In vivo biomarkers that can detect long-term neuropathologies from repetitive head impact (RHI) exposure are needed, especially for the neurodegenerative tauopathy chronic traumatic encephalopathy (CTE). Here, we evaluated plasma p -tau217 as a potential biomarker for CTE p -tau pathology, and examined the concordance between plasma p -tau217 and Aβ pathology in an at-risk for CTE sample. The sample included 180 male former football players (120 professional, 60 college), and 56 asymptomatic men without RHI (i.e., controls). Participants completed blood draws, 18F-florbetapir (Aβ+=SUVR≥1.10), and 18F-flortaucipir PET. Traumatic encephalopathy syndrome (TES) diagnoses were made. Single molecule array for plasma p -tau217 (ALZpath) was performed (≥0.6 cutoff used to maximize sensitivity). Nine participants had post-mortem tissue. ANCOVA examined group differences in p -tau217 (football vs controls; TES-CTE no, TES-CTE suggestive, TES-CTE possible/probable). Multivariable regression models tested associations between p -tau217 and florbetapir/flortaucipir PET. Covariates included age, race and APOE e4 . Sample characteristics are in Table 1. p -tau217 concentrations were higher in former football players compared to controls (est. marginal mean difference=-0.217, p  = 0.005). There were no group differences in Aβ-PET SUVR. No differences were found across TES-CTE certainty levels. In football players, higher p -tau217 was associated with higher Aβ-PET SUVR (B=1.380, 95%CI[0.597-2.155], p  = 0.001) but not when Aβ+ ( n  = 17) participants and those with kidney/liver disease ( n  = 5) were excluded. Aβ+ participants had the highest p -tau217 (Figure 1). When compared against Aβ-PET, several false Aβ-positives (high p -tau217, Aβ-) were identified, including one extreme outlier (assay related) and a cluster of Aβ- participants with p -tau217 between 0.60–1.0. There were no associations with flortaucipir SUVR (frontal, mesial temporal, left parietal). Two extreme p -tau217 outliers had autopsy-confirmed CTE stage III (AD-, Table 2). Of the remaining donors, all were AD- and four had CTE (stages II-IV) with ptau217 between 0.125-0.449. Plasma p -tau217 has usefulness in quantifying Aβ pathology but restricted utility for detection of CTE. In this at-risk for CTE sample, p -tau217 and Aβ-PET were associated at the group level. At the individual level, false Aβ-positives (and negatives) existed, including Aβ- participants with high p -tau217. We will explore whether this discrepancy is due to disease or peripheral interference with the N-terminal binding in p -tau assays.

Abstract Background: Characterizing longitudinal patterns of brain atrophy that distinguish Alzheimers disease (AD) and related neurodegeneration along with normative aging remains a major challenge. We aimed to identify data-driven longitudinal brain atrophy components and evaluate their associations with plasma AD biomarkers and cognitive outcomes in a community-based cohort. Methods: We analyzed 756 MRI scans from 300 participants in the Framingham Heart Study (mean 2.52 scans per participant; range 2 to 4). Linear mixed effects models were used to identify MRI features associated with diagnostic group (cognitively normal [CN], mild cognitive impairment [MCI], and dementia). Significant features (n=211) were entered into a longitudinal multivariate decomposition framework (ANOVA Simultaneous Component Analysis with Assorted Linear functions; ALASCA) to derive principal components (PCs) capturing patterns of structural change over time. Associations between PCs and plasma AD biomarkers (p-Tau181, total Tau(tTau), glial fibrillary acidic protein [GFAP], neurofilament light chain [NfL], amyloid-β40 [Aβ40], and amyloid-β42 [Aβ42]) were evaluated using multivariable mixed-effects models adjusted for age, sex, education, and APOE ε4 status. Cognitive measures and neuroethological measures in a subset were used to assess the functional relevance and biological associations, respectively. Results: The first three PCs explained ~95% of the variance within the modeled MRI feature (n=211) set (PC1: 75.8%, PC2: 13.8%, PC3: 5.4%). PC1 captured medial temporal atrophy involving hippocampal subfields and basolateral amygdala and was associated with worse cognition and higher plasma AD biomarkers. Neuropathological analyses showed stronger associations of PC1-related atrophy with AD-related tau pathology in the absence of concomitant TDP43 pathology. In contrast, PC2 reflected diffuse cortical gray white matter contrast alterations across association cortices and showed distinct associations with biomarkers and cognition compared to PC1, consistent with overlapping aging- and neurodegeneration-related processes. PC3 showed limited variance and no consistent associations. Conclusion: Longitudinal MRI derived components capture distinct patterns of brain structural change associated with neurodegeneration. Medial temporal trajectories are closely associated with AD and related dementia, whereas cortical alterations likely reflect mixed aging- and disease-related processes. Integration of structural MRI with plasma biomarkers provides complementary information on disease expression and heterogeneity, supporting multimodal approaches for disease characterization and risk stratification. ### Competing Interest Statement The authors declare no conflict of interest. Rhoda Au is a scientific advisor to Signant Health and NovoNordisk. ### Funding Statement This study was supported by the Framingham Heart Study, National Heart, Lung, and Blood Institute contract N01-HC-25195; National Institute on Aging grants U19-AG068753, RF1AG075832-01A1, U01-AG072577, R01-AG080810, and Framingham Heart Study Brain Aging Program (FHS-BAP) pilot grant by U19-AG068753, National Science Foundation grant DMS/NIGMS-2347698. ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: Informed consent was obtained from all study participants, and the Institutional Review Board of Boston University approved the study protocol. I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes Data set used in the preparation of this manuscript provided by the FHS-BAP and data is available on request. Please visit FHS-BAP website for more information

