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Veterans who deployed in support of Operation Enduring Freedom (OEF), Iraqi Freedom (OIF), and New Dawn (OND) commonly experience severe psychological trauma, often accompanied by physical brain trauma resulting in mild traumatic brain injury (mTBI). Prior studies of individuals with posttraumatic stress disorder (PTSD) have revealed alterations in brain structure, accelerated cellular aging, and impacts on cognition following exposure to severe psychological trauma and potential interactive effects of military-related mTBI. To date, however, little is known how such deployment-related trauma changes with time and age of injury of the affected veteran. In this study, we explored changes in cortical thickness, volume, and surface area after an average interval of approximately 2 years in a cohort of 254 OEF/OIF/OND Veterans ranging in age from 19 to 67 years. Whole-brain vertex-wise analyses revealed that veterans who met criteria for severe PTSD (Clinician-Administered PTSD Scale ≥60) at baseline showed greater negative longitudinal changes in cortical thickness, volume, and area over time. Analyses also revealed a significant severe-PTSD by age interaction on cortical measures with severe-PTSD individuals exhibiting accelerated cortical degeneration with increasing age. Interaction effects of comorbid military-related mTBI within the severe-PTSD group were also observed in several cortical regions. These results suggest that those exhibiting severe PTSD symptomatology have accelerated atrophy that is exacerbated with increasing age and history of mTBI.

Military service members returning from theaters of war are at increased risk for mental illness, but despite high prevalence and substantial individual and societal burden, the underlying pathomechanisms remain largely unknown. Exposure to high levels of emotional stress in theaters of war and mild traumatic brain injury (mTBI) are presumed factors associated with risk for the development of mental disorders.To investigate (1) whether war zone–related stress is associated with microstructural alterations in limbic gray matter (GM) independent of mental disorders common in this population, (2) whether associations between war zone–related stress and limbic GM microstructure are modulated by a history of mTBI, and (3) whether alterations in limbic GM microstructure are associated with neuropsychological functioning.This cohort study was part of the TRACTS (Translational Research Center for TBI and Stress Disorders) study, which took place in 2010 to 2014 at the Veterans Affair Rehabilitation Research and Development TBI National Network Research Center. Participants included male veterans (aged 18-65 years) with available diffusion tensor imaging data enrolled in the TRACTS study. Data analysis was performed between December 2017 to September 2021.The Deployment Risk and Resilience Inventory (DRRI) was used to measure exposure to war zone–related stress. The Boston Assessment of TBI-Lifetime was used to assess history of mTBI. Stroop Inhibition (Stroop-IN) and Inhibition/Switching (Stroop-IS) Total Error Scaled Scores were used to assess executive or attentional control functions.Diffusion characteristics (fractional anisotropy of tissue [FAT]) of 16 limbic and paralimbic GM regions and measures of functional outcome.Among 384 male veterans recruited, 168 (mean [SD] age, 31.4 [7.4] years) were analyzed. Greater war zone–related stress was associated with lower FAT in the cingulate (DRRI-combat left: P = .002, partial r = −0.289; DRRI-combat right: P = .02, partial r = −0.216; DRRI-aftermath left: P = .004, partial r = −0.281; DRRI-aftermath right: P = .02, partial r = −0.219), orbitofrontal (DRRI-combat left medial orbitofrontal cortex: P = .02, partial r = −0.222; DRRI-combat right medial orbitofrontal cortex: P = .005, partial r = −0.256; DRRI-aftermath left medial orbitofrontal cortex: P = .02, partial r = −0.214; DRRI-aftermath right medial orbitofrontal cortex: P = .005, partial r = −0.260; DRRI-aftermath right lateral orbitofrontal cortex: P = .03, partial r = −0.196), and parahippocampal (DRRI-aftermath right: P = .03, partial r = −0.191) gyrus, as well as with higher FAT in the amygdala-hippocampus complex (DRRI-combat: P = .005, partial r = 0.254; DRRI-aftermath: P = .02, partial r = 0.223). Lower FAT in the cingulate-orbitofrontal gyri was associated with impaired response inhibition (Stroop-IS left cingulate: P < .001, partial r = −0.440; Stroop-IS right cingulate: P < .001, partial r = −0.372; Stroop-IS left medial orbitofrontal cortex: P < .001, partial r = −0.304; Stroop-IS right medial orbitofrontal cortex: P < .001, partial r = −0.340; Stroop-IN left cingulate: P < .001, partial r = −0.421; Stroop-IN right cingulate: P < .001, partial r = −0.300; Stroop-IN left medial orbitofrontal cortex: P = .01, partial r = −0.223; Stroop-IN right medial orbitofrontal cortex: P < .001, partial r = −0.343), whereas higher FAT in the mesial temporal regions was associated with improved short-term memory and processing speed (left amygdala-hippocampus complex: P < .001, partial r = −0.574; right amygdala-hippocampus complex: P < .001, partial r = 0.645; short-term memory left amygdala-hippocampus complex: P < .001, partial r = 0.570; short-term memory right amygdala-hippocampus complex: P < .001, partial r = 0.633). A history of mTBI did not modulate the ass ciation between war zone–related stress and GM diffusion.This study revealed an association between war zone–related stress and alteration of limbic GM microstructure, which was associated with cognitive functioning. These results suggest that altered limbic GM microstructure may underlie the deleterious outcomes of war zone–related stress on brain health. Military service members may benefit from early therapeutic interventions after deployment to a war zone.

