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 into 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. A multi-trait analysis of delirium with Alzheimer disease 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. 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 delirium’s aetiology and guiding further research on clinically relevant biomarkers.