single cell intermediate

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, Tereza Clarence, Fotis Tsetsos, Deepika Mathur, David Burstein, Karen Therrien, Aram Hong, Clara Casey, Zhiping Shao, Marcela Alvia, Stathis Argyriou, Jennifer Monteiro Fortes, Sarah E. Murphy, Pavel Katsel, Pavan Kumar Auluck, Lisa L. Barnes, Stefano Marenco, David A. Bennett, Athan Z. Li, Biao Zeng, Chenfeng He, Chirag Gupta, Christian Dillard, Christian Porras, Colleen A. McClung, Collin Spencer, Daifeng Wang, Gennadi Ryan, Hui Yang, Jerome J. Choi, Kalpana H. Arachchilage, Lars J. Jensen, Logan C. Dumitrescu, Lyra Sheu, Madeline R. Scott, Marios Anyfantakis, Maxim Signaevsky, Monika Ahirwar, Noah Cohen Kalafut, Pengfei Dong, Pramod B. Chandrashekar, Rachel Bercovitch, Roman Kosoy, Sanan Venkatesh, Saniya Khullar, Sayali A. Alatkar, Steven Finkbeiner, Steven P. Kleopoulos, Timothy J. Hohman, Ting Jin, Vivek G. Ramaswamy, Xiang Huang, Zhenyi Wu, Lars Juhl Jensen, Kiran Kumar Girdhar, Georgios Voloudakis, Vahram H. Haroutunian, Jaroslav M. Bendl, John F. Fullard, Panos Roussos

Nature · Sep 23, 2026 · 1 min read

TL;DR

A single-cell transcriptomic atlas of over 6.3 million nuclei from 1,494 donors reveals shared cellular signatures across eight brain disorders and identifies specific neuronal, immune, and vascular changes linked to Alzheimer's disease severity.

Problem / question

The molecular mechanisms underlying complex neurodegenerative and neuropsychiatric diseases remain poorly understood, making it difficult to identify shared versus disease-specific cellular vulnerabilities across different brain disorders.

Methods

The researchers generated a population-scale single-nucleus RNA sequencing atlas of the human dorsolateral prefrontal cortex using postmortem samples from 1,494 unique donors, yielding over 6.3 million individual nuclei. The cohort included neurotypical controls and individuals with eight brain disorders: Alzheimer's disease, diffuse Lewy body disease, vascular dementia, Parkinson's disease, tauopathy, frontotemporal dementia, schizophrenia, and bipolar disorder.

Key findings

The study identified universal transcriptomic signatures across the eight diseases enriched in basic cellular functions like mRNA processing and protein localization. After removing these shared signatures, Alzheimer's disease, diffuse Lewy body disease, vascular dementia, and Parkinson's disease showed the strongest transcriptomic similarities. In Alzheimer's disease, severe cases showed a reduction in neuronal abundance alongside increases in immune and vascular cell populations, while neuropsychiatric symptoms were linked to an increased abundance of deep-layer excitatory neurons.

Why it matters

By mapping both shared and disease-specific transcriptomic changes across multiple major brain disorders at single-cell resolution, this atlas provides a foundational resource for understanding how the neurological, immune, and vascular systems interact in brain disease to identify new therapeutic targets.

Limitations

The provided text does not explicitly state specific limitations, caveats, or biases of the study.

Takeaway

Analyzing over 6.3 million brain cells across eight disorders reveals that while some gene expression changes are universal, specific conditions like Alzheimer's disease feature distinct shifts in neuronal, immune, and vascular cell populations that correlate with disease severity and psychiatric symptoms.