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Peer-reviewedCC BY-NC-NDNature

Lifespan single-cell transcriptomic atlas of the human prefrontal cortex

  • Hui Yang1,2,3,4
  • Tereza Clarence1,2,3,4
  • Madeline R. Scott5
  • Xinyi Wang1,2,3,4
  • N. M. Prashant1,2,3,4
  • Milos Pjanic1,2,3,4
  • Sanan Venkatesh1,2,3,4
  • Aram Hong1,2,3,4
  • Clara Casey1,2,3,4
  • Sarah E. Murphy1,2,3,4
  • Zhiping Shao1,2,3,4
  • Marcela Alvia1,2,3,4
56 more authors
  • Stathis Argyriou1,2,3,4
  • Alexander Kawah Yu1,2,3,4
  • Athan Z. Li6,7
  • Biao Zeng1,2,3,4
  • Chenfeng He8,7
  • Chirag Gupta8,7
  • Christian Dillard1,2,3,4
  • Christian Porras1,2,3,4
  • Collin Spencer1,2,3,4
  • Daifeng Wang8,6,7
  • David Alan Bennett9,10
  • David Burstein
  • Deepika Dayal Mathur
  • Fotis Tsetsos1,2,3,4,10
  • Gennadi Ryan11,12
  • Jennifer Monteiro Fortes1,2,3,4
  • Jerome J. Choi13,7
  • Kalpana Hanthanan Arachchilage8,7
  • Karen Therrien1,2,3,4
  • Lars J. Jensen14
  • Lisa Laverne Barnes9,10
  • Logan C. Dumitrescu15,16
  • Lyra Sheu1,2,3,4
  • Marios Anyfantakis1,2,3,4
  • Maxim Signaevsky3,4
  • Mikaela Koutrouli1,2,3,4,14
  • Monika Ahirwar11,17
  • Nicolas Y. Masse1,2,3,4
  • Noah Cohen Kalafut6,7
  • Pavel Katsel3
  • Pengfei Dong1,2,3,4
  • Pramod B. Chandrashekar8,7
  • Rachel Bercovitch1,2,3,4
  • Roman Kosoy1,2,3,4
  • Saniya Khullar8,7
  • Sayali Anil Alatkar6,7
  • Seon Kinrot1,2,3,4
  • Steven M. Finkbeiner18,12,13,19,17
  • Steven P. Kleopoulos1,2,3,4
  • Timothy J. Hohman15,16
  • Ting Jin8,7
  • Vivek G. Ramaswamy11,17
  • Xiang Huang7
  • Zhenyi Wu1,2,3,4
  • Nadejda M. Tsankova20,21,4
  • Pavan Kumar Auluck22
  • Stefano Marenco22
  • Vahram H. Haroutunian20,3,4,23

60 listed; 68 in total.

23 affiliations
  1. 1Center for Disease Neurogenomics, Icahn School of Medicine at Mount Sinai, New York, NY, USA
  2. 2Department of Genetics and Genomic Science, Icahn School of Medicine at Mount Sinai, New York, NY, USA
  3. 3Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY, USA
  4. 4Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA
  5. 5Department of Psychiatry, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA
  6. 6Department of Computer Sciences, University of Wisconsin-Madison, Madison, WI, USA
  7. 7Waisman Center, University of Wisconsin-Madison, Madison, WI, USA
  8. 8Department of Biostatistics and Medical Informatics, University of Wisconsin-Madison, Madison, WI, USA
  9. 9Department of Neurological Sciences, Rush University Medical Center, Chicago, IL, USA
  10. 10Rush Alzheimer’s Disease Center, Rush University Medical Center, Chicago, IL, USA
  11. 11Center for Systems and Therapeutics, Gladstone Institutes, San Francisco, CA, USA
  12. 12Department of Physiology, University of California San Francisco, San Francisco, CA, USA
  13. 13Department of Population Health Sciences, University of Wisconsin-Madison, Madison, WI, USA
  14. 14Novo Nordisk Foundation Center for Protein Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
  15. 15Vanderbilt Genetics Institute, Vanderbilt University Medical Center, Nashville, TN, USA
  16. 16Vanderbilt Memory & Alzheimer’s Center, Vanderbilt University Medical Center, Nashville, TN, USA
  17. 17Taube/Koret Center for Neurodegenerative Disease Research, Gladstone Institutes, San Francisco, CA, USA
  18. 18Department of Neurology, University of California San Francisco, San Francisco, CA, USA
  19. 19Neuroscience and Biomedical Sciences Graduate Programs, University of California San Francisco, San Francisco, CA, USA
  20. 20Department of Neuroscience, Icahn School of Medicine at Mount Sinai, New York, NY, USA
  21. 21Department of Pathology, Molecular, and Cell-Based Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA
  22. 22Human Brain Collection Core, National Institute of Mental Health-Intramural Research Program, Bethesda, MD, USA
  23. 23Mental Illness Research, Education and Clinical Center VISN2, James J. Peters VA Medical Center, New York, NY, USA
Open at sourceDOICite

