{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,16]],"date-time":"2026-09-16T17:47:46Z","timestamp":1789580866965,"version":"build-2803163510"},"reference-count":52,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2024,11,19]],"date-time":"2024-11-19T00:00:00Z","timestamp":1731974400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Neurol."],"abstract":"<jats:p>Traumatic brain injury (TBI) afflicts approximately 70 million people worldwide annually, with patients aged 65\u2009years and older accounting for an increasing proportion of TBI patients. Older patients also experience increased morbidity and mortality post-TBI compared to their younger counterparts. Nevertheless, clinical trials often exclude older TBI patients, and age-specific TBI treatment is lacking. We hypothesized that the <jats:italic>APOE<\/jats:italic> genotype and age-associated comorbidities, such as heart disease, are associated with unfavorable outcomes following TBI in older patients. We utilized a dataset from the <jats:italic>\u201cAll of Us research\u201d<\/jats:italic> (AoU) to study this vulnerable population post-TBI. Launched by the National Institutes of Health (NIH), AoU is a nationwide prospective cohort study aiming to enroll 1 million or more individuals by emphasizing traditionally underrepresented populations in the United States. We defined patients diagnosed with post-concussion syndromes (PCS) as those with unfavorable TBI outcomes, and we also assessed the associations between PCS observed in older patients and different comorbidities variables\/APOE genotypes via multiple logistic regression models. Consequently, APOE \u03b54 allele was strongly associated with PCS in patients aged 65 and older. Our findings provide direct evidence for developing better predictive tools and potentially improving the clinical guidance and management of older adults with TBI.<\/jats:p>","DOI":"10.3389\/fneur.2024.1452995","type":"journal-article","created":{"date-parts":[[2024,11,19]],"date-time":"2024-11-19T06:18:23Z","timestamp":1731997103000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":3,"title":["Factors associated with unfavorable outcomes in older patients with traumatic brain injury: analysis from the \u201cAll of Us\u201d research program"],"prefix":"10.3389","volume":"15","author":[{"given":"Zhangying","family":"Chen","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zihao","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alexios-Fotios A.","family":"Mentis","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anne M.","family":"Stey","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Steven J.","family":"Schwulst","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2024,11,19]]},"reference":[{"key":"ref1","doi-asserted-by":"publisher","first-page":"1","DOI":"10.15585\/mmwr.ss6609a1","article-title":"Traumatic brain injury\u2013related emergency department visits, hospitalizations, and deaths \u2014 United States, 2007 and 2013","volume":"66","author":"Taylor","year":"2017","journal-title":"MMWR Surveill Summ"},{"key":"ref2","doi-asserted-by":"publisher","first-page":"788","DOI":"10.1097\/TA.0000000000001910","article-title":"Geriatric traumatic brain injury-what we know and what we don't","volume":"85","author":"Stein","year":"2018","journal-title":"J Trauma Acute Care Surg"},{"key":"ref3","doi-asserted-by":"publisher","first-page":"112","DOI":"10.3389\/fneur.2020.00112","article-title":"The increasing age of TBI patients at a single level 1 trauma center and the discordance between GCS and CT Rotterdam scores in the elderly","volume":"11","author":"Garza","year":"2020","journal-title":"Front