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Published data suggest that compared to APOE3, APOE4 could increase the risk of neurodegeneration via higher cerebrovascular permeability. We recently proposed the concept that brain endothelial cell APOE is protective for cerebrovascular function in a genotype specific manner, APOE3 > APOE4, and therefore APOE4 brain endothelial cells may be predisposed to dysfunction during aging and disease. In addition to mechanistic implications, our concepts and methods may have therapeutic applications; identifying compounds that protect APOE4 brain endothelial cells. The goal of this proof-of-concept study was to determine whether APOE4 brain endothelial cells can be used as a phenotypic compound screen. Previously we found that APOE4 brain endothelial cells are particularly sensitive to lipopolysaccharide- (LPS) induced permeability disruption when measured by trans endothelial cell electrical resistance (TEER) in vitro. Here, we followed the NIH Assay guidance manual to convert our in vitro assay to a phenotypic screen. We scaled the isolation protocol, selected conditions for the min, mid and max signals, statistically validated the phenotypic assay, screened compounds, validated hits and tested the top hits in vivo. We scaled the isolation protocol and selected conditions for min (0.8 µg/ml LPS), mid (10 µM sildenafil/LPS) and max conditions (vehicle). Our final protocol met the reproducibility acceptance criteria for a statistically validated assay. We then screened a subset of ~ 900 molecules from the TargetMol Bioactive Library and identified two main groups compounds. The first group disrupted APOE4 brain endothelial cells as they were toxic or lowered TEER and many inhibited mTOR. The second group protected against LPS-induced TEER reduction. With relatively stringent criteria we identified 33 protective compounds that are grouped into those that inhibit growth factor receptor signaling and a range of intracellular signaling pathways. We compared the most active compounds and selected four to test in vivo. Tadalafil (PDE5 inhibitor), vorinostat (HDAC inhibitor), CCT196969 (raf inhibitor) and SGI-7079 (AXL inhibitor) mitigated acute LPS-induced cerebrovascular dysfunction in mice that express APOE4. Overall, our data supports the potential of our in vitro screen to identify compounds that prevent LPS-induced dysfunction in APOE4 brain endothelial cells. Show less

Atherosclerosis is the leading cause of heart attack and stroke worldwide. The key characteristic of atherosclerosis is accumulation of LDL cholesterol in artery walls, the subsequent infiltration by monocytes/macrophages, and the development of inflammation. Recently, we reported that plasma protein complement factor H-related 1 (FHR1) binds to the necrotic surfaces of cardiovascular plaques and induces inflammation. Moreover, the concentration of FHR1 is higher, whereas Show less

Smooth muscle cells (SMCs) exhibit remarkable plasticity, undergoing extensive phenotypic switching to generate a highly heterogeneous population within atherosclerotic plaques. While recent studies have highlighted the contribution of SMC-derived macrophage-like cells to plaque inflammation, the specific molecular drivers governing the transition to these pathogenic states remain poorly understood. Here, we re-analyzed single-cell RNA sequencing data from lineage-traced mice to dissect SMC heterogeneity during atherogenesis. Trajectory analysis revealed that SMCs transdifferentiate into a distinct pro-inflammatory macrophage-like subpopulation (macrophage 4) via an intermediate "stem-endothelial-monocyte" cell state. Integrated gene regulatory network inference and Clinically, IRF7 expression was significantly upregulated in unstable and advanced human atherosclerotic plaques, correlating strongly with inflammatory macrophage burden. These findings identify IRF7 as a critical checkpoint in maladaptive SMC phenotype switching. We demonstrate that IRF7 drives the transdifferentiation of SMCs into a pro-inflammatory macrophage-like state, thereby fueling plaque instability. Consequently, therapeutic strategies capable of inhibiting IRF7-mediated SMC plasticity may prove effective in stabilizing vulnerable atherosclerotic plaques. Show less

The APOE-ε4/ε4 genotype is the strongest genetic risk factor for sporadic Alzheimer's disease, though the relative risk is diminished in individuals with African ancestry. Through analysis of phased APOE alleles, we identify a 19 bp deletion approximately 1.1 kb distal to the APOE 3'UTR in a SPI1 microglial transcription factor binding site. The deletion is present in 60% of African American APOE-ε4 homozygotes and reduces Alzheimer's disease odds ratio relative to individuals without the deletion. The deletion also delays Alzheimer's disease onset in APOE-ε4/ε4 cases with local African ancestry at APOE. The All of Us dataset confirms reduced Alzheimer´s disease risk associated with the deletion and identifies additional variants between APOE and APOC1 that disentangle APOE-ε4 neurological and lipid-related phenotypes. Functional assays reveal that the 19 bp deletion abolishes SPI1 repression at this region. Collectively, these findings describe a protective allele at APOE in African Americans that mediates APOC1 expression, reducing relative Alzheimer´s disease risk. Show less