Although the younger age of first exposure (AFE) to American football has not been associated with neurodegenerative pathology, AFE has been associated with clinical symptoms. However, the literature is mixed. We examined the association between AFE to football and clinical outcomes before and after age 60 at death, to isolate the potential role of decreased neuropathological resilience in older age. This study included 677 deceased male football players who donated their brains to the Understanding Neurologic Injury and Traumatic Encephalopathy Brain Bank. Informants completed modified scales assessing cognition, function, behavior, and neuropsychiatric features with dementia adjudicated through consensus conferences. Regressions tested the association between AFE and dementia, chronic traumatic encephalopathy (CTE) pathology, and each scale, adjusted for multiple testing. Analyses were stratified by age 60, adjusting for age at death, duration of play, and neuropathology. Most donors (mean age = 60.9, standard deviation = 19.8) played college or professional football (n = 509, 76%). CTE was the most prevalent neuropathology (n = 471, 70%). AFE was not associated with neurodegenerative disease pathology. Among those older than 60 at death, younger AFE was associated with cognitive composite score impairment (odds ratio: 0.897, 95% confidence interval [CI]: 0.814-0.988, p = 0.027) and worse cognitive (beta: 0.04, 95% CI: 0.01-0.069, p = 0.009), neurobehavioral (beta: 0.032, 95% CI: 0.002-0.062, p = 0.035), and neuropsychiatric (beta: 0.032, 95% CI: 0.00-0.064, p = 0.048) composite scores. Younger AFE was only associated with worse informant-reported clinical outcomes in older deceased football players, independent of neurodegeneration. Our findings offer a potential explanation for the mixed literature on AFE and clinical outcomes. The effects of AFE may only manifest in older adults when cognitive reserve is depleted, neuropathological resilience is reduced, or age-related vulnerabilities interact with prior head injury exposure, worsening clinical outcomes.

Each mitochondrion contains 2-10 copies of the mitochondrial genome. Multiple mitochondria in a cell allow for mitochondrial genomes carrying different variants to co-exist within a cell or tissue, termed heteroplasmy. The extent to which mitochondrial genetic variation differs across tissues of the human body and the origins of heteroplasmic variants is largely unknown. Using next-generation sequencing of 47 paired tissues from 947 donors in the Genotype-Tissue Expression dataset, we found that 39% of unique mitochondrial DNA variants identified were present in one tissue (tissue-specific) and 7% of unique variants were found in several but not all tissues of a donor. Tissue-specific variants were more likely to be transversions, nonsynonymous, deleterious, and present at lower variant allele fractions compared to variants shared across all tissues within a donor. Tissues primarily composed of proliferative cell types had the most tissue-specific variants, while highly energetic tissues had the least. The number of tissue-specific variants was associated with donor age for the tissues with the most tissue-specific variants. We determined that most of the heteroplasmic variants likely arise de novo after tissue differentiation. Our study suggests that mitochondrial DNA variants arise throughout an individual's lifetime in a tissue-dependent manner, which may have disease implications.

