Single-cell atlas of transcriptomic vulnerability across brain disorders

. Here, to gain deeper insights into the aetiology of different brain diseases, we used specimens from 1,494 unique donors to generate a population-scale single-cell transcriptomic atlas of the human dorsolateral prefrontal cortex, comprising over 6.3 million individual nuclei. The cohort includes neurotypical controls, as well as donors affected by eight common and complex brain disorders: Alzheimer's disease (AD), diffuse Lewy body disease (DLBD), vascular dementia (Vas), Parkinson's disease (PD), tauopathy, frontotemporal dementia, schizophrenia, and bipolar disorder. We show that interindividual variation accounts for a substantial portion of gene expression variation. By comparing transcriptomic variation across diseases, we reveal universal signatures enriched in basic cellular functions such as mRNA processing and protein localization. After discounting these cross-disease signatures, we show stronger genetic and transcriptomic concordance among AD, DLBD, Vas and PD. Furthermore, we characterize transcriptomic variation among different AD phenotypes, distinct from those observed in healthy ageing, revealing a reduction in neuronal abundance in individuals with more severe AD, coupled with an increase in immune and vascular cell populations. Exploring the neuropsychiatric symptoms (NPSs) that frequently accompany AD, we find an increased abundance of deep-layer excitatory neurons associated with a broad range of NPSs. By constructing transcriptome trajectories that capture AD progression, we implicate cell-type-specific responses in the early and late stages of AD. Our disease atlas provides a perspective of the transcriptomic landscape in neurodegenerative and neuropsychiatric disorders, shedding light on shared and distinct processes involving the neurological-immune-vascular systems, and identifying potential targets for therapeutic intervention.

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Publication Details

Journal
Nature
Published
2026-09-23
DOI
https://doi.org/10.1038/s41586-025-09573-z
Citations
5
Primary Topic
Single-cell and spatial transcriptomics
Type
article
Field-Weighted Citation Impact
12.52

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Single-cell atlas of transcriptomic vulnerability across brain disorders

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Single-cell atlas of transcriptomic vulnerability across brain disorders

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article en
5 citations

Abstract

. Here, to gain deeper insights into the aetiology of different brain diseases, we used specimens from 1,494 unique donors to generate a population-scale single-cell transcriptomic atlas of the human dorsolateral prefrontal cortex, comprising over 6.3 million individual nuclei. The cohort includes neurotypical controls, as well as donors affected by eight common and complex brain disorders: Alzheimer's disease (AD), diffuse Lewy body disease (DLBD), vascular dementia (Vas), Parkinson's disease (PD), tauopathy, frontotemporal dementia, schizophrenia, and bipolar disorder. We show that interindividual variation accounts for a substantial portion of gene expression variation. By comparing transcriptomic variation across diseases, we reveal universal signatures enriched in basic cellular functions such as mRNA processing and protein localization. After discounting these cross-disease signatures, we show stronger genetic and transcriptomic concordance among AD, DLBD, Vas and PD. Furthermore, we characterize transcriptomic variation among different AD phenotypes, distinct from those observed in healthy ageing, revealing a reduction in neuronal abundance in individuals with more severe AD, coupled with an increase in immune and vascular cell populations. Exploring the neuropsychiatric symptoms (NPSs) that frequently accompany AD, we find an increased abundance of deep-layer excitatory neurons associated with a broad range of NPSs. By constructing transcriptome trajectories that capture AD progression, we implicate cell-type-specific responses in the early and late stages of AD. Our disease atlas provides a perspective of the transcriptomic landscape in neurodegenerative and neuropsychiatric disorders, shedding light on shared and distinct processes involving the neurological-immune-vascular systems, and identifying potential targets for therapeutic intervention.

NatureVol. 657(8133)
University of Copenhagen (DK), Rush University Medical Center (US), Allen Institute for Brain Science (US), Gladstone Institutes (US), University of Wisconsin–Madison (US), University of Pittsburgh (US), University of California, San Francisco (US), Novo Nordisk Foundation (DK), James J. Peters VA Medical Center (US), Taube Koret Center (US), National Institute of Mental Health (US), Vanderbilt University Medical Center (US), Icahn School of Medicine at Mount Sinai (US)
U.S. Department of Veterans Affairs, University of Wisconsin-Madison, University of Washington, Gladstone Institutes, Rush University, Novo Nordisk, National Institutes of Health, Charles F. and Joanne Knight Alzheimer Disease Research Center, Washington University in St. Louis, National Institute on Aging, National Institute of Mental Health
Good health and well-being
Openalex Percentile: Top 1%
Single-cell and spatial transcriptomics
12.52
DOIOpen Access PDFOpenAlex
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