Vascular damage, including cerebral amyloid angiopathy (CAA) and non-amyloid cerebral small vessel disease (CSVD), has been linked to glymphatic dysfunction, which may contribute to Alzheimer's disease (AD) pathology and cognitive decline. We investigated the associations among vascular damage, glymphatic function measured by the DTI-ALPS (Diffusion Tensor Imaging-Analysis Along the Perivascular Space) index, AD plasma biomarkers, and cognitive decline. This study includes 1,249 participants recruited from Samsung Medical Center. We performed linear regression analysis to identify factors associated with the DTI-ALPS index. Further, linear regression analysis with vascular imaging markers, including CAA and CSVD summary scores, as predictors and DTI-ALPS index as an outcome was performed to investigate the effect of vascular pathology on glymphatic function. We conducted mediation analyses to investigate whether the DTI-ALPS index mediates the effect of vascular imaging markers on plasma biomarkers (phosphorylated tau 217 [p-tau 217], glial fibrillary acidic protein [GFAP], and neurofilament light chain [NFL]). Additionally, mediation analyses with the DTI-ALPS index as a predictor, each plasma biomarker as a mediator, and annual MMSE or CDR-SOB change as an outcome to investigate whether plasma biomarkers mediate the effect of the DTI-ALPS index on longitudinal cognitive decline. First, the DTI-ALPS index was negatively associated with both CAA (β [95% CI] = -0.163 [-0.214, -0.112], p < 0.0001) and CSVD (β [95% CI] = -0.195 [-0.247, -0.143], p < 0.0001) summary scores after controlling for age, sex, BMI status, and APOE genotype. Second, the DTI-ALPS index fully mediated the relationship between these vascular markers and p-tau 217 (CSVD summary score, indirect effect β [95% CI] = 0.016 [0.010, 0.023], p < 0.001; CAA summary score, indirect effect β [95% CI] = 0.013 [0.008, 0.020], p < 0.001) and GFAP (CSVD summary score, indirect effect β [95% CI] = 0.015 [0.008, 0.022], p < 0.001; CAA summary score, indirect effect β [95% CI] = 0.012 [0.007, 0.019], p < 0.001), while partially mediating the relationship for NFL, regardless of Aβ uptake on PET. Finally, the DTI-ALPS index was significantly associated with cognitive decline and this association was partially mediated by plasma biomarkers. These findings highlight glymphatic dysfunction as a key mechanism linking vascular pathology with tau, inflammation and neurodegeneration, independent of Aβ uptakes. Show less

The gut microbiome is a modifiable factor in cancer survivorship. Diet represents the most practical intervention for modulating the gut microbiome. However, diet-microbiome relationships in prostate-cancer survivors remain poorly characterized. We conducted a comprehensive analysis of diet-microbiome associations in 79 prostate-cancer survivors (ages 62-81) enrolled in a randomized exercise intervention trial, 59.5% of whom still have active metastatic disease. Dietary intake was assessed using the Diet History Questionnaire (201 variables) and analyzed using three validated dietary pattern scores: Mediterranean Diet Adherence Score (MEDAS), Healthy Eating Index-2015 (HEI-2015), and the Mediterranean-Dash Intervention for Neurodegenerative Delay (MIND) diet score. Gut microbiome composition was characterized via 16S rRNA sequencing. Dimensionality reduction strategies, including theory-driven diet scores and data-driven machine learning (Random Forest, and Least Absolute Shrinkage and Selection Operator (LASSO)), were used. Statistical analyses included beta regression for alpha diversity, Permutational Multivariate Analysis of Variance (PERMANOVA) for beta diversity (both Bray-Curtis and Sørensen metrics), and Microbiome Multivariable Associations with Linear Models (MaAsLin2) with negative binomial regression for taxa-level associations. All models tested interactions with exercise intervention, Show less

The purpose of this study was to estimate the prevalence and number of cerebral microbleeds (CMBs) in a Hispanic and Latino cohort from various self-identified backgrounds and test associations with age, vascular risk factors, APOE (apolipoprotein E), and cognitive function. The 3T brain magnetic resonance imaging exams were obtained on SOL-INCA-MRI (Study of Latinos-Investigation of Neurocognitive Aging-MRI) magnetic resonance imaging study participants, a community-based study. CMB number was counted and categorized as: (1) any CMB, (2) lobar only, (3) deep only, (4) mixed, (5) deep+mixed, and (6) lobar+mixed. We examined whether prevalence of CMBs varied by age, sex, education, Hispanic background, cardiovascular risk factors (hypertension, diabetes, Framingham Risk Score), APOE genotype, and cognition. A total of 2455 participants were included who were 63.0±8.4 years of age, 67.9% women, and 62.2% high school education or higher. CMBs prevalence was 11.7% (8.3% lobar only, 2.0% deep only, 1.4% mixed locations). After adjusting for age, sex, and education, a high Framingham Risk Score was associated with the presence of CMBs of all types, except lobar only. Prevalent stroke/transient ischemic attack was associated with higher likelihood of deep-only CMBs. For participants with cognitive impairment, the adjusted prevalence of mixed CMBs (2.2% versus 1.1%, High vascular risk scores, self-reported history of stroke/transient ischemic attack, and cognitive status were associated with a higher likelihood of CMBs, especially in deep regions. Show less