Maladaptive anger and aggression are common in US military veterans and increase risk for impaired social relationships and functioning, justice-involvement and violence. Early life (before age 18) adversity predisposes veterans to later life psychopathology, though the link to increased later life anger is unclear. We analysed cross-sectional data of 158 post-9/11 veterans from the Translational Research Center for Traumatic Brain Injury and Stress Disorders study with and without a history of early life adversity (ns = 109 and 49, respectively). We explored the relationship among major clinical variables and current veteran anger (Dimensions of Anger Reactions) and whether the associations with these variables differed among participants with and without a history of retrospective self-reported early life adversity (Childhood Trauma Questionnaire). In the overall sample, posttraumatic stress disorder (PTSD) and depression severities had the strongest associations with current veteran anger (βs = 0.261 and 0.263; p-values = 0.0022 and 0.0103, respectively). In the subsample without early life adversity, only PTSD severity was significantly associated with anger (β = 0.577, p = 0.0004). In the early life adversity subsample, this strong association weakened and was no longer significant (β = 0.168, p = 0.1007); instead, anxiety and depression severities showed moderate associations with anger (βs = 0.243 and 0.287, p-values = 0.0274 and 0.0130, respectively). Findings suggest that clinicians should screen veterans with history of early life adversity for depression and anxiety when anger is present.

Cross-sectional work suggests that deployment-related posttraumatic sequelae are associated with increased disability in U.S. veterans deployed following the September 11, 2001 (9/11), terrorist attacks. However, few studies have examined the psychiatric and somatic variables associated with changes in functional disability over time. A total of 237 post-9/11 veterans completed comprehensive assessments of psychiatric and cognitive functioning, as well as a disability questionnaire, at baseline and 2-year follow-up. At baseline, higher levels of PTSD, depressive, and pain-related symptoms were associated with baseline global functional disability, semipartial r(2) = .036-.044. Changes in symptoms of PTSD, depression, pain, and sleep, but not anxiety or alcohol use, were independently associated with changes in functional disability, semipartial r(2) = .017-.068. Baseline symptoms of these conditions were unrelated to changes in disability, and cognitive performance was unrelated to disability at any assessment point. Together, this suggests that changes in psychiatric and somatic symptoms are tightly linked with changes in functional disability and should be frequently monitored, and even subclinical symptoms may be a target of intervention.

BACKGROUND: Post-9/11 veterans exhibit high prevalence of deployment stress, psychological conditions, and traumatic brain injury (TBI) which impact reintegration, especially among those with a history of interpersonal early life trauma (I-ELT). The relative importance of each risk factor is unclear. PURPOSE: We examined major deployment and clinical exposures of reintegration challenges among veterans with and without I-ELT. METHOD: We analyzed cross-sectional data of 155 post-9/11 veterans from the Translational Research Center for TBI and Stress Disorders study. FINDINGS: Depression severity had the strongest association with reintegration challenges, followed by posttraumatic stress disorder (PTSD) severity, post-deployment stress, and deployment safety concerns. Deployment safety concerns had a stronger, significant association among veterans with I-ELT. In nearly every model, PTSD and depression severities were weaker for veterans with I-ELT, compared to those without. DISCUSSION: Clinicians should consider the relative risk of concurrent clinical conditions and trauma histories when considering veterans' reintegration needs.

