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Disentangling the effect of sex from brain size on brain organization and cognitive functioning

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Abstract

Neuroanatomical sex differences estimated in neuroimaging studies are confounded by total intracranial volume (TIV) as a major biological factor. Employing a matching approach widely used for causal modeling, we disentangled the effect of TIV from sex to study sex-differentiated brain aging trajectories, their relation to functional networks and cytoarchitectonic classes, brain allometry, and cognition. Using data from the UK Biobank, we created subsamples that removed, maintained, or exaggerated the TIV differences in the original sample. We compared regional and vertex-level sex estimates across subsamples. The overall sex-related differences diminished in head size–matched subsamples, suggesting that most of the observed variability results from TIV differences. Furthermore, bidirectional sex differences in brain neuroanatomy emerged that were previously masked by the effect of TIV. Allometry remained fairly consistent across lifespan and was not sex-differentiated. Finally, the matching process changed the direction of the estimated sex differences in “verbal and numerical reasoning” and “working memory”, suggesting that behavioral sex difference investigations can benefit from additional biological analysis to uncover the underlying factors contributing to cognition. Taken together, we provide new evidence disentangling sex differences from TIV as a relevant biological confound.

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Data Availability

The data used in this work was obtained from the UKBB under approved application 45551. UKBB data can be accessed through their access management system (https://www.ukbiobank.ac.uk/enable-your-research/apply-foraccess).

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Acknowledgements

This research was conducted using the UKBB Resource under approved application 45551. We thank the UKBB participants and team for their work in collecting, processing, and disseminating these data for analysis. The authors also acknowledge use of Compute Canada (https://alliancecan.ca/en) resources for performing the image processing analyses in the presented work.

Funding

This research was undertaken thanks in part to funding from the Canada First Research Excellence Fund and Fonds de recherche du Québec, awarded to the Healthy Brains, Healthy Lives (HBHL) initiative at McGill University. MD also reports receiving research funding from the Canadian Institutes of Health Research (CIHR), and Fonds de Recherche du Québec-Santé (FRQS). YZ reports receiving research funding from the FRQS Chercheurs boursiers en Intelligence artificielle, as well as Natural Sciences and Engineering Research (NSERC) discovery grant.

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Author notes

  1. Mahsa Dadar and Yashar Zeighami contributed equally to this work.

Authors and Affiliations

  1. Cerebral Imaging Center, Douglas Mental Health University Institute, 6875 Boulevard LaSalle, Montréal, QC, H4H 1R3, Canada

    Aliza Brzezinski-Rittner, Roqaie Moqadam, M. Mallar Chakravarty, Mahsa Dadar & Yashar Zeighami

  2. Department of Psychiatry, McGill University, 1033 Pine Avenue West, Montreal, QC, H3A 1A1, Canada

    Aliza Brzezinski-Rittner, M. Mallar Chakravarty, Mahsa Dadar & Yashar Zeighami

  3. Integrated Program in Neuroscience, McGill University, 1033 Pine Avenue West, Montreal, QC, H3A 1A1, Canada

    Aliza Brzezinski-Rittner, Yasser Iturria-Medina, M. Mallar Chakravarty, Mahsa Dadar & Yashar Zeighami

  4. Faculty of Medicine, University of Montreal, 2900 Edouard Montpetit Blvd, Montreal, QC, H3T 1J4, Canada

    Roqaie Moqadam

  5. Centre de Recherche, Institut Universitaire de Gériatrie de Montréal, 4565 Queen Mary Rd, Montreal, QC, H3W 1W5, Canada

    Roqaie Moqadam

  6. Neurology and Neurosurgery Department, Montreal Neurological Institute. 3801 Rue University, Montreal, QC, H3A 2B4, Canada

    Yasser Iturria-Medina

  7. McConnell Brain Imaging Centre, Montreal Neurological Institute. 3801 Rue University, Montreal, QC, H3A 2B4, Canada

    Yasser Iturria-Medina

  8. Ludmer Centre for Neuroinformatics & Mental Health, 3755 Côte-Ste-Catherine, Montreal, QC, H3T 1E2, Canada

    Yasser Iturria-Medina

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  1. Aliza Brzezinski-Rittner
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Contributions

A.B.R.: conceptualization, formal analysis, interpretation of findings, methodology, visualization, writing—original draft, writing—review and editing. R.M.: formal analysis, review and editing Y.I.M.: conceptualization, review and editing. M.C.: conceptualization, review and editing. M.D.: conceptualization, formal analysis, interpretation of findings, methodology, visualization, writing—original draft, writing—review and editing. Y.Z.: conceptualization, formal analysis, interpretation of findings, methodology, visualization, writing—original draft, writing—review and editing.

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Correspondence to Aliza Brzezinski-Rittner, Mahsa Dadar or Yashar Zeighami.

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Brzezinski-Rittner, A., Moqadam, R., Iturria-Medina, Y. et al. Disentangling the effect of sex from brain size on brain organization and cognitive functioning. GeroScience 47, 247–262 (2025). https://doi.org/10.1007/s11357-024-01486-5

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