Implementation of preemptive DNA sequence-based pharmacogenomics testing across a large academic medical center: The Mayo-Baylor RIGHT 10K Study.

PURPOSE: The Mayo-Baylor RIGHT 10K Study enabled preemptive, sequence-based pharmacogenomics (PGx)-driven drug prescribing practices in routine clinical care within a large cohort. We also generated the tools and resources necessary for clinical PGx implementation and identified challenges that need to be overcome. Furthermore, we measured the frequency of both common genetic variation for which clinical guidelines already exist and rare variation that could be detected by DNA sequencing, rather than genotyping. METHODS: Targeted oligonucleotide-capture sequencing of 77 pharmacogenes was performed using DNA from 10,077 consented Mayo Clinic Biobank volunteers. The resulting predicted drug response-related phenotypes for 13 genes, including CYP2D6 and HLA, affecting 21 drug-gene pairs, were deposited preemptively in the Mayo electronic health record. RESULTS: For the 13 pharmacogenes of interest, the genomes of 79% of participants carried clinically actionable variants in 3 or more genes, and DNA sequencing identified an average of 3.3 additional conservatively predicted deleterious variants that would not have been evident using genotyping. CONCLUSION: Implementation of preemptive rather than reactive and sequence-based rather than genotype-based PGx prescribing revealed nearly universal patient applicability and required integrated institution-wide resources to fully realize individualized drug therapy and to show more efficient use of health care resources.

The effect of linguistic modification on English as a second language (ESL) nursing student retention.

English-as-a-second-language (ESL) nursing students fail out of nursing programs at a far higher rate than native English speakers. There are many reasons for this trend, however academic failure related to poor performance on multiple-choice (MC) exams, is the most common. Objective The purpose of this interventional comparative research study was to determine the effect of linguistic modification (LM) of MC exam questions on score and timing of ESL compared to native English-speaking nursing students. Method Two-factor analysis of variance and a mixed-effects regression were applied to the data from 69 participants. Results Statistical significance was noted as related to time. All students took significantly less time to complete the LM questions in comparison to the standard questions. Conclusion LM is a process that should be used by nursing faculty to create fair evaluation instruments for all nursing students.

Cytosolic proteins lose solubility as amyloid deposits in a transgenic mouse model of Alzheimer-type amyloidosis.

The extracellular accumulation of ß-amyloid peptide is a key trigger in the pathogenesis of Alzheimer's disease (AD). In humans, amyloid deposition precedes the appearance of intracellular inclusion pathology formed by cytosolic proteins such as Tau, α-synuclein and TDP-43. These secondary pathologies have not been observed in mice that model Alzheimer-type amyloidosis by expressing mutant amyloid precursor protein, with or without mutant presenilin 1. The lack of secondary pathology in these models has made it difficult to establish how amyloid deposition initiates the cascade of events that leads to secondary intracellular pathology that characterizes human AD. In transgenic mice that model Alzheimer-type amyloidosis, we sought to determine whether there is evidence of altered cytosolic protein folding by assessing whether amyloid deposition causes normally soluble proteins to misfold. Using a method that involved detergent extraction and sedimentation coupled with proteomic approaches, we identified numerous cytosolic proteins that show specific losses in solubility as amyloid accumulates. The proteins identified included glycolytic enzymes and members of the 14-3-3 chaperone family. A substantial accumulation of lysine 48-linked polyubiquitin was also detected. Overall, the data demonstrate that the accumulation of amyloid by some manner causes the loss of solubility intracellular cytosolic proteins.

Reversible pathologic and cognitive phenotypes in an inducible model of Alzheimer-amyloidosis.

Transgenic mice that express mutant amyloid precursor protein (APPsi) using tet-Off vector systems provide an alternative model for assessing short- and long-term effects of Aß-targeting therapies on phenotypes related to the deposition of Alzheimer-type amyloid. Here we use such a model, termed APPsi:tTA, to determine what phenotypes persist in mice with high amyloid burden after new production of APP/Aß has been suppressed. We find that 12- to 13-month-old APPsi:tTA mice are impaired in cognitive tasks that assess short- and long-term memories. Acutely suppressing new APPsi/Aß production produced highly significant improvements in performing short-term spatial memory tasks, which upon continued suppression translated to superior performance in more demanding tasks that assess long-term spatial memory and working memory. Deficits in episodic-like memory and cognitive flexibility, however, were more persistent. Arresting mutant APPsi production caused a rapid decline in the brain levels of soluble APP ectodomains, full-length APP, and APP C-terminal fragments. As expected, amyloid deposits persisted after new APP/Aß production was inhibited, whereas, unexpectedly, we detected persistent pools of solubilizable, relatively mobile, Aß42. Additionally, we observed persistent levels of Aß-immunoreactive entities that were of a size consistent with SDS-resistant oligomeric assemblies. Thus, in this model with significant amyloid pathology, a rapid amelioration of cognitive deficits was observed despite persistent levels of oligomeric Aß assemblies and low, but detectable solubilizable Aß42 peptides. These findings implicate complex relationships between accumulating Aß and activities of APP, soluble APP ectodomains, and/or APP C-terminal fragments in mediating cognitive deficits in this model of amyloidosis.

