A single-nucleus transcriptome atlas of cell diversity in human prefrontal cortex across the postnatal lifespan

Brain aging is a major risk factor for cerebrovascular and neurodegenerative diseases, yet continuous cell-type changes across the human lifespan remain incompletely defined. Here, we integrate 15 prefrontal cortex (PFC) snRNA-seq datasets from 158 neurologically healthy donors (19–101 years) to construct an atlas of 587,878 nuclei. Using decade-wise comparisons and donor-level sensitivity analyses, we identify cell-type-specific transcriptomic remodeling across adulthood, with prominent early-adult and midlife remodeling windows.

Across major cell classes, synapse-related programs tend to decline with age, while distinct subpopulations show changes at different life stages. Astrocytes in older decades display increased apoptosis- and inflammation-related programs, consistent with reactive-like states. Microglia show a later-life shift toward activated programs with elevated chemotaxis and inflammatory signaling.

Integrating plasma proteomics with the atlas highlights FUT9 as a candidate plasma biomarker associated with brain aging. Our study provides a reference for prioritizing specific cell types and age windows for future anti-CNS aging interventions. We are grateful to xiyoucloud for providing computational infrastructure.

We are also grateful to Li Chen for the comments and suggestions on the manuscript. This study was supported by National Natural Science Foundation of China (82501796, 82360275), Yunnan Provincial Department of Science and Technology—Kunming Medical University Special Projects (202601AY070001-107), Yunnan Provincial Department of Science and Technology Science and Technology Plan Project (202405AC350104; 202301AY070001-020), Kunming Health Science and Technology Talent Training Project (Thousand project, 2024-SW (Reserve)-72; 2024-SW (Reserve)-73), Health research Project of Kunming City (2025-03-09-018), Innovation Project of the Yunnan Caiyun Postdoctoral Program (2026CYBH03), and Scientific research project of the Provincial Clinical Medical Center of Yunnan Province (2024YNLCYXZX0278, 2024YNLCYXZX0280). These authors contributed equally: Rui-Ze Niu, Meng-Yuan Zhang, Zhi-Lan Yang.

Affiliated Mental Health Center of Kunming Medical University, Kunming, China Rui-Ze Niu, Meng-Yuan Zhang, Zhi-Lan Yang, Cai-Hua Yang, Ying-Ying Zhang & Tian-Hao Bao Laboratory Zoology Department, Kunming Medical University, Kunming, China The Second Affiliated Hospital of Kunming Medical University, Kunming, China Zhi-Lan Yang, Wei-Wei Wang & Tian-Hao Bao School of Forensic Medicine, Kunming Medical University, Kunming, China Correspondence to Jia Liu or Tian-Hao Bao. The authors declare no competing interests. Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

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