Prospective memory performance in veterans with and without histories of mild traumatic brain injury: effect of the apolipoprotein E (APOE) ε4 genotype.

OBJECTIVE: Identifying factors that moderate cognitive outcomes following mild traumatic brain injury (mTBI) is crucial. Prospective memory (PM) is a cognitive domain of interest in mTBI recovery as it may be especially sensitive to TBI-related changes. Since studies show that genetic status - particularly possession of the apolipoprotein E (APOE) ε4 allele - can modify PM performance, we investigated associations between mTBI status and APOE-ε4 genotype on PM performance in a well-characterized sample of Veterans with neurotrauma histories. METHODS: 59 Veterans (mTBI = 33, Military Controls [MCs] = 26; age range: 24-50; average years post-injury = 10.41) underwent a structured clinical interview, neuropsychological assessment, and genotyping. The Memory for Intentions Test (MIST) measured PM across multiple subscales. ANCOVAs, adjusting for age and posttraumatic stress symptoms, tested the effects of mTBI status (mTBI vs. MC) and ε4 status (ε4+ vs. ε4-) on MIST scores. RESULTS: Veterans with mTBI history performed more poorly compared to MCs on the MIST 15-min delay (p=.002, ηp2 =.160), Time Cue (p = .003, ηp2 =.157), and PM Total (p = .016, ηp2 =.102). Those with at least one copy of the ε4 allele performed more poorly compared to ε4- Veterans on the MIST 15-min delay (p = .011, ηp2 =.113) and PM Total (p = .048, ηp2 = .071). No significant interactions were observed between mTBI and APOE-ε4 status on MIST outcomes (ps>.25). Within the mTBI group, APOE-ε4+ Veterans performed worse than APOE-ε4- Veterans on the MIST 15-min delay subscale (p = .031, ηp2 = .150). CONCLUSIONS: mTBI history and APOE-ε4 genotype status were independently associated with worse PM performance compared to those without head injury histories or possession of the APOE-e4 genotype. Performance on the MIST 15-min delay was worse in Veterans with both risk factors (mTBI history and APOE-ε4 positivity). Findings suggest that genetic status may modify outcomes even in relatively young Veterans with mTBI histories. Future research examining longitudinal associations and links to neuroimaging and biomarker data are needed.

An extra X chromosome among adult women in the Million Veteran Program: A more benign perspective of trisomy X.

Despite affecting in 1 in every 1000 females, remarkably little is known about trisomy X syndrome (47,XXX), especially among older adults who are undiagnosed. In this study, we aimed to determine the prevalence of 47,XXX among females enrolled in the Million Veterans Program (MVP; mean age 50.2 ± 13.6 years), and compare broad health outcomes between females with 47,XXX and 46,XX matched controls. We identified 61 females with an additional X chromosome, corresponding to a prevalence of 103 per 100,000 females; 27.9% had been clinically diagnosed. Females with 47,XXX had taller stature (+6.1 cm, p < 0.001), greater rate of outpatient encounters (p = 0.026), higher odds of kidney disease (odds ratio [OR] = 12.3; 95% confidence interval [CI] 2.9-51.8), glaucoma (OR = 5.1; 95% CI 1.5-13.9), and congestive heart failure (OR = 5.6; 95% CI 1.4-24.2), and were more likely to be unemployed (p = 0.008) with lower annual income (p = 0.021) when compared with 46,XX controls of the same age and genetic ancestry. However, there were no differences in the rates of other encounter types, Charlson Comorbidity Index, all other medical and psychological diagnoses, military service history or quality of life metrics. In conclusion, in this aging and predominately undiagnosed sample, 47,XXX conferred few differences when compared with matched controls, offering a more reassuring perspective to the trisomy X literature.

Prevalence, Morbidity, and Mortality of Men With Sex Chromosome Aneuploidy in the Million Veteran Program Cohort.

