Nature, volume 632, issue 8026, pages 858-868

Single-cell multiregion dissection of Alzheimer’s disease

Hansruedi Mathys ^{1, 2, 3, 4}

Carles Boix ^{5, 6, 7}

Leyla Anne Akay ^{1, 2}

Ziting Judy Xia ^{1, 2, 8}

Jose Davila Velderrain ⁹

Ayesha P Ng ^{1, 2}

Xueqiao Jiang ^{1, 2}

Ghada Abdelhady ³

Kyriaki Galani ^{5, 6}

Julio Mantero ^{5, 6}

Neil Band ^{5, 6, 10}

Benjamin T James ^{5, 6}

Sudhagar Babu ³

Fabiola Galiana-Melendez ^{1, 2}

Kate Louderback ^{1, 2}

Dmitry Prokopenko ¹¹

Rudolph E. Tanzi ¹¹

David A Bennett ¹²

Li-An Tsai ^{1, 2, 6}

M. Kellis ^{5, 6}

Show full list: 20 authors

Hide authors affiliations

Picower Institute for Learning and Memory, MIT, Cambridge, USA |

Department of Brain and Cognitive Sciences, MIT, Cambridge, USA |

University of Pittsburgh Brain Institute, University of Pittsburgh School of Medicine, Pittsburgh, USA |

⁴

Department of Neurobiology, University of Pittsburgh School of Medicine, Pittsburgh, USA |

⁵

Computer Science and Artificial Intelligence Laboratory, MIT, Cambridge, USA |

⁶

Broad Institute of MIT and Harvard, Cambridge, USA |

⁷

Computational and Systems Biology Program, MIT, Cambridge, USA |

⁸

Harvard-MIT Health Sciences and Technology Program, MIT, Cambridge, USA

⁹

Human Technopole, Milan, Italy |

¹⁰

Department of Computer Science, Stanford University, Stanford, USA |

¹¹

Genetics and Aging Research Unit, McCance Center for Brain Health, Department of Neurology, Massachusetts General Hospital and Harvard Medical School, Boston, USA

¹²

Rush Alzheimer’s Disease Center, Chicago, USA |

Publication type: Journal Article

Publication date: 2024-07-24

Springer Nature

Journal: Nature

scimago Q1

SJR: 18.509

CiteScore: 90.0

Impact factor: 50.5

ISSN: 00280836, 14764687

DOI: 10.1038/s41586-024-07606-7

Copy DOI

Abstract

Alzheimer’s disease is the leading cause of dementia worldwide, but the cellular pathways that underlie its pathological progression across brain regions remain poorly understood^1–3. Here we report a single-cell transcriptomic atlas of six different brain regions in the aged human brain, covering 1.3 million cells from 283 post-mortem human brain samples across 48 individuals with and without Alzheimer’s disease. We identify 76 cell types, including region-specific subtypes of astrocytes and excitatory neurons and an inhibitory interneuron population unique to the thalamus and distinct from canonical inhibitory subclasses. We identify vulnerable populations of excitatory and inhibitory neurons that are depleted in specific brain regions in Alzheimer’s disease, and provide evidence that the Reelin signalling pathway is involved in modulating the vulnerability of these neurons. We develop a scalable method for discovering gene modules, which we use to identify cell-type-specific and region-specific modules that are altered in Alzheimer’s disease and to annotate transcriptomic differences associated with diverse pathological variables. We identify an astrocyte program that is associated with cognitive resilience to Alzheimer’s disease pathology, tying choline metabolism and polyamine biosynthesis in astrocytes to preserved cognitive function late in life. Together, our study develops a regional atlas of the ageing human brain and provides insights into cellular vulnerability, response and resilience to Alzheimer’s disease pathology.