Alzheimer's disease (AD) is characterized by amyloid plaques that form complex microenvironments in the brain. However, the molecular composition of these plaques and their temporal regulation are not well defined. Here, we developed a sensitive workflow for quantitative proteomic profiling of single plaques using refined laser capture microdissection and data-independent acquisition mass spectrometry (LCM-DIA-MS). From >200 plaques and control regions in AD mouse models (5xFAD and APP-KI) and human brains, we quantified >7,000 proteins, revealing stage-dependent, cell-type-related remodeling of the amyloid proteome (amyloidome). Temporal profiling uncovered early immune and lysosomal activation followed by engagement of RNA processing and synaptic pathways. Cross-model and cross-species analyses determined a conserved amyloidome including APOE, MDK, PTN, and HTRA1, validated by co-localization in imaging analysis. Network analysis highlighted modules in lipid transport, vesicle organization, and autophagy. These findings establish amyloid plaques as conserved, dynamic multicellular hubs that link amyloid accumulation to downstream cellular events. Show less

Abdominal aortic aneurysm (AAA) is a chronic, inflammatory and degenerative vascular disease. Previous studies have demonstrated that stimulator of interferon genes (STING) is involved in multiple inflammatory diseases. However, the role of STING in AAA formation and its possible mechanisms have yet to be investigated. Here, we investigated the role of STING in the development of AAA using two murine AAA models induced by porcine pancreatic elastase (PPE)/β-aminopropionitrile (BAPN) or angiotensin II (Ang II). The STING signaling pathway was significantly activated in AAA tissues from both mice and patients. Sting mutation slowed AAA formation, as confirmed by reduced AAA incidence, maximal abdominal aortic diameter, elastin disruption, collagen deposition, and inhibited immune cell infiltration in AAA mice. RNA-sequencing analysis revealed that compared with the control, Sting mutation inhibited inflammatory and immune responses in AAA tissues. Similar effects were observed after pharmacological inhibition of STING in Ang II infused ApoE Show less

Socioeconomic disadvantage (SED) has been associated with poorer brain health, yet its underlying pathology remains incompletely understood. We examined whether neighborhood-level SED, measured using the Area Deprivation Index (ADI), relates to amyloid deposition assessed with amyloid positron emission tomography (PET). Participants (n = 1,110) underwent cognitive assessment using the mini mental state examination (MMSE) and PET scanning with amyloid-specific tracers. Associations between national and state ADI and MMSE and global amyloid burden were evaluated using linear models adjusting for age, sex, and APOE-ε4 carrier status. In 1,110 participants, higher neighborhood socioeconomic deprivation was associated with lower MMSE scores, with both national and state ADI measures showing significant inverse associations independent of age and sex (all p < 0.001). Higher ADI was significantly associated with greater amyloid burden among cognitively unimpaired participants (β = 0.18, Neighborhood socioeconomic disadvantage is associated with worse cognitive performance and for the first time were shown to be associated with amyloid accumulation during the preclinical phase of AD. These findings underscore the need to consider socioeconomic context in early-stage risk assessment and may help inform targeted prevention strategies aimed at reducing disparities in dementia outcomes. Show less

Atherosclerosis (AS) serves as the pathological foundation for numerous cardiovascular and cerebrovascular diseases and is highly comorbid with depression. The mechanisms underlying this co-morbidity are exceptionally complex, posing significant challenges to effective clinical treatment. Consequently, our study aims to explore the potential biomarkers and mechanisms involved in developing atherosclerosis co-depression disease. We performed differential expression analysis, protein-protein interaction analysis, Gene Ontology (GO) function enrichment analysis, and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis on co-differentiated genes using AS and depression-related datasets from the GEO database. Potential biomarkers were identified through ROC curve analysis. To evaluate the effectiveness of the model, we established an animal model of AS comorbid with depressive disorder and performed a series of assessments, including the sugar-water preference test, open field test, tail suspension test, lipid profile analysis, and pathological examination of aortic sections. Additionally, RNA sequencing analysis of brain tissue, Golgi staining, and detection of synaptic function-related proteins were performed in AS comorbid depressed mice. Finally, in vitro cellular experiments were conducted to further validate the molecular targets and underlying mechanisms. We identified 968 differentially expressed genes associated with AS and 472 differentially expressed genes associated with depression, with 30 genes co-differentially expressed. Protein-protein interaction (PPI) analysis revealed that CCR5, CCR2, NPY, and OPRM1 were strongly associated with AS co-depression, while ROC analysis indicated that Shank2, MDGA2, and S100B were diagnostic markers for AS with depression. Differentially expressed genes were closely associated with the chemokine signaling pathway, neuroactive ligand-receptor interaction, cytokine-cytokine receptor interaction, and taste transduction. Animal studies demonstrated that ApoE Our study identified seven candidate AS co-depression biomarkers and verified that inflammation-induced damage to synaptic plastic rows is an important mechanism of AS co-depression, providing new insights into the diagnosis and treatment of AS co-depression disorders. Show less