Importance: The reported phenotypes of men with 47,XXY and 47,XYY syndromes include tall stature, multisystem comorbidities, and poor health-related quality of life (HRQOL). However, knowledge about these sex chromosome aneuploidy (SCA) conditions has been derived from studies in the less than 15% of patients who are clinically diagnosed and also lack diversity in age and genetic ancestry. Objectives: To determine the prevalence of clinically diagnosed and undiagnosed X or Y chromosome aneuploidy among men enrolled in the Million Veteran Program (MVP); to describe military service metrics of men with SCAs; and to compare morbidity and mortality outcomes between men with SCA with and without a clinical diagnosis vs matched controls. Design, Setting, and Participants: This cross-sectional study used a case-control recruitment design to select biological males enrolled in the MVP biobank in the US Veterans Administration health care system from 2011 to 2022. Cases were participants with 47,XXY syndrome or 47,XYY syndrome, matched 1:5 with controls based on sex, age, and genetic ancestry. Data were analyzed from January 2022 to December 2023. Exposure: Genomic identification of an additional X or Y chromosome. Main Outcomes and Measures: Outcomes of interest included prevalence of men with SCAs from genomic analysis; clinical SCA diagnosis; Charlson Comorbidity Index; rates of outpatient, inpatient, and emergency encounters per year; self-reported health outcomes; and standardized mortality ratio. Results: Of 595 612 genotyped males in the MVP, 862 had an additional X chromosome (47,XXY) and 747 had an extra Y chromosome (47,XYY), with the highest prevalence among men with East Asian (47,XXY: 10 of 7313 participants; 47,XYY: 14 of 7313 participants) and European (47,XXY: 725 of 427 143 participants; 47,XYY: 625 of 427 143 participants) ancestry. Mean (SD) age at assessment was 61 (12) years, at which point 636 veterans (74.X%) with 47,XXY and 745 veterans (99%) with 47,XYY remained undiagnosed. Individuals with 47,XXY and 47,XYY had similar military service history, all-cause standardized mortality ratio, and age of death compared with matched controls. Individuals with SCA, compared with controls, had higher Charlson Comorbidity Index scores (47,XXY: mean [SD], 4.30 [2.72] vs controls: mean [SD], 3.90 [2.47]; 47,XYY: mean [SD], 4.45 [2.90] vs controls: mean [SD], 3.82 [2.50]) and health care utilization (eg, median [IQR] outpatient encounters per year: 47,XXY, 22.6 [11.8-37.8] vs controls, 16.8 [9.4-28]; 47,XYY: 21.4 [12.4-33.8] vs controls: 17.0 [9.4-28.2]), while several measures of HRQOL were lower (eg, mean [SD] self-reported physical function: 47,XXY: 34.2 [12] vs control mean [SD] 37.8 [12.8]; 47,XYY: 36.3 [11.6] vs control 37.9 [12.8]). Men with a clinical diagnosis of 47,XXY, compared with individuals without a clinical diagnosis, had higher health care utilization (eg, median [IQR] encounters per year: 26.6 [14.9-43.2] vs 22.2 [11.3-36.0]) but lower Charlson Comorbidity Index scores (mean [SD]: 3.7 [2.7] vs 4.5 [4.1]). Conclusion and Relevance: In this case-control study of men with 47,XXY and 47,XYY syndromes, prevalence of SCA was comparable with estimates in the general population. While these men had successfully served in the military, they had higher morbidity and reported poorer HRQOL with aging. Longer longitudinal follow-up of this sample will be informative for clinical and patient-reported outcomes, the role of ancestry, and mortality statistics.

Symptom Attribution and Neuropsychological Outcomes Among Treatment-Seeking Veterans With a History of Traumatic Brain Injury.

OBJECTIVE: In this cross-sectional study, the authors aimed to examine relationships between illness perception, measured as symptom attribution, and neurobehavioral and neurocognitive outcomes among veterans with a history of traumatic brain injury (TBI). METHODS: This study included 55 treatment-seeking veterans (N=43 with adequate performance validity testing) with a remote history of TBI (80% with mild TBI). Veterans completed a clinical interview, self-report questionnaires, and a neuropsychological assessment. A modified version of the Neurobehavioral Symptom Inventory (NSI) was administered to assess neurobehavioral symptom endorsement and symptom attribution. Composite scores were calculated from standardized cognitive tests to assess specific aspects of objective cognitive functioning, including memory, executive functioning, attention and working memory, and processing speed. RESULTS: The symptoms most frequently attributed to TBI included forgetfulness, poor concentration, slowed thinking, and headaches. There was a significant positive association between symptom attribution and overall symptom endorsement (NSI total score) (r=0.675) and endorsement of specific symptom domains (NSI symptom domain scores) (r=0.506-0.674), indicating that greater attribution of symptoms to TBI was associated with greater symptom endorsement. Furthermore, linear regressions showed that symptom attribution was significantly associated with objective cognitive functioning, whereas symptom endorsement generally did not show this relationship. Specifically, greater attribution of symptoms to TBI was associated with worse executive functioning (ß=-0.34), attention and working memory (ß=-0.43), and processing speed (ß=-0.35). CONCLUSIONS: These findings suggest that veterans who routinely attribute neurobehavioral symptoms to their TBI are at greater risk of experiencing poor long-term outcomes, including elevated symptom endorsement and worse objective cognition. Although more research is needed to understand how illness perception influences outcomes in this population, these preliminary results highlight the importance of early psychoeducation regarding the anticipated course of recovery following TBI.

Evaluation of clinical outcomes and employment status in veterans with dual diagnosis of traumatic brain injury and spinal cord injury.

