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Single-cell atlas of transcriptomic vulnerability across brain disorders
Donghoon Lee, Mikaela Koutrouli, Nicolas Y. Masse, Gabriel E. Hoffman, Seon Kinrot, Xinyi Wang, N. M. Prashant, Milos Pjanic et al.. Nature, 2026-09-23
Topic: Brain proteins, microglia and lab models
. 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.
Key findings
- 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.
Why it matters
This large single-cell atlas of the brain's prefrontal cortex compared gene activity across Alzheimer's and other brain disorders, finding that more severe Alzheimer's was tied to fewer neurons and more immune and vascular cells. It describes disease patterns rather than testing any treatment, so it does not show how to cure or prevent Alzheimer's.
Study details
- Evidence strengthModerate
How this study scored 52/100
Published in a top-tier journal. Scored zero for study design, sample size, effect reported, studied in people and randomised / blinded because the record does not state it.
| Component | Points | Why |
|---|---|---|
| Journal tier | 10 / 10 | Tier 1 — top-tier general journal (Nature) |
| Journal's citation record | 4 / 4 | Nature: journal h-index 1,841 (OpenAlex, 2026-10-29) |
| Study design | 0 / 12 | No study design recorded — scores zero, not guessed (not stated in the record — scored 0) |
| Strength of evidence | 3 / 5 | Rated “moderate” in our summary |
| Peer-review validation | 10 / 10 | Peer-reviewed. Published as an article in a named peer-reviewed journal. |
| How recent | 5 / 5 | 2026 — within 1 year(s) of the newest study here |
| Sample size | 0 / 4 | Participant count not stated — scores zero (not stated in the record — scored 0) |
| Effect reported | 0 / 3 | No effect size reported — scores zero (not stated in the record — scored 0) |
| Studied in people | 0 / 3 | Not stated whether this was studied in people — scores zero (not stated in the record — scored 0) |
| Randomised / blinded | 0 / 2 | No randomisation or blinding stated — scores zero (not stated in the record — scored 0) |
| Times cited | 2 / 7 | Cited 5 times (OpenAlex, 2026-10-10) |
| Citations per year | 1 / 5 | 2.5 citations a year over 2 year(s) since 2026 |
| Impact for its field and year | 4 / 6 | Cited 9.7× the average for papers of its field and year (OpenAlex FWCI) |
| Cited by studies here | 0 / 6 | No other study in this library cites it |
| Still being cited | 1 / 4 | Cited 5 times in 2024–2026 (2026 still in progress; OpenAlex) |
| Senior author's track record | 3 / 4 | Last-listed author Panos Roussos: h-index 94 (OpenAlex, whole career) |
| Institution's track record | 2 / 3 | University of California, San Francisco: institution h-index 1,915 (OpenAlex) |
| Multi-centre collaboration | 3 / 3 | OpenAlex lists 12 institution(s) in 2 countries |
| Indexed in PubMed | 2 / 2 | Indexed in PubMed (PMID 42778699) |
| Free to read | 2 / 2 | Free to read |
| Total | 52 / 100 | — |
What each of these 20 components measures, and what this score is not →
Read the original
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Built from the record alzhub holds for this paper, not looked up. Volume, issue and page numbers are not held in the record. The record's author list ends in “et al.”, so not every author is named. Check the citation against the original before you use it.
APA 7th
Lee, D., Koutrouli, M., Masse, N. Y., Hoffman, G. E., Kinrot, S., Wang, X., et al. (2026). Single-cell atlas of transcriptomic vulnerability across brain disorders. Nature. https://doi.org/10.1038/s41586-025-09573-z
Vancouver
Lee D, Koutrouli M, Masse NY, Hoffman GE, Kinrot S, Wang X, et al. Single-cell atlas of transcriptomic vulnerability across brain disorders. Nature. 2026. doi:10.1038/s41586-025-09573-z. PMID: 42778699.
BibTeX
@article{lee2026-42778699,
author = {Lee, Donghoon and Koutrouli, Mikaela and Masse, Nicolas Y. and Hoffman, Gabriel E. and Kinrot, Seon and Wang, Xinyi and Prashant, N. M. and Pjanic, Milos and others},
title = {{Single-cell atlas of transcriptomic vulnerability across brain disorders}},
journal = {Nature},
year = {2026},
doi = {10.1038/s41586-025-09573-z},
pmid = {42778699},
url = {https://doi.org/10.1038/s41586-025-09573-z}
}
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