The association and mechanisms between biotin and dementia remain unclear. We investigated the association through a population and animal study. UK Biobank data were used to evaluate the association of biotin with incident dementia and brain structural alteration. To validate our findings, we established a biotin-deficient mouse model, and performed behavioural tests, immunofluorescence, RT-qPCR, Western blotting, and molecular docking. In humans, higher biotin intake was significantly associated with reduced risks of all-cause dementia (moderate: 0.83 [0.74-0.94]; high: 0.78 [0.68-0.89]), Alzheimer's disease (AD, moderate: 0.74 [0.61-0.89]; high: 0.79 [0.64-0.98]), and delayed-onset dementia (DOD, moderate: 0.810 [0.715-0.918]; high: 0.776 [0.672-0.896]), but not vascular dementia (VD) and early-onset dementia (EOD). Neuroimaging results revealed a "pseudo-atrophy" pattern-reduced cortical volume with increased tissue intensity-resembling structural remodelling rather than neurodegeneration. In mice, biotin deficiency triggered region-specific alteration of APP, PSEN1, and APOE in the hippocampus and prefrontal cortex. It was accompanied by elevated Aβ42 levels and an increased Aβ42/40 ratio. Molecular docking suggested that biotin physically interacts with the catalytic pocket of PSEN1 and the receptor-binding domain of APOE. Dietary biotin is associated with a lower risk of dementia, especially AD, potentially by inhibiting amyloidogenic processing and modulating APOE-mediated clearance. The observed neuroimaging and molecular patterns suggest that maintaining adequate biotin intake is a viable strategy for dementia prevention. This work was supported by the National Natural Science Foundation of China (No. 82273619). Show less

Extracorporeal cardiac shock wave (ECSW) therapy enhances the function of endothelial colony-forming cells (ECFCs), but whether it can serve as a preconditioning strategy to enhance myocardial infarction (MI) therapy remains unclear. This study investigated the efficacy and mechanism of intravenously delivered ECSW-preconditioned ECFCs (SW-ECFCs) in a rat MI model. ECFCs were isolated from the bone marrow of ApoE Transcriptomic analysis revealed significant enrichment of the PI3K/AKT pathway in SW-ECFCs. Functionally, ECSW enhanced ECFCs migration, tube formation, proliferation, and VEGF-A secretion, while reducing apoptosis; these effects were largely abolished by PI3K inhibition. In vivo, serum levels of CK, CK-MB, and LDH were significantly elevated in all MI groups compared to the Sham group (P < 0.01), indicating comparable initial injury. However, no significant differences were observed among treatment groups (P > 0.05). SW-ECFCs transplantation significantly improved cardiac function, reduced infarct size, fibrosis, and apoptosis, and enhanced angiogenesis (P < 0.05). These benefits were associated with increased levels of p-AKT, p-eNOS, and BCL-2 protein as well as nitric oxide content, while suppressing the expression of cleaved caspase-3 (P < 0.05). Crucially, all these therapeutic benefits were largely abolished by PI3K inhibition. In conclusion, this study demonstrates that preconditioning ECFCs with ECSW significantly enhances their therapeutic efficacy for myocardial infarction, improving both cardiac function and structural repair. These benefits are mediated primarily through activation of the PI3K/AKT signaling pathway, which augments cell homing, paracrine activity, and survival, thereby providing a novel and promising strategy for cardiac regeneration. Show less

BackgroundOthers have examined heterogeneity in Alzheimer's disease (AD); however, few have used longitudinal data while accounting for variation in disease stage. We used latent classes to model heterogeneity in the trajectories of three cognitive domains (memory, language, and executive functioning) starting at AD dementia diagnosis.ObjectiveOur aim was to describe the patterns of heterogeneity in cognitive decline across cognitive domains during the course of AD and to contextualize our findings by assessing associations with demographic factors and neuropathological measures.MethodsWe used cognitive data from the Religious Orders Study, the Rush Memory and Aging Project, and the Minority Aging Research Study in a multi-dimensional joint latent class mixed model, which allowed us to estimate cognitive trajectories that varied across cognitive domains and latent classes. We accounted for the uncertainty in latent class assignment and corrected for multiple hypotheses when assessing the association of the latent classes with demographic and neuropathological variables.ResultsWe identified five latent classes differentiated by level of impairment (high to low) and rate of decline (slow to fast). Within each latent class, the pattern of decline did not differ substantially across cognitive domains. Classes were associated with Show less