PURPOSE: To examine clinical outcomes and employment status in Veterans with and without a dual diagnosis of traumatic brain injury (TBI) and spinal cord injury (SCI). METHODS: This cross-sectional study examined a national sample of Veterans enrolled in the VA Million Veteran Program who completed the Comprehensive TBI Evaluation (CTBIE) as part of the Veterans Health Administration's TBI Screening and Evaluation Program. Veterans (N = 12,985) were classified into the following TBI/SCI groups using CTBIE data: those with a dual diagnosis of TBI and SCI (TBI+/SCI+); those with a history of TBI but no SCI (TBI+/SCI-); and those with no history of TBI or SCI (TBI-/SCI-; i.e., the control group). CTBIE-derived outcomes included neurobehavioral symptoms, comorbid psychiatric symptoms, pain and pain interference, and employment status. RESULTS: Chi-square analyses showed significant associations between TBI/SCI group and all clinical outcomes evaluated (all p's < .001; V = 0.07-0.11). In general, the TBI+/SCI+ and TBI +/SCI- groups endorsed comparable levels of neurobehavioral symptoms, psychiatric symptoms, and pain, but significantly greater rates of symptoms and pain relative to the TBI-/SCI- group. Effect sizes for all pairwise comparisons were small (φ = 0.01-0.11). Finally, there was no significant association between TBI/SCI group and employment status (p = .170; V = 0.02), with all three groups showing relatively comparable rates of unemployment. CONCLUSIONS: Regardless of SCI status, Veterans with TBI history endorsed poorer clinical outcomes than Veterans without TBI and SCI. However, rates of unemployment were similarly high across all three groups. Findings suggest that any Veteran completing the CTBIE may be at risk for poor clinical and employment outcomes.

Exploring Interactions Between Traumatic Brain Injury History and Gender on Medical Comorbidities in Military Veterans: An Epidemiological Analysis in the VA Million Veteran Program.

Epidemiological studies of medical comorbidities and possible gender differences associated with traumatic brain injury (TBI) are limited, especially among military veterans. The purpose of this study was to examine relationships between TBI history and a wide range of medical conditions in a large, national sample of veterans, and to explore interactions with gender. Participants of this cross-sectional epidemiological study included 491,604 veterans (9.9% TBI cases; 8.3% women) who enrolled in the VA Million Veteran Program (MVP). Outcomes of interest were medical comorbidities (i.e., neurological, mental health, circulatory, and other medical conditions) assessed using the MVP Baseline Survey, a self-report questionnaire. Logistic regression models adjusting for age and gender showed that veterans with TBI history consistently had significantly higher rates of medical comorbidities than controls, with the greatest differences observed across mental health (odds ratios [ORs] = 2.10-3.61) and neurological (ORs = 1.57-6.08) conditions. Similar patterns were found when evaluating men and women separately. Additionally, significant TBI-by-gender interactions were observed, particularly for mental health and neurological comorbidities, such that men with a history of TBI had greater odds of having several of these conditions than women with a history of TBI. These findings highlight the array of medical comorbidities experienced by veterans with a history of TBI, and illustrate that clinical outcomes differ for men and women with TBI history. Although these results are clinically informative, more research is needed to better understand the role of gender on health conditions in the context of TBI and how gender interacts with other social and cultural factors to influence clinical trajectories following TBI. Ultimately, understanding the biological, psychological, and social mechanisms underlying these comorbidities may help with tailoring TBI treatment by gender and improve quality of life for veterans with TBI history.

Phenotyping Depression After Mild Traumatic Brain Injury: Evaluating the Impact of Multiple Injury, Gender, and Injury Context.

The chronic mental health consequences of mild traumatic brain injury (TBI) are a leading cause of disability. This is surprising given the expectation of significant recovery after mild TBI, which suggests that other injury-related factors may contribute to long-term adverse outcomes. The objective of this study was to determine how number of prior injuries, gender, and environment/context of injury may contribute to depressive symptoms after mild TBI among deployed United States service members and veterans (SMVs). Data from the Long-term Impact of Military-Relevant Brain Injury Consortium Prospective Longitudinal Study was used to assess TBI injury characteristics and depression scores previously measured on the Patient Health Questionnaire-9 (PHQ-9) among a sample of 1456 deployed SMVs. Clinical diagnosis of mild TBI was defined via a multi-step process centered on a structured face-to-face interview. Logistical and linear regressions stratified by gender and environment of injury were used to model depressive symptoms controlling for sociodemographic and combat deployment covariates. Relative to controls with no history of mild TBI (n = 280), the odds ratios (OR) for moderate/severe depression (PHQ-9 ≥ 10) were higher for SMVs with one mild TBI (n = 358) OR: 1.62 (95% confidence interval [CI] 1.09-2.40, p = 0.016) and two or more mild TBIs (n = 818) OR: 1.84 (95% CI 1.31-2.59, p < 0.001). Risk differences across groups were assessed in stratified linear models, which found that depression symptoms were elevated in those with a history of multiple mild TBIs compared with those who had a single mild TBI (p < 0.001). Combat deployment-related injuries were also associated with higher depression scores than injuries occurring in non-combat or civilian settings (p < 0.001). Increased rates of depression after mild TBI persisted in the absence of post-traumatic stress disorder. Both men and women SMVs separately exhibited significantly increased depressive symptom scores if they had had combat-related mild TBI. These results suggest that contextual information, gender, and prior injury history may influence long-term mental health outcomes among SMVs with mild TBI exposure.

