TY - JOUR
KW - Alzheimer's disease
KW - Bipolar disorder
KW - Neurodegeneration
KW - Parkinson's disease
KW - Schizophrenia
AU - Donghoon Lee
AU - Mikaela Koutrouli
AU - Nicolas Y. Masse
AU - Gabriel E. Hoffman
AU - Seon Kinrot
AU - Xinyi Wang
AU - Prashant N. M.
AU - Milos Pjanic
AU - Tereza Clarence
AU - Fotios Tsetsos
AU - Deepika Mathur
AU - David Burstein
AU - Karen Therrien
AU - Aram Hong
AU - Clara Casey
AU - Zhiping Shao
AU - Marcela Alvia
AU - Stathis Argyriou
AU - Jennifer Monteiro Fortes
AU - Sarah R. Murphy
AU - Pavel Katsel
AU - Pavan K. Auluck
AU - Lisa L. Barnes
AU - Stefano Marenco
AU - David A. Bennett
AU - Lars Juhl Jensen
AU - Kiran Girdhar
AU - Georgios Voloudakis
AU - Vahram Haroutunian
AU - Jaroslav Bendl
AU - John F. Fullard
AU - Panos Roussos
AB - Neurodegenerative and neuropsychiatric diseases impose a considerable societal and public health burden. However, our understanding of the molecular mechanisms underlying these highly complex conditions remains limited1,2. 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.
BT - Nature
DA - 2026-09
DO - 10.1038/s41586-025-09573-z
IS - 8133
LA - en
N2 - Neurodegenerative and neuropsychiatric diseases impose a considerable societal and public health burden. However, our understanding of the molecular mechanisms underlying these highly complex conditions remains limited1,2. 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.
PY - 2026
SP - 988
EP - 1002
T2 - Nature
TI - Single-cell atlas of transcriptomic vulnerability across brain disorders
UR - https://www.nature.com/articles/s41586-025-09573-z
VL - 657
Y2 - 2026-09-25
SN - 1476-4687
ER -