Abundant data link ApoE (apolipoprotein E)-ε2 with favorable outcomes in several neurological settings and in healthy subjects, but studies in relation to stroke outcomes are few. ApoE-ε2 activities are associated with poststroke cortical oscillations, which themselves are correlated with poststroke outcomes. The aim of this cohort study was to determine whether cortical oscillations could represent an endophenotype mediating the effects of ApoE-ε2 on poststroke function. In 33 patients with recent stroke, resting EEG activity (3 minutes), APOE genotype, and functional outcome (GG scores) were measured. ANCOVAs and partial Pearson correlations were performed to validate the prerequisites for mediation analyses, in which EEG cortical power was tested as a mediator of the relationship between APOE-ε2 and functional outcome. ApoE-ε2 carriers showed higher ipsilesional beta power and lower ipsilesional theta power, both of which were linked to better functional outcomes. The principal mediation analysis revealed an indirect effect of ApoE-ε2 on functional outcome via ipsilesional M1 beta power (ACME, 14.79 [0.9-34.6], The mediation analysis results suggests that ApoE-ε2 supports a pro-repair environment, which may translate into more favorable cortical dynamics after stroke. Cortical oscillatory activity may be considered as an endophenotype that mediates the effects of ApoE-ε2 on functional outcome and could potentially be leveraged as a biomarker to develop personalized interventions targeting stroke recovery. Show less

Structural MRI analysis for Alzheimer's disease (AD) is limited by balancing group-level comparability in standard space with anatomical fidelity in native space. We therefore propose a multi-space, hybrid-feature framework, integrating radiomics and network metrics from both spaces to classify AD and predict mild cognitive impairment (MCI) progression. An integrated dual-space analytical framework was applied to T1-weighted MRI data. Models were developed on 1,477 participants from Alzheimer's Disease Neuroimaging Initiative (ADNI) and externally tested on an independent cohort of 1,349 participants from National Alzheimer's Coordinating Center (NACC). The framework extracts parallel radiomic and graph-based network features from both Montreal Neurological Institute (MNI) standard space and native space. These features were used to build machine learning models for three-class diagnosis (NC vs. MCI vs. AD) and 6-year prognostic prediction of MCI-to-AD conversion. For each task, the models using standard-space, native-space, and combined-space features were systematically compared. Model interpretation was performed using Shapley Additive Explanations (SHAP), and the features were validated against established AD biomarkers. The combined-space model demonstrated superior performance in both diagnostic classification (Macro-Averaged AUC: 0.96 in ADNI cohort, 0.94 in NACC cohort) and prognostic prediction of MCI-to-AD conversion (C-index: 0.83; HRs: 7.60, 95%CIs: 4.57-12.64). The extracted features in the ADNI cohort demonstrated significant correlations with APOE ε4 genotype, cognitive scores, and CSF biomarkers. Integrating multi-scale features from both standard and native spaces enhances AD diagnosis and prognosis accuracy more effectively than conventional single-space analysis. Show less

Growing evidence supports that epigenetic dysregulation through histone deacetylases (HDACs) plays a critical role in synaptic dysfunction and memory loss in Alzheimer’s disease (AD), and that HDACs have been highlighted as an attractive class of targets for AD therapy. Moreover, restoring Wnt/β-catenin signaling, which is greatly suppressed in AD brains, is a promising therapeutic strategy. CI-994 is an orally active class I HDAC inhibitor that has undergone several phase II/III clinical trials on cancer treatment. Importantly, CI-994 can cross the blood–brain barrier and is a cognitive enhancer. Wnt activity was initially examined by Wnt reporter activity assay in Wnt3A-expression HEK293 cells, and profiling HDAC inhibition was performed against 10 individual HDACs. Activities of CI-994 on class I HDACs and Wnt/β-catenin signaling were further tested in HEK293 cells, LRP6-expressing HT1080 cells and neuronal SH-SY5Y cells. The therapeutic effects of CI-994 were examined in patient-specific iPSC-derived neurons and cerebral organoids carrying We herein report that CI-994 is not only a potent class I HDAC inhibitor but also an activator of Wnt/β-catenin signaling. Mechanistically, activation of Wnt/β-catenin signaling by CI-994 is associated with stabilizing Wnt co-receptor LRP6 protein and modulating HDAC activity. Importantly, CI-994 significantly increases histone acetylation, activates Wnt/β-catenin signaling, and decreases tau phosphorylation in patient-specific iPSC-derived cerebral organoids carrying Our findings suggest that CI-994 can be repurposed as a novel therapeutic agent for AD therapy. The online version contains supplementary material available at 10.1186/s13195-026-01982-0. Show less

