Alzheimer's Risk Allele Linked to PTSD, Depression After TBI

Batya Swift Yasgur, MA, LSW

May 24, 2018

Individuals with the apolipoprotein (APOE) ε4 genetic polymorphism who have sustained a traumatic brain injury (TBI) are at greater risk for neuropsychiatric symptoms than those with similar injuries but a normal genetic profile, new research suggests.

Investigators compared military veterans who had sustained a TBI and tested positive for the APOE ε4 allele with those who tested negative and with a control group who had not sustained a TBI.

In the TBI group, those with APOE ε4 had significantly higher rates of posttraumatic stress disorder (PTSD), depression, and anxiety than did those without the ε4 allele.

In veterans who had not sustained a TBI, however, differences in symptoms did not differ between those with and without the ε4 allele.

"The results of our study suggest a relationship between APOE ε4 status and elevated depression, anxiety, and PTSD symptoms," lead author Victoria Merritt, PhD, postdoctoral fellow at the VA San Diego Healthcare System, California, told Medscape Medical News.

"If these results are consistently replicated, it is conceivable that genetic testing may be a useful tool to consider in the early states of treatment in order to identify patients who may be at risk for developing chronic mental health symptoms," said Merritt.

The study was published online February 20 in the Journal of Neurotrauma.

"Logical Starting Point"

Several theories have been proposed to account for the well-established connection between TBI and subsequent PTSD, depression, and anxiety, the authors write. These have included environmental conditions and biological mechanisms, particularly pathophysiologic changes and the influence of genetic predispositions.

The APOE gene, which encodes ApoE, has been "the most widely studied gene with respect to its role in recovery and outcome following TBI," write the investigators.

ApoE is "a lipoprotein that transports and metabolizes lipids (such as cholesterol) within the central nervous system (CNS), and it is primarily involved in neuronal maintenance, growth, and repair," they explain.

The APOE gene comprises three alleles, one of which — APOE ε4 — has been long associated with Alzheimer's disease risk and is considered to be a risk factor for neuropathology following CNS compromise.

"While we have some understanding of the various environmental factors, such as combat exposure and type of injury, that influence outcome following military TBI, we do not know as much about how biological factors, such as genetic polymorphisms, may play a role in clinical outcomes," co-investigator Lisa Delano-Wood, PhD, told Medscape Medical News.

"Given the robust effects of the ε4 genotype in neurodegenerative conditions such as Alzheimer's disease, we thought this particular gene seemed to be a logical starting point from which we could begin to understand the extent to which genetics may be associated with TBI outcome," said Delano-Wood, staff psychologist at VA San Diego Healthcare System and associate professor in the Department of Psychiatry at the University of California San Diego School of Medicine.

Potential Role         

To investigate the potential role of ε4 status in psychiatric distress following TBI, the researchers assessed 133 veterans (79.9% male; average age, 32.35 years), including 79 with a history of TBI (87.3% and 12.7% with mild and moderate TBI, respectively) and 54 without a history of TBI, known as military controls (MCs).  

The average time from TBI injury to assessment was approximately 6 years. The veterans had predominantly been involved in the Iraq and Afghanistan conflicts. 

On average, participants had 14.33 years of education, and approximately half (51%) self-identified as Caucasian, followed by Hispanic/Latino, African American, Asian/Pacific Islander, and other (27.1%, 9.0%, 8.3%, and 4.5%, respectively).

Participants were required to provide a buccal DNA sample to ascertain APOE genotype. A quarter (24.8%) of the overall sample had at least one ε4 allele. Among the TBI participants, 22.8% were classified as ε4 positive and 77.2% were classified as ε4 negative.

The VA/DoD Clinical Practice Guideline for the Management of Concussion/Mild TBI was used to define and classify TBI as "mild" or "moderate."

Veterans with a history of severe TBI, a history of a neurologic disorder or serious medical illness, a history of psychotic disorder, or current substance abuse disorder were excluded from the study.

Outcome measures included score on the Beck Depression Inventory-II (BDI-II), the Beck Anxiety Inventory (BAI), and the PTSD Checklist-Military Version (PCL-M).

TBI Plus ε4 Implicated

A main effect of group was found with depression, as measured by BDI-II total score (main effect of group, F[1, 129] = 59.60, P < .001, ηp 2 = 0.316), which was significantly greater for TBI participants than for MCs (mean, 20.89 [standard deviation, 12.87] and 5.85 [8.65], respectively).

The main effect of ϵ4 allele status was not significant (F[1, 129] = 2.07, P = .152, ηp 2 = 0.016).

However, the interaction between group and ϵ4 allele status was significant (F[1, 129] = 4.01, P = .047, ηp 2 = 0.030); the TBI ε4-positive veterans had higher BDI-II scores than did the TBI ε4-negative veterans (F[1, 142] = 6.77, P = .010, ηp 2 = 0.050).

By contrast, there were no significant group differences by APOE ϵ4 status for MCs (F[1, 129] = 0.14, P = .708, ηp 2 = 0.001).

Findings were similar for anxiety and PTSD, as measured by the BAI and PCL-M scores, respectively — with greater scores for TBI participants than for MCs, higher scores for ε4-positive veterans than for ε4-negative veterans, and no difference in scores between ε4-positive and ε4-negative veterans in the MC group.

The researchers found a similar pattern when they removed participants with moderate TBI from the analyses and also when they controlled for combat exposure and ethnicity.

"While we cannot say with certainty, we think that the APOE gene may have some kind of special influence on frontal subcortical brain regions, since these areas are often negatively impacted after head injury and play a very important role in regards to regulating emotions and affective states, as well as psychiatric distress," noted Merritt.

In particular, "it seems as though it is the combination of TBI and ε4 status that contributes to the elevated postinjury psychiatric distress," she said.       

"Well-done Addition"

Commenting for Medscape Medical News, Ryan Tierney, PhD, associate professor of instruction and kinesiology, College of Public Health at Temple University, Philadelphia, Pennsylvania, called the study "a well-done addition to some of the literature that's out there on the APOE gene, particularly the ε4 variation."

The findings are consistent with research suggesting that this gene variation is "related to varying levels of brain injury and outcome generally, meaning that if someone has the ε4 variant, they're at greater risk for poor outcome after the TBI," said Tierney, who was not involved with this study.

However, "although the researchers did define 'mild' and 'moderate' TBI, these definitions can vary from study to study."

Additionally, "more folks who had combat exposure tended to be in the TBI group, compared to the military controls, who had less combat exposure — an important difference because just being involved in combat can increase one's odds of performing poorly on some of these psychological tests," Tierney pointed out.

Future studies might "include in the control group more people who had been involved in battle but had not sustained a TBI," he added.

Delano-Wood observed that, "Identifying a link between biological markers, such as genetics, and clinical outcome following TBI has important implications on a broader scale because neurobehavioral and psychiatric sequelae, as well as cognitive deficits, are often associated with increased service utilization, disability, and decreased quality of life in those with TBI."

"We think our findings lay the foundation for a better understanding of how genetics may contribute to clinical recovery following TBI and may also have relevance to treatments that are currently being developed and optimized within a precision medicine context," she said.

The study was supported by grants from Veterans Affairs, the Department of Defense, and the National Institute of Neurological Disorders and Stroke of the National Institutes of Health. The study authors and Tierney have disclosed no relevant financial relationships.

J Neurotrauma. Published online February 20, 2018. Abstract

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