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

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 Maniega, Maria Valdés Hernández, Ellen Backhouse, Karen Ferguson, Mark E. Bastin, Joanna Wardlaw, Javier de la Fuente, Andrew D. Grotzinger, Michelle Luciano, W. David Hill, Ian J. Deary, Elliot M. Tucker-Drob and Simon R. Cox
Additional contact information
Anna E. Fürtjes: The University of Edinburgh
Isabelle F. Foote: University of Colorado Boulder
Charley Xia: The University of Edinburgh
Gail Davies: The University of Edinburgh
Joanna Moodie: The University of Edinburgh
Adele Taylor: The University of Edinburgh
David C. Liewald: The University of Edinburgh
Paul Redmond: The University of Edinburgh
Janie Corley: 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
Karen Ferguson: 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
W. David Hill: The University of Edinburgh
Ian J. Deary: The University of Edinburgh
Elliot M. Tucker-Drob: The University of Texas at Austin
Simon R. Cox: The University of Edinburgh

Nature Communications, 2025, vol. 16, issue 1, 1-15

Abstract: 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.

Date: 2025
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DOI: 10.1038/s41467-025-61978-6

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