Neurol"},{"key":"ref4","doi-asserted-by":"publisher","first-page":"1590","DOI":"10.1111\/j.1532-5415.2006.00894.x","article-title":"Traumatic brain injury in older adults: epidemiology, outcomes, and future implications","volume":"54","author":"Thompson","year":"2006","journal-title":"J Am Geriatr Soc"},{"key":"ref5","doi-asserted-by":"publisher","first-page":"167","DOI":"10.1164\/rccm.201903-0673OC","article-title":"Long-term outcomes after severe traumatic brain injury in older adults. A registry-based cohort study","volume":"201","author":"Maiden","year":"2020","journal-title":"Am J Respir Crit Care Med"},{"key":"ref6","doi-asserted-by":"publisher","first-page":"889","DOI":"10.1089\/neu.2017.5371","article-title":"Geriatric traumatic brain injury: epidemiology, outcomes, knowledge gaps, and future directions","volume":"35","author":"Gardner","year":"2018","journal-title":"J Neurotrauma"},{"key":"ref7","article-title":"Evaluating the effects of APOE4 after mild traumatic brain injury in experimental models","volume-title":"Brain Neurotrauma: Molecular, neuropsychological, and rehabilitation aspects","author":"Mannix","year":"2015"},{"key":"ref8","doi-asserted-by":"publisher","first-page":"400","DOI":"10.3389\/fnhum.2017.00400","article-title":"The BDNF Val66Met polymorphism affects the vulnerability of the brain structural network","volume":"11","author":"Park","year":"2017","journal-title":"Front Hum Neurosci"},{"key":"ref9","doi-asserted-by":"publisher","first-page":"123","DOI":"10.1080\/08977190410001723308","article-title":"Brain-derived neurotrophic factor","volume":"22","author":"Binder","year":"2004","journal-title":"Growth factors (Chur, Switzerland)"},{"key":"ref10","doi-asserted-by":"publisher","first-page":"1393","DOI":"10.1002\/jnr.25200","article-title":"Targeting p53 for neuroinflammation: new therapeutic strategies in ischemic stroke","volume":"101","author":"Gao","year":"2023","journal-title":"J Neurosci Res"},{"key":"ref11","doi-asserted-by":"publisher","first-page":"578","DOI":"10.1093\/jmcb\/mjz052","article-title":"Common genetic variants in the TP53 pathway and their impact on cancer","volume":"11","author":"Barnoud","year":"2019","journal-title":"J Mol Cell Biol"},{"key":"ref12","doi-asserted-by":"publisher","first-page":"677","DOI":"10.1038\/srep00677","article-title":"COMT Val158Met polymorphism interacts with stressful life events and parental warmth to influence decision making","volume":"2","author":"He","year":"2012","journal-title":"Sci Rep"},{"key":"ref13","doi-asserted-by":"publisher","first-page":"245","DOI":"10.1002\/ajmg.b.32141","article-title":"Catechol-O-methyltransferase gene val158met polymorphism and depressive symptoms during early childhood","author":"Sheikh","year":"2013","journal-title":"Am J Med Genet B Neuropsychiatr Genet"},{"key":"ref14","doi-asserted-by":"publisher","first-page":"1361832","DOI":"10.3389\/fnins.2024.1361832","article-title":"Cognitive impairment in Chinese traumatic brain injury patients: from challenge to future perspectives","volume":"18","author":"Liu","year":"2024","journal-title":"Front Neurosci"},{"key":"ref15","doi-asserted-by":"publisher","first-page":"437","DOI":"10.1001\/jamaneurol.2022.0114","article-title":"Traumatic brain injury in older adults-a public health perspective","volume":"79","author":"Waltzman","year":"2022","journal-title":"JAMA Neurol"},{"key":"ref16","first-page":"668","article-title":"The \"all of us\" research program","volume-title":"N Engl J Med","author":"Denny","year":"2019"},{"key":"ref17","doi-asserted-by":"publisher","first-page":"806","DOI":"10.3390\/jcm10040806","article-title":"Prevalence of post-concussion-like symptoms in the general injury population and the association with health-related quality of life, health care use, and