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Spinal cord injury (SCI) leads to severe sensory, motor, and autonomic dysfunction with limited treatment options. Ginsenosides, the primary bioactive compounds derived from Panax ginseng, have demonstrated neuroprotective potential in SCI. This systematic review aims to evaluate the preclinical evidence regarding the multi-target mechanisms of ginsenosides in SCI Methods: A comprehensive literature search was conducted following PRISMA guidelines across PubMed, Web of Science, and Google Scholar up to January 2025. Of the 385 identified articles, 22 studies met the inclusion criteria, which focused on the pharmacological effects of ginsenosides in SCI using both in vivo and in vitro models. Data on mechanisms, models, and outcomes were systematically synthesized Results: Ginsenosides exerted multi-target neuroprotective effects in SCI models, including antiinflammatory actions via suppression of TLR4/NF-κB and MAPK signaling, leading to reduced TNF-α, IL-1β, and IL-6, antioxidant activity through Nrf2/HO-1 pathway activation, enhancing SOD, CAT, and GSH, anti-apoptotic effects via ASK1/JNK inhibition, lowering caspase-9/3 and Bax while elevating the Bcl-2/Bax ratio, regulation of autophagy by activating PI3K/Akt to prevent excessive self-digestion, promotion of neural repair through upregulation of neurotrophic factors (NGF, bFGF, BDNF, and GDNF) and extracellular matrix components (laminin, fibronectin), inhibition of spinal cord edema via increased AQP4 expression, and facilitation of nerve regeneration by promoting astrocyte-to-neuron conversion and olfactory ensheathing cell migration Discussion: The findings highlight the synergistic mechanisms of ginsenosides in addressing key pathological processes in SCI, including inflammation, oxidative stress, apoptosis, and impaired neural regeneration. While preclinical evidence underscores their therapeutic promise, the translational potential requires validation through rigorous clinical trials to confirm efficacy, safety, and applicability in humans Conclusion: Ginsenosides exhibit multi-target neuroprotective effects in SCI models, positioning them as promising candidates for therapeutic development. Further clinical studies are essential to advance their application in SCI treatment. Show less

Alzheimer's disease (AD) is marked by progressive cognitive decline and memory loss. Emerging evidence underscores the role of long non-coding RNAs (lncRNAs), particularly nuclearenriched abundant transcript 1 (NEAT1), in AD pathogenesis. NEAT1, a pivotal lncRNA that regulates diverse cellular processes, shows dysregulated expression in AD and impairs neuronal survival. This review explores NEAT1's molecular mechanisms, biomarker potential, and therapeutic relevance. NEAT1 contributes to AD pathology by acting as a competitive endogenous RNA (ceRNA) that sequesters protective microRNAs, including miR-124 and miR-107, thereby dysregulating downstream targets. It facilitates PINK1 degradation and potentially drives mitochondrial dysfunction and neuronal injury. Elevated NEAT1 levels are associated with amyloid-beta accumulation, tau hyperphosphorylation, and NF-κB-mediated neuroinflammation. Preclinical studies suggest that modulating NEAT1 expression can alleviate AD‑like pathology, making NEAT1 a promising target for intervention. Increased plasma NEAT1 in patients indicates its value as a non-invasive early diagnostic biomarker. NEAT1 regulates multiple AD-related pathways, including IGF1R, TRAF2, BACE1, CREB/BDNF, and Nrf2/NQO1, and interacts with lncRNAs linked to metabolic and neurodegenerative diseases, such as XIST and KCNQ1OT1. By influencing amyloid processing, synaptic function, mitochondrial health, and inflammatory responses, NEAT1 emerges as a central regulator in AD. Targeting NEAT1 offers dual benefits: advancing precision diagnostics and enabling multi-pathway therapeutic approaches. This review underscores NEAT1's significance as both a biomarker and therapeutic target, providing insights for future strategies to mitigate the burden of AD. Show less

Future directions in incretin research: Three major directions currently shape therapeutic innovation in incretin research: multi-receptor agonism, oral drug development, and mechanistic reappraisal of glucose-dependent insulinotropic polypeptide (GIP) physiology. These advances indicate that incretin-based therapies should be understood within an integrated enteroinsular network rather than through isolated hormone actions. DPP-4, dipeptidyl peptidase-4; GCGR, glucagon receptor; GIPR, GIP receptor; GLP-1, glucagon-like peptide-1; GLP-1R, GLP-1 receptor; T2D, type 2 diabetes. Show less