Divergent effects of the H50Q and G51D SNCA mutations on the aggregation of α-synuclein.

The discoveries of mutations in SNCA were seminal findings that resulted in the knowledge that α-synuclein (αS) is the major component of Parkinson's disease-associated Lewy bodies. Since the pathologic roles of these protein inclusions and SNCA mutations are not completely established, we characterized the aggregation properties of the recently identified SNCA mutations, H50Q and G51D, to provide novel insights. The properties of recombinant H50Q, G51D, and wild-type αS to polymerize and aggregate into amyloid were studied using (trans,trans)-1-bromo-2,5-bis-(4-hydroxy)styrylbenzene fluorometry, sedimentation analyses, electron microscopy, and atomic force microscopy. These studies showed that the H50Q mutation increases the rate of αS aggregation, whereas the G51D mutation has the opposite effect. However, H50Q and G51D αS could still be similarly induced to form intracellular aggregates from the exposure to exogenous amyloidogenic seeds under conditions that promote their cellular entry. Both mutant αS proteins, but especially G51D, promoted cellular toxicity under cellular stress conditions. These findings reveal that the novel pathogenic SNCA mutations, H50Q and G51D, have divergent effects on aggregation properties relative to the wild-type protein, with G51D αS demonstrating reduced aggregation despite presenting with earlier disease onset, suggesting that these mutants promote different mechanisms of αS pathogenesis. The α-synuclein (SNCA) mutations, H50Q and G51D, cause Parkinson's disease. We found that H50Q increases and G51D decreases the rate of α-synuclein aggregation in vitro, and cells over-expressing the mutant proteins show decreased viability when stressed, compared to wild type. G51D is the first SNCA mutation to show decreased α-synuclein aggregation, suggesting a distinct disease mechanism to other SNCA mutations.

Steroids as γ-secretase modulators.

Aggregation and accumulation of Aß42 play an initiating role in Alzheimer's disease (AD); thus, selective lowering of Aß42 by γ-secretase modulators (GSMs) remains a promising approach to AD therapy. Based on evidence suggesting that steroids may influence Aß production, we screened 170 steroids at 10 µM for effects on Aß42 secreted from human APP-overexpressing Chinese hamster ovary cells. Many acidic steroids lowered Aß42, whereas many nonacidic steroids actually raised Aß42. Studies on the more potent compounds showed that Aß42-lowering steroids were bonafide GSMs and Aß42-raising steroids were inverse GSMs. The most potent steroid GSM identified was 5ß-cholanic acid (EC50=5.7 µM; its endogenous analog lithocholic acid was virtually equipotent), and the most potent inverse GSM identified was 4-androsten-3-one-17ß-carboxylic acid ethyl ester (EC50=6.25 µM). In addition, we found that both estrogen and progesterone are weak inverse GSMs with further complex effects on APP processing. These data suggest that certain endogenous steroids may have the potential to act as GSMs and add to the evidence that cholesterol, cholesterol metabolites, and other steroids may play a role in modulating Aß production and thus risk for AD. They also indicate that acidic steroids might serve as potential therapeutic leads for drug optimization/development.

Substrate-targeting gamma-secretase modulators.