return to work","volume":"10","author":"van der Vlegel","year":"2021","journal-title":"J Clin Med"},{"key":"ref18","doi-asserted-by":"publisher","first-page":"741","DOI":"10.3233\/NRE-141072","article-title":"Permanent post concussion symptoms after mild head injury: a systematic review of age and gender factors","volume":"34","author":"King","year":"2014","journal-title":"NeuroRehabilitation"},{"key":"ref19","doi-asserted-by":"publisher","first-page":"224","DOI":"10.1097\/HTR.0000000000000470","article-title":"Comorbid conditions among adults 50 years and older with traumatic brain injury: examining associations with demographics, healthcare utilization, institutionalization, and 1-year outcomes","volume":"34","author":"Kumar","year":"2019","journal-title":"J Head Trauma Rehabil"},{"key":"ref20","doi-asserted-by":"publisher","first-page":"e0212463","DOI":"10.1371\/journal.pone.0212463","article-title":"Data model harmonization for the all of us research program: transforming i2b2 data into the OMOP common data model","volume":"14","author":"Klann","year":"2019","journal-title":"PLoS One"},{"key":"ref21","doi-asserted-by":"publisher","first-page":"1158483","DOI":"10.3389\/fnhum.2023.1158483","article-title":"Prevalence of comorbidities post mild traumatic brain injuries: a traumatic brain injury model systems study","volume":"17","author":"Sudhakar","year":"2023","journal-title":"Front Hum Neurosci"},{"key":"ref22","article-title":"Chronic pain in Neurotrauma: implications on spinal cord and traumatic brain injury","volume-title":"Brain Neurotrauma: Molecular, neuropsychological, and rehabilitation aspects","author":"Moshourab","year":"2015"},{"key":"ref23","doi-asserted-by":"publisher","first-page":"e17517","DOI":"10.7759\/cureus.17517","article-title":"Evaluation of electrolyte imbalance in patients with traumatic brain injury admitted in the central ICU of a tertiary care Centre: a prospective observational study","volume":"13","author":"Dey","year":"2021","journal-title":"Cureus"},{"key":"ref24","doi-asserted-by":"publisher","first-page":"e229478","DOI":"10.1001\/jamanetworkopen.2022.9478","article-title":"Association of Traumatic Brain Injury with the risk of developing chronic cardiovascular, endocrine, neurological, and psychiatric disorders","volume":"5","author":"Izzy","year":"2022","journal-title":"JAMA Netw Open"},{"key":"ref25","doi-asserted-by":"publisher","first-page":"129","DOI":"10.1037\/1082-989x.8.2.129","article-title":"The dominance analysis approach for comparing predictors in multiple regression","volume":"8","author":"Azen","year":"2003","journal-title":"Psychol Methods"},{"key":"ref26","doi-asserted-by":"publisher","first-page":"628","DOI":"10.1080\/02699052.2022.2033842","article-title":"Traumatic brain injury, cardiovascular disease, and risk of dementia among older US veterans","volume":"36","author":"Kornblith","year":"2022","journal-title":"Brain Inj"},{"key":"ref27","doi-asserted-by":"publisher","first-page":"871","DOI":"10.1016\/j.neuron.2012.11.020","article-title":"Apolipoprotein e sets the stage: response to injury triggers neuropathology","volume":"76","author":"Mahley","year":"2012","journal-title":"Neuron"},{"key":"ref28","doi-asserted-by":"publisher","first-page":"1350","DOI":"10.1016\/j.neurobiolaging.2007.11.014","article-title":"APOE genotype-specific differences in the innate immune response","volume":"30","author":"Vitek","year":"2009","journal-title":"Neurobiol Aging"},{"key":"ref29","doi-asserted-by":"publisher","first-page":"767","DOI":"10.14348\/molcells.2014.0248","article-title":"Apolipoprotein E in synaptic plasticity and Alzheimer's disease: potential cellular and molecular mechanisms","volume":"37","author":"Kim","year":"2014","journal-title":"Mol