To investigate the association between quantitative retinal vascular parameters and coronary artery disease (CAD) and to evaluate the efficacy of a retinal phenotype-based diagnostic model as a non-invasive tool for early CAD screening. A retrospective cross-sectional study. A single-centre study conducted at the Cardiovascular Center of Beijing Tongren Hospital, Capital Medical University, China, between January and October 2024. 417 patients with suspected angina undergoing their first coronary angiography (CAG) were enrolled. Inclusion criteria were age >18 years and high-quality fundus photography within 24 hours pre-CAG. Major exclusions were prior coronary interventions, severe systemic/valvular heart diseases and ocular conditions impairing retinal vascular visualisation. The primary outcome was the association between quantitative retinal vascular parameters and the presence of CAD (defined as ≥50% stenosis). Secondary outcomes included the diagnostic performance area under the receiver operating characteristic curve (AUROC) of three predictive models: one based on quantitative retinal vascular parameters alone, one based on traditional risk factors and a combined model integrating both retinal and clinical variables. This study enrolled 417 patients undergoing initial CAG. Compared with non-CAD controls (n=190), patients with CAD (n=227) had higher prevalence of hypertension, dyslipidaemia and diabetes, along with elevated levels of fasting blood glucose, lipoprotein(a) (Lp(a)), triglyceride (TG) and glycated haemoglobin (HbA1c) (all p<0.05). Quantitative fundus analysis revealed that multiple retinal vascular parameters were independently associated with CAD after multivariable adjustment, including fractal dimension (FD), vessel density (VD) and specific zonal measures of vessel diameter and tortuosity (all p<0.05). Multivariable logistic regression incorporating both fundus and clinical variables identified the following independent predictors of CAD: a decrease in FD (OR=0.26, 95% CI 0.16 to 0.41, p<0.01), reduced optic disc long-to-short axis ratio (OR=0.04, 95% CI 0.004 to 0.46, p=0.01) and optic disc-to-macula distance (OR=0.91, 95% CI 0.86 to 0.97, p<0.01), male sex, dyslipidaemia and elevated levels of Lp(a), TG, low-density lipoprotein cholesterol and HbA1c (all p<0.05). The final diagnostic model achieved an AUROC of 0.802 (95% CI 0.76 to 0.845), with a sensitivity of 0.797 and a specificity of 0.679 at the optimal cut-off. Internal validation via bootstrap resampling (1000 iterations) confirmed the robustness of the identified predictors. Our findings, derived from an artificial intelligence-based fully automated quantitative retinal vascular parameters measurement method, revealed that multiple quantitative fundus parameters-including FD, VD and other morphological parameters were significantly associated with CAD risk. The CAD diagnostic model we developed demonstrates strong performance and high interpretability, making it suitable for early CAD screening and diagnosis. Show less

Atherosclerosis (AS) is the main pathological basis of atherosclerosis-related cardiovascular and cerebrovascular diseases. The phenotypic conversion and death mechanisms of vascular smooth muscle cells (VSMCs) are crucial during its development. This study reveals the molecular mechanisms of the C1qbp-DLAT axis and the U2AF2 (U2 Small Nuclear RNA Auxiliary Factor 2)-NEAT1 network in regulating cuproptosis in AS. In this study, an ApoE The study revealed elevated copper ion levels and dysregulated cuproptosis-related genes in an AS model. U2AF2 stabilized C1qbp mRNA, enhancing C1qbp protein expression, which promoted DLAT oligomerization to regulate cuproptosis. LncRNA NEAT1 facilitated this process by scaffolding U2AF2-C1qbp mRNA interaction. Targeted inhibition of U2AF2 significantly improved AS pathological characteristics, reduced lipid deposition, collagen deposition and macrophage infiltration within the plaque, increased smooth muscle cell content and lowered serum levels of total cholesterol (TC), total triglyceride (TG) and low-density lipoprotein cholesterol (LDL-C). This study revealed the role of the U2AF2-C1qbp-copper death regulatory axis in the development of AS, providing new targets and a theoretical basis for the treatment of AS. Targeted inhibition of U2AF2 may become an effective strategy to delay progression of AS. Show less