Huntington’s disease (HD) is a fatal neurodegenerative disorder characterized by a triad of behavioral symptoms: involuntary movement, emotional change, and cognitive dysfunction. Although alterations in WNT signaling have been reported in HD, its precise role in pathogenesis remains unclear. In this study, we found that astrocytic WNT5B mRNA and protein levels are elevated in the striatum of both HD patients and HD model mice. The noncanonical WNT5B signaling pathway induced sustained expression of matrix metallopeptidase 14 (MMP14), an extracellular matrix (ECM)-degrading enzyme, via activation of the NFATc2 transcription factor in both human and primary mouse astrocytes. Robust upregulation of MMP14 led to ECM degradation, medium spiny neuron (MSN) damage, and increased mutant huntingtin aggregation in N171-82Q HD transgenic mice. Furthermore, WNT5B gain-of-function exacerbated neuropathology, impaired motor coordination, and shortened the lifespan of N171-82Q mice. We further demonstrated that the overexpression of the estrogen receptor α (ERα) suppresses NFATc2 transcriptional activity in vitro. A targeted therapy for the WNT5B-NFATc2-MMP14 signaling pathway by genistein, a phytoestrogen, reduced MMP14 transcription by antagonizing NFATc2 activity and preventing ECM degradation in N171-82Q mice. Genistein treatment also ameliorated neuropathology and motor deficits and prolonged the lifespan of HD mice. Together, these findings define a molecular pathological mechanism in which astrocytic MMP14 transcription, driven by the noncanonical WNT5B signaling pathway, promotes ECM degradation and MSN damage and accelerates neurodegeneration in HD. Modulation of the noncell-autonomous WNT5B-NFATc2-MMP14 signaling pathway by genistein may serve as a potential therapeutic strategy for mitigating HD pathogenesis.

Importance:Repetitive head impacts (RHI) from American football have been associated with later-life cognitive and neuropsychiatric changes. Findings have been limited by small samples, focus on elite players, and lack of appropriate control groups. Objective:To assess the association between American football participation and cognitive and neuropsychiatric function in men 40 years or older. Design, Setting, and Participants:In this cross-sectional study, online data from male football players in the Head Impact & Trauma Surveillance Study (HITSS) were collected between March 7, 2022, and April 9, 2025. In a subanalysis, football players were matched to Brain Health Registry controls without RHI. Exposures:RHI proxies, including self-reported total years of football play, highest level of play, position, and age of first exposure. Main Outcomes and Measures:Linear regression models with multiway cluster-robust SEs compared performance of players vs controls on computerized cognitive tests (Cambridge Automated Neuropsychological Battery Paired Associates Learning Test First Attempt Memory Score [PALFAMS] and Total Errors Adjusted [PALTEA]), subjective cognitive concerns (Everyday Cognition Scale [ECog]), and depressive symptoms (Geriatric Depression Scale 15 [GDS-15]). Multivariable linear regressions, analyses of covariance, and binary logistic regression models tested associations between RHI proxies and PALFAMS, PALTEA, ECog, GDS-15, and additional neuropsychiatric (Behavior Rating Inventory of Executive Function-Adult [BRIEF-A] Behavioral Regulation Index [BRI]) and cognitive (BRIEF-A Meta-Cognition Index [MI]) measures. Models were adjusted for age, race, educational level, and vascular risk. Results:The study sample included 3970 male former American football players (mean [SD] age, 55.93 [10.00] years) enrolled in HITSS. Two substudies were performed: (1) all 3970 football players and (2) 943 players and controls (mean [SD] age, 58.46 [10.37] years), including 661 football players and 282 Brain Health Registry controls. Overall, all study participants were highly educated (561 [85%] had a ≥4-year degree). Compared with controls, players had worse scores on PALFAMS (B = -0.64; 95% CI, -1.23 to 0.05; β = -0.15; P = .03), PALTEA (B = 0.31; 95% CI, 0.07-0.54; β = 0.18; P = .01), ECog (B = 0.11; 95% CI, 0.07-0.15; β = 0.38; P < .001), and GDS-15 (B = 0.62; 95% CI, 0.39-0.86; β = 0.37; P < .001). Among the 3970 total players (mean [SD] years of education, 16.11 [2.20]), professional players had worse scores than college and high school or youth players. Years of play was associated with higher ECog (B = 0.006; 95% CI, 0.003-0.009; adjusted P < .001), MI (B = 0.17; 95% CI, 0.02-0.32; adjusted P = .04), BRI (B = 0.27; 95% CI, 0.16-0.37; adjusted P < .001), GDS-15 (B = 0.03; 95% CI, 0.009-0.04; adjusted P = .003), and PALTEA (B = 0.03; 95% CI, 0.004-0.06; adjusted P = .04) scores. Conclusions and Relevance:In this cross-sectional study of former American football players, prior American football participation was associated with worse later-life cognitive and neuropsychiatric function. These findings support a dose-response association with years and level of play, providing context to help clinicians and researchers assess the risk of symptoms among former players.

