The role of age in the relationship between brain structure and cognition: moderator or confound?

Overview

1. Oxford Centre for Functional MRI of the Brain (FMRIB), Oxford Centre for Integrative Neuroimaging, Nuffield Department of Clinical Neurosciences, University of Oxford, John Radcliffe Hospital, Headley Way, Headington, Oxford, Oxfordshire OX3 9DU, United Kingdom
2. Center of Functionally Integrative Neuroscience, Department of Clinical Medicine, Aarhus University, Building 1710, Universitetsbyen 3, 8000 Aarhus, Denmark
3. Oxford Centre for Human Brain Activity (OHBA), Oxford Centre for Integrative Neuroimaging, Department of Psychiatry, University of Oxford, Warneford Hospital, Warneford Lane, Headington, Oxford, Oxfordshire OX3 7JX, United Kingdom
4. Centre de Recerca Matemàtica, Campus UAB, Carrer de l'Albareda, Edifici C, 08193 Bellaterra, Barcelona, Spain

Abstract

Understanding how differences in brain structure relate to differences in cognition across the lifespan is essential for addressing age-related cognitive decline. Since age is strongly associated with both brain structure and cognition, predictive models often risk simply capturing age effects. To mitigate this risk, deconfounding is typically applied to remove the effects of age. Here, beyond treating age as a confound, we treat it as a moderator by estimating brain-cognition associations separately across age groups. This captures age-stratified changes in how brain structure and cognitive performance are statistically connected. For this view to hold, variations in brain structure linked to differences in cognitive performance in older subjects (eg related to disease) would differ from those in younger subjects. Using structural brain imaging data from the UK Biobank we found an asymmetry in generalisability: models trained on younger subjects successfully predicted cognition in older subjects, but models trained on older subjects failed to generalize to younger individuals. These findings reveal a trade-off between model specificity and generalisability, suggesting the optimal approach—whether age-specific or pooled—depends on the research or clinical goal for the target population.

Reproduced under the paper's license (CC BY), from the paper cited above.

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Data

Datasets cited

• ukbiobank.ac.uk/enable-your-research, at UK Biobank; found in “Data availability”

Data availability

Data were obtained from the UK Biobank under application 8107. Access to UK Biobank data is available to bona fide researchers via application to UK Biobank (https://www.ukbiobank.ac.uk/enable-your-research). Derived data supporting the findings of this study are available from the corresponding author upon reasonable request, subject to UK Biobank’s data access policies.

Reproduced under the paper's license (CC BY), from the paper cited above.

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Version 1, 30 September 2026: the first record

Recorded: type, language, journal, volume, issue, pages, dates, 5 authors, 5 keywords, 13 MeSH terms, 8 funders, 48 references.

Cite

This paper

Griffin, B., Gohil, C., Woolrich, M. W., Smith, S. M., & Vidaurre, D. (2026). The role of age in the relationship between brain structure and cognition: moderator or confound? Cerebral cortex (New York, N.Y. : 1991), 36(3), bhag024. https://doi.org/10.1093/cercor/bhag024

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