Summary: A massive genetic analysis of over one million people has revealed that APOE, long known for its role in Alzheimer’s disease, also independently increases a person’s risk of delirium. The researchers found that this effect cannot be explained solely by dementia, showing that APOE directly contributes to delirium vulnerability in otherwise cognitively healthy individuals.
Additional blood-based markers, detectable more than a decade before diagnosis, further strengthened the case that delirium has deep biological roots. The study also identified PON3 as a potential protective factor, opening new avenues for drug development and prevention strategies.
Key Facts:
- APOE Link: APOE increases delirium risk even when dementia is accounted for.
- Predictive Biomarkers: Blood proteins tied to brain injury and inflammation forecast delirium years in advance.
- Therapeutic Potential: PON3 emerged as a protective candidate, suggesting new drug targets.
Source: University of Edinburgh
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.”
Funding: 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.
Key Questions Answered:
A: APOE significantly increases delirium susceptibility, even without dementia.
A: Multiple proteins predicted risk years in advance, including markers of injury and inflammation.
A: The protein PON3 may offer protection and could guide repurposing of existing drugs.
Editorial Notes:
- This article was edited by a Neuroscience News editor.
- Journal paper reviewed in full.
- Additional context added by our staff.
About this genetics and neurology research news
Author: Guy Atkinson
Source: University of Edinburgh
Contact: Guy Atkinson – University of Edinburgh
Image: The image is credited to Neuroscience News
Original Research: Open access.
“Dissecting the genetic and proteomic risk factors for delirium” by Vasilis Raptis et al. Nature Aging
Abstract
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 the Apolipoprotein 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.
