Gene Variant May Increase Psychiatric Risk After TBI

Summary: A new study has linked the APOE4 gene to mental health issues some people face following TBI. Researchers report people with the APOE4 gene had significantly higher scores for depression, PTSD and anxiety following TBI than those without the genetic variant.

Source: Veterans Affairs Research Communications

A variant of the APOE gene may be linked to worse psychiatric symptoms in people who have had a traumatic brain injury, found a Veterans Affairs San Diego Healthcare System study. Study participants with both the gene variant and at least one TBI had more severe symptoms of PTSD, anxiety, and depression than comparison participants.

The results appeared online Feb. 20, 2018, in the Journal of Neurotrauma.

TBI has long been connected with increased risk of psychiatric disorders such as PTSD, depression, and anxiety. A past study of more than 13,000 veterans by the Minneapolis VA Center for Chronic Disease Outcomes Research found that more than 80 percent of those who had suffered a TBI also had a diagnosis of a psychiatric disorder. The same study found that veterans who had a TBI were three times more likely to have PTSD than those who had not.

The new San Diego study also found that patients with TBI had greater PTSD, depression, and anxiety symptoms than those without. The researchers sought to build on that finding by delving into the biological link between TBI exposure and psychiatric disorders.

Apolipoprotein E is a protein that transports and metabolizes lipids such as cholesterol in the central nervous system. It is involved in the maintenance, growth, and repair of neurons. The protein is encoded by a gene referred to as APOE. APOE has three possible variants. One form of the APOE gene (APOE4) is considered a risk factor for Alzheimer’s disease. Previous studies have shown in Vietnam veterans and Iraq/Afghanistan veterans that the APOE4 gene may increase the risk of PTSD.

The researchers set out to test whether the APOE4 gene puts people at greater risk of psychiatric distress when combined with TBI. They collected DNA from 133 veterans of the wars in Afghanistan and Iraq to test for the APOE4 gene. Of these participants, 79 had a mild or moderate TBI, while 54 had no TBI history.

In the participant group with TBI, those with the APOE4 gene had significantly higher symptom scores for PTSD, depression, and anxiety, compared with those with a different variant of APOE. The APOE4 variant was linked to worse symptoms for participants with both mild and moderate TBI.

In the group without a TBI, the researchers found no differences in depression, anxiety, and PTSD symptoms between those with or without APOE4.

Dr. Victoria C. Merritt, first author on the paper, concludes, “Genetic risk may help to explain the poorer long-term clinical outcomes often observed in veterans with neurotrauma histories.”

The results are interesting because APOE4 seems to be linked to worse psychiatric symptoms only when TBI is involved, according to the researchers. Beyond suggesting a connection between APOE4 and the three conditions studied, the results “also lend support to the broader theory that genetic risk factors influence psychiatric distress following TBI,” they write.

The researchers suggest several possible explanations for why those with APOE4 may be at higher risk for psychiatric distress after TBI. First, the APOE4 variant may primarily affect the frontal subcortical regions of the brain, which are often impacted following TBI. These regions are involved in emotion regulation and psychiatric distress. Second, it is possible that APOE4 increases the risk of vascular disease, which has been shown to increase the risk of depression. Third, the presence of APOE4 may cause neurodegenerative effects, whereas the other forms of the gene do not. While more research will be needed to narrow down the cause, “the findings suggest that there may be a [genetic] basis for the complex presentation of symptoms often observed in this vulnerable population,” says Merritt.

In the group without a TBI, the researchers found no differences in depression, anxiety, and PTSD symptoms between those with or without APOE4. image is in the public domain.

The study is the first to explore the link between APOE and psychiatric symptoms specifically connected to TBI. More studies are needed to fully understand how this gene interacts with head trauma to contribute to mental health symptoms, say the researchers.

