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

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...

Full description

Saved in:

Bibliographic Details
Published in:	Cell Vol. 186; no. 20; pp. 4365 - 4385.e27
Main Authors:	Mathys, Hansruedi, Peng, Zhuyu, Boix, Carles A., Victor, Matheus B., Leary, Noelle, Babu, Sudhagar, Abdelhady, Ghada, Jiang, Xueqiao, Ng, Ayesha P., Ghafari, Kimia, Kunisky, Alexander K., Mantero, Julio, Galani, Kyriaki, Lohia, Vanshika N., Fortier, Gabrielle E., Lotfi, Yasmine, Ivey, Jason, Brown, Hannah P., Patel, Pratham R., Chakraborty, Nehal, Beaudway, Jacob I., Imhoff, Elizabeth J., Keeler, Cameron F., McChesney, Maren M., Patel, Haishal H., Patel, Sahil P., Thai, Megan T., Bennett, David A., Kellis, Manolis, Tsai, Li-Huei
Format:	Journal Article
Language:	English
Published:	United States Elsevier Inc 28-09-2023
Subjects:	Aged Alzheimer Disease - metabolism Alzheimer Disease - pathology Alzheimer's disease Brain - metabolism Brain - pathology Cognition Cognitive Dysfunction - metabolism cognitive impairment cognitive resilience cohesin complex DNA damage response Humans inhibitory neurons neurodegeneration Neurons - metabolism single-cell transcriptomic atlas DNA damage response neurodegeneration cohesin complex cognitive impairment single-cell transcriptomic atlas cognitive resilience Alzheimer's disease inhibitory neurons
Online Access:	Get full text
Tags:	Add Tag No Tags, Be the first to tag this record!

Description
Summary:	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. [Display omitted] •Single-cell atlas of the aged human prefrontal cortex across 427 individuals•Coordinated increase of the cohesin complex and DNA damage response factors in AD•Selectively vulnerable somatostatin inhibitory neuron subtypes are depleted in AD•Subsets of inhibitory neurons are linked with preserved cognitive function in old age A single-cell atlas of the aged human prefrontal cortex across 2.3 million nuclei isolated from 427 ROSMAP study participants reveals cellular and molecular correlates of high cognitive function, dementia, and resilience to Alzheimer’s disease pathology.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 AUTHOR CONTRIBUTIONS Lead contact: lhtsai@mit.edu This study was designed by H.M., C.B., D.A.B., M.K., and L.-H.T., and directed and coordinated by H.M., M.K., and L.-H.T. H.M, A.P.N, X.J, J.M, and K.G carried out sample preparations and single-cell RNA profiling. H.M. and C.B. led the computational analysis. Z.P., M.B.V., and N.L. carried out experimental validation experiments. G.A., X.J., A.P.N., K.G., S.B., A.K.K., V.N.L., G.E.F., Y.L., J.B.I., H.P.B, P.R.P, N. C., J.I.B., E.J.I, C.F.K., M.M.M., H.H.P., S.P.P., and M.T.T. helped with the computational analysis. D.A.B. contributed samples and data. H.M., C.B., G.A., D.A.B., M.K., and L.-H.T. wrote the manuscript.
ISSN:	0092-8674 1097-4172 1097-4172
DOI:	10.1016/j.cell.2023.08.039