Beyond Diagnosis: Investigating How Biologically Informed Risk for Severe Mental Illness Shapes Cognitive Ageing in the General Population (360G-Wellcome-338294_Z_25_Z)

Severe mental illnesses (SMIs) are chronic psychiatric disorders characterized by cognitive deficits, emotional distress, and functional impairment. Cognitive dysfunction is increasingly recognized as a core feature of SMIs, significantly impacting long-term outcomes. Recent research indicates that individuals with a high molecular risk for SMIs, even without a clinical diagnosis, exhibit elevated dementia risk and poorer cognitive performance. This suggests that biological liability to SMI, captured through genetic, epigenetic, proteomic, and metabolic markers, exists on a continuum influencing phenotypic changes in aging populations and contributing to early cognitive decline. Traditional categorical diagnostic frameworks often miss this subclinical variation. This project aims to model SMI liability as a continuous biological construct and investigate its association with cognitive aging and brain health. Utilizing multi-omic profiling, neuroimaging, and advanced statistical methods in large-scale population cohorts, we will identify cross-sectional and longitudinal patterns linking common and unique multi-omic risk for SMI with aging-related cognitive and neuroimaging outcomes. Ultimately, this work seeks to enhance the detection of subclinical cognitive vulnerability, enabling earlier identification, targeted interventions, and promotion of healthier aging across populations.