Cell"},{"key":"ref30","doi-asserted-by":"publisher","first-page":"1349","DOI":"10.1001\/jama.1997.03550160069041","article-title":"Effects of age, sex, and ethnicity on the association between apolipoprotein E genotype and Alzheimer disease. A meta-analysis. APOE and Alzheimer disease Meta analysis consortium","volume":"278","author":"Farrer","year":"1997","journal-title":"JAMA"},{"key":"ref31","doi-asserted-by":"publisher","first-page":"287","DOI":"10.1016\/j.neuron.2009.06.026","article-title":"The role of apolipoprotein E in Alzheimer's disease","volume":"63","author":"Kim","year":"2009","journal-title":"Neuron"},{"key":"ref32","doi-asserted-by":"publisher","first-page":"4854","DOI":"10.1002\/alz.14052","article-title":"Effect of apolipoprotein E \u03b54 and its modification by sociodemographic characteristics on cognitive measures in south Asians from LASI-DAD","volume":"20","author":"Wang","year":"2024","journal-title":"Alzheimers Dement"},{"key":"ref33","doi-asserted-by":"publisher","first-page":"e2413459","DOI":"10.1001\/jamanetworkopen.2024.13459","article-title":"Collaborative Care for Chronic Pain after Traumatic Brain Injury: a randomized clinical trial","volume":"7","author":"Hoffman","year":"2024","journal-title":"JAMA Netw Open"},{"key":"ref34","doi-asserted-by":"publisher","first-page":"106","DOI":"10.1038\/nrneurol.2012.263","article-title":"Apolipoprotein E and Alzheimer disease: risk, mechanisms and therapy","volume":"9","author":"Liu","year":"2013","journal-title":"Nat Rev Neurol"},{"key":"ref35","doi-asserted-by":"publisher","first-page":"104","DOI":"10.1016\/j.neubiorev.2017.01.039","article-title":"Age changes in pain perception: a systematic-review and meta-analysis of age effects on pain and tolerance thresholds","volume":"75","author":"Lautenbacher","year":"2017","journal-title":"Neurosci Biobehav Rev"},{"key":"ref36","doi-asserted-by":"publisher","first-page":"e81154","DOI":"10.7554\/eLife.81154","article-title":"The meningeal transcriptional response to traumatic brain injury and aging","volume":"12","author":"Bolte","year":"2023","journal-title":"eLife"},{"key":"ref37","doi-asserted-by":"publisher","first-page":"2659","DOI":"10.1038\/s41380-022-01511-z","article-title":"The blood-brain barrier in aging and neurodegeneration","volume":"27","author":"Knox","year":"2022","journal-title":"Mol Psychiatry"},{"key":"ref38","doi-asserted-by":"publisher","first-page":"90","DOI":"10.1038\/nature10357","article-title":"The ageing systemic milieu negatively regulates neurogenesis and cognitive function","volume":"477","author":"Villeda","year":"2011","journal-title":"Nature"},{"key":"ref39","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1016\/j.jalz.2011.10.007","article-title":"National Institute on Aging-Alzheimer's Association guidelines for the neuropathologic assessment of Alzheimer's disease","volume":"8","author":"Hyman","year":"2012","journal-title":"Alzheimers Dement"},{"key":"ref40","doi-asserted-by":"publisher","first-page":"50","DOI":"10.1016\/j.expneurol.2011.12.016","article-title":"Effects of aging on blood brain barrier and matrix metalloproteases following controlled cortical impact in mice","volume":"234","author":"Lee","year":"2012","journal-title":"Exp Neurol"},{"key":"ref41","doi-asserted-by":"publisher","first-page":"e164199","DOI":"10.1172\/JCI164199","article-title":"TIMP2 ameliorates blood-brain barrier disruption in traumatic brain injury by inhibiting Src-dependent VE-cadherin internalization","volume":"134","author":"Tang","year":"2023","journal-title":"J Clin Invest"},{"key":"ref42","doi-asserted-by":"publisher","first-page":"ENEURO.0031-23.2023","DOI":"10.1523\/ENEURO.0031-23.2023","article-title":"Noncanonical