Mechanisms of increased Alzheimer’s disease pathology with R47H and R62H TREM2 variants - Summary - MDSpire

Mechanisms of increased Alzheimer’s disease pathology with R47H and R62H TREM2 variants

  • By

  • Nurun N. Fancy

  • Nanet Willumsen

  • Vicky M. N. Chau

  • Samuel L. Boulger

  • Harry J. Whitwell

  • Wenhao Wang

  • Baptiste Avot

  • Michael Thomas

  • Jonathan Talbot-Martin

  • Stergios Tsartsalis

  • Combiz Khozoie

  • Aisling McGarry

  • Eleonore Schneegans

  • Riad Yagoubi

  • To Ka Dorcas Cheung

  • Marianna Papageorgopoulou

  • Emily Adair

  • Benjamin Cooper

  • Karen Davey

  • Amy M. Smith

  • William Scotton

  • John Hardy

  • Paul M. Matthews

  • Johanna S. Jackson

  • June 15, 2026

  • 0 min

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Objective:

To investigate the cellular pathology associated with TREM2 variants R47H and R62H in Alzheimer’s disease (AD) and their interaction with the protective CD33 variant, emphasizing its relevance to disease mechanisms.

Approach:
    Key Findings:
    • TREM2 variants R47H and R62H are associated with increased AD risk, with R47H conferring the greatest relative risk, suggesting a need for targeted therapeutic strategies.
    • TREM2 KO and R47H models show reduced β-amyloid clearance and increased neuritic plaque density, indicating potential pathways for intervention.
    • Distinct astrocytic and neuronal response signatures are associated with TREM2 variants in the context of β-amyloid load, highlighting the complexity of AD pathology.
    Interpretation:

    The study provides evidence of the mechanistic relationships between microglia, astrocytes, and neurons in the pathology of AD, highlighting the differential effects of TREM2 variants.

    Limitations:
    • The study is limited to post-mortem brain tissue, which may not fully represent the dynamic processes occurring in living patients; further longitudinal studies are needed.
    • Potential confounding factors from other genetic variants and environmental influences were not fully addressed, which could impact the interpretation of results.
    Conclusion:

    The findings suggest that TREM2 variants influence cellular interactions and pathology in AD, warranting further investigation into their roles in disease mechanisms and potential therapeutic targets.

Original Source(s)

Mechanisms of increased Alzheimer’s disease pathology with R47H and R62H TREM2 variants

  • by Nurun N. Fancy, Nanet Willumsen, Vicky M. N. Chau, Samuel L. Boulger, Harry J. Whitwell, Wenhao Wang, Baptiste Avot, Michael Thomas, Jonathan Talbot-Martin, Stergios Tsartsalis, Combiz Khozoie, Aisling McGarry, Eleonore Schneegans, Riad Yagoubi, To Ka Dorcas Cheung, Marianna Papageorgopoulou, Emily Adair, Benjamin Cooper, Karen Davey, Amy M. Smith, William Scotton, John Hardy, Paul M. Matthews, Johanna S. Jackson

  • June 15, 2026

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