While a history of TBI is associated with an increased risk of neurodegenerative disease, associated mechanisms remain largely unknown. Neuroinflammation is commonly implicated as playing a role in progressive neurodegeneration in general, yet little is known about the adaptive response of neuroinflammation in TBI or how it may contribute to progressive pathologies. To parse out components of the adaptive response, we assessed for intraparenchymal T-cell infiltration in two different translational large animal (swine) models of TBI, inertial injury and focal contusion. We characterized the extent and distribution of T cells post-injury and their association with blood-brain barrier disruption and axonal pathology. T-cell infiltration following focal TBI followed a spatiotemporal progression from gray matter at 72 hours to both gray and white matter at 6 months post-injury, consistent with recruitment into the parenchyma and then white matter. Inertial injury did not lead to substantial T-cell infiltration despite BBB breakdown and axonal pathology. We did not find a spatial correlation between blood-brain barrier breakdown or axonal pathology and T-cell infiltration in focal TBI. These data suggest that there is an active adaptive response to TBI, particularly in tissue proximal to contusions. A large animal model that reproducibly demonstrates chronic T-cell infiltration may allow for examination of the downstream effects of the adaptive response to TBI, and whether targeting this adaptive response may reduce chronic inflammation and improve recovery.

Traumatic brain injury (TBI) is recognized as a major risk factor for neurodegenerative disease (NDD). Autopsy studies frequently describe chronic traumatic encephalopathy neuropathologic change (CTE-NC) in individuals with histories of repetitive head impact (RHI) exposure, often with accompanying comorbid neurodegenerative proteinopathies. Of these, deposition of abnormally phosphorylated TDP-43 (pTDP-43) has been reported but the prevalence and distribution of pTDP-43 in CTE-NC and its distinction from that encountered in wider NDD are uncertain. Here, patients with a history of RHI and documented NDD (n = 30), and age-matched controls with no known TBI or RHI exposure, either with (n = 24) or without (n = 18) NDD, were identified within the CONNECT-TBI archive. Standardized brain tissue sections stained for pTDP-43 were assessed. pTDP-43 pathology prevalence was similar among RHI patients (40%) and controls with NDD (33%). pTDP-43 was typically localized (limbic-predominant age-related TDP-43 encephalopathy neuropathologic change [LATE-NC] stage 1 to 2) in amygdala and hippocampus in controls with NDD and following RHI exposure without CTE-NC. In contrast, this pathology was often widespread and of high stage (LATE-NC stage 3; P = .0045) in patients with CTE-NC. Thus, CTE-NC may be associated with more widespread pTDP-43 pathology than encountered in aging or those with NDD and no history of TBI/RHI.

Proton magnetic resonance spectroscopy (1H MRS) enables non-invasive biochemical sampling of tissues, potentially aiding diagnosis, prognosis and monitoring of various pathologies, while providing novel imaging biomarkers. Ultra-high-field (UHF) imaging at 7 tesla (7T) benefits from improved spectral dispersion due to an increase in chemical shift differences between metabolites, and a higher signal-to-noise ratio (SNR), making 1H MRS at 7T a particularly promising diagnostic tool for identifying and separating metabolites not clearly resolved at lower field strengths. However, 1H MRS at UHF presents technical challenges related to the short RF wavelength at 7T, resulting in B1 transmit field inhomogeneity, and the increased magnetic susceptibility gradients leading to B0 field inhomogeneity. Appropriate MRS methods are required to address these issues. In this article, we describe the technical aspects and challenges of 1H MRS at 7T, based on the experience in our centre, where single voxel 1H MRS has featured prominently in clinical 7T research applications for several years. We present data from six patients with glial tumours, including three who were post-operative, in whom post-surgical metalware affects the specific absorption rate (SAR), along with two patients with neuroinflammatory conditions and two with neurodegenerative diseases. The potential clinical use of 1H MRS for these pathologies and its possible integration as a promising biomarker into advanced imaging pathways are discussed.

