N Nature Aging · Nov 24, 2025 Dissecting the genetic and proteomic risk factors for delirium Delirium is an acute change in cognition, common in hospitalized older adults, and associated with high healthcare and human cost; however, delirium’s genetic and proteomic background remains poorly understood. Here we conducted a genetic meta-analysis on delirium using multi-ancestry data from the UK Biobank, FinnGen, All of Us Research Program and Michigan Genomics Initiative cohorts (n=1,059,130; 11,931 cases), yielding theApolipoprotein E(APOE) gene as a strong delirium risk factor independently of dementia. A multi-trait analysis of delirium with Alzheimer disease identified five delirium genetic risk loci. Plasma proteins associated with up to 16-year incident delirium in UK Biobank (n=32,652; 541 cases) revealed protein biomarkers implicating brain vulnerability, inflammation and immune response processes. Incorporating proteomic and genetic evidence via Mendelian randomization, colocalization and druggability analyses, we indicate potentially useful drug target proteins for delirium. Combining proteins,APOE-ε4 status and demographics significantly improved incident delirium prediction compared to demographics alone. Our results provide insight into delirium’s etiology and may guide further research on clinically relevant biomarkers. Ageing Genome-wide association studies Neurological disorders Proteomics biology
N Nature Aging · Oct 03, 2025 Genome-wide analysis of brain age identifies 59 associated loci and unveils relationships with mental and physical health Neuroimaging and machine learning are advancing research into the mechanisms of biological aging. In this field, ‘brain age gap’ has emerged as a promising magnetic resonance imaging-based biomarker that quantifies the deviation between an individual’s biological and chronological age of the brain. Here we conducted an in-depth genomic analysis of the brain age gap and its relationships with over 1,000 health traits. Genome-wide analyses in up to 56,348 individuals unveiled a heritability of 23–29% attributable to common genetic variants and highlighted 59 associated loci (39 novel). The leading locus encompassesMAPT, encoding the tau protein central to Alzheimer’s disease. Genetic correlations revealed relationships with mental health, physical health, lifestyle and socioeconomic traits, including depressed mood, diabetes, alcohol intake and income. Mendelian randomization indicated a causal role of high blood pressure and type 2 diabetes in accelerated brain aging. Our study highlights key genes and pathways related to neurogenesis, immune-system-related processes and small GTPase binding, laying the foundation for further mechanistic exploration. Ageing Brain Genetics of the nervous system Genome-wide association studies Neural ageing biology