Selective lowering of Abeta42 levels (the 42-residue isoform of the amyloid-beta peptide) with small-molecule gamma-secretase modulators (GSMs), such as some non-steroidal anti-inflammatory drugs, is a promising therapeutic approach for Alzheimer's disease. To identify the target of these agents we developed biotinylated photoactivatable GSMs. GSM photoprobes did not label the core proteins of the gamma-secretase complex, but instead labelled the beta-amyloid precursor protein (APP), APP carboxy-terminal fragments and amyloid-beta peptide in human neuroglioma H4 cells. Substrate labelling was competed by other GSMs, and labelling of an APP gamma-secretase substrate was more efficient than a Notch substrate. GSM interaction was localized to residues 28-36 of amyloid-beta, a region critical for aggregation. We also demonstrate that compounds known to interact with this region of amyloid-beta act as GSMs, and some GSMs alter the production of cell-derived amyloid-beta oligomers. Furthermore, mutation of the GSM binding site in the APP alters the sensitivity of the substrate to GSMs. These findings indicate that substrate targeting by GSMs mechanistically links two therapeutic actions: alteration in Abeta42 production and inhibition of amyloid-beta aggregation, which may synergistically reduce amyloid-beta deposition in Alzheimer's disease. These data also demonstrate the existence and feasibility of 'substrate targeting' by small-molecule effectors of proteolytic enzymes, which if generally applicable may significantly broaden the current notion of 'druggable' targets.

Novel Monoclonal Antibody Specific toward Amyloid-ß Binds to a Unique Epitope within the N-Terminal Region.

Amyloid-ß (Aß) deposition throughout the neuroaxis is a classical hallmark of several neurodegenerative diseases, most notably Alzheimer's disease (AD). Aß peptides of varied length and diverse structural conformations are deposited within the parenchyma and vasculature in the brains of individuals with AD. Neuropathologically, Aß pathology can be assessed using antibodies to label and characterize their features, which in turn leads to a more extensive understanding of the pathological process. In the present study, we generated a novel monoclonal antibody, which we found to be specific for the N-terminal region of Aß. This antibody reacted to amyloid precursor protein expressed in cultured cells and labels Aß plaques and cerebral amyloid angiopathy in brain tissue from a mouse model of amyloidosis as well as post-mortem brain tissue from patients diagnosed with AD. This highly specific novel antibody will serve as a unique tool for future studies investigating Aß deposition in novel mouse models and cross-sectional studies using post-mortem human tissue.

Integrative proteomics identifies a conserved Aß amyloid responsome, novel plaque proteins, and pathology modifiers in Alzheimer's disease.

Alzheimer's disease (AD) is a complex neurodegenerative disorder that develops over decades. AD brain proteomics reveals vast alterations in protein levels and numerous altered biologic pathways. Here, we compare AD brain proteome and network changes with the brain proteomes of amyloid ß (Aß)-depositing mice to identify conserved and divergent protein networks with the conserved networks identifying an Aß amyloid responsome. Proteins in the most conserved network (M42) accumulate in plaques, cerebrovascular amyloid (CAA), and/or dystrophic neuronal processes, and overexpression of two M42 proteins, midkine (Mdk) and pleiotrophin (PTN), increases the accumulation of Aß in plaques and CAA. M42 proteins bind amyloid fibrils in vitro, and MDK and PTN co-accumulate with cardiac transthyretin amyloid. M42 proteins appear intimately linked to amyloid deposition and can regulate amyloid deposition, suggesting that they are pathology modifiers and thus putative therapeutic targets. We posit that amyloid-scaffolded accumulation of numerous M42+ proteins is a central mechanism mediating downstream pathophysiology in AD.

Retention in endoplasmic reticulum 1 (RER1) modulates amyloid-ß (Aß) production by altering trafficking of γ-secretase and amyloid precursor protein (APP).

BACKGROUND: Aß production is influenced by intracellular trafficking of secretases and amyloid precursor protein (APP). RESULTS: Retention in endoplasmic reticulum 1 (RER1) regulates the trafficking of γ-secretase and APP, thereby influences Aß production. CONCLUSION: RER1, an ER retention/retrieval factor for γ-secretase and APP, modulates Aß production. SIGNIFICANCE: RER1 and its influence on γ-secretase and APP may be implicated for a safe strategy to target Aß production. The presence of neuritic plaques containing aggregated amyloid-ß (Aß) peptides in the brain parenchyma is a pathological hallmark of Alzheimer disease (AD). Aß is generated by sequential cleavage of the amyloid ß precursor protein (APP) by ß- and γ-secretase, respectively. As APP processing to Aß requires transport through the secretory pathway, trafficking of the substrate and access to the secretases are key factors that can influence Aß production (Thinakaran, G., and Koo, E. H. (2008) Amyloid precursor protein trafficking, processing, and function. J. Biol. Chem. 283, 29615-29619). Here, we report that retention in endoplasmic reticulum 1 (RER1) associates with γ-secretase in early secretory compartments and regulates the intracellular trafficking of γ-secretase. RER1 overexpression decreases both γ-secretase localization on the cell surface and Aß secretion and conversely RER1 knockdown increases the level of cell surface γ-secretase and increases Aß secretion. Furthermore, we find that increased RER1 levels decrease mature APP and increase immature APP, resulting in less surface accumulation of APP. These data show that RER1 influences the trafficking and localization of both γ-secretase and APP, thereby regulating the production and secretion of Aß peptides.