INTRODUCTION: Since 2006, efforts have been made to increase the accurate identification of traumatic brain injuries (TBIs) in post-9/11 military personnel. The Boston Assessment of TBI-Lifetime (BAT-L) is the first validated instrument designed specifically to diagnose TBIs throughout the life span in post-9/11 Veterans. The objective was to compare the diagnostic accuracy of the BAT-L with medical records from the Department of Defense (DoD). MATERIAL AND METHODS: Traumatic brain injury diagnosis for 153 Veterans deployed in 2011 enrolled in the Translational Research Center for TBI and Stress Disorder longitudinal cohort study from the BAT-L clinical interview was compared to DoD online medical records to determine diagnostic prevalence and injury severity for all head injury cases during deployment. Sensitivity, specificity, Cohen's kappa, and Kendall's tau-b were calculated for TBI diagnosis and severity. Concordant TBI cases and discordant TBI cases were compared using chi-square and t-test analyses. This study has been approved by VA Boston by Institutional Review Boards for human participants' protection. RESULTS: Correspondence of TBI diagnoses from the BAT-L with DoD records was fair (κ = 0.42; sensitivity = 72.7%; specificity = 82.8%). Comparison of injury severity also showed fair correspondence (κ = 0.41). Missing TBI diagnostic data from DoD records were frequent; 43% of TBIs reported on the BAT-L did not have any documentation of assessment or diagnoses in DoD records. CONCLUSION: This study addresses a critical gap in research by comparing the diagnostic accuracy of a validated, semi-structured clinical interview with available medical records. Diagnosis of TBIs via the BAT-L was both sensitive and specific when compared to DoD records, supporting the validity of the BAT-L for retrospective assessment of military TBI. However, diagnostic correspondence was only fair. This lack of diagnostic agreement was related to multiple factors including lack of documentation at the time of injury by DoD, differences in assessment and goals, and other combat-related motivational factors associated with failure to report injuries while deployed. Several policies have been implemented to address underreporting and under-documentation of TBIs, yet challenges remain. Recommendations for evaluating TBI are presented. Accurate diagnosis of TBI is necessary for appropriate treatment planning, as well as service-related compensation.

BACKGROUND: Posttraumatic stress disorder (PTSD) is heritable and a potential consequence of exposure to traumatic stress. Evidence suggests that a quantitative approach to PTSD phenotype measurement and incorporation of lifetime trauma exposure (LTE) information could enhance the discovery power of PTSD genome-wide association studies (GWASs). METHODS: A GWAS on PTSD symptoms was performed in 51 cohorts followed by a fixed-effects meta-analysis (N = 182,199 European ancestry participants). A GWAS of LTE burden was performed in the UK Biobank cohort (N = 132,988). Genetic correlations were evaluated with linkage disequilibrium score regression. Multivariate analysis was performed using Multi-Trait Analysis of GWAS. Functional mapping and annotation of leading loci was performed with FUMA. Replication was evaluated using the Million Veteran Program GWAS of PTSD total symptoms. RESULTS: GWASs of PTSD symptoms and LTE burden identified 5 and 6 independent genome-wide significant loci, respectively. There was a 72% genetic correlation between PTSD and LTE. PTSD and LTE showed largely similar patterns of genetic correlation with other traits, albeit with some distinctions. Adjusting PTSD for LTE reduced PTSD heritability by 31%. Multivariate analysis of PTSD and LTE increased the effective sample size of the PTSD GWAS by 20% and identified 4 additional loci. Four of these 9 PTSD loci were independently replicated in the Million Veteran Program. CONCLUSIONS: Through using a quantitative trait measure of PTSD, we identified novel risk loci not previously identified using prior case-control analyses. PTSD and LTE have a high genetic overlap that can be leveraged to increase discovery power through multivariate methods.

Previous work identified a cognitive subtype of PTSD with impaired executive function (i.e., impaired EF-PTSD subtype) and aberrant resting-state functional connectivity between frontal parietal control (FPCN) and limbic (LN) networks. To better characterize this cognitive subtype of PTSD, this study investigated (1) alterations in specific FPCN and LN subnetworks and (2) chronicity of PTSD symptoms. In a post-9/11 veteran sample (N = 368, 89% male), we identified EF subgroups using a standardized neuropsychological battery and a priori cutoffs for impaired, average, and above-average EF performance. Functional connectivity between two subnetworks of the FPCN and three subnetworks of the LN was assessed using resting-state fMRI (n = 314). PTSD chronicity over a 1–2-year period was assessed using a reliable change index (n = 175). The impaired EF-PTSD subtype had significantly reduced negative functional connectivity between the FPCN subnetwork involved in top-down control of emotion and two LN subnetworks involved in learning/memory and social/emotional processing. This impaired EF-PTSD subtype had relatively chronic PTSD, while those with above-average EF and PTSD displayed greater symptom reduction. Lastly, FPCN-LN subnetworks partially mediated the relationship between EF and PTSD chronicity (n = 121). This study reveals (1) that an impaired EF-PTSD subtype has a specific pattern of FPCN-LN subnetwork connectivity, (2) a novel above-average EF-PTSD subtype displays reduced PTSD chronicity, and (3) both cognitive and neural functioning predict PTSD chronicity. The results indicate a need to investigate how individuals with this impaired EF-PTSD subtype respond to treatment, and how they might benefit from personalized and novel approaches that target these neurocognitive systems.

