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Neuropathological correlates and genetic architecture of microglial activation in elderly human brain

Author

Listed:
  • Daniel Felsky

    (Columbia University Medical Center
    Broad Institute of MIT and Harvard)

  • Tina Roostaei

    (Columbia University Medical Center)

  • Kwangsik Nho

    (Indiana University School of Medicine)

  • Shannon L. Risacher

    (Indiana University School of Medicine)

  • Elizabeth M. Bradshaw

    (Columbia University Medical Center)

  • Vlad Petyuk

    (Pacific Northwest National Laboratory)

  • Julie A. Schneider

    (Rush University Medical Center
    Rush University Medical Center)

  • Andrew Saykin

    (Indiana University School of Medicine)

  • David A. Bennett

    (Rush University Medical Center
    Rush University Medical Center)

  • Philip L. De Jager

    (Columbia University Medical Center
    Broad Institute of MIT and Harvard)

Abstract

Microglia, the resident immune cells of the brain, have important roles in brain health. However, little is known about the regulation and consequences of microglial activation in the aging human brain. Here we report that the proportion of morphologically activated microglia (PAM) in postmortem cortical tissue is strongly associated with β-amyloid, tau-related neuropathology, and the rate of cognitive decline. Effect sizes for PAM measures are substantial, comparable to that of APOE ε4, the strongest genetic risk factor for Alzheimer’s disease, and mediation models support an upstream role for microglial activation in Alzheimer’s disease via accumulation of tau. Further, we identify a common variant (rs2997325) influencing PAM that also affects in vivo microglial activation measured by [11C]-PBR28 PET in an independent cohort. Thus, our analyses begin to uncover pathways regulating resident neuroinflammation and identify overlaps of PAM’s genetic architecture with those of Alzheimer’s disease and several other traits.

Suggested Citation

  • Daniel Felsky & Tina Roostaei & Kwangsik Nho & Shannon L. Risacher & Elizabeth M. Bradshaw & Vlad Petyuk & Julie A. Schneider & Andrew Saykin & David A. Bennett & Philip L. De Jager, 2019. "Neuropathological correlates and genetic architecture of microglial activation in elderly human brain," Nature Communications, Nature, vol. 10(1), pages 1-12, December.
    • Handle: RePEc:nat:natcom:v:10:y:2019:i:1:d:10.1038_s41467-018-08279-3
    DOI: 10.1038/s41467-018-08279-3
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    Cited by:

    1. Hyun-Sik Yang & Ling Teng & Daniel Kang & Vilas Menon & Tian Ge & Hilary K. Finucane & Aaron P. Schultz & Michael Properzi & Hans-Ulrich Klein & Lori B. Chibnik & Julie A. Schneider & David A. Bennett, 2023. "Cell-type-specific Alzheimer’s disease polygenic risk scores are associated with distinct disease processes in Alzheimer’s disease," Nature Communications, Nature, vol. 14(1), pages 1-13, December.
    2. Oscar L. Rodriguez & Yana Safonova & Catherine A. Silver & Kaitlyn Shields & William S. Gibson & Justin T. Kos & David Tieri & Hanzhong Ke & Katherine J. L. Jackson & Scott D. Boyd & Melissa L. Smith , 2023. "Genetic variation in the immunoglobulin heavy chain locus shapes the human antibody repertoire," Nature Communications, Nature, vol. 14(1), pages 1-18, December.

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