A major genetic risk factor for delirium has been identified in a landmark study that analysed the DNA of more than one million people worldwide.
The study found that APOE, a gene already well known for its role in Alzheimer's disease, also increases a person's risk of developing delirium – a common medical condition characterised by a state of sudden mental confusion.
Experts say this effect cannot be explained solely by the gene's link to dementia, suggesting it also plays a distinctive, direct role in delirium.
The discovery opens the door to targeted treatments and new ways to prevent the progression from delirium to dementia, researchers say.
Delirium affects around one in four hospitalised older adults and is linked with higher risk of death, longer hospital stays, and a two- to three-fold increase in future dementia risk in survivors. Despite its prevalence and impact, no specific treatments exist.
Researchers from the University of Edinburgh's Usher and Roslin Institutes and School of Mathematics carried out the largest and most diverse genetic analysis of delirium to date, drawing on data from the UK, USA and Finland.
They found that APOE's effect on delirium risk remained significant even after adjusting for the presence of dementia, providing strong evidence that APOE contributes to delirium susceptibility in people without dementia.
The overlap between delirium and Alzheimer's disease risk genes may help explain why delirium so often precedes or accelerates cognitive decline, scientists say.
Researchers also examined blood samples in the UK Biobank from 32,000 individuals who developed delirium, collected up to 16 years before any diagnosis. They identified several blood-based proteins that can predict delirium risk years in advance, including markers of brain injury and inflammation – some of which have never previously been linked to delirium.
The study also points to new treatment possibilities. One protein, PON3, was linked with protection against delirium and may be a promising drug target. PON3 is thought to be involved in the processing of some cholesterol-lowering drugs, called statins, in the body, suggesting these existing medicines might be repurposed to help lower delirium risk, although experts say further research is needed.
Vasilis Raptis, main author of the study from the University of Edinburgh, said: "The study provides the strongest evidence to date that delirium has a genetic component. Our next step is to understand how DNA modifications and changes in gene expression in brain cells can lead to delirium."
Albert Tenesa, Professor of Quantitative Genetics at the University of Edinburgh, said: "The findings shed new light on the biological foundations of delirium, suggesting that brain vulnerability, and systemic and nervous system inflammation may all play important roles. This opens new avenues for investigation not just of delirium itself, but also the poorly understood and very important link between delirium and future risk of dementia."
The study is published in the journal Nature Aging: https://www.nature.com/articles/s43587-025-01018-6 [URL will become active after embargo lifts]. It was funded by the Vivensa Foundation and the Legal & General Group. The data was provided by UK Biobank, FinnGen, All of Us Research Programme and the Michigan Genomics Initiative.
