Single-cell multiregion dissection of Alzheimer’s disease

Hansruedi Mathys, Carles A. Boix, Leyla Anne Akay, Ziting Xia, Jose Davila-Velderrain, Ayesha P. Ng, Xueqiao Jiang, Ghada Abdelhady, Kyriaki Galani, Julio Mantero, Neil Band, Benjamin T. James, Sudhagar Babu, Fabiola Galiana-Melendez, Kate Louderback, Dmitry Prokopenko, Rudolph E. Tanzi, David A. Bennett, Li-Huei Tsai () and Manolis Kellis ()
Additional contact information
Hansruedi Mathys: MIT
Carles A. Boix: MIT
Leyla Anne Akay: MIT
Ziting Xia: MIT
Jose Davila-Velderrain: Human Technopole
Ayesha P. Ng: MIT
Xueqiao Jiang: MIT
Ghada Abdelhady: University of Pittsburgh School of Medicine
Kyriaki Galani: MIT
Julio Mantero: MIT
Neil Band: MIT
Benjamin T. James: MIT
Sudhagar Babu: University of Pittsburgh School of Medicine
Fabiola Galiana-Melendez: MIT
Kate Louderback: MIT
Dmitry Prokopenko: Massachusetts General Hospital and Harvard Medical School
Rudolph E. Tanzi: Massachusetts General Hospital and Harvard Medical School
David A. Bennett: Rush Alzheimer’s Disease Center
Li-Huei Tsai: MIT
Manolis Kellis: MIT

Nature, 2024, vol. 632, issue 8026, 858-868

Abstract: 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 understood1–3. 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.

Date: 2024
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DOI: 10.1038/s41586-024-07606-7

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