activity of tissue inhibitor of Metalloproteinases 2 (TIMP2)","volume":"10","author":"Britton","year":"2023","journal-title":"Improves Cogn Synapse Density in Aging eNeuro"},{"key":"ref43","doi-asserted-by":"publisher","first-page":"208","DOI":"10.3389\/fnagi.2017.00208","article-title":"Microglial activation in traumatic brain injury","volume":"9","author":"Donat","year":"2017","journal-title":"Front Aging Neurosci"},{"key":"ref44","doi-asserted-by":"publisher","first-page":"328","DOI":"10.1186\/s12974-020-02005-x","article-title":"Cellular infiltration in traumatic brain injury","volume":"17","author":"Alam","year":"2020","journal-title":"J Neuroinflammation"},{"key":"ref45","doi-asserted-by":"publisher","first-page":"e143777","DOI":"10.1172\/JCI143777","article-title":"Brain-gut axis dysfunction in the pathogenesis of traumatic brain injury","volume":"131","author":"Hanscom","year":"2021","journal-title":"J Clin Invest"},{"key":"ref46","doi-asserted-by":"publisher","first-page":"E1896","DOI":"10.1073\/pnas.1800165115","article-title":"Normal aging induces A1-like astrocyte reactivity","volume":"115","author":"Clarke","year":"2018","journal-title":"Proc Natl Acad Sci USA"},{"key":"ref47","doi-asserted-by":"publisher","first-page":"269","DOI":"10.1016\/j.celrep.2017.12.039","article-title":"The aging astrocyte transcriptome from multiple regions of the mouse brain","volume":"22","author":"Boisvert","year":"2018","journal-title":"Cell Rep"},{"key":"ref48","doi-asserted-by":"publisher","first-page":"267","DOI":"10.1097\/SHK.0000000000002027","article-title":"Microglia and infiltrating T-cells adopt long-term, age-specific, transcriptional changes after traumatic brain injury in mice","volume":"59","author":"Chen","year":"2023","journal-title":"Shock (Augusta, Ga)"},{"key":"ref49","doi-asserted-by":"publisher","first-page":"112","DOI":"10.1097\/SHK.0000000000002256","article-title":"ANTI-CD49D antibody treatment improves survival and attenuates neurocognitive deficits after traumatic brain injury in aged mice","volume":"61","author":"Chen","year":"2024","journal-title":"Shock (Augusta, Ga)"},{"key":"ref50","doi-asserted-by":"publisher","first-page":"431","DOI":"10.1089\/neu.2010.1519","article-title":"Preclinical efficacy testing in middle-aged rats: nicotinamide, a novel neuroprotectant, demonstrates diminished preclinical efficacy after controlled cortical impact","volume":"28","author":"Swan","year":"2011","journal-title":"J Neurotrauma"},{"key":"ref51","doi-asserted-by":"publisher","first-page":"461","DOI":"10.1007\/s11682-018-9865-5","article-title":"Evaluation of taurine neuroprotection in aged rats with traumatic brain injury","volume":"13","author":"Gupte","year":"2019","journal-title":"Brain Imaging Behav"},{"key":"ref52","doi-asserted-by":"publisher","first-page":"1624","DOI":"10.3390\/pharmaceutics13101624","article-title":"Traumatic brain injury: an age-dependent view of post-traumatic Neuroinflammation and its treatment","volume":"13","author":"Delage","year":"2021","journal-title":"Pharmaceutics"}],"container-title":["Frontiers in Neurology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fneur.2024.1452995\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,11,19]],"date-time":"2024-11-19T06:18:28Z","timestamp":1731997108000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fneur.2024.1452995\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,11,19]]},"references-count":52,"alternative-id":["10.3389\/fneur.2024.1452995"],"URL":"https:\/\/doi.org\/10.3389\/fneur.2024.1452995","relation":{},"ISSN":["1664-2295"],"issn-type":[{"value":"1664-2295","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,11,19]]},"article-number":"1452995"}}