Abstract

The dorsolateral prefrontal cortex (DLPFC) underpins higher cognitive functions and is highly susceptible to age-related decline. However, a comprehensive, lifespan-resolved map of its cellular and molecular programs has been lacking. Here, we constructed the first single-nucleus transcriptomic atlas of the human DLPFC, spanning the full lifespan, profiling over 1.3 million nuclei from 284 postmortem samples ranging in age from 0-97 years. This unprecedented resource reveals three distinct transcriptomic phases: dynamic developmental remodeling, midlife stability, and late-life molecular reactivation. Non-linear modeling of age trends uncovers ten distinct trajectories, including a neuronal resilience program peaking in early adolescence and glial aging programs marked by immune activation in late adulthood. Pseudotime analyses reconstruct lineage maturation from fetal progenitors to aged states, identifying gene modules linked to neurodevelopmental and neurodegenerative disease risk. Spatial transcriptomics confirm these dynamic programs, mapping excitatory neuron modules to specific cortical layers and glial signatures to distinct gray–white matter domains. Notably, we identify circadian reprogramming in late adulthood, with loss of neuronal core clock rhythmicity and emergence of stress-adaptive glial rhythms. Together, this study provides the first anatomically resolved, cell-type–specific, and lifespan-wide reference for the human DLPFC, establishing a foundational resource for understanding brain development, aging, and disease vulnerability.

