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Updated: Sep 18, 2025

Symmetric Bihemispheric Postmortem Brain Cutting to Study Healthy and Pathological Brain Conditions in Humans
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A large-scale ENIGMA multisite replication study of brain age in depression.

Laura K M Han1,2, Richard Dinga3, Ramona Leenings4,5

  • 1Centre for Youth Mental Health, The University of Melbourne, Parkville, VIC, Australia.

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Summary

Depressed individuals show a brain age gap, with their brains appearing approximately one year older than their chronological age. This finding was replicated across multiple independent cohorts, confirming subtle but reliable brain aging effects in depression.

Keywords:
Biological agingBrain ageDepressionENIGMA consortiumReplication study

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Area of Science:

  • Neuroimaging
  • Psychiatry
  • Aging

Background:

  • Previous studies suggest a
  • brain age gap
  • in individuals with depression, but findings vary due to methodological differences.
  • The ENIGMA brain age model aimed to validate previous findings on the brain age gap in depression.

Purpose of the Study:

  • To validate the ENIGMA brain age model by replicating the brain age gap in depression in independent cohorts.
  • To assess the effect size of the brain age gap in depression across diverse datasets.
  • To investigate potential moderating factors influencing the brain age gap in depression.

Main Methods:

  • Utilized a pre-trained ENIGMA brain age model based on 77 FreeSurfer brain regions.
  • Applied the model to predict brain age in 751 controls and 766 individuals with depression from 13 new cohorts.
  • Employed meta-regressions to analyze the impact of cohort characteristics on the brain age gap.

Main Results:

  • The ENIGMA brain age model demonstrated reasonable generalization to new control cohorts (R² = 0.47).
  • Depressed individuals exhibited a significantly higher brain age gap (+1 year, Cohen's d = 0.15), consistent with prior research.
  • FreeSurfer version and scanner vendor (Philips) significantly moderated the brain age gap estimates.

Conclusions:

  • The study validates the ENIGMA brain age algorithm and replicates the brain age gap in depression with a similar effect size.
  • Large-scale analyses across 32 cohorts confirm reliable, subtle brain aging effects in adult depression.
  • Further research is needed to identify factors contributing to the observed variance in the brain age gap between cohorts.