Importance: Much research investigates sequelae arising from traumatic brain injury (TBI), however few studies investigate risk factors for TBI in the first instance. This could have implications for representativeness, risk mitigation and prevention. Objectives: Test for associations between multiple sociodemographic and individual difference variables, and their interaction with sex, on risk of subsequent incident TBI. Design, setting and participants: General population prospective cohort, UK Biobank. Main outcomes and measures: Baseline lifestyle, cognitive, personality and sociodemographic variables versus risk of later TBI, ascertained via ICD-10 codes. We used Cox regressions, and tested 11 predictors individually, then adjusted for baseline age and sex, then combined in one multivariable model. Results: After exclusions, 5764/500,035 (1.15%) participants recorded a TBI over median 14 years follow-up. Most predictors were individually associated with increased risk of TBI in expected directions. The largest associations were for male sex (versus female; hazard ratio [HR] = 1.56, 95% confidence intervals [CIs] = 1.48-1.65) and self-reported ‘risk-taker’ status (HR = 1.28, 95 CIs = 1.21-1.36). These remained significant in multivariable regressions. There was significant interaction between educational attainment and sex, where degree possession (versus not) was protective in males only (HR = 0.76, 95% CIs = 0.70-0.82, all P <0.001). Conclusion and relevance: Prominent risk factors for TBI include male sex and identifying as a ‘risk-taker’. Higher educational attainment was protective in males. Studies comparing TBI cases versus controls routinely underestimate premorbid group differences. These findings represent targetable opportunities for public health intervention.

Background: Traumatic brain injury (TBI) is a known risk factor for dementia and earlier mortality, but its association with psychological health is less well-characterized. We tested for associations between TBI and depression, each ascertained multiple ways, and in opposing directions (depression predicting TBI; TBI predicting depression). Methods: Using UK Biobank data (N=502,356) we investigated bi-directional associations between TBI (ICD-10 coded broad- or narrow-band TBI) and depression (self-report and/or incident ICD-10 coded). We tested this in each direction: baseline historic TBI predicting the incidence of subsequent depression and, separately, baseline depression predicting the incidence of a first subsequent TBI. All analyses were adjusted for age at UK Biobank baseline assessment, sex, educational attainment, deprivation, smoking history, alcohol intake, physical and neurological health conditions. Results: In participants with history of TBI (versus not), there was increased risk of subsequent incident depression, compared with participants with no documented TBI history (e.g. narrow-band TBI fully-adjusted hazard ratio [HR] = 2.18 risk of depression; 95% confidence interval [CI] = 1.87 to 2.55; P<0.001). In the other direction there was evidence that people with history of lifetime depression had significantly increased risk of subsequent incident TBI (e.g. HR = 1.76 of narrow-band TBI, 95% CI = 1.61 to 1.94, P<0.001). Conclusion: We show significant associations between TBI and depression: depression was a risk factor for subsequent TBI in previously unaffected participants, but also vice-versa. Psychological support should be considered post-TBI, however clinical management should consider premorbid psychological health as a possible contributing factor.

