Cellular communities reveal trajectories of brain ageing and Alzheimer’s disease

Gilad Sahar Green, Masashi Fujita, Hyun-Sik Yang, Mariko Taga, Anael Cain, Cristin McCabe, Natacha Comandante-Lou, Charles C. White, Anna K. Schmidtner, Lu Zeng, Alina Sigalov, Yangling Wang, Aviv Regev, Hans-Ulrich Klein, Vilas Menon (), David A. Bennett, Naomi Habib () and Philip L. Jager ()
Additional contact information
Gilad Sahar Green: The Hebrew University of Jerusalem
Masashi Fujita: Columbia University Irving Medical Center
Hyun-Sik Yang: Harvard Medical School
Mariko Taga: Columbia University Irving Medical Center
Anael Cain: The Hebrew University of Jerusalem
Cristin McCabe: Broad Institute of MIT and Harvard
Natacha Comandante-Lou: Columbia University Irving Medical Center
Charles C. White: Broad Institute of MIT and Harvard
Anna K. Schmidtner: The Hebrew University of Jerusalem
Lu Zeng: Columbia University Irving Medical Center
Alina Sigalov: Columbia University Irving Medical Center
Yangling Wang: Rush University Medical Center
Aviv Regev: Broad Institute of MIT and Harvard
Hans-Ulrich Klein: Columbia University Irving Medical Center
Vilas Menon: Columbia University Irving Medical Center
David A. Bennett: Rush University Medical Center
Naomi Habib: The Hebrew University of Jerusalem
Philip L. Jager: Columbia University Irving Medical Center

Nature, 2024, vol. 633, issue 8030, 634-645

Abstract: Abstract Alzheimer’s disease (AD) has recently been associated with diverse cell states1–11, yet when and how these states affect the onset of AD remains unclear. Here we used a data-driven approach to reconstruct the dynamics of the brain’s cellular environment and identified a trajectory leading to AD that is distinct from other ageing-related effects. First, we built a comprehensive cell atlas of the aged prefrontal cortex from 1.65 million single-nucleus RNA-sequencing profiles sampled from 437 older individuals, and identified specific glial and neuronal subpopulations associated with AD-related traits. Causal modelling then prioritized two distinct lipid-associated microglial subpopulations—one drives amyloid-β proteinopathy while the other mediates the effect of amyloid-β on tau proteinopathy—as well as an astrocyte subpopulation that mediates the effect of tau on cognitive decline. To model the dynamics of cellular environments, we devised the BEYOND methodology, which identified two distinct trajectories of brain ageing, each defined by coordinated progressive changes in certain cellular communities that lead to (1) AD dementia or (2) alternative brain ageing. Thus, we provide a cellular foundation for a new perspective on AD pathophysiology that informs personalized therapeutic development, targeting different cellular communities for individuals on the path to AD or to alternative brain ageing.

Date: 2024
References: Add references at CitEc
Citations:

Downloads: (external link)
https://www.nature.com/articles/s41586-024-07871-6 Abstract (text/html)
Access to the full text of the articles in this series is restricted.

Related works:
This item may be available elsewhere in EconPapers: Search for items with the same title.

Export reference: BibTeX RIS (EndNote, ProCite, RefMan) HTML/Text

Persistent link: https://EconPapers.repec.org/RePEc:nat:nature:v:633:y:2024:i:8030:d:10.1038_s41586-024-07871-6

Ordering information: This journal article can be ordered from
https://www.nature.com/

DOI: 10.1038/s41586-024-07871-6

Access Statistics for this article

Nature is currently edited by Magdalena Skipper

More articles in Nature from Nature
Bibliographic data for series maintained by Sonal Shukla () and Springer Nature Abstracting and Indexing ().