Dissecting the genetic and proteomic risk factors for delirium

Delirium is an acute change in cognition, common in hospitalised older adults, and associated with high healthcare and human cost. In this work we shed light on the currently poorly understood genetic and proteomic background of delirium. We conducted the largest to date multi-ancestry analysis of genetic variants associated with delirium (1,059,130 individuals, 11,931 cases), yielding the Apolipoprotein E (APOE) gene as a strong risk factor with possible population and age-varying effects. APOE genetic effect on delirium remained significant after adjusting for dementia and Alzheimer disease (AD) and in dementia-free cohorts. A multi-trait analysis of delirium with AD identified 5 delirium genetic risk loci. Investigation of plasma proteins associated with up to 16-years incident delirium (32,652 individuals, 541 cases) revealed known and novel protein biomarkers, implicating brain vulnerability, inflammation and immune response processes. Incorporating proteomic and genetic evidence via mendelian randomisation, colocalisation and druggability analyses, we indicate putatively useful drug target proteins for delirium. Integrating proteins and APOE genetic risk with demographics significantly improved incident delirium prediction compared to demographics alone. Our results pave the way to better understanding deliriums aetiology and guide further research on clinically relevant biomarkers.