Symptom attribution is a stronger predictor of PVT-failure than symptom endorsement in treatment-seeking Veterans with remote mTBI history: A pilot study.

OBJECTIVE: To examine relationships between performance validity testing (PVT), neurobehavioral symptom endorsement, and symptom attribution in Veterans with a history of mild traumatic brain injury (mTBI). METHOD: Participants included treatment-seeking Veterans (n = 37) with remote mTBI histories who underwent a neuropsychological assessment and completed a modified version of the Neurobehavioral Symptom Inventory (NSI) to assess symptom endorsement and symptom attribution (the latter evaluated by having Veterans indicate whether they believed each NSI symptom was caused by their mTBI). Veterans were divided into two subgroups, PVT-Valid (n = 25) and PVT-Invalid (n = 12). RESULTS: Independent samples t-tests showed that two of five symptom endorsement variables and all five symptom attribution variables were significantly different between PVT groups (PVT-Invalid > PVT-Valid; Cohen's d = 0.67-1.02). Logistic regression analyses adjusting for PTSD symptoms showed that symptom endorsement (Nagelkerke's R2 = .233) and symptom attribution (Nagelkerke's R2 = .279) significantly distinguished between PVT groups. According to the Wald criterion, greater symptom endorsement (OR = 1.09) and higher attribution of symptoms to mTBI (OR = 1.21) each reliably predicted PVT-failure. CONCLUSIONS: While both symptom endorsement and symptom attribution were significantly associated with PVT-failure, our preliminary results suggest that symptom attribution is a stronger predictor of PVT-failure. Results highlight the importance of assessing symptom attribution to mTBI in this population.

Genome-wide association study of traumatic brain injury in U.S. military veterans enrolled in the VA million veteran program.

Large-scale genetic studies of traumatic brain injury (TBI) are lacking; thus, our understanding of the influence of genetic factors on TBI risk and recovery is incomplete. This study aimed to conduct a genome-wide association study (GWAS) of TBI in VA Million Veteran Program (MVP) enrollees. Participants included a multi-ancestry cohort (European, African, and Hispanic ancestries; N = 304,485; 111,494 TBI cases, 192,991 controls). TBI was assessed using MVP survey data and International Classification of Diseases (ICD) codes from the Veterans Health Administration's electronic health record. GWAS was performed using logistic regression in PLINK, and meta-analyzed in METAL. FUMA was used for post-GWAS analysis. Genomic structural equation modeling (gSEM) was conducted to investigate underlying genetic associations with TBI, and bivariate MiXeR was used to estimate phenotype specific and shared polygenicity. SNP-based heritability was 0.060 (SE = 0.004, p = 7.83×10-66). GWAS analysis identified 15 genome-wide significant (GWS) loci at p < 5×10-8. Gene-based analyses revealed 14 gene-wide significant genes; top genes included NCAM1, APOE, FTO, and FOXP2. Gene tissue expression analysis identified the brain as significantly enriched, particularly in the frontal cortex, anterior cingulate cortex, and nucleus accumbens. Genetic correlations with TBI were significant for risk-taking behaviors and psychiatric disorders, but generally not significant for the neurocognitive variables investigated. gSEM analysis revealed stronger associations with risk-taking traits than with psychiatric traits. Finally, the genetic architecture of TBI was similar to polygenic psychiatric disorders. Neurodegenerative disorders including Alzheimer's and Parkinson's disease showed much less polygenicity, however, the proportion of shared variance with TBI was high. This first well-powered GWAS of TBI identified 15 loci including genes relevant to TBI biology, and showed that TBI is a heritable trait with comparable genetic architecture and high genetic correlation with psychiatric traits. Our findings set the stage for future TBI GWASs that focus on injury severity and diversity and chronicity of symptom sequelae.

Research Letter: TBI Severity Moderates the Association Between Subjective and Objective Attention in Older Veterans.

OBJECTIVE: This study examined the moderating effect of traumatic brain injury (TBI) history on subjective and objective cognition across multiple cognitive domains. SETTING, PARTICIPANTS, AND DESIGN: Participants included 242 Vietnam-era veterans with a history of no TBI (n = 86), mild TBI (n = 74), or moderate-to-severe TBI (n = 82) from the observational Department of Defense-Alzheimer's Disease Neuroimaging Initiative (DoD-ADNI) study. MAIN MEASURES: Objective cognition was the outcome and was measured using neuropsychological measures in the domains of memory, attention/executive functioning, and language. Subjective cognition was measured using the memory, divided attention, and language subscales from the Everyday Cognition (ECog) measure. TBI severity status was the moderating variable. RESULTS: Veterans with a history of moderate-to-severe TBI had a stronger negative association between subjective and objective attention relative to participants without a TBI (P = .002). Although this association did not differ between mild TBI and no TBI history groups (P = .100), the association between subjective and objective attention for the mild TBI group was intermediate to the no TBI and moderate-to-severe TBI history groups. TBI status did not moderate associations between subjective and objective memory or language. CONCLUSION: Results highlight the importance of assessing subjective and objective cognition in older veterans and the relevance of attention in the context of TBI history. More work is needed to better understand the intersection of TBI and aging and how these factors may be used to guide individualized assessment and treatment approaches for older veterans.

