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Basic Science and Pathogenesis.

Diana J Zajac1, Gillian K Carling2, Li Fan3

  • 1Cleveland Clinic, Cleveland, OH, USA.

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|December 24, 2025
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Summary
This summary is machine-generated.

Alzheimer's Disease risk variants APOE4 and TREM2-R47H impact glial cells. This study reveals TREM2-R47H affects oligodendrocyte transcriptional profiles, an effect worsened by APOE4, suggesting novel therapeutic targets.

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Area of Science:

  • Neuroscience
  • Genetics
  • Cell Biology

Background:

  • Alzheimer's Disease (AD) is linked to APOE4 and TREM2-R47H risk variants impacting glial cells.
  • TREM2-mediated oligodendrocyte-microglial crosstalk is not well understood.
  • This research explores TREM2's role in oligodendrocyte transcriptional regulation.

Purpose of the Study:

  • Investigate cell-type specific transcriptional changes in mice with humanized APOE4 and TREM2-R47H genotypes.
  • Examine the association of cell subclusters with genotype, sex, and tau-positivity.
  • Compare findings in mice with a human cohort.

Main Methods:

  • Single-nuclei RNA-sequencing of frontal cortex in P301S+ mice with humanized APOE/TREM2 genotypes.
  • Analysis of cell subcluster abundance and classification via gene network modules and enrichment analysis.
  • Comparison of mouse data with a human cohort of AD and control individuals.

Main Results:

  • APOE-TREM2 status showed TREM2-R47H-specific effects and synergistic APOE4-R47H effects on oligodendrocytes, OPCs, and inhibitory neurons.
  • Identified OPC and oligodendrocyte subclusters strongly associated with TREM2-R47H, exacerbated by APOE genotype.
  • Human cohort data corroborated synergistic effects of APOE4 and TREM2-R47H on oligodendrocyte subclusters.

Conclusions:

  • Synergistic effects of APOE4 and TREM2-R47H carriers impact OPC, oligodendrocyte, and inhibitory neuron abundance and transcription.
  • OPCs and oligodendrocytes show strong TREM2-R47H association, amplified by APOE genotype, consistent in human data.
  • Further research into joint APOE-TREM2 genotypes can advance understanding of AD glial alterations and inform therapeutic strategies.