Abdelhady, G., Jiang, X., Ng, A. P., Ghafari, K., et al. (2023) · Cell · doi:10.1016/j.cell.2023.08.039 · Cited by 495
Self-citationIntegrated multimodal cell atlas of Alzheimer’s disease
Gabitto, M. I., Travaglini, K. J., Rachleff, V. M., Kaplan, E. S., Long, B., Ariza, J., Ding, Y., Mahoney, J. T., Dee, N., Goldy, J., et al. (2024) · Nature Neuroscience · doi:10.1038/s41593-024-01774-5 · Cited by 397
“Several cellular taxonomies for myeloid immune cells in the brain have been proposed using snRNA-seq data from healthy and diseased humans 7,12,13 .”
Bryois, J., Calini, D., Macnair, W., Foo, L., Urich, E., Ortmann, W., Iglesias, V. A., Selvaraj, S., Nutma, E., Marzin, M., et al. (2022) · Nature Neuroscience · doi:10.1038/s41593-022-01128-z · Cited by 311
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Metadata
- Authors
- Cain, A., Taga, M., McCabe, C., Green, G. S., Hekselman, I., White, C. C., Lee, D. I., Gaur, P., Rozenblatt-Rosen, O., Zhang, F., Yeger-Lotem, E., Bennett, D. A., Yang, H.-S., Regev, A., Menon, V., Habib, N., & De Jager, P. L.
- Affiliations
- Hebrew University of Jerusalem (IL)
- Columbia University Irving Medical Center (US)
- Ben-Gurion University of the Negev (IL)
- Broad Institute (US)
- Rush University Medical Center (US)
- Corresponding author
- Menon, Vilas
- Habib, Naomi
- ORCID
- Venue
- Nature Neuroscience
- Published
- 2023-06-19
- Volume
- 26
- Issue
- 7
- Pages
- 1267-1280
- ISSN
- 1097-6256 (ISSN-L)
- 1546-1726
- PMC
- PMC10789499
- OpenAlex
- W4381189833
- Cited by
- 142
- References
- 70
- Citations by year
- 2026: 34 · 2025: 33 · 2024: 36 · 2023: 20
- FWCI
- 10.96
- Type
- journal article
- Language
- en
- Open access
- green
- doi.org
- Licence
- Locations
- Nature Neuroscience (publishedVersion)
- bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- Howard Hughes Medical Institute
- Rush University
- Chan Zuckerberg Initiative
- Israel Science Foundation (1709/19)
- Klarman Cell Observatory, Broad Institute
- National Institute on Aging (R01AG017917, P30 AG72975, P30-AG 10161, R01‐AG17917, R01 AG15819, U01AG046152, R01AG015819, P30AG010161, U01AG061356, R21AG075754, R01AG066831, RF1AG057473, RF1AG036042, U54AG076040, P30AG072975)
- H2020 European Research Council (853409)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Single-cell and spatial transcriptomics
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Alzheimer's disease research and treatments
- Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
- Keywords
- Alzheimer's disease, brain aging, frontal cortex, somatostatin interneurons, oligodendrocytes, endothelial cells, glial cells, cognitive decline, dementia, single-nucleus RNA sequencing, cell-cell interactions
- MeSH terms
- Aging, Alzheimer Disease, Brain, Humans, Neocortex, Endothelial Cells, Cognitive Dysfunction
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