Neuroscience: Detailed brain maps probe development, ageing, decline and disease (Nature)

The largest-known map of gene expression in the human prefrontal cortex region of the brain is presented in Nature this week. Additional papers in Nature and Nature Portfolio journals analyse more than 6.3 million gene expression profiles from the brains of 1,494 deceased donors from the PsychAD programme. The research offers insights into how the prefrontal cortex region develops across the human lifespan, which could be used to study ageing, cognitive decline and disease susceptibility.

The human brain undergoes vast developmental changes throughout early life and late adulthood; these changes affect cognitive abilities, behaviour and vulnerability to disease. Analysing patterns of gene expression at different life stages may shed light on how brain changes occur, which could be used to study both normal ageing and the development of neurodegenerative and neuropsychiatric diseases. The prefrontal cortex region is involved in key cognitive functions (such as problem solving, planning and emotional regulation) and is sensitive to age-related decline, making it an ideal part of the brain to study. This region is the focus for the PsychAD programme, which aims to investigate the processes that underlie disorders such as Alzheimer’s disease.

One of the papers from the PsychAD Consortium, published in Nature, describes the largest population-scale single-cell transcriptomic atlas of the human dorsolateral prefrontal cortex reported to date. Hui Yang and colleagues assess 1.3 million gene expression profiles from the brains of 284 neurotypical donors ranging in age from infancy to late adulthood, finding evidence of how gene expression changes over time. These changes correlate with brain remodelling during early development, stability during midlife (up to around 24 years of age), subsequent declines in composition after this age and reprogramming of cells after 65 years of age. The authors also identify associations between changes in gene expression and neuronal resilience in early life and neuronal vulnerability in late life.

In a second Nature paper, Donghoon Lee and colleagues present an atlas of gene expression changes associated with brain diseases. They assess the full PsychAD dataset (6.3 million gene expression profiles from 1,494 donors), which includes neurotypical individuals as well as donors with brain disorders such as Alzheimer’s disease and other forms of dementia, Parkinson’s disease, schizophrenia and bipolar disorder. All of the studied diseases appear to share some similarities in gene expression associated with basic cellular functions. However, there were notably strong similarities in gene expression alterations between the different forms of dementia and Parkinson’s disease, particularly in genes involved in neuronal development and synaptic function.

A third Nature paper by Sanan Venkatesh and colleagues maps how genetic risk for brain disorders affects specific cell types across diverse populations spanning European, African and American ancestries. They uncover thousands of previously hidden gene–trait associations and reveal conserved cell-type-specific mechanisms. The findings provide deeper insights into the biological underpinnings of neuropsychiatric and neurodegenerative disorders, the authors conclude.

Additional papers from the PsychAD Consortium will be published in Nature Medicine, Nature Genetics and Nature Communications. In an accompanying News & Views, Jennifer Below suggests that the results from the PsychAD programme provide a “resource for understanding healthy and disease-related changes in the prefrontal cortex,” with “... broad potential to advance the discovery of genes associated with neuropsychiatric, neurodegenerative, behavioural, cognitive and emotional traits.”

• Article
• Open access
• Published: 23 September 2026

Yang, H., Clarence, T., Scott, M.R. et al. Lifespan single-cell transcriptomic atlas of the human prefrontal cortex. Nature 657, 1003–1015 (2026). https://doi.org/10.1038/s41586-026-10271-7

• Article
• Open access
• Published: 23 September 2026

Lee, D., Koutrouli, M., Masse, N.Y. et al. Single-cell atlas of transcriptomic vulnerability across brain disorders. Nature 657, 988–1002 (2026). https://doi.org/10.1038/s41586-025-09573-z

• Article
• Open access
• Published: 23 September 2026

Venkatesh, S., Kosoy, R., Wu, Z. et al. Single-nucleus transcriptome-wide association study of human brain disorders. Nature 657, 1016–1026 (2026). https://doi.org/10.1038/s41586-026-10836-6

• Article
• Open access
• Published: 23 September 2026

He, C., Li, A.Z., Hanthanan Arachchilage, K. et al. AI-based characterization of Alzheimer’s disease phenotypes from population-scale single-cell data. Nat Med (2026). https://doi.org/10.1038/s41591-025-04128-1

• Article
• Open access
• Published: 23 September 2026

Zeng, B., Yang, H., N. M, P. et al. Single-nucleus atlas of cell-type specific genetic regulation in the human brain. Nat Genet (2026). https://doi.org/10.1038/s41588-026-02733-5

News: Landmark map of human brain’s gene activity holds clues to Alzheimer’s disease and more
https://www.nature.com/articles/d41586-026-02947-x

News & Views: Vast cellular gene-expression atlas could transform how scientists understand brain ageing and disease
https://www.nature.com/articles/d41586-026-02770-4

Collection: PsychAD Consortium
https://www.nature.com/collections/jfibicjjjg

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