Brain atrophy subtypes are increasingly recognized in Alzheimer’s disease (AD) dementia. However, their relevance across the real-world memory clinic spectrum, from subjective cognitive impairment (SCI) and mild cognitive impairment (MCI) to AD and non-AD dementias, remains unclear. This cross-sectional study aimed to identify MRI-based atrophy subtypes in a relatively young memory clinic and examine associations with demographic, cerebrospinal fluid (CSF) biomarkers, and cerebrovascular burden to inform precision medicine approaches. We included all consecutive patients (SCI to dementia), evaluated at the Karolinska University-Hospital Memory Clinic (Stockholm, Sweden) between 2018 and 2023 with available clinical and 3T MRI data. Subtypes were defined using FreeSurfer-derived volumetric measures and a validated algorithm combining categorical classification (typical, limbic predominant, cortical predominant, minimal atrophy) with continuous indices of typicality (cortical predominant–limbic predominant) and severity (minimal atrophy–typical). Demographics, cognitive profiles, Among 809 patients (median age 60.0 years [interquartile-range 56.0–63.0], 56.1% female), 38.2% had SCI, 44.4% MCI, and 17.4% dementia. CSF biomarkers were available in 596 (73.7%). Limbic predominant and typical subtypes had more males (59.3% and 50.0%, respectively; group-wise p < 0.001), higher APOE ε4 frequency (47.7% and 41.0%, p = 0.02), greater cerebrovascular burden, and poorer memory. These subtypes were more often Aβ positive (46.1% and 46.5%, p = 0.01). A cortical predominant pattern was frequent in females (66.0%, p < 0.001), while minimal atrophy was associated with milder cognitive impairment (49.0% SCI, 45.5% MCI) and higher depressive symptoms. In Aβ-positive patients (n = 231), typical and limbic subtypes had higher p-tau181 (median: 83.0 and 84.5 pg/mL, respectively; p < 0.001), NFL (1120.0 and 1125.0 pg/mL, p < 0.001), and lower Aβ42/40 ratios (0.051 and 0.049, p = 0.02). Findings remained consistent across continuous atrophy measures and in the 14.9% (n = 89) eligible for anti-Aβ therapy. MRI-based atrophy subtypes exhibit distinct clinical and biomarker profiles, consistently observed in Aβ-positive and anti-Aβ-therapy-eligible patients. These findings support their diagnostic utility in memory clinics and relevance for biologically targeted AD trials. The online version contains supplementary material available at 10.1186/s13195-026-01972-2. Show less

Plasma phosphorylated tau 217 (p-tau217) has shown strong potential as a blood-based biomarker for detecting amyloid pathology in Alzheimer's disease. This study evaluated the diagnostic and prognostic utility of plasma biomarkers, including p-tau217, in participants from the Japanese Alzheimer's Disease Neuroimaging Initiative (J-ADNI) cohort. We analyzed paired plasma and CSF samples from 172 J-ADNI participants. CSF and plasma biomarkers were quantified using the LUMIPULSE platform, and the same plasma samples were analyzed using the Simoa platform. The diagnostic accuracy for detecting amyloid pathology and the prognostic value of plasma p-tau217 biomarkers were assessed. Associations between plasma p-tau217 and polygenic risk scores (PRS), as well as potential confounding factors, were examined. Plasma p-tau217 levels measured using Lumipulse and Simoa assays were highly correlated (p < 0.001). All plasma p-tau217 assays showed high diagnostic accuracy for CSF Aβ42/Aβ40-defined amyloid pathology (AUC = 0.98). A single cutoff point based on the Youden index for p-tau217 and p-tau217/Aβ42 achieved >90% specificity and >90% sensitivity. The predefined FDA-approved two-cutoff model for p-tau217/Aβ42 was applicable to this cohort. PRS was significantly associated with plasma p-tau217 independently of APOE genotypes. Subjects with higher plasma p-tau217 levels showed a significantly increased risk of conversion to dementia and larger longitudinal cognitive declines. Plasma p-tau217 levels were significantly influenced by the body mass index, estimated glomerular filtration rate, and high-density lipoprotein cholesterol. Plasma p-tau217 and p-tau217/Aβ42 are robust biomarkers for AD diagnosis and prognosis in the Japanese population. Show less

Chronic obstructive pulmonary disease (COPD) frequently coexists with extrapulmonary comorbidities, most notably cardiovascular diseases (CVD). However, the mechanisms linking COPD to CVD, particularly atherosclerotic CVD, remain poorly understood. Extracellular vesicles (EVs), as key mediators of inter-organ communication, may participate in this pathological connection. This study aims to determine whether EVs derived from airway epithelial cells (AECs) of individuals with COPD contribute to endothelial dysfunction and atherosclerosis. EVs were isolated from primary airway epithelial cells of COPD patients and matched controls. Their effects on endothelial cell function were assessed in vitro by evaluating inflammation, apoptosis, and monocyte adhesion. ApoE-/- mice were intravenously injected with these EVs to examine their impact on atherosclerotic lesion development. Differentially expressed microRNAs were identified, and the regulatory relationship between miR-141-3p and PDCD4 was validated through molecular assays. Additionally, miR-141-3p supplementation was performed to determine its therapeutic potential in mitigating endothelial injury and atherosclerosis. COPD AECs-derived EVs markedly increased endothelial inflammation, apoptosis, and monocyte adhesion compared with control EVs. In ApoE-/- mice, COPD-derived EVs accelerated the formation of atherosclerotic plaques. Mechanistic analyses revealed that miR-141-3p was significantly downregulated in COPD EVs and directly targeted the 3' untranslated region of PDCD4 to regulate its transcription, leading to dysregulation of PDCD4/NF-κB signaling in endothelial cells. Restoration of miR-141-3p levels in COPD-derived EVs alleviated endothelial injury and reduced atherosclerotic lesion progression both in vitro and in vivo. This study identifies a previously unrecognized mechanism by which COPD AECs-derived EVs may promote atherosclerotic CVD via miR-141-3p-mediated regulation of PDCD4 and subsequent activation of NF-κB signaling. These findings highlight miR-141-3p as a promising therapeutic target to reduce vascular complications in COPD. Show less

