Summary: A large genetic and proteomic study involving over one million people has shown that the APOE gene, previously best known for its connection to Alzheimer’s disease, also independently raises the risk of delirium. The effect persists even when dementia is taken into account, indicating APOE can increase vulnerability to delirium in people who are otherwise cognitively healthy. The study also identified blood-based protein markers detectable more than a decade before diagnosis and highlighted PON3 as a potential protective factor, offering new directions for treatment and prevention.
Researchers combined large datasets from multiple countries to perform the most extensive and diverse genetic analysis of delirium to date. Their findings point to biological mechanisms — including brain vulnerability and inflammatory processes — that underlie delirium risk and its connection to later cognitive decline.
Key Facts:
- APOE link: The APOE gene increases delirium risk independently of its role in dementia.
- Predictive biomarkers: Blood proteins associated with brain injury and inflammation can predict delirium up to 16 years before onset.
- Therapeutic potential: The protein PON3 emerged as a candidate protective factor and a possible target for drug repurposing or development.
Source: University of Edinburgh
A major genetic risk factor for delirium has been identified. In a landmark multi-ancestry analysis that pooled genetic information from cohorts across the UK, the USA and Finland, investigators found that the Apolipoprotein E (APOE) gene is a major genetic contributor to delirium risk. Importantly, this association remained strong after accounting for diagnosed dementia, indicating a direct role for APOE in delirium susceptibility.
Delirium is an acute and fluctuating disturbance of attention and awareness that affects roughly one in four older adults admitted to hospital. It is associated with longer hospital stays, increased short-term mortality and a two- to three-fold higher risk of subsequent dementia among survivors. Despite this burden, there are currently no specific, widely accepted treatments for delirium.
The research team from the University of Edinburgh’s Usher and Roslin Institutes and School of Mathematics performed a genetic meta-analysis using data from more than 1,059,000 individuals (11,931 cases of delirium). They report that APOE stands out as a strong genetic risk factor for delirium independent of dementia status. A further multi-trait analysis combining delirium and Alzheimer’s disease data identified five genetic loci associated with delirium risk, highlighting shared and distinct biology between the two conditions.
To explore proteomic predictors, investigators analysed plasma samples from the UK Biobank collected up to 16 years before delirium diagnosis (32,652 participants, 541 subsequent cases). Several circulating proteins, including markers of neural injury and systemic inflammation, were associated with future delirium. Some of these proteins have not previously been connected to delirium, strengthening the argument that biological changes long precede clinical symptoms.
Among the proteomic findings, PON3 stood out as associated with reduced delirium risk and may be a promising drug target. PON3 is implicated in lipid metabolism and may influence how the body processes certain medications such as statins. While this suggests potential for repurposing existing drugs, the authors emphasize that additional research is required before any clinical recommendations can be made.
Combining genetic data (including APOE-ε4 status), proteomic markers and demographic information produced significantly better predictions of incident delirium than demographic factors alone. The study integrated genetic and proteomic evidence using Mendelian randomization, colocalization and druggability analyses to identify potentially actionable targets and guide future experimental work.
Vasilis Raptis, the lead author, stated that the research offers the strongest evidence to date for a genetic component to delirium and that the next steps are to map how DNA variants and gene expression changes in brain cells result in clinical vulnerability. Professor Albert Tenesa added that the findings illuminate biological pathways — including brain vulnerability and inflammation — that may underpin both delirium and its link to later dementia.
Funding: The study was supported by the Vivensa Foundation and the Legal & General Group. Genetic and proteomic data were provided by UK Biobank, FinnGen, the All of Us Research Program and the Michigan Genomics Initiative.
Key Questions Answered:
Q: What major genetic factor raises delirium risk?
A: APOE significantly increases susceptibility to delirium, even when dementia is accounted for.
Q: What did blood analyses reveal about future delirium risk?
A: Multiple plasma proteins, including markers of brain injury and inflammation, predict delirium years before diagnosis.
Q: What treatment possibilities emerged from the findings?
A: PON3 was linked to reduced delirium risk and may guide future drug development or repurposing strategies, pending further validation.
Editorial Notes:
- This article was edited by a Neuroscience News editor.
- The journal paper was reviewed in full.
- Additional context was added by the editorial staff.
About this genetics and neurology research news
Author: Guy Atkinson
Source: University of Edinburgh
Contact: Guy Atkinson – University of Edinburgh
Image: Image credit given to Neuroscience News
Original Research: Open access. “Dissecting the genetic and proteomic risk factors for delirium” by Vasilis Raptis et al., published in Nature Aging. DOI: 10.1038/s43587-025-01018-6
Abstract
Dissecting the genetic and proteomic risk factors for delirium
Delirium is an acute change in cognition that is common among hospitalized older adults and is associated with substantial healthcare and human costs. Yet the genetic and proteomic contributors to delirium have been poorly characterized. This study performed a multi-ancestry genetic meta-analysis across several large cohorts (n = 1,059,130; 11,931 cases), identifying APOE as a strong delirium risk factor independent of dementia. A joint analysis of delirium and Alzheimer’s disease pinpointed five genetic loci linked to delirium susceptibility.
Proteomic analyses of plasma collected up to 16 years before diagnosis in UK Biobank participants (n = 32,652; 541 cases) revealed protein biomarkers that implicate brain vulnerability, inflammation and immune response pathways in incident delirium. Integrating proteomic and genetic findings through Mendelian randomization, colocalization and druggability assessments highlighted potentially useful therapeutic targets. Models that combined protein markers, APOE-ε4 status and demographic factors improved prediction of future delirium compared with demographic information alone. These results advance understanding of delirium’s biology and may inform future biomarker and treatment research.