Importance:Exposure to repetitive head impacts (RHI) is associated with increased risk of a range of neurodegenerative diseases, including Alzheimer disease and amyotrophic lateral sclerosis. However, while the protein pathologies in the brains of individuals with the RHI-associated pathology of chronic traumatic encephalopathy (CTE) are well described, the spinal cord pathology in at-risk individuals remains poorly understood. Objective:To evaluate spinal cord pathologies associated with RHI exposure or CTE neuropathologic change (CTE-NC) in the brain. Design, Setting, and Participants:This case-control study of a retrospective autopsy series (June 2019 to August 2025) was performed among autopsied individuals who served as RHI-exposed cases or controls in a multicenter brain bank collaboration. Data analysis was performed from January 2024 to November 2025. Exposures:RHI history and CTE-NC presence. Main Outcomes and Measures:Informant-reported clinical history as well as symptoms and immunohistochemistry for phosphorylated tau (p-tau), phosphorylated TAR DNA-binding protein 43 (p-TDP-43), α-synuclein, and amyloid-β (Aβ), as well as amyloid precursor protein and human leukocyte antigen DR. Results:Of 70 autopsied individuals (62 male, 8 female; mean [SD] age, 64.40 [13.94] years), 20 showed CTE-NC in the brain. All cases with CTE-NC exhibited spinal cord p-tau deposits, especially in cases aged 65 years or older with prior RHI (n = 14), often showing extensive spinal tau pathology as both neuronal (all 14 cases) and astrocytic (12 of 14 cases [86%]) p-tau deposits. Spinal p-tau pathology was associated with microglial activation and motor symptoms. Notably, among the individuals with CTE-NC and prior RHI who were aged 65 years or older, additional spinal protein pathologies were present, comprising p-TDP-43 inclusions (9 of 14 cases [64%]), Aβ deposits (13 of 14 cases [93%]), and α-synuclein deposits (7 of 14 cases [50%]), with all 4 of these pathologies present in 4 individuals (29%). In total, across all 20 CTE-NC cases, p-TDP-43 inclusions were confined to the spinal cord in 5 of the 10 individuals with spinal p-TDP-43 pathology. In contrast, among 50 individuals without CTE-NC, typically sparse p-tau deposits were seen in only 27 (54%). Among the 23 confirmed cases with a history of RHI, 16 (70%) exhibited CTE-NC, while 7 (30%) did not. Spinal tau pathology was more severe in those with CTE-NC; however, astrocytic tau pathology was also present in the group without CTE-NC, unlike in controls without RHI or CTE. Conclusions and Relevance:This case-control study provides autopsy evidence of a high prevalence of complex spinal pathology in individuals with CTE-NC, supporting the concept of trauma-related encephalomyelopathy. The frequent co-occurrence of p-TDP-43, Aβ, and α-synuclein pathologies in individuals aged 65 years or older with CTE-NC suggests that cumulative trauma might contribute to widespread misfolded protein aggregation.

The discovery of chronic traumatic encephalopathy neuropathologic change (CTE-NC) in the brains of former athletes has generated an explosion in public and scientific interest. As CTE-NC can only be diagnosed postmortem, consensus diagnostic criteria have been developed for the proposed clinical correlate, that is, traumatic encephalopathy syndrome (TES). However, the diagnostic accuracy of TES criteria in predicting CTE-NC remains unproven and considerable concerns exist regarding the specificity of proposed clinical features. Here we reviewed antemortem clinical records for 1,038 cases in a neurodegenerative brain bank. Neuropathological evaluation for CTE-NC was then conducted in all cases. In total, 25 (2.4%) cases fulfilled the criteria for a diagnosis of TES, of which six demonstrated CTE-NC (positive predictive value = 24.0%, 95% confidence interval 9.4-45.1%). Of the remaining 1,013 cases, CTE-NC was present in seven (0.69%). The diagnostic accuracy of TES for CTE-NC was driven by exposure to repetitive head impacts rather than proposed clinical features. There was no difference in the prevalence of core or supportive clinical features of TES among cases with CTE-NC compared to a matched sample. The poor performance of TES criteria raises substantial concern for its potential negative psychological impact on current and former contact sport athletes, who may be incorrectly diagnosed with a progressive neurodegenerative pathology.