The lived experience of Chinese medical tourists receiving cancer care: A qualitative study.

AIM: The purpose of this study was to describe and explore the lived experience of Chinese medical tourists receiving cancer care in clinical settings in the United States. DESIGN: A qualitative phenomenological design. METHODS: In this study, Hermeneutic phenomenology was used to interview 11 participants on WeChat, a popular social media platform of China. Hermeneutic phenomenology methods and hermeneutic circles were used to analyse data. RESULTS: Five themes identified were: the application process involves various challenges; overcoming transportation and language barriers; feeling content with healthcare received in the United States; nearly perfect experience, except for long waiting times; and high cost of being a medical tourist. CONCLUSION: Despite the cost and complexity of cancer treatment, Chinese medical tourists valued their experience in US clinical settings. Although, they experienced real challenges, they overcame obstacles with self-determination and varied resources. Therefore, culturally appropriate healthcare is highly recommended. RELEVANCE TO CLINICAL PRACTICE: The findings of this study are relevant for clinical practice, particularly cancer care to medical tourists in the United States. To better support the Chinese medical tourists with cancer, various strategies and techniques, as reported in this study, could be helpful. It is highly recommended to provide healthcare providers to enable them to understand and respect the diversity norms of other cultures.

A C1qTNF3 collagen domain fusion chaperones diverse secreted proteins and anti-Aß scFvs: Applications for gene therapies.

Enhancing production of protein cargoes delivered by gene therapies can improve efficacy by reducing the amount of vector or simply increasing transgene expression levels. We explored the utility of a 126-amino acid collagen domain (CD) derived from the C1qTNF3 protein as a fusion partner to chaperone secreted proteins, extracellular "decoy receptor" domains, and single-chain variable fragments (scFvs). Fusions to the CD domain result in multimerization and enhanced levels of secretion of numerous fusion proteins while maintaining functionality. Efficient creation of bifunctional proteins using the CD domain is also demonstrated. Recombinant adeno-associated viral vector delivery of the CD with a signal peptide resulted in high-level expression with minimal biological impact as assessed by whole-brain transcriptomics. As a proof-of-concept in vivo study, we evaluated three different anti-amyloid Aß scFvs (anti-Aß scFvs), alone or expressed as CD fusions, following viral delivery to neonatal CRND8 mice. The CD fusion increased half-life, expression levels, and improved efficacy for amyloid lowering of a weaker binding anti-Aß scFv. These studies validate the potential utility of this small CD as a fusion partner for secretory cargoes delivered by gene therapy and demonstrate that it is feasible to use this CD fusion to create biotherapeutic molecules with enhanced avidity or bifunctionality.

Individual and Military Factors That Modify the Association Between Recent Sexual Trauma and Health Outcomes Among U.S. Service Members and Veterans.

Sexual trauma (ST), which includes both sexual harassment and sexual assault, is associated with a variety of adverse mental and physical health outcomes in military and civilian populations. However, little is known about whether certain individual or military attributes or prior experiences may modify the relationship between recent ST and mental or physical health outcomes. Data from a longitudinal cohort study of current and former military members were used to examine whether individual and military factors modify the association between recent ST and health outcomes (posttraumatic stress disorder, depression, multiple somatic symptoms, and insomnia). Results indicated that demographic (sex, sexual orientation, race/ethnicity) and military factors (service branch, service component, military separation) generally did not modify the main effect of ST on the outcomes examined. On the other hand, factors known to be protective (spirituality, social support) and risk factors (childhood trauma, combat deployment, and mental health status) did modify the effect of ST on multiple outcomes examined; notably, protective effects were diminished among those who experienced recent ST. Protective factors were associated with the lowest risk of adverse outcomes among those with no ST, while risk reduction was less among survivors of ST. Diminished impacts also were found for cumulative risk factors, with the influence of multiple individual risk factors associated with increased risk but in a subadditive manner. We conclude that the effect of recent ST on the outcomes examined was persistent in the presence of potential protective factors, but that it may be impacted by ceiling effects in combination with other risk factors.