BACKGROUND: Posttraumatic stress disorder (PTSD) is associated with inflammation and various forms of chronic disease. The Absent in Melanoma 2 (AIM2) gene has been implicated in mechanisms of inflammation and anxiety, and methylation at a particular locus in this gene (cg10636246) has previously been shown to influence the association between PTSD and elevated C-reactive protein levels in blood. METHOD: We tested if this association might extend to other indicators of inflammation and to plasma-based measures of neuropathology in a cohort of post-9/11 US military veterans. Using a Bayesian approach, mediation models were tested cross-sectionally (n = 478) and longitudinally (n = 298). Peripheral markers of inflammation and neuropathology were measured with ultra-sensitive Single Molecule Array (Simoa®) technology. RESULTS: Analyses revealed indirect effects of PTSD symptom severity on peripheral indices of both inflammation (interleukin [IL]6, IL-10, tumor necrosis factor-α; indirect standardized [std.] ß range = 0.018-0.023, all p-values adjusted for multiple testing [p(adj) ] < 0.05) and neuropathology (neurofilament light [NFL]; indirect std. ß = -0.018, p(adj)  = 0.02) via AIM2 methylation. This indirect effect was also evident when predicting IL-10 at a follow-up assessment (indirect std. ß = -0.018, p(adj)  = 0.04) controlling for baseline IL-10. CONCLUSIONS: Given that AIM2 methylation mediated the association between PTSD symptoms and multiple inflammatory and neuropathology markers, our results suggest that AIM2 methylation may offer clinical utility for indexing risk for adverse health outcomes associated with these peripheral indices of inflammation and neuropathology. Results also suggest a possible shared etiology underlying the frequent co-occurrence of inflammation and neuropathology.

OBJECTIVE: More than one-third of women in the United States experience intimate partner violence (IPV) in their lifetime, increasing their risk for traumatic brain injury (TBI). Despite the prevalence of TBI among IPV survivors, research is sparse in comparison with parallel populations (eg, military, accidents, sports). This pilot study aimed to provide a preliminary investigation of the effect of TBI on brain morphometry and resting-state functional connectivity in women who experience IPV. PARTICIPANTS: A total of 45 community-dwelling women survivors of IPV who screened positive for posttraumatic stress disorder (PTSD). DESIGN: Participants completed comprehensive assessments of trauma exposure, PTSD, TBI history, and brain neurological health. Twenty-three participants (51.1%) met diagnostic criteria for lifetime TBI. Of these, 15 participants experienced 1 or more TBIs resulting from IPV. The remaining participants experienced TBI from non-IPV exposures (eg, sports/motor vehicle accident). Surface-based neuroimaging analyses were performed to examine group differences in cortical thickness and in functional connectivity of amygdala and isthmus cingulate seeds to examine emotion regulation and the default mode network, respectively. MAIN MEASURES: Boston Assessment of Traumatic Brain Injury-Lifetime for Intimate Partner Violence (BAT-L/IPV); Clinician Administered PTSD Scale (CAPS); structural and functional neuroimaging. RESULTS: History of lifetime TBI in women IPV survivors was associated with differences in cortical thickness as well as functional connectivity between the isthmus cingulate seed and a variety of regions, including superior parietal and frontal cortices. Individuals with IPV-related TBI showed lower cortical thickness in the right paracentral gyrus than individuals with TBI from other non-IPV etiologies. CONCLUSION: Significant differences in brain structure and connectivity were observed in individuals with IPV and TBI. A lower mean cortical thickness of the paracentral gyrus was associated with TBI due to IPV than TBI from other etiologies. Although preliminary, findings from this pilot study present a step toward identifying potential mechanisms by which IPV and TBI secondary to IPV impact brain health in women.