Measurement Invariance of the Neurobehavioral Symptom Inventory in Male and Female Million Veteran Program Enrollees Completing the Comprehensive Traumatic Brain Injury Evaluation.

This study evaluated measurement invariance across males and females on the Neurobehavioral Symptom Inventory (NSI) in U.S. military veterans enrolled in the VA Million Veteran Program. Participants (N = 17,059; males: n = 15,450; females: n = 1,609) included Veterans who took part in the VA Traumatic Brain Injury (TBI) Screening and Evaluation Program and completed the NSI. Multiple-group confirmatory factor analyses investigated measurement invariance of the NSI 4-factor model. The configural (comparative fit index [CFI] = 0.948, root mean square error of approximation [RMSEA] = 0.060) and metric (CFI = 0.948, RMSEA = 0.058) invariance models showed acceptable fit. There was a minor violation of scalar invariance (Δχ2 = 232.50, p < .001); however, the degree of noninvariance was mild (ΔCFI = -0.002, ΔRMSEA=0.000). Our results demonstrate measurement invariance across sex, suggesting that the NSI 4-factor model can be used to accurately assess symptoms in males and females following TBI. Findings highlight the importance of considering validity of measurement across study groups to increase confidence that a measure is interpreted similarly by respondents from different subgroups.

Prevalence, Morbidity, and Mortality of 1,609 Men with Sex Chromosome Aneuploidy: Results from the Diverse Million Veteran Program Cohort.

Importance: The reported phenotypes of men with 47,XXY and 47,XYY syndromes include tall stature, multisystem comorbidities, and poor health-related quality of life (HRQoL). However, knowledge about these sex chromosome aneuploidy (SCA) conditions has been derived from studies in the <15% of patients who are clinically diagnosed and also lack diversity in age and genetic ancestry. Objectives: Determine the prevalence of clinically diagnosed and undiagnosed X or Y chromosome aneuploidy among men enrolled in the Million Veteran Program (MVP); describe military service metrics of men with SCAs; compare morbidity and mortality outcomes between men with SCA with and without a clinical diagnosis to matched controls. Design: Cross-sectional, case-control. Setting: United States Veterans Administration Healthcare System. Participants: Biologic males enrolled in the MVP biobank with genomic identification of an additional X or Y chromosome (cases); controls matched 1:5 on sex, age, and genetic ancestry. Main Outcomes and Measures: Prevalence of men with SCAs from genomic analysis; clinical SCA diagnosis; Charlson Comorbidity Index (CCI); rates of outpatient, inpatient, and emergency encounters per year; self-reported health outcomes; standardized mortality ratio (SMR). Results: An additional X or Y chromosome was present in 145 and 125 per 100,000 males in the MVP, respectively, with the highest prevalence among men with European and East Asian ancestry. At a mean age of 61±12 years, 74% of male veterans with 47,XXY and >99% with 47,XYY remained undiagnosed. Individuals with 47,XXY (n=862) and 47,XYY (n=747) had similar military service history, all-cause SMR, and age of death compared to matched controls. CCI and healthcare utilization were higher among individuals with SCA, while several measures of HRQoL were lower. Men with a clinical diagnosis of 47,XXY had higher healthcare utilization but lower comorbidity score compared to those undiagnosed. Conclusion and Relevance: One in 370 males in the MVP cohort have SCA, a prevalence comparable to estimates in the general population. While these men have successfully served in the military, they have higher morbidity and report poorer HRQoL with aging. Longer longitudinal follow-up of this sample will be informative for clinical and patient-reported outcomes, the role of ancestry, and mortality statistics. KEY POINTS: Comparable to the general population, approximately 1 in 370 male veterans have a sex chromosome aneuploidy, but most are undiagnosed.Men with X or Y chromosome aneuploidy successfully complete US miliary duty with similar service history compared to their 46,XY peers.Medical comorbidities and healthcare utilization metrics are higher in male veterans with 47,XXY and 47,XYY during aging, however life expectancy is similar to matched controls.

Diversity and Scale: Genetic Architecture of 2,068 Traits in the VA Million Veteran Program.

Genome-wide association studies (GWAS) have underrepresented individuals from non-European populations, impeding progress in characterizing the genetic architecture and consequences of health and disease traits. To address this, we present a population-stratified phenome-wide GWAS followed by a multi-population meta-analysis for 2,068 traits derived from electronic health records of 635,969 participants in the Million Veteran Program (MVP), a longitudinal cohort study of diverse U.S. Veterans genetically similar to the respective African (121,177), Admixed American (59,048), East Asian (6,702), and European (449,042) superpopulations defined by the 1000 Genomes Project. We identified 38,270 independent variants associating with one or more traits at experiment-wide P<4.6×10-11 significance; fine-mapping 6,318 signals identified from 613 traits to single-variant resolution. Among these, a third (2,069) of the associations were found only among participants genetically similar to non-European reference populations, demonstrating the importance of expanding diversity in genetic studies. Our work provides a comprehensive atlas of phenome-wide genetic associations for future studies dissecting the architecture of complex traits in diverse populations.