Chronic traumatic encephalopathy (CTE) is a progressive neurodegenerative disease found in individuals with a history of repetitive head injury (RHI) received through playing contact sports. Currently, CTE can only be diagnosed after death through the identification of perivascular neuronal hyperphosphorylated tau (pTau) pathology, found at the depth of the cortical sulcus. Although the pathognomonic lesion is found among all cases, pTau deposition is patchy and heterogeneous among individuals. To determine whether the heterogeneity of CTE masks more subtle ordering or additional disease variants, we applied the unsupervised machine learning algorithm subtype and stage inference (SuStaIn) on fully quantitative pTau density data from 26 brain regions in 207 CTE cases and 75 control cases. SuStaIn identified three distinct pathological progression subtypes: 93 cases were classified as Subtype 1 (cortical predominant) and showed dense, rapidly progressing cortical pTau akin to the classically described CTE neuropathology; Subtype 2 (cortical sparing–hippocampal enhanced) had 105 cases that exhibited a reduced cortical pTau burden that progressed slower, but also had pronounced hippocampal involvement in a CTE-specific pattern; and Subtype 3 (copathology altered) consisted of 28 older cases with higher CTE stage, was enriched for comorbid pathologies (pTDP43, Aβ, hippocampal sclerosis, and arteriolosclerosis), and had enhanced pTau in regions highly related to those additional pathologies. Clinically, impaired performance in the Functional Activities Questionnaire (FAQ) correlated with pTau regional burden and severity only in cases with Subtype 1 pathology, suggesting the enhanced cortical pTau pathology was linked to greater functional decline. Overall, these findings help characterize the heterogeneity in CTE progression, validate key pathological variants, and will be crucial for refining diagnostic criteria and advancing in-life diagnosis.

Abstract INTRODUCTION Subjective cognitive complaints (SCC) can precede Alzheimer's disease and related dementias. SCC in the absence of objective impairment is termed subjective cognitive decline (SCD). This study aimed to characterize SCC and SCD among a sample of aging individuals with and without prior repetitive head impact (RHI) exposure, the former of whom are at risk for chronic traumatic encephalopathy (CTE). METHODS RHI‐exposed (N = 167) and non–RHI‐exposed (N = 317) Boston University Alzheimer's Disease Research Center (ADRC) participants and their informants completed subjective measures assessing memory and executive function. Participants completed objective tests of these domains. RESULTS RHI exposure was associated with greater self‐ and informant‐reported SCC and with over four‐fold increased odds of SCD among cognitively unimpaired participants (odds ratio = 4.10, p < 0.001). SCC was associated with objective measures in RHI and non‐RHI participants. DISCUSSION Among RHI‐exposed individuals, SCC align with objective cognitive performance. SCD warrants investigation as potential early indicator of RHI‐related neuropathologies.

Importance:In vivo biomarkers for detecting neuropathologies from repetitive head impacts (RHI), including chronic traumatic encephalopathy (CTE), are needed. Objective:To evaluate the utility of plasma phosphorylated tau 217 (p-tau217), assess its performance as a beta-amyloid (Aβ) biomarker in participants with RHI exposure at risk for CTE, and explore concordance with CTE neuropathology in a postmortem subsample. Design, Setting, and Participants:This longitudinal, multicenter, case-control study used data from the Diagnostics, Imaging, and Genetics Network for the Objective Study and Evaluation of CTE (DIAGNOSE CTE) Research Project, collected from September 2016 to October 2023. Participants were former American football players (case participants) and asymptomatic men unexposed to RHI (control participants). A subsample had available neuropathologic data. Exposures:RHI, traumatic encephalopathy syndrome (TES) diagnoses, and levels of CTE certainty. Main Outcomes and Measures:Plasma p-tau217 (classified as positive [≥0.63 pg/mL], intermediate [0.40-0.62 pg/mL], and negative [<0.40 pg/mL]), Aβ-positron emission tomography (PET; 18F-florbetapir; with Aβ-positive defined as a standardized uptake value ratio [SUVR] ≥1.10), and tau-PET (18F-flortaucipir). TES diagnoses were assigned by multidisciplinary consensus conference. Analyses of postmortem brains controlled for age, race, and APOE ε4 status. Results:Among 231 participants (mean [SD] age, 57.75 [8.25] years), 177 were former football players (117 professional and 60 college) and 54 were unexposed participants. Former football players had higher baseline mean (SD) p-tau217 concentrations than unexposed participants (0.35 [0.26] pg/mL vs 0.27 [0.14] pg/mL; P = .008), although this was driven by a higher proportion of Aβ-PET-positive participants among former players. Plasma p-tau217 increased over time across the sample (B = 0.207 [95% CI, 0.117-0.298]; P < .001), with no significant time × exposure group interactions. Among football players, p-tau217 showed no time × group interactions with TES diagnosis, TES-CTE certainty, or RHI metrics. Higher p-tau217 concentration correlated with higher global Aβ-PET SUVR (B = 0.058 [95% CI, 0.053-3.501; P = .01), with a few discordant cases (5 participants were p-tau217-negative and Aβ-PET-positive; 7 participants were p-tau217-positive and Aβ-PET-negative). P-tau217 had similar areas under the curve for projecting Aβ-PET positivity as cerebrospinal fluid (CSF) p-tau181/Aβ42 and CSF Aβ40/42 measures (p-tau217: AUC, 0.88 [95% CI, 0.80-0.96]; CSF p-tau181/Aβ42: AUC, 0.89 [95% CI, 0.79-1.00]; CSF Aβ40/42: AUC, 0.85 [95% CI, 0.72-0.98]). Among 9 brain donors, 6 had CTE (stages II-IV; none with Alzheimer disease). Seven had negative or intermediate p-tau217, concordant with Aβ-PET. Two p-tau217 outliers with stage III CTE had normal concentrations upon additional testing. Conclusions and Relevance:The findings of this study suggest that plasma p-tau217 concentration is unlikely to be useful for the detection of CTE, but it does show utility for ruling out Aβ pathology in participants at risk for CTE.

