Detection of advanced brain aging in schizophrenia and its structural underpinning by using normative brain age metrics

•Novel metrics are proposed using the brain age paradigm with normative modeling.•Normative brain age is validated to reveal advanced aging in schizophrenia.•Men with schizophrenia have older brain age than women with the disorder.•The brain age in white matter is positively associated with the negative symptom.•The precuneus and uncinate fasciculus are markedly related to the advanced aging. Conceptualizing mental disorders as deviations from normative functioning provides a statistical perspective for understanding the individual heterogeneity underlying psychiatric disorders. To broaden the understanding of the idiosyncrasy of brain aging in schizophrenia, we introduced an imaging-derived brain age paradigm combined with normative modeling as novel brain age metrics. We constructed brain age models based on GM, WM, and their combination (multimodality) features of 482 normal participants. The normalized predicted age difference (nPAD) was estimated in 147 individuals with schizophrenia and their 130 demographically matched controls through normative models of brain age metrics and compared between the groups. Regression analyses were also performed to investigate the associations of nPAD with illness duration, onset age, symptom severity, and intelligence quotient. Finally, regional contributions to advanced brain aging in schizophrenia were investigated. The results showed that the individuals exhibited significantly higher nPAD (P