Multi-cellular 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 an open question. Here we pursued it by assembling a high-resolution cellular map of the aging frontal cortex by single nucleus RNA-seq of 24 individuals with different clinicopathologic characteristics. We used the map to infer the neocortical cellular architecture of 638 individuals profiled by bulk RNA-seq, providing the sample size necessary for identifying statistically robust associations. We uncovered diverse cell populations associated with AD, including inhibitory neuronal subtypes and oligodendroglial states. We further recovered a network of multicellular communities, each composed of coordinated subpopulations of neuronal, glial and endothelial cells, and 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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Studies have shown that RORB-expressing excitatory neurons in the EC and the frontal cortex, as well as SST-positive interneurons in the frontal cortex, are more prone to neuronal susceptibility than other parts of the brain.
“Studies have shown that RORB-expressing excitatory neurons in the EC [45] and the frontal cortex [56], as well as SST-positive interneurons in the frontal cortex [8], are more prone to neuronal susceptibility than other parts of the brain.”
From Abnormal accumulation of extracellular vesicles in hippocampal dystrophic axons and regulation by the primary cilia in Alzheimer's disease (2023) · cites this paper as [8]
The ‘Cell population frequencies’ section reports that SST-positive inhibitory neurons were relatively more common in healthy individuals and says this suggests potential vulnerability in Alzheimer’s disease. The study examines the dorsolateral prefrontal cortex, but it does not show that these neurons are more vulnerable than neurons in other brain regions. Citation [8] is attached to the SST-positive interneuron clause, not the RORB claims. (LLM, conf=0.85)
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References 88 · Cited by 143
Research works printed but not linked: 1
- Yang, A. C. et al. A human brain vascular atlas reveals diverse cell mediators of Alzheimer's disease risk. bioRxiv (2021).
- Authors
- Cain, A., Taga, M., McCabe, C., Green, G., 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
- Publisher
- openRxiv
- Published
- 2020-12-23
- Volume
- 26
- Issue
- 7
- Pages
- 1267-1280
- ISSN
- 1097-6256 (ISSN-L)
- PMC
- PMC10789499
- OpenAlex
- W4381189833
- Cited by
- 143
- References
- 88
- Citations by year
- 2026: 35 · 2025: 33 · 2024: 36 · 2023: 20 · 2022: 17 · 2021: 2
- FWCI
- 10.95
- Type
- journal article
- Language
- en
- Open access
- green
- doi.org
- 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, 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
- Health Sciences › Medicine › Physiology › 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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