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Cite

BibTeXRIS
BibTeX
@article{yang2026lifespan,
  title = {{Lifespan single-cell transcriptomic atlas of the human prefrontal cortex}},
  author = {Hui Yang and Tereza Clarence and Madeline R. Scott and Xinyi Wang and N. M. Prashant and Milos Pjanic and Sanan Venkatesh and Aram Hong and Clara Casey and Sarah E. Murphy and Zhiping Shao and Marcela Alvia and Stathis Argyriou and Alexander Kawah Yu and Athan Z. Li and Biao Zeng and Chenfeng He and Chirag Gupta and Christian Dillard and Christian Porras and Collin Spencer and Daifeng Wang and David Alan Bennett and David Burstein and Deepika Dayal Mathur and Fotis Tsetsos and Gennadi Ryan and Jennifer Monteiro Fortes and Jerome J. Choi and Kalpana Hanthanan Arachchilage and Karen Therrien and Lars J. Jensen and Lisa Laverne Barnes and Logan C. Dumitrescu and Lyra Sheu and Marios Anyfantakis and Maxim Signaevsky and Mikaela Koutrouli and Monika Ahirwar and Nicolas Y. Masse and Noah Cohen Kalafut and Pavel Katsel and Pengfei Dong and Pramod B. Chandrashekar and Rachel Bercovitch and Roman Kosoy and Saniya Khullar and Sayali Anil Alatkar and Seon Kinrot and Steven M. Finkbeiner and Steven P. Kleopoulos and Timothy J. Hohman and Ting Jin and Vivek G. Ramaswamy and Xiang Huang and Zhenyi Wu and Nadejda M. Tsankova and Pavan Kumar Auluck and Stefano Marenco and Vahram H. Haroutunian},
  journal = {Nature},
  year = {2026},
  month = sep,
  doi = {10.1038/s41586-026-10271-7},
  url = {https://doi.org/10.1038/s41586-026-10271-7},
  note = {CC BY-NC-ND},
}
RIS
TY  - JOUR
TI  - Lifespan single-cell transcriptomic atlas of the human prefrontal cortex
AU  - Hui Yang
AU  - Tereza Clarence
AU  - Madeline R. Scott
AU  - Xinyi Wang
AU  - N. M. Prashant
AU  - Milos Pjanic
AU  - Sanan Venkatesh
AU  - Aram Hong
AU  - Clara Casey
AU  - Sarah E. Murphy
AU  - Zhiping Shao
AU  - Marcela Alvia
AU  - Stathis Argyriou
AU  - Alexander Kawah Yu
AU  - Athan Z. Li
AU  - Biao Zeng
AU  - Chenfeng He
AU  - Chirag Gupta
AU  - Christian Dillard
AU  - Christian Porras
AU  - Collin Spencer
AU  - Daifeng Wang
AU  - David Alan Bennett
AU  - David Burstein
AU  - Deepika Dayal Mathur
AU  - Fotis Tsetsos
AU  - Gennadi Ryan
AU  - Jennifer Monteiro Fortes
AU  - Jerome J. Choi
AU  - Kalpana Hanthanan Arachchilage
AU  - Karen Therrien
AU  - Lars J. Jensen
AU  - Lisa Laverne Barnes
AU  - Logan C. Dumitrescu
AU  - Lyra Sheu
AU  - Marios Anyfantakis
AU  - Maxim Signaevsky
AU  - Mikaela Koutrouli
AU  - Monika Ahirwar
AU  - Nicolas Y. Masse
AU  - Noah Cohen Kalafut
AU  - Pavel Katsel
AU  - Pengfei Dong
AU  - Pramod B. Chandrashekar
AU  - Rachel Bercovitch
AU  - Roman Kosoy
AU  - Saniya Khullar
AU  - Sayali Anil Alatkar
AU  - Seon Kinrot
AU  - Steven M. Finkbeiner
AU  - Steven P. Kleopoulos
AU  - Timothy J. Hohman
AU  - Ting Jin
AU  - Vivek G. Ramaswamy
AU  - Xiang Huang
AU  - Zhenyi Wu
AU  - Nadejda M. Tsankova
AU  - Pavan Kumar Auluck
AU  - Stefano Marenco
AU  - Vahram H. Haroutunian
PY  - 2026
DA  - 2026/09/23
JO  - Nature
DO  - 10.1038/s41586-026-10271-7
UR  - https://doi.org/10.1038/s41586-026-10271-7
AB  - The dorsolateral prefrontal cortex (DLPFC) underpins higher cognitive functions and is highly susceptible to age-related decline. However, a comprehensive, lifespan-resolved map of its cellular and molecular programs has been lacking. Here, we constructed the first single-nucleus transcriptomic atlas of the human DLPFC, spanning the full lifespan, profiling over 1.3 million nuclei from 284 postmortem samples ranging in age from 0-97 years. This unprecedented resource reveals three distinct transcriptomic phases: dynamic developmental remodeling, midlife stability, and late-life molecular reactivation. Non-linear modeling of age trends uncovers ten distinct trajectories, including a neuronal resilience program peaking in early adolescence and glial aging programs marked by immune activation in late adulthood. Pseudotime analyses reconstruct lineage maturation from fetal progenitors to aged states, identifying gene modules linked to neurodevelopmental and neurodegenerative disease risk. Spatial transcriptomics confirm these dynamic programs, mapping excitatory neuron modules to specific cortical layers and glial signatures to distinct gray–white matter domains. Notably, we identify circadian reprogramming in late adulthood, with loss of neuronal core clock rhythmicity and emergence of stress-adaptive glial rhythms. Together, this study provides the first anatomically resolved, cell-type–specific, and lifespan-wide reference for the human DLPFC, establishing a foundational resource for understanding brain development, aging, and disease vulnerability.
SN  - 0028-0836
SN  - 1476-4687
ER  -