Network subtypes of cortical similarity reveal molecular correlates of normative and compensatory ageing associated with longevity-gene expression

Background: Ageing is marked by widespread cortical changes, but the molecular underpinning and network-level mechanisms associated with this variability remain poorly understood. Methods: We analysed structural MRI data from 952 adults aged 18--94 using morphometric similarity networks, subtype and stage inference, and cortical transcriptomics. Intranetwork connectivity was examined within the three cortical networks and compared with cortical expression patterns of longevity-associated genes. Results: Based on distinct intra-network morphometric similarity patterns and their associations with longevity genes, two ageing-related subtypes emerged. The normative-ageing subtype (metabolic-immune) showed connectivity profiles consistent with typical age-related decline and was enriched for genes involved in metabolism, insulin signalling, and immune regulation. The compensatory subtype (stress-repair) displayed more preserved intra-network connectivity and was associated with genes linked to stress response, DNA repair, and proteostasis. Although the two subtypes overlapped in oxidative stress and neurodegeneration pathways, they showed divergent molecular signatures associated with different cortical ageing patterns. Conclusion: By integrating network-based morphometry with transcriptomics, we establish a modelling approach that distinguishes normative decline from compensatory adaptation in cortical ageing and provides biologically informed markers of brain ageing.