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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.

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.

We examined whether intraindividual variability (IIV) across tests of executive functions (EF-IIV) is elevated in Veterans with a history of mild traumatic brain injury (mTBI) relative to military controls (MCs) without a history of mTBI. We also explored relationships among EF-IIV, white matter microstructure, and posttraumatic stress disorder (PTSD) symptoms. A total of 77 Veterans (mTBI = 43, MCs = 34) completed neuropsychological testing, diffusion tensor imaging (DTI), and PTSD symptom ratings. EF-IIV was calculated as the standard deviation across six tests of EF, along with an EF-Mean composite. DSI Studio connectometry analysis identified white matter tracts significantly associated with EF-IIV according to generalized fractional anisotropy (GFA). After adjusting for EF-Mean and PTSD symptoms, the mTBI group showed significantly higher EF-IIV than MCs. Groups did not differ on EF-Mean after adjusting for PTSD symptoms. Across groups, PTSD symptoms significantly negatively correlated with EF-Mean, but not with EF-IIV. EF-IIV significantly negatively correlated with GFA in multiple white matter pathways connecting frontal and more posterior regions. Veterans with mTBI demonstrated significantly greater IIV across EF tests compared to MCs, even after adjusting for mean group differences on those measures as well as PTSD severity. Findings suggest that, in contrast to analyses that explore effects of mean performance across tests, discrepancy analyses may capture unique variance in neuropsychological performance and more sensitively capture cognitive disruption in Veterans with mTBI histories. Importantly, findings show that EF-IIV is negatively associated with the microstructure of white matter pathways interconnecting cortical regions that mediate executive function and attentional processes.

Objective:Many Operation Enduring Freedom/Operation Iraqi Freedom (OEF/OIF) Veterans have sustained a mild traumatic brain injury (mTBI) during their military service and a substantial “miserable minority” frequently report significant cognitive complaints long after injury. Although existing studies have shown associations between genetic factors (e.g., apolipoprotein E [APOE] and brain-derived neurotrophic factor [BDNF]) and cognitive performance in this vulnerable population, the TBI-genetics literature has generally been varied and inconsistent. Although past findings suggest that individuals who possess APOE £4 and BDNF Met alleles have worse cognitive outcomes after mTBI, this has not been consistently reported. Additionally, the influence of any gene-by-gene interactions on cognition has not been sufficiently explored and therefore remains a critical area of interest. Thus, we examined relationships between APOE and BDNF genotypes on neuropsychological function in a well-characterized sample of younger Veterans with mTBI histories.Participants and Methods:Participants included Veterans with a history of mTBI who adequately completed performance validity testing. In total, 78 Veterans (84.6% male; age: M=32.95, SD=7.00; race/ethnicity: 51.3% White, 28.2% Hispanic/Latino, and 20.5% Another Race/Ethnicity) completed a structured clinical interview to collect detailed information on TBI history and underwent a comprehensive neuropsychological exam. A buccal swab was also collected to determine APOE and BDNF allele status for each participant. Three cognitive composite scores were computed reflecting memory (8 items), attention/processing speed (7 items), and executive functioning (10 items). Two-way analyses of covariance (ANCOVAs) adjusting for age, sex, and race/ethnicity were used to assess the effects of APOE (ε4+ vs. ε4-) and BDNF (Met+ vs. Met-) on cognitive functioning (ε4+/Met-: n=12, ε4+/Met+: n=8, £4-/Met-: n=35, and ε4-/Met+: n=23).Results:ANCOVAs revealed no significant main effects for APOE or BDNF genotypes on cognitive functioning; however, there was a significant APOE x BDNF genotype interaction for all three cognitive composites (memory: p=.026, np2=.068; attention/processing speed: p=.045, np2=.055; and executive functioning: p=.031, np2=.064). Specifically, the interaction was such that Veterans in the ε4+/Met+ group demonstrated the poorest cognitive functioning relative to all other allele group combinations (ε4+/Met-, ε4-/Met+, ε4-/Met-).Conclusions:The results of this preliminary study demonstrate that, compared to the other genetic subgroups in the TBI sample, Veterans with APOE £4 and BDNF Met alleles demonstrated the poorest cognitive functioning across several domains known to be negatively affected in the context of head injury (i.e., memory, attention/processing speed, and executive functioning). These findings are the first to show an APOE x BDNF interaction in Veterans with histories of mTBI. Furtherresearch is necessary to replicate and extend this study in larger samples. Moreover, future work should incorporate neuroimaging variables to better interrogate structural and functional correlates of these observed genetic polymorphism associations in Veterans with mTBI histories.