The San Diego VA team is furthering this work by examining the relationship between APOE4 and cognitive outcomes in veterans with and without TBI histories. They are also looking at whether APOE4 affects post-concussion symptoms such as headaches and dizziness. Future research will also examine the how these findings relate to the biology of the brain using advanced neuroimaging methods.

Merritt explains that the work will add important insight on TBI, and may eventually point toward new treatments.

“Ultimately, we feel that this research is essential to developing a more complete understanding of the multitude of factors that impact recovery following neurotrauma,” she said, “and such work may have relevance to the development of future treatments.”

About this neuroscience research article

Funding: The research was funded by the Department of Veterans Affairs, Department of Defense, National Institutes of Health.

Source: Christopher J. Menzie – Veterans Affairs Research Communications
Publisher: Organized by
Image Source: image is in the public domain.
Original Research: Abstract for “Apolipoprotein E (APOE) ε4 Genotype is Associated with Elevated Psychiatric Distress in Veterans with a History of Mild to Moderate Traumatic Brain Injury” by Dr. Victoria C. Merritt, Ms. Alexandra L. Clark, Mr. Scott F Sorg, Ms. Nicole D. Evangelista, Ms. Madeleine Werhane, Dr. Mark W Bondi, Dr. Dawn M Schiehser, and Dr. Lisa Delano-Wood in eJournal of Neurotrauma. Published May 2018.

Cite This Article

[cbtabs][cbtab title=”MLA”]Veterans Affairs Research Communications “Gene Variant May Increase Psychiatric Risk After TBI.” NeuroscienceNews. NeuroscienceNews, 14 May 2018.
<>.[/cbtab][cbtab title=”APA”]Veterans Affairs Research Communications (2018, May 14). Gene Variant May Increase Psychiatric Risk After TBI. NeuroscienceNews. Retrieved May 14, 2018 from[/cbtab][cbtab title=”Chicago”]Veterans Affairs Research Communications “Gene Variant May Increase Psychiatric Risk After TBI.” (accessed May 14, 2018).[/cbtab][/cbtabs]


Apolipoprotein E (APOE) ε4 Genotype is Associated with Elevated Psychiatric Distress in Veterans with a History of Mild to Moderate Traumatic Brain Injury

Since few studies have examined the relationship between the APOE gene and clinical outcomes following military-related traumatic brain injury (TBI), we aimed to determine whether the ε4 allele of the APOE gene influences neuropsychiatric symptoms in Veterans with a history of mild to moderate TBI. Participants included 133 Veterans (TBI=79, military controls [MC]=54) who underwent APOE genotyping and were divided into ε4+ (TBI=18, MC=15) and ε4- (TBI=61, MC=39) groups. All participants underwent evaluation of psychological distress using the Beck Depression Inventory-II (BDI-II), Beck Anxiety Inventory (BAI), and PTSD Checklist-Military Version (PCL-M). Two-way analyses of variance were conducted to examine the effect of group (TBI vs. MC) and APOE-ε4 status (ε4+ vs. ε4-) across symptom measures. There was a significant main effect of group across all symptom measures (TBI>MC; all p-values <.001), no main effect of ε4 genotype (p=.152-.222), and a significant interaction of group by ε4 genotype across all measures (p=.027-.047). Specifically, for TBI participants, ε4+ Veterans demonstrated significantly higher symptom scores across all measures when compared to ε4- Veterans (p=.007-.015). For MC participants, ε4 status had no effect on the severity of psychiatric symptom scores (p=.585-.708). Our results demonstrate that, in our well-characterized sample of Veterans with history of neurotrauma, possession of the ε4 allele conveys risk for increased symptomatology (i.e., depression, anxiety, PTSD) even well outside of the acute phase of injury. Findings suggest a meaningful relationship between APOE genotype and psychiatric distress following TBI, and they suggest that there is a brain basis for the complex neuropsychiatric presentation often observed in this vulnerable population. Future longitudinal studies are needed in order to further our understanding of how genetic factors influence response to TBI.

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