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Measurement characteristics and genome-wide correlates of lifetime brain atrophy estimated from a single MRI

Author

Listed:
  • Anna E. Fürtjes

    (The University of Edinburgh
    The University of Edinburgh)

  • Isabelle F. Foote

    (University of Colorado Boulder)

  • Charley Xia

    (The University of Edinburgh
    The University of Edinburgh)

  • Gail Davies

    (The University of Edinburgh
    The University of Edinburgh)

  • Joanna Moodie

    (The University of Edinburgh
    The University of Edinburgh)

  • Adele Taylor

    (The University of Edinburgh
    The University of Edinburgh)

  • David C. Liewald

    (The University of Edinburgh
    The University of Edinburgh)

  • Paul Redmond

    (The University of Edinburgh
    The University of Edinburgh)

  • Janie Corley

    (The University of Edinburgh
    The University of Edinburgh)

  • Andrew M. McIntosh

    (The University of Edinburgh)

  • Heather C. Whalley

    (The University of Edinburgh)

  • Susana Muñoz Maniega

    (The University of Edinburgh)

  • Maria Valdés Hernández

    (The University of Edinburgh)

  • Ellen Backhouse

    (The University of Edinburgh
    The University of Edinburgh)

  • Karen Ferguson

    (The University of Edinburgh
    The University of Edinburgh)

  • Mark E. Bastin

    (The University of Edinburgh)

  • Joanna Wardlaw

    (The University of Edinburgh)

  • Javier de la Fuente

    (The University of Texas at Austin)

  • Andrew D. Grotzinger

    (University of Colorado Boulder)

  • Michelle Luciano

    (The University of Edinburgh
    The University of Edinburgh)

  • W. David Hill

    (The University of Edinburgh
    The University of Edinburgh)

  • Ian J. Deary

    (The University of Edinburgh
    The University of Edinburgh)

  • Elliot M. Tucker-Drob

    (The University of Texas at Austin)

  • Simon R. Cox

    (The University of Edinburgh
    The University of Edinburgh)

Abstract

As a cardinal marker of brain ageing, lifetime brain atrophy obtained from a cross-sectional magnetic resonance image promises to boost statistical power to uncover novel genetic mechanisms of neurodegeneration. By analysing five young and old adult cohorts, we perform the most definitive study on lifetime brain atrophy’s measurement and correlates. It is simply calculated from the relationship between total brain volume and intracranial volume, using the difference, ratio, or regression-residual method. Lifetime brain atrophy is correlated with well-validated neuroradiological atrophy ratings (r = 0.37–0.44), cognitive decline (r = 0.36), frailty (r = 0.24), and longitudinally-measured atrophic changes (r = 0.36). Lifetime brain atrophy computed with the difference method yields phenotypic and genetic signal similar to baseline intracranial volume (rg = 0.75), in contrast to the residual method, which also best captures brain shrinkage. Lifetime brain atrophy is highly heritable (h2SNP = 41%[95%CI = 38–43%]), and the strongest genome-wide association (N = 43,110) implicates WNT16, a gene linked with neurodegenerative diseases.

Suggested Citation

  • Anna E. Fürtjes & Isabelle F. Foote & Charley Xia & Gail Davies & Joanna Moodie & Adele Taylor & David C. Liewald & Paul Redmond & Janie Corley & Andrew M. McIntosh & Heather C. Whalley & Susana Muñoz, 2025. "Measurement characteristics and genome-wide correlates of lifetime brain atrophy estimated from a single MRI," Nature Communications, Nature, vol. 16(1), pages 1-15, December.
    • Handle: RePEc:nat:natcom:v:16:y:2025:i:1:d:10.1038_s41467-025-61978-6
    DOI: 10.1038/s41467-025-61978-6
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