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

Ageing is marked by widespread cortical changes, but the molecular underpinning and network connectivity shaping this variability remain poorly understood. We analysed structural MRI from 952 adults aged 18–94 using morphometric similarity networks, subtype/stage inference, and cortical transcriptomics. Based on intra-network connectivity within three major cortical networks and their associations with longevity genes, two robust 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 linked to stress-response, DNA repair, and proteostasis genes. Although the two subtypes overlap in oxidative stress and neurodegeneration pathways, their distinct molecular signatures capture biologically meaningful differences in cortical ageing. By integrating network-based morphometry with transcriptomics, we establish a novel framework to distinguishes normative decline from compensatory adaptation in ageing profiles to provide biologically informed markers of brain ageing.