Aß Amyloid Scaffolds the Accumulation of Matrisome and Additional Proteins in Alzheimer's Disease.

We report a highly significant correlation in brain proteome changes between Alzheimers disease (AD) and CRND8 APP695NL/F transgenic mice. However, integrating protein changes observed in the CRND8 mice with co-expression networks derived from human AD, reveals both conserved and divergent module changes. For the most highly conserved module (M42, matrisome) we find many proteins accumulate in plaques, cerebrovascular amyloid (CAA), dystrophic processes, or a combination thereof. Overexpression of two M42 proteins, midkine (Mdk) and pleiotrophin (PTN), in CRND8 mice brains leads to increased accumulation of A ß ; in plaques and in CAA; further, recombinant MDK and PTN enhance A ß ; aggregation into amyloid. Multiple M42 proteins, annotated as heparan sulfate binding proteins, bind to fibrillar A ß 42 and a non-human amyloid fibril in vitro. Supporting this binding data, MDK and PTN co-accumulate with transthyretin (TTR) amyloid in the heart and islet amyloid polypeptide (IAPP) amyloid in the pancreas. Our findings establish several critical insights. Proteomic changes in modules observed in human AD brains define an A ß ; amyloid responsome that is well conserved from mouse model to human. Further, distinct amyloid structures may serve as scaffolds, facilitating the co-accumulation of proteins with signaling functions. We hypothesize that this co-accumulation may contribute to downstream pathological sequalae. Overall, this contextualized understanding of proteomic changes and their interplay with amyloid deposition provides valuable insights into the complexity of AD pathogenesis and potential biomarkers and therapeutic targets.

Lysine 624 of the amyloid precursor protein (APP) is a critical determinant of amyloid ß peptide length: support for a sequential model of γ-secretase intramembrane proteolysis and regulation by the amyloid ß precursor protein (APP) juxtamembrane region.

γ-Secretase is a multiprotein intramembrane cleaving aspartyl protease (I-CLiP) that catalyzes the final cleavage of the amyloid ß precursor protein (APP) to release the amyloid ß peptide (Aß). Aß is the primary component of senile plaques in Alzheimer's disease (AD), and its mechanism of production has been studied intensely. γ-Secretase executes multiple cleavages within the transmembrane domain of APP, with cleavages producing Aß and the APP intracellular domain (AICD), referred to as γ and ε, respectively. The heterogeneous nature of the γ cleavage that produces various Aß peptides is highly relevant to AD, as increased production of Aß 1-42 is genetically and biochemically linked to the development of AD. We have identified an amino acid in the juxtamembrane region of APP, lysine 624, on the basis of APP695 numbering (position 28 relative to Aß) that plays a critical role in determining the final length of Aß peptides released by γ-secretase. Mutation of this lysine to alanine (K28A) shifts the primary site of γ-secretase cleavage from 1-40 to 1-33 without significant changes to ε cleavage. These results further support a model where ε cleavage occurs first, followed by sequential proteolysis of the remaining transmembrane fragment, but extend these observations by demonstrating that charged residues at the luminal boundary of the APP transmembrane domain limit processivity of γ-secretase.

Diversity in Nursing Education: Middle Eastern Students.

BACKGROUND: Culturally diverse students face barriers to success in nursing school. One troublesome obstacle is the faculty-student relationship. This study explored Middle Eastern nursing students in Jordan and identified Eastern-Western cultural differences that may occur in the United States. METHOD: Existential descriptive phenomenology and feminist theoretical framework were used to design, collect data, and analyze results for 24 final-semester students. Six themes were identified: dissatisfaction, time, negativity, gender, culture, and utopia. Findings indicate Middle Eastern students and families have a different view of nursing than U.S. faculty members. RESULTS: Strong influences of family, culture, and community directly relate this study's conclusions to Middle Eastern students studying in the U.S. These findings may prevent faculty-student misunderstandings, diminished student academic performance, and loss of culturally diverse U.S. nurses. CONCLUSION: The faculty-student relationship benefits from an understanding of the cultural challenges and experiences identified by Middle Eastern nursing students studying in the U.S. [J Nurs Educ. 2022;61(10):570-578.].

Soluble brain homogenates from diverse human and mouse sources preferentially seed diffuse Aß plaque pathology when injected into newborn mouse hosts.

