Long before confusion sets in, your genes and blood may already be signaling trouble. This study of more than a million people reveals the hidden biological warnings that could transform how we predict and prevent delirium.
Study: Dissecting the genetic and proteomic risk factors for delirium. Image credit: PeopleImages/Shutterstock.com
Delirium is a state of acute cognitive alteration. It affects one in four hospitalized older people, with a high impact on healthcare costs and human wellbeing. A recent paper published in the journal Nature Aging explores the genetic and proteomic profile of delirium.
Why delirium and dementia often overlap clinically
Delirium refers to a distinct neurocognitive condition characterized by disorientation, impaired attention, altered cognition, and altered awareness. It develops quickly, may last for a few hours or days, and often occurs during acute illness or injury, surgical or otherwise. It burdens healthcare costs, about USD 182 billion per year in Europe, and is linked to a higher mortality rate, and survivors often have a longer hospital stay.
People with dementia, including Alzheimer’s disease (AD), are more likely to become delirious than non-dementia individuals in the same triggering situation. Conversely, people who develop delirium have higher odds of developing dementia in the future.
Interestingly, both conditions share some common features. For instance, both involve disrupted cognitive function and disturbances of perception, and altered sleep-wake cycles. However, there are marked differences in their mode of onset and duration.
Delirium is thought to follow systemic inflammation that causes neuroinflammation, weakening of the blood-brain barrier, and neuronal injury. Dementia also shares some of these mechanisms. This has led to interest in exploring whether these conditions are causally related to each other, for instance, by neurodegeneration occurring as a result of neuroinflammation.
As the world population ages, dementia prevalence and incidence are on the rise, and so is delirium. Studies on its genetic risk factors have primarily focused on one or a few genes, especially the Apolipoprotein E (APOE) gene, but no clear associations have emerged. This gene encodes a protein that transports fats both in the brain and the rest of the body. It is a risk marker for AD because of its central role in the deposition of amyloid-beta plaques, neuroinflammation, and disrupted fat metabolism in the brain.
The APOE-ε4 haplotype has recently been suggested to substantially elevate the risk of delirium in Europeans, but this has not been confirmed in individuals of other ancestries. The advancement of genetic studies, particularly genome-wide association studies (GWAS), enables the entire genome to be searched for potential risk factors; however, delirium has not been addressed in the same manner.
Proteins that are increased in delirium include interleukin (IL)-6 and C-reactive protein (CRP), neurofilament light chain (NEFL) associated with axonal injury, and abnormal proteins like β-amyloid that accumulate in Alzheimer’s disease (AD).
The current study analyzes a large sample of GWAS datasets from patients with delirium. The aim was to identify high-risk protein markers in over 32,000 patients who were followed up for periods ranging from 1 to 16 years to determine which of them developed delirium. It also aimed to validate the integrated results using Mendelian randomization (MR).
This technique uses the distribution of genetic variants to estimate the causality of observed associations between risk factors and outcomes. They also assessed colocalization, along with druggability testing, to identify potential therapeutic targets.
The study also examined the data for genetic traits common to AD and delirium to more effectively detect genetic risk markers for delirium. They aimed to use both genetic and proteomic markers to identify proteins that might be usefully targeted by drugs to prevent or manage delirium.
The study used data on ancestry from multiple cohorts, including the UK Biobank, FinnGen, All of Us Research Program and Michigan Genomics Initiative, with a total of 1,059,130 subjects yielding a total of 11,931 delirium cases.
APOE-ε4 emerges as delirium’s dominant genetic signal
The researchers found that variants at the APOE gene and its immediate proximity significantly predicted the risk of delirium. The APOE-ε4 haplotype predicts increased AD risk and was thus indirectly associated with a higher risk of delirium. In agreement with earlier studies, the APOE-ε4–associated risk effect was stronger among Europeans, Finns, and South Asians compared to Africans, Hispanics, or those of mixed American ancestry.
However, it was also independently and directly associated with a higher risk of delirium in a dose-dependent fashion. This remained significant after stratifying the patients by age for GWAS, including only patients who were at least 60 years of age.
Prior research shows that APOE-ε4 drives exaggerated neuroinflammation in response to injuries, reducing the strength of the blood-brain barrier and promoting the piling up of β-amyloid after injury, as well as driving white matter disruption. This lends biological plausibility to it as a driver of delirium risk. However, further work is required to test whether previously cognitively normal APOE-ε4 carriers are more likely to develop new-onset dementia following an episode of delirium.
Next, genetic data from patients with both Alzheimer’s disease and delirium were analyzed to detect shared genetic loci that could indicate an increased risk of delirium. This analysis identified five loci that were replicated, suggesting that their genetic determinants are partially shared.
The proteomics study revealed that certain proteins were predicted to increase delirium risk years before the onset of delirium. These include markers of neuronal injury, such as NEFL, likely due to associated brain vulnerability. However, it remains unclear whether elevated NEFL reflects preclinical neurodegeneration or early brain vulnerability independent of dementia.
Other protein markers were associated with systemic and neuronal inflammation, as well as with specific immune responses, suggesting their potential role in driving delirium. Some of these proteins, especially PON3, which showed a protective direction but yielded mixed support in replication analyses, may be druggable targets.
The researchers found that a combination of proteins, APOE-ε4 status, and demographic factors performed best at predicting the onset of delirium, compared to demographic factors alone. APOE protein levels themselves showed only a nominal (not genome-wide significant) association in the proteomic analysis.
Genetic and protein data point to a shared pathology
This is the largest study to date on the genetic and proteomic underpinnings of delirium.
Our results provide insight into delirium’s etiology and may guide further research on clinically relevant biomarkers.
The genetic and proteomic analyses suggest that delirium shares a common origin with dementia, which may help to better understand how delirium arises and how it can be accurately predicted to help mitigate the risk ahead of time.
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