Central nervous system (CNS) associated T-cells are present in the meninges and perivascular spaces of healthy brain tissue, but their recruitment into the brain parenchyma is increased by inflammation and hyperphosphorylated tau (p-tau) accumulation. Chronic traumatic encephalopathy (CTE) is a progressive tauopathy associated with exposure to repetitive head impacts (RHI) and definitively diagnosed by the presence of a pathognomonic perivascular p-tau lesion, most commonly at the sulcal depths of the dorsolateral frontal cortex (DLF). Exposure to RHI and CTE is associated with substantial neuroinflammation; however, the involvement of T cells is unknown. Here, we used post-mortem human brain tissue to assess T-cell accumulation in the DLF of 58 individuals exposed to RHI, including 19 with neuropathologically verified Low CTE (stage I-II), 23 with neuropathologically verified High CTE (stage III-IV), and 16 without CTE, as well as 18 controls unexposed to RHI and without CTE. Multiplex immunofluorescence was utilized to label T-cells, microglia, p-tau, and synapses in the leptomeninges, sulcal gray matter, crest gray matter, and white matter. We found that infiltrating T-cells were significantly increased in the sulci across all groups compared to controls, with distinct subtypes in RHI without CTE, compared to Low or High CTE. In addition, T-cell infiltration correlated with the duration of RHI, as measured by years of sports play, and synaptic loss. Meningeal and infiltrating T-cells were elevated in sulci with p-tau depositions and spatially related to MHC2 expressing cells. Meningeal T-cells were also significantly correlated with a younger onset of behavioral symptoms. These data suggest that T-cells may play a role in the chronic inflammation and degeneration associated with RHI and CTE.

INTRODUCTION:The relationship between peripheral vascular health, including endothelia, cognitive decline, and Alzheimer's disease (AD) dementia risk is unclear. METHODS:In this study, 2844 dementia-free Framingham Offspring participants (mean age 60.6 years, 53.2% women) had baseline brachial artery flow-mediated dilation (FMD%) and reactive hyperemia (RH). Participants were then followed for a median of 17 years for incident AD and underwent plasma biomarker testing and brain magnetic resonance imaging. RESULTS:FMD% (hazard ratio [HR] = 0.83, 95% confidence interval [CI] 0.76 to 0.91, p < 0.001) and RH (HR = 0.89, 95% CI 0.79 to 0.99, p = 0.049) were negatively associated with incident AD dementia after adjusting for confounders. Associations were stronger in individuals with elevated C-reactive protein. Poor vascular function correlated with higher plasma AD biomarkers, smaller brain volumes, greater white matter injury, and increased cerebral microbleeds. DISCUSSION:Poor FMD% and RH may serve as a prognostic biomarker for cerebrovascular pathology, including endothelial dysfunction in the AD brain.