Apolipoprotein E (APOE) ε4 is the strongest genetic risk factor for Alzheimer's disease (AD). However, it is known that other pathways independent of APOE also play a role in AD. Disentangling APOE-dependent and independent effects is instrumental for understanding the biology of AD. We conducted an APOE-stratified multi-omic analysis in multiple large datasets to identify AD-associated plasma proteins and metabolites. More than 64% of the identified proteins were not found in non-APOE stratified studies, and 17% of the proteins showed APOE-specific trends. Mitochondrial dysfunction was associated in AD independently of APOE and was accompanied by disruptions in glucose and lipid metabolism and cell death and increased in inflammatory signaling activation. Lipid upregulation was found in AD cases when compared with controls with the same APOE genotype, indicating that additional factors beyond APOE affect lipid regulation and AD risk. These findings may be informative in guiding the development of effective medications for AD. Show less

BackgroundEducation promotes cognitive reserve (CR), potentially buffering Alzheimer's disease pathology (ADP). However, the education-CR relationship may differ by population and genetic background.ObjectiveTo examine education, Show less

The gradual decline of endothelial function and the intensification of inflammatory responses form the basis for the occurrence and development of age-related diseases such as atherosclerosis (AS). Mitochondrial dysfunction-manifested by excessive reactive oxygen species (ROS) production, reduced mitochondrial membrane potential, and impaired mitophagic flux-and sterile inflammation are hallmarks of aged vasculature. We investigated whether bolstering mitochondrial quality control via the novel cell-penetrating antioxidant PEP-1-Catalase (CAT) could mitigate these key features of vascular aging. To model age-associated vascular pathology, ApoE⁻/⁻ mice were fed a high-fat diet (HFD) and treated with PEP-1-CAT. Endothelial cell function, plaque burden, and inflammation were analyzed. In vitro, human endothelial cells (HUVECs) were subjected to inflammatory stress and treated with PEP-1-CAT, with or without modulators of mitophagy. We assessed mitochondrial ROS, membrane potential, NOD-like receptor protein 3 (NLRP3) inflammasome activation, and the PINK1-Parkin pathway. PEP-1-CAT treatment significantly ameliorated atherogenesis and improved features of plaque stability in mice. It suppressed vascular oxidative stress, restored mitochondrial membrane potential, enhanced mitophagic flux, and inhibited NLRP3-driven inflammation. In endothelial cells, PEP-1-CAT attenuated mitochondrial oxidative stress and dysfunction. Crucially, it activated the PINK1-Parkin pathway to promote mitophagy, which was essential for its anti-inflammatory effects, as mitophagy inhibition abrogated the suppression of the NLRP3 inflammasome. Our findings demonstrate that targeting mitochondrial health with PEP-1-CAT alleviates hallmarks of atherosclerotic vascular pathology, including endothelial dysfunction and inflammation, by enhancing mitophagy. This strategy of restoring mitochondrial quality control presents a promising therapeutic approach to delay atherosclerotic vascular pathology. Show less

Opioid use is disproportionately high among People with HIV (PWH). Although combined anti-retroviral therapy (ART) can dampen HIV-associated dementia, a large fraction of PWH continue to experience neurocognitive deficits which are further exacerbated by opioid use. In the present study, we performed single cell transcriptomic profiling of cerebrospinal fluid (CSF) immune cells to explore their functional characteristics in opioid mediated neurological disorders among PWH using the SIV/rhesus macque model. In this study, we utilized CSF cells from morphine- and saline-administered, SIV-infected, ART-treated rhesus macaques (RMs). The CSF scRNA-Seq was performed longitudinally at baseline, post ramp-up with morphine (pre-infection), during acute infection, and after suppression of viremia to profile cell-specific transcriptomic signatures that mirror the CNS pathogenesis observed in opioid-dependent PWH. We observed the presence of all major immune cells in CSF, including CD4 + T Chronic opioid exposure reprograms CSF monocytes toward a DAM state that persists despite ART-mediated viral suppression, driving maladaptive immune-glial crosstalk and progressive neurocognitive dysfunction in morphine-dependent macaques with possible implications for neuroinflammation and neurodegenerative disorders that are observed in PWH. Show less

Abdominal aortic aneurysm (AAA) is a life-threatening condition with limited pharmacological therapies. The pathological progression of AAA is closely attributed to the phenotypic switching of vascular smooth muscle cells (VSMCs). NFS1 is the rate-limiting enzyme for the synthesis of iron-sulfur proteins, and the roles of NFS1 in AAA initiation and development have not been explored. Angiotensin II (Ang II) infusion-induced AAA animal model with Apoe Show less