Understanding pathways from genetic variation to cognitive impairment is critical for dementia prevention, risk stratification and the development of treatments. While genetic risk factors for dementia are known to associate with cross-sectional differences in biomarkers (e.g. lipids) in healthy people, potential influence over longitudinal trajectories is not understood.We leveraged genetic, general health and two-wave biomarker data from n = 17,817 UK Biobank participants. The outcomes were change in 26 common circulating blood biomarkers including inflammatory, cardiometabolic and lipid families. The presence of apolipoprotein (APOE) e4 ‘risk’ and e2 ‘protective’ alleles were tested separately versus ‘neutral’ e3e3 genotype, as were associations of non-APOE polygenic risk for Alzheimer’s disease. Biomarker change values were corrected for baseline levels, age, deprivation, sex, timepoint interval, smoking history, medication history, deprivation, genotyping chip and 10 genetic principal components (fully-adjusted).The average interval between assessments was 4.30 years (standard deviation; SD = 0.92). For e4 (versus e3e3), four associations were significant: accelerated change in total cholesterol, apolipoprotein b (ApoB) and low-density lipoprotein (LDL) each in the direction of poorer health (standardized β range = 0.021 SDs to 0.036 more change relative to e3e3), and c-reactive protein protectively (β = -0.059; all P < 0.001). For e2 allele presence, there were three significant associations: change in ApoB, total cholesterol and LDL in protective directions (β range = -0.057 to -0.090). There were no APOE genotypic interactions with baseline age, sex, or medication history, nor significant findings associated with non-APOE (Alzheimer’s disease) polygenic risk.APOE e genotype significantly modifies particularly lipid trajectories across time – most strongly ApoB levels. This adds nuance to lipids as a dementia risk factor, and, clinically, suggests more frequent lipid assessments in e4 carriers in that context. Our findings provide a plausible partial biological explanation for APOE’s progressive influence on neurocognitive health.

It is unclear to what extent genetic risk offsets the protective effects of better premorbid cognitive health on the risk of Alzheimer’s disease (AD). We tested for associations between measures of premorbid cognitive health, apolipoprotein (APOE) e4 ‘risk’ genotype, and their interaction, with risk of incident AD and age of diagnosis, in UK Biobank participants aged ≥55 years at baseline, adjusted for potential confounders. During follow-up, 3,505/252,340 (1.39%) participants received an incident diagnosis of AD. There were significant associations between better performance on each cognitive test with lower risk of incident AD, and later age at diagnosis. However, the benefit of better baseline cognitive scores on AD risk was significantly attenuated in APOE e4 carriers. These data demonstrate that the association between premorbid cognitive health and subsequent risk of AD is influenced by APOE e4 genotype. This has implications for risk stratification and targeted intervention.

Tau pathology in the brain associated with chronic traumatic encephalopathy (CTE) is well established, but details regarding protein pathology in the spinal cord remain unclear. Furthermore, CTE is frequently comorbid with other neurodegenerative diseases. Spinal cords from 28 cases, including CTE ( n  = 14), Alzheimer's disease (AD, n  = 6), one further case with repetitive head impacts but not CTE lesions in the brain and controls ( n  = 7; 4 with spinal stenosis), were examined using immunohistochemistry for p -tau, TDP-43, α-synuclein, and A-beta. Misfolded protein deposition in the spinal cord was common in CTE: p -tau (14/14, 100%), p -TDP-43 (9/14, 64%), Aβ (13/14, 93%), and α-Syn (7/14, 50%). Quadruple misfolded protein deposition was observed in four CTE cases. Neuronal tau pathology was present in all CTE cases. Notably, prominent astrocytic tau pathology was observed in 12/14 cases (86%). However, no such pathology was observed in AD or control cases. p -TDP-43 pathology was frequently detected in the spinal cords of CTE cases. Four cases exhibited spinal cord-specific p -TDP-43 inclusions without LATE/FTLD-TDP. Aβ deposition was observed in most CTE spinal cords, with two spinal cord-positive cases lacking cerebrum deposition, highlighting a brain-spinal cord discrepancy. All seven CTE cases with α-Syn pathology in the spinal cord had Lewy body pathology in the brain. Our findings demonstrate repetitive traumatic events may lead to tau pathology not only in the brain but also in the spinal cord. The prominent astrocytic tau pathology observed in CTE appears to be a unique feature, as it was not present in AD and control cases. The frequent co-presence of tau with TDP-43, Aβ, and α-Syn pathologies suggests that repetitive traumatic events contribute to concomitant misfolded protein accumulation.