Background: Polygenic risk scores for Alzheimer's disease (AD), organized by gene networks shared between the blood and brain, may provide insights into underlying disease mechanisms common to both tissues. Methods: We derived a blood-brain network-based polygenic risk score (nbPRS) from AD-associated genetic variants for three blood-brain networks, selected by the preservation of blood and brain gene co-expression networks, and AD association. Participants from the Alzheimer's Disease Neuroimaging Initiative (ADNI, n = 1109), Framingham Heart Study (FHS, n = 8310), the Religious Orders Study Memory Aging Project (ROSMAP, n = 1215), and Mount Sinai Brain Bank (MSBB, n = 323) were stratified into low- and high-nbPRS subgroups, then profiled using longitudinal and cross-sectional data. We compared the conversion from normal cognition to AD between nbPRS subgroups. Genes differentially expressed among low- and high-nbPRS individuals were profiled with classical neuropathological markers and we investigated potential biologically relevant pathways for the genes significantly expressed in high-risk individuals. Results: Individuals with high nbPRS in three AD-associated networks (M2, M6, M14) demonstrated significant impairment in executive function and memory performance, whereas high-risk individuals in networks M2 and M14 had significantly reduced hippocampal volume. We observed high-risk individuals in M2 and M14 developed AD at twice the rate of low-risk individuals in these networks. HLA genes were differentially expressed with transcriptome-wide significance among low- and high-nbPRS individuals in M14 and associated with neuroinflammatory and tau pathology. Conclusions: Polygenic risk scores derived from blood and brain networks can differentiate individuals with a high risk of AD conversion.

Total RNA, depleted of ribosomal RNA, is commonly used for RNA sequencing to capture both polyadenylated and non-polyadenylated transcripts, whereas poly(A) tail-targeting protocols can either enrich (Poly(A)-selection) or deplete (Poly(A)-depletion) the polyadenylated fraction. To ascertain the best library strategy for capturing long non-coding RNAs (lncRNAs, > 200nt) and circular RNAs (circRNAs) in aged brains, we applied three protocols (total ribo-depleted, poly(A)-selected, and poly(A)-depleted) to 128 human hippocampus samples. Our results show that both ribo-depleted and poly(A)-depleted perform well for lncRNA and circRNA profiling, with the poly(A)-depleted protocol generally detecting a slightly higher number of non-coding RNAs. Additionally, we compared poly(A)-selected and -depleted data for predicting the poly(A) status of hippocampal transcripts. The proportion of non-polyadenylated transcripts was higher than previously found. This study demonstrates how the choice of library construction affects outcomes, helping to make informed methodological choices when studying brain non-coding RNAs. In addition, we examined, for the first time, whether the poly(A) status of protein-coding mRNAs is associated with AD and AD-related dementias.

BACKGROUND:Cumulative head trauma, encompassing repetitive head impacts (RHI) and traumatic brain injury (TBI), has been associated with later-life neurodegenerative disease. Studies on parkinsonism/Parkinson's disease (PD) have evaluated RHI and TBI in isolation, yielding mixed results. Cumulative head trauma may better predict PD risk. OBJECTIVE:To examine independent and cumulative effects of RHI through soccer participation and TBI history on PD diagnosis and age at diagnosis. METHODS:We used a cross-sectional cohort design with data from the Fox Insight study. Participants completed self-report questionnaires on PD diagnosis, TBI (no TBI, TBI with loss of consciousness [LOC], TBI without LOC), and sport participation. Multivariable logistic regressions examined the effects of soccer, TBI group, and their interaction on PD diagnosis. Cox proportional hazards examined associations with time to PD diagnosis. Covariates included age, sex, race, education, income, body mass index, heart disease/diabetes, and family PD history. RESULTS:Among 1231 participants (mean[SD] age = 66.12[10.60]), 278 played soccer (953 non-contact and collision sport [CCS] athletes). Participants reported no TBI (390[33%]), TBI without LOC (495[43%]), or TBI with LOC (258[23%]). Overall, 768(62%) reported a PD diagnosis (mean[SD] age at diagnosis = 59.02[9.86]). A significant soccer × TBI interaction indicated that soccer players with TBI with LOC had 2.6× higher odds of PD compared to non-CCS athletes without TBI (OR [95% CI] = 2.600[1.085-6.305], P = 0.033). Former soccer players with TBI with LOC had a 15.6% higher hazard of early PD diagnosis (HR = 1.469, P = 0.027) compared to non-CCS athletes with no TBI. CONCLUSION:Cumulative head trauma (RHI + TBI) increased PD risk and lowered age at onset. © 2026 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Loss-of-function mutations in DNAJC6, encoding the cochaperone auxilin (HSP40 family), cause familial juvenile-onset Parkinson’s disease (PD). Given the chaperone role of DNAJC6 in cellular homeostasis in adult neurons, we hypothesized that DNAJC6 dysfunction may not be limited to juvenile-onset disorders but could also be associated with adult-onset brain diseases. Here, we show that DNAJC6 expression is significantly downregulated in postmortem substantia nigra tissues and transcriptomic datasets from patients with late-onset sporadic PD. Consistently, human pluripotent stem cell–derived midbrain cultures exhibited reduced DNAJC6 expression under multiple PD-associated conditions. Mechanistically, DNAJC6 loss resulted from impaired transcription mediated by the midbrain-specific factors NURR1/FOXA2 and reduced protein stability regulated by LRRK2. Beyond neurons, DNAJC6 was robustly expressed in astrocytes and similarly downregulated in sporadic PD contexts. Astrocytic DNAJC6 deficiency impaired phagocytic, autolysosomal, and mitochondrial functions while promoting a proinflammatory phenotype, thereby exacerbating neurodegenerative pathology. Importantly, epigenetic restoration of DNAJC6 in neurons and astrocytes using a CRISPRa-AAV9 system in the substantia nigra of an α-synuclein–induced PD mouse model alleviated behavioral deficits and neuropathology. These findings provide evidence that DNAJC6 dysregulation is associated with pathogenic processes in sporadic PD and suggest that targeting neuronal and astrocytic DNAJC6 could represent a potential disease-modifying strategy.

