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

Daniel Felsky1,2, Tina Roostaei1, Kwangsik Nho3

  • 1Center for Translational and Computational Neuroimmunology, Department of Neurology, Columbia University Medical Center, 630 West 168th Street, New York, NY, 10032, USA.

Nature Communications
|January 26, 2019
PubMed

Insights

Activated microglia in aging brains are linked to Alzheimer's disease pathology and cognitive decline. A specific genetic variant influences this activation, suggesting new therapeutic targets for neuroinflammation.

Area of Science:

  • Neuroscience
  • Immunology
  • Genetics

Background:

  • Microglia are crucial brain immune cells, but their activation in aging humans is poorly understood.
  • Understanding microglial activation is key to addressing age-related cognitive decline and neurodegenerative diseases.

Purpose of the Study:

  • To investigate the role and regulation of microglial activation in the aging human brain.
  • To explore the association between microglial activation, Alzheimer's disease (AD) neuropathology, and cognitive decline.
  • To identify genetic factors influencing microglial activation.

Main Methods:

  • Analysis of postmortem human cortical tissue to quantify morphologically activated microglia (PAM).
  • Statistical association studies linking PAM with neuropathology (amyloid, tau) and cognitive decline rates.
  • Mediation modeling to determine the role of microglial activation in AD pathogenesis.
  • Genetic association analysis of a common variant (rs2997325) with PAM and in vivo microglial activation using PET imaging.

Main Results:

  • A significant association was found between PAM and β-amyloid and tau neuropathology.
  • PAM strongly correlated with the rate of cognitive decline, with effect sizes comparable to APOE ε4.
  • Microglial activation was identified as an upstream factor in tau accumulation in AD.
  • A common genetic variant, rs2997325, was linked to both PAM and in vivo microglial activation.

Conclusions:

  • Microglial activation is a significant factor in the aging brain, associated with AD pathology and cognitive decline.
  • Genetic factors, like rs2997325, influence microglial activation, offering potential therapeutic targets.
  • These findings illuminate pathways of neuroinflammation and its genetic overlap with AD and other traits.

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