Traumatic brain injury (TBI) is recognized as one major, potentially modifiable risk factor for neurodegenerative disease (NDD). Autopsy studies describe a range of neuropathologies in a proportion of individuals surviving late after TBI, most frequently the tau associated pathology, chronic traumatic encephalopathy neuropathologic change (CTE-NC). In addition to tau, other NDD pathologies are described. Of these, deposition of abnormally phosphorylated transactive response DNA-binding protein 43 (pTDP-43) has been reported in association with CTE-NC. However, to date the prevalence and distribution of pTDP-43 in CTE-NC and its distinction from pathology of wider NDD has not been formally assessed. Patients with history of exposure to repetitive mild traumatic brain injury (rmTBI) and documented NDD (n = 30), together with age-matched controls with no known TBI exposure, either with (n = 24) or without (n = 18) NDD, were identified within the CONNECT-TBI archive. Whole slide digital images of standardized brain tissue sections stained for pTDP-43 (1D3) were reviewed, and the pattern and distribution of pathology mapped. Overall, prevalence of pTDP-43 pathology was similar among rmTBI patients (40%) and their age-matched controls with NDD (33%; p = 0.7778). However, while pTDP-43 was typically localized in controls with NDD and in rmTBI patients without CTE-NC (limbic-predominant age-related TDP-43 encephalopathy [LATE] stage 1-2), in patients with CTE-NC this pathology was more often widespread and high stage (LATE stage 3; p = 0.0045). These results demonstrate rmTBI is associated with higher stage LATE pathology than in equivalent age matched controls and individuals with wider, non-TBI related NDD. Further studies are required to characterize the association between TBI and TDP-43 proteinopathy, including the contribution, if any, of this pathology to clinical sequelae of TBI related neurodegenerative disease.

Importance:History of traumatic brain injury (TBI) or repetitive head impacts is associated with an increased risk of neurodegenerative disease. This association has attracted attention in recent years through the relationship between contact sports participation and the increased risk of a number of neurodegenerative diseases, including motor neuron disease or amyotrophic lateral sclerosis (ALS). However, to date, the association between TBI in the community and ALS risk remains uncertain. Objective:To leverage population-level health records to explore the association between a history of TBI and subsequent ALS risk. Design, Setting, and Participants:This retrospective cohort study accessed UK-wide electronic health record (EHR) data from individuals 18 years or older with TBI history and age-, sex-, and area deprivation-matched general population comparators. EHR data were available from January 1, 2005, to December 31, 2020, with database interrogation performed on February 11, 2021, and data analysis conducted between June 1, 2023, and October 3, 2024. Exposure:Documented history of TBI. Main Outcomes and Measures:Outcomes were obtained by individual-level linkage to EHR data available via Clinical Practice Research Datalink. Risk of ALS was evaluated using Cox proportional hazards regression models to investigate its association with TBI. Results:Overall, 85 690 adults with a history of TBI and 257 070 matched adults with no history of TBI were included, for a total of 342 760 participants (50.1% male; mean [SD] age, 50.7 [17.6] years). During a median 5.72 (IQR, 3.07-8.82) years of follow-up, providing 2.13 million person-years of follow-up, 150 incident ALS cases were recorded, resulting in 7.05 cases per 100 000 person-years. Risk of ALS was higher among individuals with a history of TBI compared with individuals without a TBI history (hazard ratio [HR], 2.61; 95% CI, 1.88-3.63). However, this association was time dependent, with risk confined to the 2 years following TBI (HR, 6.18; 95% CI, 3.47-11.00), but not thereafter. Conclusions and Relevance:In this retrospective cohort study of 342 760 adults, an association between TBI and subsequent risk of ALS was identified. However, this association was confined to the 2 years immediately following injury. As such, the association between TBI and higher ALS risk may indicate reverse causality, with TBI in some individuals perhaps reflecting a consequence of early, subclinical ALS.