Subjective memory complaints are associated with decreased cortical thickness in Veterans with histories of mild traumatic brain injury.

Objective: Memory problems are frequently endorsed in Veterans following mild traumatic brain injury (mTBI), but subjective complaints are poorly associated with objective memory performance. Few studies have examined associations between subjective memory complaints and brain morphometry. We investigated whether self-reported memory problems were associated with objective memory performance and cortical thickness in Veterans with a history of mTBI. Methods: 40 Veterans with a history of remote mTBI and 29 Veterans with no history of TBI completed the Prospective-Retrospective Memory Questionnaire (PRMQ), PTSD Checklist (PCL), California Verbal Learning Test-2nd edition (CVLT-II), and 3 T T1 structural magnetic resonance imaging. Cortical thickness was estimated in 14 a priori frontal and temporal regions. Multiple regressions adjusting for age and PCL scores examined associations between PRMQ, CVLT-II scores, and cortical thickness within each Veteran group. Results: Greater subjective memory complaints on the PRMQ were associated with lower cortical thickness in the right middle temporal gyrus (ß = 0.64, q = .004), right inferior temporal gyrus (ß = 0.56, q = .014), right rostral middle frontal gyrus (ß = 0.45, q = .046), and right rostral anterior cingulate gyrus (ß = 0.58, q = .014) in the mTBI group but not the control group (q's > .05). These associations remained significant after adjusting for CVLT-II learning. CVLT-II performance was not associated with PRMQ score or cortical thickness in either group. Conclusions: Subjective memory complaints were associated with lower cortical thickness in right frontal and temporal regions, but not with objective memory performance, in Veterans with histories of mTBI. Subjective complaints post-mTBI may indicate underlying brain morphometry independently of objective cognitive testing.

Association of African Ancestry-Specific APOE Missense Variant R145C With Risk of Alzheimer Disease.

Importance: Numerous studies have established the association of the common APOE ε2 and APOE ε4 alleles with Alzheimer disease (AD) risk across ancestries. Studies of the interaction of these alleles with other amino acid changes on APOE in non-European ancestries are lacking and may improve ancestry-specific risk prediction. Objective: To determine whether APOE amino acid changes specific to individuals of African ancestry modulate AD risk. Design, Setting, and Participants: Case-control study including 31 929 participants and using a sequenced discovery sample (Alzheimer Disease Sequencing Project; stage 1) followed by 2 microarray imputed data sets derived from the Alzheimer Disease Genetic Consortium (stage 2, internal replication) and the Million Veteran Program (stage 3, external validation). This study combined case-control, family-based, population-based, and longitudinal AD cohorts, which recruited participants (1991-2022) in primarily US-based studies with 1 US/Nigerian study. Across all stages, individuals included in this study were of African ancestry. Exposures: Two APOE missense variants (R145C and R150H) were assessed, stratified by APOE genotype. Main Outcomes and Measures: The primary outcome was AD case-control status, and secondary outcomes included age at AD onset. Results: Stage 1 included 2888 cases (median age, 77 [IQR, 71-83] years; 31.3% male) and 4957 controls (median age, 77 [IQR, 71-83] years; 28.0% male). In stage 2, across multiple cohorts, 1201 cases (median age, 75 [IQR, 69-81] years; 30.8% male) and 2744 controls (median age, 80 [IQR, 75-84] years; 31.4% male) were included. In stage 3, 733 cases (median age, 79.4 [IQR, 73.8-86.5] years; 97.0% male) and 19 406 controls (median age, 71.9 [IQR, 68.4-75.8] years; 94.5% male) were included. In ε3/ε4-stratified analyses of stage 1, R145C was present in 52 individuals with AD (4.8%) and 19 controls (1.5%); R145C was associated with an increased risk of AD (odds ratio [OR], 3.01; 95% CI, 1.87-4.85; P = 6.0 × 10-6) and was associated with a reported younger age at AD onset (ß, -5.87 years; 95% CI, -8.35 to -3.4 years; P = 3.4 × 10-6). Association with increased AD risk was replicated in stage 2 (R145C was present in 23 individuals with AD [4.7%] and 21 controls [2.7%]; OR, 2.20; 95% CI, 1.04-4.65; P = .04) and was concordant in stage 3 (R145C was present in 11 individuals with AD [3.8%] and 149 controls [2.7%]; OR, 1.90; 95% CI, 0.99-3.64; P = .051). Association with earlier AD onset was replicated in stage 2 (ß, -5.23 years; 95% CI, -9.58 to -0.87 years; P = .02) and stage 3 (ß, -10.15 years; 95% CI, -15.66 to -4.64 years; P = 4.0 × 10-4). No significant associations were observed in other APOE strata for R145C or in any APOE strata for R150H. Conclusions and Relevance: In this exploratory analysis, the APOE ε3[R145C] missense variant was associated with an increased risk of AD among individuals of African ancestry with the ε3/ε4 genotype. With additional external validation, these findings may inform AD genetic risk assessment in individuals of African ancestry.