Found

	1 2 3
International Journal of Molecular Sciences	International Journal of Molecular Sciences, 3, 5.45% International Journal of Molecular Sciences 3 publications, 5.45%
Nature Reviews Neurology	Nature Reviews Neurology, 1, 1.82% Nature Reviews Neurology 1 publication, 1.82%
Materials and Design	Materials and Design, 1, 1.82% Materials and Design 1 publication, 1.82%
Frontiers in Neuroinformatics	Frontiers in Neuroinformatics, 1, 1.82% Frontiers in Neuroinformatics 1 publication, 1.82%
Frontiers in Neurology	Frontiers in Neurology, 1, 1.82% Frontiers in Neurology 1 publication, 1.82%
Signal Transduction and Targeted Therapy	Signal Transduction and Targeted Therapy, 1, 1.82% Signal Transduction and Targeted Therapy 1 publication, 1.82%
Biological Psychiatry	Biological Psychiatry, 1, 1.82% Biological Psychiatry 1 publication, 1.82%
Nature	Nature, 1, 1.82% Nature 1 publication, 1.82%
Environmental Health Perspectives	Environmental Health Perspectives, 1, 1.82% Environmental Health Perspectives 1 publication, 1.82%
Trends in Immunology	Trends in Immunology, 1, 1.82% Trends in Immunology 1 publication, 1.82%
Acta Neuropathologica	Acta Neuropathologica, 1, 1.82% Acta Neuropathologica 1 publication, 1.82%
EMBO Journal	EMBO Journal, 1, 1.82% EMBO Journal 1 publication, 1.82%
Neuroglia	Neuroglia, 1, 1.82% Neuroglia 1 publication, 1.82%
Acta Pharmaceutica Sinica B	Acta Pharmaceutica Sinica B, 1, 1.82% Acta Pharmaceutica Sinica B 1 publication, 1.82%
The Lancet Neurology	The Lancet Neurology, 1, 1.82% The Lancet Neurology 1 publication, 1.82%
IEEE Sensors Journal	IEEE Sensors Journal, 1, 1.82% IEEE Sensors Journal 1 publication, 1.82%
Non-coding RNA	Non-coding RNA, 1, 1.82% Non-coding RNA 1 publication, 1.82%
Neuron	Neuron, 1, 1.82% Neuron 1 publication, 1.82%
Movement Disorders	Movement Disorders, 1, 1.82% Movement Disorders 1 publication, 1.82%
Molecular Neurodegeneration	Molecular Neurodegeneration, 1, 1.82% Molecular Neurodegeneration 1 publication, 1.82%
Brain Behavior & Immunity - Health	Brain Behavior & Immunity - Health, 1, 1.82% Brain Behavior & Immunity - Health 1 publication, 1.82%
EBioMedicine	EBioMedicine, 1, 1.82% EBioMedicine 1 publication, 1.82%
Nature Medicine	Nature Medicine, 1, 1.82% Nature Medicine 1 publication, 1.82%
Neurotherapeutics	Neurotherapeutics, 1, 1.82% Neurotherapeutics 1 publication, 1.82%
Molecular Medicine	Molecular Medicine, 1, 1.82% Molecular Medicine 1 publication, 1.82%
Nature Cell Biology	Nature Cell Biology, 1, 1.82% Nature Cell Biology 1 publication, 1.82%
QRB Discovery	QRB Discovery, 1, 1.82% QRB Discovery 1 publication, 1.82%
Coordination Chemistry Reviews	Coordination Chemistry Reviews, 1, 1.82% Coordination Chemistry Reviews 1 publication, 1.82%
	1 2 3

	5 10 15 20 25
Cold Spring Harbor Laboratory	Cold Spring Harbor Laboratory, 25, 45.45% Cold Spring Harbor Laboratory 25 publications, 45.45%
Elsevier	Elsevier, 10, 18.18% Elsevier 10 publications, 18.18%
Springer Nature	Springer Nature, 9, 16.36% Springer Nature 9 publications, 16.36%
MDPI	MDPI, 5, 9.09% MDPI 5 publications, 9.09%
Frontiers Media S.A.	Frontiers Media S.A., 2, 3.64% Frontiers Media S.A. 2 publications, 3.64%
Environmental Health Perspectives	Environmental Health Perspectives, 1, 1.82% Environmental Health Perspectives 1 publication, 1.82%
Institute of Electrical and Electronics Engineers (IEEE)	Institute of Electrical and Electronics Engineers (IEEE), 1, 1.82% Institute of Electrical and Electronics Engineers (IEEE) 1 publication, 1.82%
Wiley	Wiley, 1, 1.82% Wiley 1 publication, 1.82%
Cambridge University Press	Cambridge University Press, 1, 1.82% Cambridge University Press 1 publication, 1.82%
	5 10 15 20 25

Are you a researcher?

Create a profile to get free access to personal recommendations for colleagues and new articles.

Metrics

Cite this

GOST | RIS | BibTex | MLA

Found error?

Publisher

Springer Nature

Journal

Nature

scimago Q1

SJR

18.509

CiteScore

90.0

Impact factor

50.5

ISSN

00280836 (Print)

14764687 (Electronic)

Single-cell multiregion dissection of Alzheimer’s disease

Top-30

Journals

Publishers

Are you a researcher?