TyHGB is a novel insulin resistance (IR)-related indicator, and its association with coronary heart disease (CHD) remains unclear. Additionally, studies have shown a close correlation between the diagonal earlobe crease (DELC) and CHD, yet it has not been fully applied in clinical practice to date. Therefore, this study constructed and validated a diagnostic model for CHD by combining TyHGB and DELC. A total of 1664 patients suspected of CHD who underwent coronary angiography (CAG) in the Department of Cardiology, Chengde Central Hospital from September 2021 to April 2025 were recruited for this study. Participants were categorized into a CHD group ( Age, sex, hypertension, diabetes, CR, Lp(a), TyHGB, and DELC were identified as independent risk factors for CHD through multivariate logistic regression analysis ( Both TyHGB and DELC have been identified as independent risk factors for CHD, with a linear relationship observed between TyHGB levels and CHD risk. A diagnostic model for CHD, developed by integrating TyHGB, DELC, and traditional risk factors, demonstrates strong diagnostic efficacy. The online version contains supplementary material available at 10.1186/s12944-026-02880-y. Show less

Glyphosate (GLY) is a widely used herbicide, particularly in agriculture, and its residues in plants and soil can induce toxic effects in various organisms, including humans, with the brain being especially vulnerable. Eugenol (EU), a natural antioxidant found in cloves, has demonstrated protective effects against different toxic substances. This experimental study explored whether eugenol could mitigate neurological damage triggered by glyphosate exposure in rats. A total of forty male Sprague-Dawley rats were allocated into five experimental groups consisting of control, eugenol (100 mg/kg), glyphosate (150 mg/kg), EU50 combined with glyphosate (50 mg/kg + 150 mg/kg), and EU100 combined with glyphosate (100 mg/kg + 150 mg/kg). Animals received the respective treatments by oral gavage for a period of seven days. Motor and anxiety-related behaviors were evaluated using behaviour tests, after which brain tissues were processed for histopathological analysis. Biochemical analyses included ELISA assessment of oxidative stress markers (MDA, SOD1, GSH, and GPx1), RT-PCR analysis of endoplasmic reticulum (ER) stress- and apoptosis-related genes (GRP78, ATF4, CHOP, PI3K/AKT/mTOR, BAX, and Bcl-2), Western blot evaluation of inflammatory and antioxidant signaling pathways (TLR4/NF-κB and Nrf2/HO-1/SIRT1), and immunohistochemical and immunofluorescence analyses of neuroplasticity, circadian rhythm, and autophagy markers (BDNF, BMAL1, CLOCK, Beclin-1, and LC3A/B). GLY exposure significantly increased lipid peroxidation (MDA), ER stress markers (GRP78 and CHOP), pro-inflammatory mediators (TLR4, NF-κB, TNF-α, and IL-1β), apoptotic signaling (BAX and caspase-3), and autophagy-related proteins, while suppressing antioxidant pathway components. Glyphosate exposure induced behavioral impairments accompanied by increased oxidative stress, inflammatory activation, endoplasmic reticulum stress, apoptosis, and dysregulated autophagy in cerebral cortex tissue. EU treatment dose-dependently attenuated these molecular and histopathological alterations, restored antioxidant and cellular stress responses, and significantly improved behavioral performance, indicating a protective role against GLY-induced neurotoxicity. Overall, EU may represent a promising therapeutic candidate for mitigating herbicide-induced brain injury. Show less

Neurodegenerative diseases such as Huntington's Disease (HD) have a significant impact on healthcare accessibility and costs. A fatal genetic condition, characterized by the progressive loss of striatal neurons, HD is hindered by the lack of endogenous repair in the adult brain. Recent efforts toward protecting neural circuits through neurotrophic support using brain-derived neurotrophic factor (BDNF) have been suboptimal due to the protein's short half-life and limited diffusion. Addressing this, adeno-associated viral vectors (AAV) can be employed as a delivery tool to spatially transduce cells, enabling the localised production of BDNF with consequential neuron protection and/or plasticity, yet present their own constraints. To overcome these known challenges of AAV gene delivery, an injectable, physiologically stable hydrogel-mimic of the brain's extracellular matrix was fabricated to encapsulate the AAVs. This smart system both shielded and constrained the AAV; optimising transfection and therefore elevated and sustained BDNF presentation at the target site. Here, we achieved high neuroprotection using AAVDJ-BDNF delivered through a hydrogel formed via self-assembling peptide nanoscaffolds. These findings support the notion that the spatiotemporal release of BDNF to striatal neurons, facilitated by engineered biomaterial delivery systems, demonstrates tremendous promise by enhancing the efficacy of gene therapy targeted at slowing neurodegenerative disease progression. Show less