Self-reported physical functioning, cardiometabolic health conditions, and health care utilization patterns in Million Veteran Program enrollees with Traumatic Brain Injury Screening and Evaluation Program data.

BACKGROUND: Examining the health outcomes of veterans who have completed the United States Veterans Health Administration's (VHA's) Traumatic Brain Injury (TBI) Screening and Evaluation Program may aid in the refinement and improvement of clinical care initiatives within the VHA. This study compared self-reported physical functioning, cardiometabolic health conditions, and health care utilization patterns in Million Veteran Program enrollees with TBI Screening and Evaluation Program data (collected between 2007 and 2019), with the goal of enhancing understanding of potentially modifiable health conditions in this population. METHODS: In this observational cohort study, veterans (n = 16,452) were grouped based on the diagnostic outcome of the TBI Screening and Evaluation Program: 1) negative TBI screen (Screen-); 2) positive TBI screen but no confirmed TBI diagnosis [Screen+/ Comprehensive TBI Evaluation (CTBIE)-]; or 3) positive TBI screen and confirmed TBI diagnosis (Screen+/CTBIE+). Chi-square tests and analysis of covariance were used to explore group differences in physical functioning, cardiometabolic health conditions, and health care utilization patterns, and logistic regressions were used to examine predictors of Screen+/- and CTBIE+/- group status. RESULTS: The results showed that veterans in the Screen+/CTBIE- and Screen+/CTBIE+ groups generally reported poorer levels of physical functioning (P's < 0.001, np2 = 0.02 to 0.03), higher rates of cardiometabolic health conditions (P's < 0.001, φ = 0.14 to 0.52), and increased health care utilization (P's < 0.001, φ = 0.14 to > 0.5) compared with the Screen- group; however, health outcomes were generally comparable between the Screen+/CTBIE- and Screen+/CTBIE+ groups. Follow-up analyses confirmed that while physical functioning, hypertension, stroke, healthcare utilization, and prescription medication use reliably distinguished between the Screen- and Screen+ groups (P's < 0.02, OR's 0.78 to 3.38), only physical functioning distinguished between the Screen+/CTBIE- and Screen+/CTBIE+ groups (P < 0.001, OR 0.99). CONCLUSIONS: The findings suggest that veterans who screen positive for TBI, regardless of whether they are ultimately diagnosed with TBI, are at greater risk for negative health outcomes, signifying that these veterans represent a vulnerable group that may benefit from increased clinical care and prevention efforts.

An Examination of Racial/Ethnic Differences on the Neurobehavioral Symptom Inventory Among Veterans Completing the Comprehensive Traumatic Brain Injury Evaluation: A Veterans Affairs Million Veteran Program Study.

OBJECTIVE: The purpose of this study was to explore racial/ethnic differences in neurobehavioral symptom reporting and symptom validity testing among military veterans with a history of traumatic brain injury (TBI). METHOD: Participants of this observational cross-sectional study (N = 9,646) were post-deployed Iraq-/Afghanistan-era veterans enrolled in the VA's Million Veteran Program with a clinician-confirmed history of TBI on the Comprehensive TBI Evaluation (CTBIE). Racial/ethnic groups included White, Black, Hispanic, Asian, Multiracial, Another Race, American Indian or Alaska Native, and Native Hawaiian or Other Pacific Islander. Dependent variables included neurobehavioral symptom domains and symptom validity assessed via the Neurobehavioral Symptom Inventory (NSI) and Validity-10, respectively. RESULTS: Chi-square analyses showed significant racial/ethnic group differences for vestibular, somatic/sensory, and affective symptoms as well as for all Validity-10 cutoff scores examined (≥33, ≥27, ≥26, >22, ≥22, ≥13, and ≥7). Follow-up analyses compared all racial/ethnic groups to one another, adjusting for sociodemographic- and injury-related characteristics. These analyses revealed that the affective symptom domain and the Validity-10 cutoff of ≥13 revealed the greatest number of racial/ethnic differences. CONCLUSIONS: Results showed significant racial/ethnic group differences on neurobehavioral symptom domains and symptom validity testing among veterans who completed the CTBIE. An enhanced understanding of how symptoms vary by race/ethnicity is vital so that clinical care can be appropriately tailored to the unique needs of all veterans. Results highlight the importance of establishing measurement invariance of the NSI across race/ethnicity and underscore the need for ongoing research to determine the most appropriate Validity-10 cutoff score(s) to use across racially/ethnically diverse veterans.

African ancestry GWAS of dementia in a large military cohort identifies significant risk loci.

