| Title: | Cognitive performance modulates regional brain age differences in clinical anxiety and depression |
| Journal: | Journal of Affective Disorders |
| Published: | 9 Jul 2026 |
| Pubmed: | https://pubmed.ncbi.nlm.nih.gov/42425245/ |
| DOI: | https://doi.org/10.1016/j.jad.2026.122237 |
Publication 20334
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Abstract
Anxiety and depression are associated with advanced brain age (BA) and reduced cognitive functioning, but it remains unclear to what extent these effects reflect diagnostic status versus variability in cognition. We examined whether cognition explains regional brain age differences in individuals with anxiety and depression using local BA (LBA) and LBA gap (LBAG). UK Biobank participants (N = 21,424) underwent LBA estimation from structural MRI. LBAG was analyzed using multivariate testing and hierarchical mixed-effects models to assess regional and global differences across diagnostic groups. Models were evaluated with and without adjustment for cognitive performance (principal component of cognitive tests) to isolate effects including and excluding cognition. Significant global brain age gap (GBAG) elevations were observed in anxiety and depression relative to diagnosis-free participants, with no differences between disorders, supporting a transdiagnostic pattern. Regionally, widespread LBAG elevations exist without adjusting for cognition, with mean differences of ~1.01 y (anxiety), 1.05 y (depression), and 1.14 y (comorbidity). Modeling for cognition attenuated these effects to ~0.80, 0.84, and 0.78 y, respectively (~20-25% reductions). Higher cognitive performance was associated with lower LBAG, with stronger associations in psychiatric groups than controls. Diagnostic effects are most prominent in anterior frontal and temporal cortices, whereas cognition-related associations are strongest in subcortical and ventral regions. Brain aging differences in people with anxiety and depression are partly associated with cognitive variability rather than diagnosis alone. Accounting for cognition alters interpretation of psychiatric BA effects and highlights the importance of integrating cognition into BA models when evaluating neuropsychiatric populations.</p>
6 Authors
- Owen M Vega
- Phoebe Imms
- Nikhil N Chaudhari
- Wendy J Mack
- Nahian F Chowdhury
- Andrei Irimia
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