Background As biobank‐scale cohorts emerge, there has been a great increase in the number of dementia cases available for genetic meta‐analyses, resulting in a substantial increase in the number of dementia risk variants identified and replicated. Although also increasing, the number of non‐European ancestry participants in most of these studies is still substantially lower. Although primarily European ancestry (EUR), the Million Veteran Program (MVP) contains a substantial proportion of African (AFR) and Hispanic (HIS) ancestry participants. Here, we analyzed three dementia phenotypes in MVP, and meta‐analyzed them with publicly available dementia summary statistics. Methods Three phenotypes were analyzed in MVP (Table 1): 1) Alzheimer's disease and related dementias (ADRD), defined by two or more ADRD treatment codes in electronic medical records (EMR); 2) prescriptions for medications to treat dementia (e.g. cholinesterase inhibitors), also from EMR; 3) maternal and paternal proxy dementia as reported in MVP surveys. These analyses were independent, with non‐overlapping case/control sets. We first performed GWAS of these phenotypes within MVP ancestry groups (EUR, AFR, HIS), adjusting for sex and ancestry principal components. These were used along with Bellenguez et al. 2022, and AFR statistics from Kunkle et al. 2021 to generate a EUR MVP meta‐analysis, an MVP/Bellenguez EUR meta‐analysis, and a cross‐ancestry meta‐analysis using MR Mega. Novel regions were defined as genome‐wide significant (GWS) loci at least 250KB from the peak SNP in previous GWASs, and if within 1MB of that SNP, had a pairwise r2<0.2. Results We identified 19 novel, GWS regions in EUR, five in MVP EUR, and 14 in the meta‐analysis (Table 2). We identified 11 novel regions in the cross‐ancestry meta. Two genes, PAX7 and PTPRD (not novel, but previously only observed in HIS), were unique to the AFR and HIS cohorts (Table 3). Conclusion The MVP‐specific genes may be involved in processes related to more general (not AD specific) dementia pathways or have stronger effects in males. Several of the novel genes identified in EUR and cross‐ancestry meta‐analysis are involved in neuronal development and function or have been linked to cognitive outcomes.

The purpose of this study was to evaluate whether loss of consciousness (LOC), retrograde amnesia (RA), and anterograde amnesia (AA) independently influence a particular aspect of post-concussion cognitive functioning-across-test intra-individual variability (IIV), or cognitive dispersion. Concussed athletes (N = 111) were evaluated, on average, 6.04 days post-injury (SD = 5.90; Mdn = 4 days; Range = 1-26 days) via clinical interview and neuropsychological assessment. Primary outcomes of interest included two measures of IIV-an intra-individual standard deviation (ISD) score and a maximum discrepancy (MD) score-computed from 18 norm-referenced variables. Analyses of covariance (ANCOVAs) adjusting for time since injury and sex revealed a significant effect of LOC on the ISD (p = .018, ηp2 = .051) and MD (p = .034, ηp2 = .041) scores, such that athletes with LOC displayed significantly greater IIV than athletes without LOC. In contrast, measures of IIV did not significantly differ between athletes who did and did not experience RA or AA (all p > .05). LOC, but not RA or AA, was associated with greater variability, or inconsistencies, in cognitive performance acutely following concussion. Though future studies are needed to verify the clinical significance of these findings, our results suggest that LOC may contribute to post-concussion cognitive dysfunction and may be a risk factor for less efficient cognitive functioning.

PurposeTo examine clinical outcomes and employment status in Veterans with and without a dual diagnosis of traumatic brain injury (TBI) and spinal cord injury (SCI).MethodsThis 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.ResultsChi-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.ConclusionsRegardless 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.