BACKGROUND:Approximately 30% of women experience intimate partner violence (IPV) in their lifetime, often with traumatic brain injury (TBI) exposure. Nevertheless, there has been limited research exploring lifelong brain health outcomes following IPV with TBI. To address this, we investigated the relationship between IPV, TBI and midlife mental health outcomes within an observational cohort study. METHODS:PREVENT Dementia is a cohort study with participants recruited aged 40-59 years for longitudinal measures of brain health. Participants reporting histories of IPV-related physical abuse (IPV-PA) at study recruitment were identified and compared with control participants with no IPV-PA exposure regarding histories of TBI and prevalence of lifetime and ongoing mental health outcomes using standardised assessments. RESULTS:Among 632 participants, 90 (14%) reported IPV-PA history. Compared with unexposed participants, history of IPV-PA was associated with higher TBI exposure, together with higher lifetime and ongoing diagnoses of depression, anxiety and sleep disorders, and post-traumatic stress disorder (PTSD) symptomology. Notably, the risk of ongoing and concurrent midlife mental health disorders remained despite IPV-PA exposure having ceased on average 27 years before assessment. History of TBI in individuals with IPV was associated with increased risk of ongoing PTSD symptomology and concurrent mental health outcomes. CONCLUSIONS:Our data confirm high TBI exposure among individuals with a history of IPV-PA, while also demonstrating that this population shows higher rates of ongoing adverse mental health outcomes in midlife, often decades after abuse. This work underlines the prevalence of IPV-PA and the necessity to consider TBI exposure and long-term brain health outcomes among this population.

Multiple-acyl-CoA-dehydrogenase deficiency (MADD) is a rare metabolic disorder affecting fatty acid and amino acid metabolism. Local experience and evolving literature highlights a paucity of genetically confirmed cases. A retrospective analysis of patients attending the West of Scotland neuromuscular service with a working diagnosis of late-onset MADD was undertaken. Nineteen cases were identified with median onset age of 52 years and female predominance. 8/19 presented with rhabdomyolysis and 11/19 with a subacute myopathy over mean 12.6 months. 14/19 had evidence of a provoking factor prior to clinical presentation and 16/19 had current sertraline use. All cases had abnormal acylcarnitine profiles in keeping with a MADDlike profile and abnormal skeletal muscle biopsies. Abnormal lipid accumulation was seen in 14/19, ranging from mild increase in lipid droplet size to gross lipid excess in seven cases. 4/19 were heterozygous for likely pathogenic ETFDH gene variants; no second variants were identified within the limits of testing available. All showed variable improvement following riboflavin therapy, advice on nutrition and advice on sertraline discontinuation. We suggest a late-onset MADD-like myopathy is much more common in the cohort than primary genetic MADD. Non-genetic and acquired factors may be causative, in keeping with the evolving literature.

Primary mitochondrial disease refers to a group of genetic disorders caused by pathogenic variants in either the nuclear or mitochondrial genomes, leading to an impairment of oxidative phosphorylation. We present a young female with a prominent myopathic phenotype associated with an episode of cardiac decompensation. MRI of lower limb musculature revealed a selective pattern of fatty infiltration and muscle oedema. Skeletal muscle biopsy confirmed significant evidence of mitochondrial histopathological abnormalities characterised by multiple respiratory chain deficiencies whilst complete sequencing of the entire mitochondrial genome identified a rare, likely pathogenic m.8362T>G MT-TK gene (NC_012920.1) variant at high levels of heteroplasmy, which we confirmed to be maternally-inherited.