Background: Seeding of pathology related to Alzheimer's disease (AD) and Lewy body disease (LBD) by tissue homogenates or purified protein aggregates in various model systems has revealed prion-like properties of these disorders. Typically, these homogenates are injected into adult mice stereotaxically. Injection of brain lysates into newborn mice represents an alternative approach of delivering seeds that could direct the evolution of amyloid-ß (Aß) pathology co-mixed with either tau or α-synuclein (αSyn) pathology in susceptible mouse models. Methods: Homogenates of human pre-frontal cortex were injected into the lateral ventricles of newborn (P0) mice expressing a mutant humanized amyloid precursor protein (APP), human P301L tau, human wild type αSyn, or combinations thereof. The homogenates were prepared from AD and AD/LBD cases displaying variable degrees of Aß pathology and co-existing tau and αSyn deposits. Behavioral assessments of APP transgenic mice injected with AD brain lysates were conducted. For comparison, homogenates of aged APP transgenic mice that preferentially exhibit diffuse or cored deposits were similarly injected into the brains of newborn APP mice. Results: We observed that lysates from the brains with AD (Aß+, tau+), AD/LBD (Aß+, tau+, αSyn+), or Pathological Aging (Aß+, tau-, αSyn-) efficiently seeded diffuse Aß deposits. Moderate seeding of cerebral amyloid angiopathy (CAA) was also observed. No animal of any genotype developed discernable tau or αSyn pathology. Performance in fear-conditioning cognitive tasks was not significantly altered in APP transgenic animals injected with AD brain lysates compared to nontransgenic controls. Homogenates prepared from aged APP transgenic mice with diffuse Aß deposits induced similar deposits in APP host mice; whereas homogenates from APP mice with cored deposits induced similar cored deposits, albeit at a lower level. Conclusions: These findings are consistent with the idea that diffuse Aß pathology, which is a common feature of human AD, AD/LBD, and PA brains, may arise from a distinct strain of misfolded Aß that is highly transmissible to newborn transgenic APP mice. Seeding of tau or αSyn comorbidities was inefficient in the models we used, indicating that additional methodological refinement will be needed to efficiently seed AD or AD/LBD mixed pathologies by injecting newborn mice.

Aging in poverty: making the case for comprehensive care management.

A model for holistic care management that would enhance outcomes for economically vulnerable older adults who receive an array of disjointed services administered through the older Americans Act (OAA) and local Area Agencies on Aging (AAA) is proposed. Fragmented service delivery is typically wasteful and ineffectual, but comprehensive care management that includes an autonomous care manager, a single interagency plan of care and ongoing monitoring that is client-centered may protect those aging in poverty from negative health outcomes.

Remodeling Alzheimer-amyloidosis models by seeding.

Alzheimer's disease (AD) is among the most prevalent neurodegenerative diseases, with brain pathology defined by extracellular amyloid beta deposits and intracellular tau aggregates. To aid in research efforts to improve understanding of this disease, transgenic murine models have been developed that replicate aspects of AD pathology. Familial AD is associated with mutations in the amyloid precursor protein and in the presenilins (associated with amyloidosis); transgenic amyloid models feature one or more of these mutant genes. Recent advances in seeding methods provide a means to alter the morphology of resultant amyloid deposits and the age that pathology develops. In this review, we discuss the variety of factors that influence the seeding of amyloid beta pathology, including the source of seed, the time interval after seeding, the nature of the transgenic host, and the preparation of the seeding inoculum.

Consistent Honor, Persistent Disadvantage: American Indian and Alaska Native Veteran Health in the National Survey of Veterans.

Objective: To examine self-rated health and activities of daily living (ADLs) limitations among American Indian and Alaska Native (AI/AN) veterans relative to white veterans. Methods: We use the 2010 National Survey of Veterans and limit the sample to veterans who identify as AI/AN or non-Hispanic white. We calculated descriptive statistics, confidence intervals, and used logistic regression. Results: AI/AN veterans are younger, have lower levels of income, and have higher levels of exposure to combat and environmental hazards compared to white veterans. We found that AI/AN veterans are significantly more likely to report fair/poor health controlling for socioeconomic status and experience an ADL controlling for age, health behaviors, socioeconomic status, and military factors. Discussion: The results indicate that AI/AN veterans are a disadvantaged population in terms of their health and disability compared to white veterans. AI/AN veterans may require additional support from family members and/or Veteran Affairs to address ADLs.