Purpose This study examined the clinical utility of post-traumatic stress disorder (PTSD), low resilience, poor sleep, and lifetime blast exposure as risk factors for predicting future neurobehavioral outcome following traumatic brain injury (TBI). Methods Participants were 591 U.S. military service members and veterans who had sustained a TBI ( n  = 419) or orthopedic injury without TBI ( n  = 172). Participants completed the Neurobehavioral Symptom Inventory, PTSD Checklist, and the TBI-Quality of Life (TBI-QOL) scale at baseline and follow-up. Results Using the four risk factors at baseline, 15 risk factor combinations were examined by calculating odds ratios to predict poor neurobehavioral outcome at follow-up (i.e., number of abnormal scores across five TBI-QOL scales [e.g., Fatigue, Depression]). The vast majority of risk factor combinations resulted in odds ratios that were considered to be clinically meaningful (i.e., ≥ 2.5) for predicting poor outcome. The risk factor combinations with the highest odds ratios included PTSD singularly, or in combination with poor sleep and/or low resilience (odds ratios = 4.3–72.4). However, poor sleep and low resilience were also strong predictors in the absence of PTSD (odds ratios = 3.1–29.8). Conclusion PTSD, poor sleep, and low resilience, singularly or in combination, may be valuable risk factors that can be used clinically for targeted early interventions.

As few studies have examined the relationship between the apolipoprotein E (APOE) gene and clinical outcomes after 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, Beck Anxiety Inventory, and PTSD Checklist-Military Version. 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 <0.001), no main effect of ε4 genotype (p = 0.152–0.222), and a significant interaction of group by ε4 genotype across all measures (p = 0.027–0.047). Specifically, for TBI participants, ε4+ veterans demonstrated significantly higher symptom scores across all measures when compared to ε4– veterans (p = 0.007–0.015). For MC participants, ε4 status had no effect on the severity of psychiatric symptom scores (p = 0.585–0.708). 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, and post-traumatic stress disorder), even well outside of the acute phase of injury. Findings suggest a meaningful relationship between APOE genotype and psychiatric distress post-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.

Background Cardiovascular diseases (CVDs) such as peripheral artery disease (PAD) and coronary artery disease (CAD) are risk factors for Alzheimer's disease (AD) and related dementias (ADRD). The APOE‐ε4 variant, which codes for a cholesterol transporter protein, is the largest AD genetic risk factor, increases LDL cholesterol and triglycerides, and augments the risk of cardiovascular disease. In this study of participants in the US Department of Veterans Affairs’ Million Veteran Program (MVP), we examined the interactive effects of APOE‐ε4 status with CVDs (PAD, CAD, myocardial infarction, hypertension, and hyperlipidemia) on ADRD prevalence. Method Our cohort included MVP participants of European ancestry age 65 and older with available genotype data (n = 11,112 ADRD cases and 170,361 controls). Cross‐sectional logistic regression analyses were performed using the GEM (Gene–Environment interaction analysis in Millions of samples) software package and included fitting an omnibus test for gene by environment (GxE) interactions between additively‐coded ε4 and the CVDs as a group, followed by GxE analysis of individual CVDs. Additive‐scale interactions were measured using the Relative Excess Risk due to Interaction (RERI) statistic. ADRD was derived from International Classification of Diseases (ICD) codes using our validated algorithm. We used validated algorithms for MI and PAD identified in the VA's Centralized Interactive Phenomics Resource (CIPHER). CAD, hypertension, and hyperlipidemia cases were identified using Phecodes. Result CVDs showed both strong main‐effect associations with ADRD (ORs 1.55 to 1.82, all p < 1099; see Table). Both the omnibus test (p = 5x10‐12) and the individual CVD interaction terms were significant (p from 7x10‐8 to 0.025). RERI estimates indicated significant positive additive‐scale interactions (see example figure illustrating additive hypertension x ε4 interaction). Conclusion These additive‐scale interactions are more directly interpretable than multiplicative‐scale interactions. They indicate that the prevalence of ADRD associated with cardiovascular disease increases with the number of inherited APOE‐ε4 alleles (e.g. from 3.3% greater ADRD frequency associated with hypertension at age 80 for those with 0 ε4 copies to 5.6% for those with 2 copies; see Figure). Combining genetic testing with information about health comorbidities could contribute to more accurate dementia risk assessment within the Veteran population, and likely within other populations as well.