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; Simon R. Cox

doi:10.1038/s41467-025-61978-6

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 LucianoW. David Hill, Ian J. Deary, Elliot M. Tucker-Drob, Simon R. Cox

^*Corresponding author for this work

Research output: Contribution to journal › Article › peer-review

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.

Original language	English
Article number	6725
Number of pages	15
Journal	Nature Communications
Volume	16
Issue number	1
Early online date	21 Jul 2025
DOIs	https://doi.org/10.1038/s41467-025-61978-6
Publication status	Published - 2025

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Fürtjes, A. E., Foote, I. F., Xia, C., Davies, G., Moodie, J., Taylor, A., Liewald, D. C., Redmond, P., Corley, J., McIntosh, A. M., Whalley, H. C., Muñoz Maniega, S., Valdés Hernández, M., Backhouse, E., Ferguson, K., Bastin, M. E., Wardlaw, J., de la Fuente, J., Grotzinger, A. D., ... Cox, S. R. (2025). Measurement characteristics and genome-wide correlates of lifetime brain atrophy estimated from a single MRI. Nature Communications, 16(1), Article 6725. https://doi.org/10.1038/s41467-025-61978-6

@article{1617f5d56dd147d28939058c0b8692d2,

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

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{\textquoteright}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.",

author = "F{\"u}rtjes, \{Anna E.\} and Foote, \{Isabelle F.\} and Charley Xia and Gail Davies and Joanna Moodie and Adele Taylor and Liewald, \{David C.\} and Paul Redmond and Janie Corley and McIntosh, \{Andrew M.\} and Whalley, \{Heather C.\} and \{Mu{\~n}oz Maniega\}, Susana and \{Vald{\'e}s Hern{\'a}ndez\}, Maria and Ellen Backhouse and Karen Ferguson and Bastin, \{Mark E.\} and Joanna Wardlaw and \{de la Fuente\}, Javier and Grotzinger, \{Andrew D.\} and Michelle Luciano and Hill, \{W. David\} and Deary, \{Ian J.\} and Tucker-Drob, \{Elliot M.\} and Cox, \{Simon R.\}",

note = "Conception and design of the study: A.E.F., S.R.C., I.J.D. Data acquisition and curation (e.g., MRI processing or visual atrophy ratings): A.T., D.L., P.R., J.C., A.M.M., H.C.W., S.M.M., M.V.H., E.B., K.F., M.E.B., J.W., IJD, S.R.C. Data analysis and visualisation: A.E.F. Data interpretation: A.E.F., C.X., W.D.H., I.J.D., S.R.C. Coding: A.E.F. Provided GWAS summary stats for neurodegenerative diseases: I.F.F. Provided structural equation model code: J.M. Writing first draft: A.E.F. Writing and editing: A.E.F., I.F.F., GD, A.M.M. H.C.W., J.W., J.F., A.G., M.L., J.M., I.J.D., E.M.T., S.R.C.",

year = "2025",

doi = "10.1038/s41467-025-61978-6",

language = "English",

volume = "16",

journal = "Nature Communications",

issn = "2041-1723",

publisher = "Nature Publishing Group",

number = "1",

}

Fürtjes, AE, Foote, IF, Xia, C, Davies, G , Moodie, J, Taylor, A, Liewald, DC, Redmond, P, Corley, J , McIntosh, AM , Whalley, HC , Muñoz Maniega, S , Valdés Hernández, M , Backhouse, E , Ferguson, K , Bastin, ME , Wardlaw, J, de la Fuente, J, Grotzinger, AD, Luciano, M, Hill, WD, Deary, IJ, Tucker-Drob, EM & Cox, SR 2025, 'Measurement characteristics and genome-wide correlates of lifetime brain atrophy estimated from a single MRI', Nature Communications, vol. 16, no. 1, 6725. https://doi.org/10.1038/s41467-025-61978-6

TY - JOUR

T1 - Measurement characteristics and genome-wide correlates of lifetime brain atrophy estimated from a single MRI

AU - Fürtjes, Anna E.

AU - Foote, Isabelle F.

AU - Xia, Charley

AU - Davies, Gail

AU - Moodie, Joanna

AU - Taylor, Adele

AU - Liewald, David C.

AU - Redmond, Paul

AU - Corley, Janie

AU - McIntosh, Andrew M.

AU - Whalley, Heather C.

AU - Muñoz Maniega, Susana

AU - Valdés Hernández, Maria

AU - Backhouse, Ellen

AU - Ferguson, Karen

AU - Bastin, Mark E.

AU - Wardlaw, Joanna

AU - de la Fuente, Javier

AU - Grotzinger, Andrew D.

AU - Luciano, Michelle

AU - Hill, W. David

AU - Deary, Ian J.

AU - Tucker-Drob, Elliot M.

AU - Cox, Simon R.

N1 - Conception and design of the study: A.E.F., S.R.C., I.J.D. Data acquisition and curation (e.g., MRI processing or visual atrophy ratings): A.T., D.L., P.R., J.C., A.M.M., H.C.W., S.M.M., M.V.H., E.B., K.F., M.E.B., J.W., IJD, S.R.C. Data analysis and visualisation: A.E.F. Data interpretation: A.E.F., C.X., W.D.H., I.J.D., S.R.C. Coding: A.E.F. Provided GWAS summary stats for neurodegenerative diseases: I.F.F. Provided structural equation model code: J.M. Writing first draft: A.E.F. Writing and editing: A.E.F., I.F.F., GD, A.M.M. H.C.W., J.W., J.F., A.G., M.L., J.M., I.J.D., E.M.T., S.R.C.

PY - 2025

Y1 - 2025

N2 - 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.

AB - 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.

UR - https://doi.org/10.5281/zenodo.15282759

UR - https://annafurtjes.github.io/BrainAtrophy_Genetics/

UR - https://osf.io/gydmw/

U2 - 10.1038/s41467-025-61978-6

DO - 10.1038/s41467-025-61978-6

M3 - Article

SN - 2041-1723

VL - 16

JO - Nature Communications

JF - Nature Communications

IS - 1

M1 - 6725

ER -

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

Abstract

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Factors of biological ageing: does it all go together when it goes?

From genetic sequence to phenotypic consequence: Genetic and environmental links between cognitive ability, socioeconomic position, and health

The Lothian Birth Cohort 1936 Waves 6 and 7

Lifetime brain atrophy estimated from a single MRI: measurement characteristics and genome-wide correlates

Edinburgh Imaging Facility

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

Abstract

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Projects

Factors of biological ageing: does it all go together when it goes?

From genetic sequence to phenotypic consequence: Genetic and environmental links between cognitive ability, socioeconomic position, and health

The Lothian Birth Cohort 1936 Waves 6 and 7

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Lifetime brain atrophy estimated from a single MRI: measurement characteristics and genome-wide correlates

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Edinburgh Imaging Facility

Cite this