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Somatic mutations reveal the ontogeny of microglia in human aging

Nature
July 31, 2026
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Abstract

Microglia are the resident macrophages of the central nervous system1. In mice, microglia seed the brain during embryogenesis and can be maintained throughout life with minimal input from adult hematopoiesis2-4. The origins of human microglia are less clear, but recent evidence suggests that marrow-derived cells contribute to the human microglial pool in certain individuals5-9. Here, to investigate the ontogeny of human microglia, we develop an approach that uses the collection of accumulated somatic mutations which uniquely labels each clone of cells to track the infiltration of marrow-derived cells into the human brain. Applying this approach to 20 aged individuals, we find evidence of an influx of marrow-derived cells into the brain in all examined individuals. Single cell analysis, including single cell lineage tracing using mitochondrial DNA variants, demonstrates that these infiltrating cells are similar to microglia and can comprise a large fraction of the microglial pool. Analysis of human cohort data demonstrates a protective association between most types of clonal hematopoiesis and Alzheimer’s disease. In sum, this work uncovers a widespread influx of myeloid cells into the healthy human brain which contributes to the pool of human microglia and becomes common with aging.

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Subjects

Author information

Author notes

  1. Quanming Shi & Howard Y. Chang

    Present address: Amgen Research, South San Francisco, CA, USA

  2. Wenxi Zhang

    Present address: Department of Medicine, University of California San Francisco, San Francisco, CA, USA

  3. Krishna L. Bharani

    Present address: Department of Pathology, The Ohio State University Wexner Medical Center, Columbus, OH, USA

  4. C. Dirk Keene

    Present address: Department of Pathology, University of California San Diego, La Jolla, CA, USA

Authors and Affiliations

  1. Department of Pathology, Stanford University, Stanford, CA, USA

    Julia A. Belk, Yaowen Zhang, Emily E. Reilly, Daniel Dan Liu, Maarten van der Linde, Lisa Ma, Debasmita Paul, Alejandro Medina Enciso, Raja Kalluru, Jacob Weiss, Chunfang Zhu, Syed Bukhari, Dipabarna Bhattacharya, Matthew R. Chrostek, Daniel C. Nachun, Christopher M. Arends, Jayakrishnan Gopakumar, Isak W. Tengesdal, Ademar Bynum, Shaneice Mitchell, Katalin Sandor, Wenxi Zhang, Inma Cobos, Donald E. Born, Robert B. West, Krishna L. Bharani, Hannes Vogel, Thomas J. Montine, Irving L. Weissman, Magdalena Matusiak, Jody E. Hooper & Siddhartha Jaiswal

  2. Department of Dermatology, Stanford University, Stanford, CA, USA

    Quanming Shi, Rui Li, Arnav Chakravarthy & Howard Y. Chang

  3. Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Stanford, CA, USA

    Daniel Dan Liu, Nicole Womack-Gambrel, Anna E. Eastman, Suyash Raj & Irving L. Weissman

  4. Department of Pathology, Leiden University Medical Centre, Leiden, The Netherlands

    Maarten van der Linde

  5. Sarafan ChEM-H, Stanford University, Stanford, CA, USA

    Alejandro Medina Enciso

  6. Department of Genetics, Stanford University, Stanford, CA, USA

    Daniel Richard, Anne Brunet & Howard Y. Chang

  7. Department of Pathology and Immunology, Washington University School of Medicine in Saint Louis, Saint Louis, MO, USA

    Simone Brioschi & Marco Colonna

  8. Center for Neuroimmunology and Glial Biology, Institute of Molecular Medicine, University of Texas Health Science Center, Houston, TX, USA

    Simone Brioschi

  9. Taub Institute for Research on Alzheimer’s Disease and the Aging Brain, College of Physicians and Surgeons, Columbia University, New York, NY, USA

    Badri N. Vardarajan

  10. Department of Neurology, College of Physicians and Surgeons, Columbia University and the New York Presbyterian Hospital, New York, NY, USA

    Badri N. Vardarajan

  11. Department of Laboratory Medicine and Pathology, University of Washington School, of Medicine, Seattle, WA, USA

    Caitlin S. Latimer & C. Dirk Keene

Authors

  1. Julia A. Belk
  2. Yaowen Zhang
  3. Emily E. Reilly
  4. Quanming Shi
  5. Daniel Dan Liu
  6. Nicole Womack-Gambrel
  7. Maarten van der Linde
  8. Lisa Ma
  9. Debasmita Paul
  10. Alejandro Medina Enciso
  11. Raja Kalluru
  12. Jacob Weiss
  13. Rui Li
  14. Anna E. Eastman
  15. Chunfang Zhu
  16. Arnav Chakravarthy
  17. Syed Bukhari
  18. Dipabarna Bhattacharya
  19. Suyash Raj
  20. Daniel Richard
  21. Simone Brioschi
  22. Matthew R. Chrostek
  23. Daniel C. Nachun
  24. Christopher M. Arends
  25. Jayakrishnan Gopakumar
  26. Isak W. Tengesdal
  27. Ademar Bynum
  28. Shaneice Mitchell
  29. Katalin Sandor
  30. Wenxi Zhang
  31. Badri N. Vardarajan
  32. Inma Cobos
  33. Donald E. Born
  34. Robert B. West
  35. Anne Brunet
  36. Marco Colonna
  37. Krishna L. Bharani
  38. Hannes Vogel
  39. Thomas J. Montine
  40. Caitlin S. Latimer
  41. Irving L. Weissman
  42. Magdalena Matusiak
  43. Jody E. Hooper
  44. C. Dirk Keene
  45. Howard Y. Chang
  46. Siddhartha Jaiswal

Corresponding authors

Correspondence to Julia A. Belk, Howard Y. Chang or Siddhartha Jaiswal.

Supplementary information

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Cite this article

Belk, J.A., Zhang, Y., Reilly, E.E. et al. Somatic mutations reveal the ontogeny of microglia in human aging. Nature (2026). https://doi.org/10.1038/s41586-026-10939-0

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  • DOI: https://doi.org/10.1038/s41586-026-10939-0

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