Single-cell atlas reveals correlates of high cognitive function, dementia, and resilience to Alzheimer's disease pathology

Hansruedi Mathys; Zhuyu Peng; Carles A Boix; Matheus B Victor; Noelle Leary; Sudhagar Babu; Ghada Abdelhady; Xueqiao Jiang; Ayesha P Ng; Kimia Ghafari; Alexander K Kunisky; Julio Mantero; Kyriaki Galani; Vanshika N Lohia; Gabrielle E Fortier; Yasmine Lotfi; Jason Ivey; Hannah P Brown; Pratham R Patel; Nehal Chakraborty; Jacob I Beaudway; Elizabeth J Imhoff; Cameron F Keeler; Maren M McChesney; Haishal H Patel; Sahil P Patel; Megan T Thai; David A Bennett; Manolis Kellis; Li-Huei Tsai

doi:10.1016/j.cell.2023.08.039

Single-cell atlas reveals correlates of high cognitive function, dementia, and resilience to Alzheimer's disease pathology

Cell. 2023 Sep 28;186(20):4365-4385.e27. doi: 10.1016/j.cell.2023.08.039.

Authors

Hansruedi Mathys¹, Zhuyu Peng², Carles A Boix³, Matheus B Victor², Noelle Leary², Sudhagar Babu⁴, Ghada Abdelhady⁴, Xueqiao Jiang², Ayesha P Ng², Kimia Ghafari⁴, Alexander K Kunisky⁴, Julio Mantero³, Kyriaki Galani³, Vanshika N Lohia⁴, Gabrielle E Fortier⁴, Yasmine Lotfi⁴, Jason Ivey⁴, Hannah P Brown⁴, Pratham R Patel⁴, Nehal Chakraborty⁴, Jacob I Beaudway⁴, Elizabeth J Imhoff⁴, Cameron F Keeler⁴, Maren M McChesney⁴, Haishal H Patel⁴, Sahil P Patel⁴, Megan T Thai⁴, David A Bennett⁵, Manolis Kellis⁶, Li-Huei Tsai⁷

Affiliations

¹ Picower Institute for Learning and Memory, MIT, Cambridge, MA 02139, USA; Department of Brain and Cognitive Sciences, MIT, Cambridge, MA 02139, USA; University of Pittsburgh Brain Institute and Department of Neurobiology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261, USA. Electronic address: mathysh@pitt.edu.
² Picower Institute for Learning and Memory, MIT, Cambridge, MA 02139, USA; Department of Brain and Cognitive Sciences, MIT, Cambridge, MA 02139, USA.
³ Computer Science and Artificial Intelligence Laboratory, MIT, Cambridge, MA 02139, USA; Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
⁴ University of Pittsburgh Brain Institute and Department of Neurobiology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261, USA.
⁵ Rush Alzheimer's Disease Center, Chicago, IL 60612, USA.
⁶ Computer Science and Artificial Intelligence Laboratory, MIT, Cambridge, MA 02139, USA; Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA. Electronic address: manoli@mit.edu.
⁷ Picower Institute for Learning and Memory, MIT, Cambridge, MA 02139, USA; Department of Brain and Cognitive Sciences, MIT, Cambridge, MA 02139, USA; Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA. Electronic address: lhtsai@mit.edu.

PMID: 37774677
PMCID: PMC10601493 (available on 2024-09-28)
DOI: 10.1016/j.cell.2023.08.039

Abstract

Alzheimer's disease (AD) is the most common cause of dementia worldwide, but the molecular and cellular mechanisms underlying cognitive impairment remain poorly understood. To address this, we generated a single-cell transcriptomic atlas of the aged human prefrontal cortex covering 2.3 million cells from postmortem human brain samples of 427 individuals with varying degrees of AD pathology and cognitive impairment. Our analyses identified AD-pathology-associated alterations shared between excitatory neuron subtypes, revealed a coordinated increase of the cohesin complex and DNA damage response factors in excitatory neurons and in oligodendrocytes, and uncovered genes and pathways associated with high cognitive function, dementia, and resilience to AD pathology. Furthermore, we identified selectively vulnerable somatostatin inhibitory neuron subtypes depleted in AD, discovered two distinct groups of inhibitory neurons that were more abundant in individuals with preserved high cognitive function late in life, and uncovered a link between inhibitory neurons and resilience to AD pathology.

Keywords: Alzheimer's disease; DNA damage response; cognitive impairment; cognitive resilience; cohesin complex; inhibitory neurons; neurodegeneration; single-cell transcriptomic atlas.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Aged
Alzheimer Disease* / metabolism
Alzheimer Disease* / pathology
Brain* / metabolism
Brain* / pathology
Cognition
Cognitive Dysfunction / metabolism
Humans
Neurons / metabolism

Abstract

Publication types

MeSH terms

Grants and funding