Mild traumatic brain injury (mTBI) is among the most common injuries sustained by post-9/11 veterans; however, these injuries often occur within the context of psychological trauma. Blast exposure, even in the absence of a diagnosable TBI, leads to changes in neural connectivity and congitive functioning. Therefore, considering clinical comorbidities and injury characteristics is critical to understanding the long-term effects of mTBI. Research is moving towards identifying diagnostic and prognostic blood-based biomarkers for TBI; however, few studies include other prevalent clinical and medical comorbidities related to deployment. Here, we present the initial cross-sectional relationships between plasma biomarkers, clinical, and medical comorbidities in a well-characterized longitudinal sample of 550 post-9/11 veteran men and women. We examined biomarkers associated with inflammation (interleukin 6 and 10, tumor necrosis factor α, and eotaxin) and neurodegeneration (neurofilament light, glial fibrillary acidic protein (GFAP), tau, brain derived neurotrophic factor, amyloid ß 40 and 42, phosphorylated neurofilament heavy chain, and neuron specific enolase). Univariate analyses of covariance (ANCOVA) were conducted to determine mean level differences between close blast (blasts that occur within 0-10 meters) and mTBI groups. Our primary findings were twofold: (1) Inflammatory markers were consistently higher in participants exposed to close blasts and were strongly related to deployment-related psychopathology. (2) GFAP was consistently lower in participants exposed to blast and mTBI and lower GFAP was associated with more severe psychological symptoms. More research is clearly needed; however, our findings indicate that chronic increased inflammation and decreased GFAP may be related to close blast exposure.

Veterans who served in post-9/11 conflicts and experience deployment trauma sequelae frequently endorse disability and dissatisfaction with life. Although correlated, disability and life dissatisfaction represent distinct constructs with separate implications for quality of life. We examined associations between deployment trauma sequelae, disability and life dissatisfaction in 288 post-9/11 Veterans. Participants completed assessments of psychiatric, somatic and social functioning. Self-reports evaluating disability and life dissatisfaction were used to group participants based on established criteria (i.e., Disability and Dissatisfaction, Disability Only, Dissatisfaction Only, or No Disability or Dissatisfaction). Multinomial logistic regressions revealed that greater post-traumatic stress disorder (PTSD) and depressive symptom severity were independently associated with increased odds of being in the Disability and Dissatisfaction group, the Disability Only group and the Dissatisfaction Only group, relative to the No Disability or Dissatisfaction group. Number of prior mild traumatic brain injuries (mTBI) was not associated with disability or dissatisfaction after accounting for other trauma sequelae. Social support attenuated the relationship between depression and membership in the Disability and Dissatisfaction group. Participants who reported greater dissatisfaction than disability endorsed greater depression and mTBI frequency. Overall, PTSD and depression convey a heightened risk of both disability and life dissatisfaction, while social support may be protective.

The Clinician-Administered PTSD Scale (CAPS) is used to measure posttraumatic stress symptoms (PTSS) and diagnose posttraumatic stress disorder (PTSD). However, its use, particularly in settings involving longitudinal assessment, has been complicated by changes in the diagnostic criteria between the fourth and fifth editions of the Diagnostic and Statistical Manual of Mental Disorders (i.e., DSM-IV and DSM-5, respectively). The current sample included trauma-exposed U.S. veterans who were deployed in support of military operations following the September 11, 2001, terrorist attacks (N = 371) and were enrolled in a longitudinal study focused on deployment-related stress and traumatic brain injury. A hybrid clinical interview using item wording from the CAPS for DSM-IV (CAPS-IV) with the addition of items unique to the CAPS for DSM-5 (CAPS-5) was used to assess both DSM-IV and DSM-5 PTSD diagnostic criteria, allowing for the calculation of separate total scores and diagnoses. Diagnostic agreement, sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), and interrater reliability between CAPS-IV and CAPS-5 were evaluated for the entire sample and stratified by gender. We found high diagnostic agreement (92.9%-95.4%), sensitivity (94.4%-98.2%), specificity (91.7%-92.8%), PPV (89.5%-93.0%), NPV (95.7%-98.1%), and interrater reliability,κ = 0.86-0.91,) for both men and women. The current study supports the use of a hybrid PTSD diagnostic interview assessing both DSM-IV and DSM-5 diagnostic criteria, particularly in situations such as longitudinal studies that may require a feasible method of incorporating changes in diagnostic criteria from the DSM-IV to the DSM-5.