While genome wide association studies (GWASs) of Alzheimer's Disease (AD) in European (EUR) ancestry cohorts have identified approximately 83 potentially independent AD risk loci, progress in non-European populations has lagged. In this study, data from the Million Veteran Program (MVP), a biobank which includes genetic data from more than 650,000 US Veteran participants, was used to examine dementia genetics in an African descent (AFR) cohort. A GWAS of Alzheimer's disease and related dementias (ADRD), an expanded AD phenotype including dementias such as vascular and non-specific dementia that included 4012 cases and 18,435 controls age 60+ in AFR MVP participants was performed. A proxy dementia GWAS based on survey-reported parental AD or dementia (n = 4385 maternal cases, 2256 paternal cases, and 45,970 controls) was also performed. These two GWASs were meta-analyzed, and then subsequently compared and meta-analyzed with the results from a previous AFR AD GWAS from the Alzheimer's Disease Genetics Consortium (ADGC). A meta-analysis of common variants across the MVP ADRD and proxy GWASs yielded GWAS significant associations in the region of APOE (p = 2.48 × 10-101), in ROBO1 (rs11919682, p = 1.63 × 10-8), and RNA RP11-340A13.2 (rs148433063, p = 8.56 × 10-9). The MVP/ADGC meta-analysis yielded additional significant SNPs near known AD risk genes TREM2 (rs73427293, p = 2.95 × 10-9), CD2AP (rs7738720, p = 1.14 × 10-9), and ABCA7 (rs73505251, p = 3.26 × 10-10), although the peak variants observed in these genes differed from those previously reported in EUR and AFR cohorts. Of the genes in or near suggestive or genome-wide significant associated variants, nine (CDA, SH2D5, DCBLD1, EML6, GOPC, ABCA7, ROS1, TMCO4, and TREM2) were differentially expressed in the brains of AD cases and controls. This represents the largest AFR GWAS of AD and dementia, finding non-APOE GWAS-significant common SNPs associated with dementia. Increasing representation of AFR participants is an important priority in genetic studies and may lead to increased insight into AD pathophysiology and reduce health disparities.

Alzheimer's disease and related dementias among aging veterans: Examining gene-by-environment interactions with post-traumatic stress disorder and traumatic brain injury.

INTRODUCTION: Post-traumatic stress disorder (PTSD) and traumatic brain injury (TBI) confer risk for Alzheimer's disease and related dementias (ADRD). METHODS: This study from the Million Veteran Program (MVP) evaluated the impact of apolipoprotein E (APOE) ε4, PTSD, and TBI on ADRD prevalence in veteran cohorts of European ancestry (EA; n = 11,112 ADRD cases, 170,361 controls) and African ancestry (AA; n = 1443 ADRD cases, 16,191 controls). Additive-scale interactions were estimated using the relative excess risk due to interaction (RERI) statistic. RESULTS: PTSD, TBI, and APOE ε4 showed strong main-effect associations with ADRD. RERI analysis revealed significant additive APOE ε4 interactions with PTSD and TBI in the EA cohort and TBI in the AA cohort. These additive interactions indicate that ADRD prevalence associated with PTSD and TBI increased with the number of inherited APOE ε4 alleles. DISCUSSION: PTSD and TBI history will be an important part of interpreting the results of ADRD genetic testing and doing accurate ADRD risk assessment.

APOE & BDNF polymorphisms interact to affect memory performance at baseline in adolescent athletes.

Although several single-nucleotide polymorphisms have been associated with cognitive functioning in a variety of healthy and clinical samples, the influence of gene × gene interactions on cognition is poorly understood. The purpose of this study was to examine interactive relationships between apolipoprotein E (APOE) and brain-derived neurotrophic factor (BDNF) polymorphisms on cognitive functioning in a sample of healthy adolescent athletes. Participants of this cross-sectional study included 78 student-athletes (52.6% male; age: M = 13.31, SD = 1.23). Athletes completed the Immediate Post-Concussion and Cognitive Testing (ImPACT) computerized battery at baseline. APOE and BDNF genotypes were determined with buccal samples (APOE ε4+: n = 26; APOE ε4-: n = 52; BDNF Met+: n = 23; BDNF Met-: n = 55). Two-way analyses of variance (ANOVAs) were used to evaluate the associations among APOE (ε4+ vs. ε4-) and BDNF (Met+ vs. Met-) genotypes and the ImPACT cognitive composites and two-factor model. No main effects were observed for either APOE or BDNF genotypes across the cognitive outcomes. However, there was a significant APOE × BDNF genotype interaction for the verbal (p=.009, ηp2=.091) and visual (p = .012, ηp2=.082) memory composites and the memory factor (p = .001, ηp2=.133), such that ε4+/Met+ carriers demonstrated poorer performance relative to other allele combinations. No significant interactions were observed for the visual motor speed (p = .263, ηp2=.017) or reaction time (p = .825, ηp2=.001) composites or the speed factor (p = .205, ηp2=.022). Our findings suggest an important relationship between APOE and BDNF genotypes on verbal and visual memory performance in healthy adolescent athletes. Clinicians may use this information to offer individualized concussion management based on individual athlete characteristics related to genetics and cognition.