Multicellular communities are perturbed in the aging human brain and Alzheimer’s disease

Anael Cain, Mariko Taga, Cristin McCabe, Gilad S. Green, Idan Hekselman, Charles C. White, Dylan I. Lee, Pallavi Gaur, Orit Rozenblatt-Rosen, Feng Zhang, Esti Yeger-Lotem, David A. Bennett, Hyun Sik Yang, Aviv Regev, Vilas Menon*, Naomi Habib*, Philip L. De Jager*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

4 Scopus citations


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.

Original languageAmerican English
Pages (from-to)1267-1280
Number of pages14
JournalNature Neuroscience
Issue number7
StatePublished - Jul 2023

Bibliographical note

Publisher Copyright:
© 2023, The Author(s), under exclusive licence to Springer Nature America, Inc.


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