To quantify the Number Needed to Test (NNT) to prevent one ARIA event as a function of A Bayesian simulation study using a Beta-Binomial model to analyze genotype-stratified contingency tables. Data were derived from two published, phase 3 clinical trials: Clarity-AD (lecanemab) and TRAILBLAZER-ALZ 2 (donanemab). Aggregate data from source trials. Simulation of varying treatment discontinuation probability NNT to prevent one ARIA event (any ARIA-E, any ARIA-H, and symptomatic ARIA-E) and the fractional reduction in total ARIA events as a function of NNTs increased (worsened) significantly as The direct safety impact of Show less

Vascular inflammation contributes to the development of many chronic human diseases. Inflammatory stimuli such as interleukin (IL)-1β or disturbed blood flow trigger endothelial activation, thereby promoting leukocyte recruitment and transmigration through inflammatory signaling pathways. This study aimed to identify novel compounds capable of blocking vascular inflammation, with potential therapeutic applications in vascular inflammatory diseases such as atherosclerosis. A natural compound library was screened to identify drug candidates that inhibit IL-1β-induced endothelial inflammation. The anti-inflammatory effects of tigloylgomisin P, one of the hit compounds, were examined in bovine aortic endothelial cells stimulated with IL-1β or oscillatory (disturbed) flow. Endothelial inflammation was assessed by measuring nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) phosphorylation and nuclear translocation, monocyte adhesion to endothelial monolayers, and Smad1/5/9 phosphorylation Tigloylgomisin P suppressed IL-1β-induced NF-κB activation and reduced monocyte adhesion. In addition, it inhibited oscillatory shear stress-induced endothelial inflammation mediated by NF-κB activation and Smad1/5/9 phosphorylation. In ApoE knockout mice, administration of tigloylgomisin P decreased inflammatory marker expression in the atheroprone inner curvature of aortic arches. These findings suggest that tigloylgomisin P may represent a potential therapeutic agent for vascular inflammatory diseases such as atherosclerosis. Show less

Women face greater vulnerability to dementia and Alzheimer's disease (AD), potentially due to estrogen fluctuations across the lifespan. However, its role in vascular brain health is unclear. We investigated associations between lifelong estrogen exposure-endogenous (reproductive span) and exogenous (oral contraceptives [OC], menopausal hormone therapy [MHT])-and late-life vascular brain injury, AD-related atrophy, and We included 352 cognitively unimpaired 70-years-old women from the Gothenburg H70-1944 Birth Cohort with brain MRI and 5-year follow-up. Reproductive lifespan was calculated as age at menopause or oophorectomy minus age at menarche. OC and MHT use were self-reported. Outcomes included cerebral small vessel disease (SVD), AD-related cortical thickness, and white-matter integrity (fractional anisotropy). Linear and multinomial regression and mixed-effects models were adjusted for confounders and stratified by Extended estrogen exposure throughout life-both endogenous and exogenous-appear to support late-life cerebrovascular health in women, with potential genotype-specific neuroprotective effects. Given the current absence of sex-specific prevention guidelines for cognitive disorders, future research should clarify estrogen's longterm impact on brain health and cognition to inform personalized medicine. Show less

Cognitive dysfunction affects over 50 million individuals worldwide, with Alzheimer's disease (AD) representing two-thirds of cases. We identified Human proteomic analysis revealed eQTL mapping identified Show less

The longissimus dorsi muscle and backfat are important components of pork and complement each other in physiological function, significantly influencing key traits such as growth performance, carcass traits, and meat quality. While the transcriptomic atlas across different tissues in pigs has been widely studied, the underlying epigenetic regulatory mechanisms remain to be explored. In this study, we collected muscle and adipose tissues from hybrid offspring of lean-type (Western commercial pigs) and fat-type (Chinese indigenous pigs) pigs ( Transcriptome sequencing identified 2,908 differentially expressed genes, which are primarily involved in collagen fibril organization, skeletal muscle contraction, and muscle organ development. Whole-genome DNA methylation sequencing identified 2,787 differentially methylated genes in the promoter region. Through integrative analysis, we found 571 genes that were shared, 390 of which showed a significant negative correlation between gene expression and promoter DNA methylation. These genes are mainly involved in cholesterol metabolism, PPAR signaling pathway, cytoskeleton in muscle cell, and calcium ion signaling pathways. Notably, we discovered that the differential expression of genes such as These results suggest that DNA methylation plays an extensive and subtle regulatory role in tissue-specific gene expression, thereby facilitating different tissues to execute their specific physiological functions. This study further enriches our understanding of the integrative mechanisms between epigenetic regulation and transcriptomics in pigs and provides important theoretical foundations for precision molecular breeding. The online version contains supplementary material available at 10.1186/s12864-026-12559-4. Show less