BACKGROUND AND OBJECTIVES:Cerebral amyloid angiopathy (CAA) is common in older adults and frequently contributes to cognitive impairment and dementia. Existing in vivo diagnostic criteria for CAA (Boston Criteria) were developed primarily in patients with intracerebral hemorrhage, and their performance in memory clinic populations remains uncertain. The updated Boston Criteria v2.0 incorporate nonhemorrhagic MRI markers intended to improve case detection. We evaluated the diagnostic accuracy of the Boston Criteria v1.5 and v2.0 against neuropathologically confirmed CAA in memory clinic patients. METHODS:We performed a retrospective diagnostic accuracy study of participants from the Alzheimer's Disease Neuroimaging Initiative and National Alzheimer's Coordinating Center, selected based on availability of required brain MRI and autopsy-based neuropathology data. Patients were classified as no, possible, or probable CAA according to the Boston Criteria v1.5 and v2.0. The primary reference standard was moderate-to-severe neuropathologic CAA; analyses using any neuropathologic CAA were secondary/exploratory. Diagnostic performance was assessed using sensitivity, specificity, predictive values, likelihood ratios, F1 scores, accuracy, and area under the (receiver-operating characteristic) curve (AUC), with formal comparisons between criteria versions. RESULTS:Eighty patients were included (mean age: 81 years, interquartile range 74-86 years; 36.2% female, ∼80% with dementia and Alzheimer disease). Using moderate-to-severe CAA as the neuropathologic reference standard, probable CAA by Boston Criteria v1.5 had a sensitivity of 32% (95% CI 15%-50%), specificity 87% (77%-95%), and AUC 0.59 (0.49-0.69). Using the Boston Criteria v2.0, the corresponding values were 43% (25%-62%), 83% (72%-92%), and 0.63 (0.52-0.74), respectively. No overall performance measures were significantly different between the criteria versions. Secondary analyses using any neuropathologic CAA showed similar patterns. DISCUSSION:In memory clinic patients, both Boston Criteria versions showed only modest overall diagnostic performance against neuropathology. Compared with v1.5, Boston Criteria v2.0 showed a numerical shift toward greater sensitivity at the expense of specificity but no clear overall gain in accuracy. These findings support cautious, context-dependent interpretation of MRI-based CAA criteria in memory clinic settings and highlight the need for additional biomarkers to improve in vivo diagnosis in nonhemorrhagic populations. CLASSIFICATION OF EVIDENCE:This study provides Class II evidence that, in memory clinic populations, Boston Criteria v2.0 show a trade-off between sensitivity and specificity for probable CAA diagnosis, with only modest overall diagnostic accuracy for identifying moderate-to-severe neuropathologically defined CAA.

Repetitive head impacts (RHI) from contact and collision sports have been associated with later-life cognitive and neurobehavioral impairments, as well as neurodegenerative conditions such as chronic traumatic encephalopathy (CTE). RHI-associated clinical sequelae among female former soccer players, specifically, are not well understood. This cross-sectional study aimed to examine the relationship of RHI exposure proxies (e.g., total years of soccer play, concussion history, highest level of play, and estimated cumulative heading frequency) with clinical measures (e.g., subjective cognitive complaints, objective cognitive performance, behavioral dysregulation, and depressive symptoms) among 2,732 women, aged 40 years or above, enrolled in the Head Impact and Trauma Surveillance Study (HITSS), all of whom formerly played organized soccer. HITSS participants completed an online battery that elicited self-reported cognitive and behavioral complaints and depressive symptoms, and that assessed cognitive performing via computerized tests. Multivariable linear regression models estimated associations between soccer-related RHI proxies and outcome measures, adjusting for age and education. Among the former soccer players, longer duration of soccer play, higher level of play, greater estimated cumulative heading frequency, and concussion history were significantly associated with worse self-reported cognitive functioning, greater behavioral dysregulation, and elevated depressive symptom severity. Apart from a single association between concussion history and PAL FAMS performance, we found no other associations between RHI proxies and objective cognitive test performance. Among middle-aged women who played organized soccer, cumulative RHI exposure was associated with small but statistically significant effects for measures of subjective cognitive complaints, behavioral functioning, and depressive symptoms. Continued monitoring of this large cohort of female former soccer players will improve understanding of long-term consequences of soccer play.