Background: Adolescence is a critical period for neural development and has been associated with high rates of alcohol abuse. This research examined potential long-term brain and behavioral effects of early versus late-onset adolescent binge drinking in an adult sample of post-9/11 Veterans.Methods: We compared cortical thickness measures in Veterans with a history of binge drinking that began before the age of 15 (n = 50; mean age = 32.1 years) to those with a history of binge drinking with onset after the age of 15 (n = 300; mean age = 32.1 years). Data processing was conducted with FreeSurfer. A targeted neuropsychological battery (Digit Span test, Delis-Kaplan Executive Function System Color-Word Interference Test, California Verbal Learning Test-II) was used to examine the relationships between cortical thickness and attention, memory, and inhibition. A reference group of social drinkers with no history of early binge drinking (n = 31) was used to provide normative data.Results: Early-onset adolescent binge drinkers (EBD) had greater cortical thickness in several regions than late-onset adolescent binge drinkers (LBD); both binge-drinking groups had greater cortical thickness than the reference group. There was a stronger negative association between cortical thickness and age in EBDs than LBDs in the (i) lateral orbitofrontal cortex, (ii) supramarginal gyrus, (iii) paracentral lobule, and (iv) anterior caudal cingulate. Poorer performance on the attention and inhibition tasks in the EBDs was also associated with thicker cortices.Conclusions: This study demonstrates greater cortical thickness across frontoparietal regions in adults who began binge drinking in early versus late adolescence. A stronger negative association between cortical thickness and age in the EBDs suggests that early-onset adolescent binge drinking may be associated with accelerated cortical thinning. Thicker cortex in these regions, which are known to mediate inhibitory control, may increase impulsive behavior and contribute to the risk of alcohol addiction.Keywords: Magnetic Resonance Imaging; Veterans; alcohol; binge drinking; lifetime drinking history.

A growing number of studies have examined alterations in white matter organization in people with posttraumatic stress disorder (PTSD) using diffusion MRI (dMRI), but the results have been mixed which may be partially due to relatively small sample sizes among studies. Altered structural connectivity may be both a neurobiological vulnerability for, and a result of, PTSD. In an effort to find reliable effects, we present a multi-cohort analysis of dMRI metrics across 3047 individuals from 28 cohorts currently participating in the PGC-ENIGMA PTSD working group (a joint partnership between the Psychiatric Genomics Consortium and the Enhancing NeuroImaging Genetics through Meta-Analysis consortium). Comparing regional white matter metrics across the full brain in 1426 individuals with PTSD and 1621 controls (2174 males/873 females) between ages 18-83, 92% of whom were trauma-exposed, we report associations between PTSD and disrupted white matter organization measured by lower fractional anisotropy (FA) in the tapetum region of the corpus callosum (Cohen's d = -0.11, p = 0.0055). The tapetum connects the left and right hippocampus, for which structure and function have been consistently implicated in PTSD. Results were consistent even after accounting for the effects of multiple potentially confounding variables: childhood trauma exposure, comorbid depression, history of traumatic brain injury, current alcohol abuse or dependence, and current use of psychotropic medications. Our results show that PTSD may be associated with alterations in the broader hippocampal network.

Elevated serum C-reactive protein (CRP) and possessing an APOE ε4 allele are two of the most prominent risk factors for cognitive and neurological dysfunction in older adults, but little is known about the unique or cumulative effects of these risk factors in young-to-middle-aged adults. To further characterize these potential relationships, measures of cognition and microstructural white matter integrity were examined using data from a sample of 329 post-9/11 war veterans that was collected as part of a comprehensive evaluation that included assessment of neuropsychological functioning, MRI scanning, psychiatric diagnoses, health screening, markers of inflammation, and APOE genotypes. Hierarchical linear regression analyses revealed the CRP and APOE ε4 interaction was associated with global cognition (β = -0.633), executive functioning (β = -0.566), and global fractional anisotropy (β = -0.470), such that elevated CRP was associated with worse cognition and white matter integrity in APOE ε4 carriers. Diffusion tensor imaging (DTI) was used to determine if CRP × APOE ε4 presence was associated with regionally specific fractional anisotropy in white matter tracts. Tract-based spatial statistics revealed CRP × APOE ε4 presence was associated with fractional anisotropy in the corpus callosum, right superior longitudinal fasciculus, right posterior corona radiata, as well as the bilateral anterior and superior corona radiatas. This suggests that APOE ε4 carriers may be uniquely vulnerable to the potentially negative impact of elevated systematic inflammation to cognition and microstructural white matter integrity.