Exposure to traumatic brain injury (TBI) and/or repetitive head impacts (RHI) increase the risk of a range of neurodegenerative pathologies, including chronic traumatic encephalopathy neuropathologic change (CTE-NC). Astrocytic tau pathology reminiscent of ageing-related tau astrogliopathy is a component feature of CTE-NC in many cases. Yet the relationship between TBI/RHI exposure and wider tau astrogliopathy, beyond that of CTE-NC, remains poorly characterized. Autopsy-derived material from 556 individuals was selected to include cases with a history of moderate or severe traumatic brain injury (survival >6 months, n = 77) or a history of participation in contact sports (n = 45), for comparison with uninjured controls with (n = 397) or without (n = 37) neuropathologically confirmed neurodegenerative disease. Representative tissue sections from multiple brain regions were then immunostained for hyperphosphorylated tau (p-tau; PHF-1) and assessed in accordance with the harmonized evaluation criteria for ageing-related tau astrogliopathy. PHF-1-immunoreactive thorn-shaped astrocytes were observed more frequently in contact sports participants (75.6%) versus controls with (32.5%; P < 0.001) and without (8.1%; P < 0.001) neurodegenerative disease. In addition, although the prevalence of thorn-shaped astrocytes following moderate/severe TBI (32.5%) was similar to neurodegenerative disease controls, regression analyses demonstrated increased odds of thorn-shaped astrocytes, when adjusting for age and sex (odds ratio 2.42, 95% confidence interval 1.29-4.54). These findings were observed regardless of whether the pathognomonic lesion of CTE-NC was present in the regions examined. Intriguingly, although subpial thorn-shaped astrocytes at sulcal depths were occasionally observed in aged controls with (3.6%) and without (2.8%) neurodegenerative disease, this pathology was considerably more common following RHI/TBI (42.2%; P < 0.001). These findings support a history of RHI or TBI as an independent risk factor for the development of thorn-shaped tau astrogliopathy, over and above ageing-related tau astrogliopathy observed in ageing and wider neurodegenerative disease. Moreover, trauma might be associated with thorn-shaped astrocytes within specific distributions, including the subpial region of the cortical sulcal depths. The clinical significance of these observations will be important to determine.

Although human females appear at a higher risk of traumatic brain injury (TBI) and suffer worse outcomes than males, underlying mechanisms remain unclear. With increasing recognition that damage to white matter axons is a key pathologic substrate of TBI, we used a clinically relevant swine TBI model to explore potential sex differences in the extent of axonal pathologies in relation to axon size. Since TBI is one major risk factor for the development of Alzheimer's disease (AD), we further examined sex differences in the accumulation of amyloid precursor protein (APP) and amyloid-beta (Aβ) in damaged and degenerating axons. We used a well-characterized swine TBI model, which is scaled to mimic head rotational acceleration kinematics of human TBI. Using immunohistochemical staining, we first examined the extent of APP+ axonal pathology, which arises due to microtubule damage and impaired axonal transport, and compared the accumulation of Aβ in damaged axons between sexes. In addition, we assessed the extent of loss of the predominant axonal sodium channel (NaCh) that populates the nodes of Ranvier, Nav1.6. Moreover, using transmission electron microscopy, we evaluated differences in axonal diameter between female and males with no injury and changes in the average caliber of white matter axons after injury between the sexes. At 24 hours post-injury, female swine displayed a greater number of swollen axonal profiles accumulating APP and Aβ, particularly at brain white matter. Females also presented more widespread loss of NaChs than males. Axon degeneration for both sexes appeared to be related to individual axon architecture, reflected by a selective loss of small caliber axons after concussion. However, female brains had a higher percentage of small caliber axons, leading to more extensive axon loss after injury compared to males. These data identify sex differences in the extent of axonal pathologies in brain white matter acutely after TBI, which appears related to sex differences in axon diameter. Notably, these findings further shed light on insights that damaged and degenerating axons following TBI may provide a rich source of APP/Aβ as pathologic substrate contributing to the development of AD and its sex differences.