Background C-reactive protein (CRP) is a key marker of systemic inflammation that affects blood vessel endothelial function, including in the brain. Since endothelial dysfunction is linked to Alzheimer’s disease (AD), we investigated whether elevated CRP level interacts with genetic pathways in brain endothelial cells to influence AD risk. Methods Using AD genome-wide association study (GWAS) data, we developed multiple polygenic risk scores (PRSs) including single nucleotide polymorphisms (SNPs) in genes expressed in brain endothelial cells, excluding the APOE region, that are involved in inflammation, synaptic transmission, and other pathways. Results Analysis across three independent cohorts revealed that individuals with low inflammatory PRSs (<50%) and elevated blood CRP level were associated with an increased risk of AD; in contrast, those with high inflammatory PRSs (≥50%) did not exhibit this CRP-related AD risk increase. Further examination of individuals with a low inflammatory PRS showed that elevated CRP was associated with lower cerebrospinal fluid (CSF) Aβ42 level and temporal lobe atrophy. Among individuals with a high inflammatory PRS, elevated CRP level was negatively correlated with CSF pTau181 and brain tauopathy, suggesting a potential protective mechanism against tau pathology. Key inflammatory PRS genes, which were impacted by circulating CRP for AD, included APP, IL6ST, and FN1, are involved in amyloid pathology, wound healing, and coagulation. Conclusion Our findings highlight two distinct genetic-dose dependent backgrounds: "vulnerable" (<50% inflammatory PRS) and "resilient" (≥50% inflammatory PRS), and support a Genome-Internal Environment (G×IE) interaction model, linking peripheral inflammation to AD risk.

Chronic traumatic encephalopathy (CTE) is a progressive neurodegenerative disease associated with repeated head injuries (RHI) commonly experienced by contact sport athletes, military personnel, and domestic abuse victims. Despite growing recognition of CTE, the molecular mechanisms underlying disease progression remain poorly understood. This study aims to identify proteomic alterations associated with CTE pathology and clinical features to elucidate key biological pathways involved in disease pathogenesis. SomaScan 7k high-throughput proteomics was performed on 204 dorsolateral prefrontal cortex samples from the Boston University CTE Center Brain Bank. We identified differentially expressed proteins associated with CTE, hyperphosphorylated tau (ptau) pathology, duration of contact sports play, dementia status, and Cognitive Difficulty Scale (CDS) scores. Gene set enrichment analysis revealed that proteasome subunit proteins and related pathways were strongly associated with CTE progression and correlated with years of contact sports play. Reduction in ribosomal proteins and pathways was closely associated with ptau burden. Additionally, multiple models demonstrated significant alterations in MAPK-related cell signaling pathways. These findings advance our understanding of CTE progression and identify mechanisms correlated with key pathological features of the disease. Validation of these results could inform the development of diagnostics and treatments for CTE.

INTRODUCTION:This studyexamined the independent contribution of chronic traumatic encephalopathy (CTE) neuropathology to symptoms. METHODS:The sample included 614 brain donors with (n = 366) and without (n = 248) autopsy-confirmed CTE. Brain donors with other major neurodegenerative disease diagnoses were excluded. Informants completed cognitive and neuropsychiatric measures. Dementia was determined during diagnostic consensus conferences. RESULTS:CTE stage IV (of IV) was associated with 4.48 (95% confidence interval [CI] = 1.97-10.90) increased odds of having dementia. CTE stage III had an odds ratio of 2.12 (95% CI = 1.91-3.77). Higher CTE stage was associated with greater informant-reported cognitive symptoms (p < 0.01). There were no associations with mood/behavioral scales. DISCUSSION:CTE stage III/IV neuropathology was associated with dementia and cognitive symptoms: those with stage IV were 4.5 times more likely to have dementia than those without CTE. It is uncertain if low-stage CTE clinically manifests, and mood/behavioral symptoms likely have multifactorial causes and/or a fluctuating course. HIGHLIGHTS:Stage III and IV chronic traumatic encephalopathy (CTE) are independently associated with increased odds of having dementia. Higher CTE stage was associated with greater informant-reported cognitive symptoms. Stage I and II CTE were not associated with cognitive symptoms or dementia. CTE of any severity was not associated with informant-reported mood or behavioral symptoms.