Neurodegenerative diseases such as Alzheimer's (AD), Parkinson's (PD), Huntington's (HD), and multiple sclerosis (MS) involve progressive neuronal loss driven by dysregulated neurotransmission, neuroinflammation, oxidative stress, and mitochondrial dysfunction. Cholesterol metabolism has emerged as a critical factor involved with both central and peripheral dysregulation contributing to pathology. This review synthesizes current evidence on cholesterol's role in neurodegeneration and evaluates the therapeutic potential of statins, which act via cholesterol-dependent and other pleiotropic mechanisms. A PubMed search covering 1985-2025 publications was conducted using terms related to neurodegenerative diseases, statins, cholesterol metabolism, neuroinflammation, oxidative stress, mitochondrial dysfunction, and neuroprotection. Studies were selected to highlight mechanistic insights into cholesterol regulation in the nervous system and clinical data on statin use. Neuronal loss in neurodegeneration is driven by processes including excitotoxicity, inflammation, and mitochondrial dysfunction. Excessive reactive oxygen species activate apoptotic pathways involving Show less

Atherosclerosis (AS) is a central pathological driver underlying most cardiovascular diseases. Gut microbiota and related metabolites participate in regulating atherosclerosis. Fifty C57BL/6J ApoE Atherosclerotic plaques accumulated in the aorta and aortic sinus after HFD, while statin and high-dose GP alleviated this burden. TC, TG, LDL-C, MCP-1, MCP-3 and IL-2 showed significant increase after HFD, while statin and GP decreased LDL-C, MCP-1 and MCP-3. The goblet cells, ZO-1 and Occludin decreased after HFD, while statin and GP increased them, indicating that the intestinal barrier integrity was improved. Additionally, the composition of gut microbiota was modulated by GP. Some candidate taxa were identified, such as This study suggests that GP is beneficial for alleviating atherosclerosis in HFD-induced ApoE Show less

Postoperative delirium is common in older surgical patients, but simple blood tests to identify risk are lacking. Plasma amyloid-β oligomers measured by multimer detection (MDS-OAβ) may reflect neurodegenerative vulnerability. We enrolled 101 patients aged ≥65 years undergoing elective orthopaedic surgery with general anaesthesia. Blood was drawn preoperatively and at first delirium diagnosis or on postoperative Day 4 if no delirium. MDS-OAβ was quantified blinded. Delirium was assessed daily on postoperative Days 1-3 (DRS-R-98 and DSM). Propensity-score matching on APOE ε4 status and clinical covariates addressed Alzheimer-type vulnerability. Discrimination and thresholds (0.60, 0.72, 0.85 ng/ml) were evaluated using logistic regression and ROC analyses. Among 101 patients (44 with delirium; 57 without), preoperative MDS-OAβ concentrations were higher in those who developed delirium and correlated with delirium severity. In the overall cohort, preoperative MDS-OAβ discriminated delirium with an area under the curve of 0.855 (95% CI 0.777-0.919); in a pooled postoperative dataset (n = 205), discrimination was similar (AUC 0.884, 95% CI 0.837-0.925). The dual-threshold approach identified a low-risk group with high negative predictive value and a high-risk group with high positive predictive value, leaving an intermediate group for closer observation. Preoperative plasma MDS-OAβ may provide a scalable biomarker for perioperative risk stratification of postoperative delirium in older adults, supporting a dual-threshold strategy for targeted prevention and monitoring. Low MDS-OAβ values indicate lower risk but do not exclude POD; biomarker-guided stratification should complement, not replace, routine perioperative delirium surveillance. Show less

We aimed to test the effect of hydroxychloroquine (HCQ) treatment on atherosclerosis and plasma lipids in apolipoprotein E deficient (ApoE Forty-seven (47) mice were divided into two treatment groups: an HCQ group administered 10 mg/kg/day in drinking water for 16 weeks and a control group with no HCQ. All mice were maintained on a standard chow diet containing 5% fat and had free access to water. At 32 weeks of age, blood was drawn for plasma lipid determination and the proximal aorta was removed to measure the atherosclerotic area and evaluate the expression of eNOS and HIF-1α by immunohistochemistry. The HCQ group consisted of 16 mice (10 males, six females), while the control group consisted of 31 mice (17 males, 14 females). HCQ significantly reduced the atherosclerotic area (mm HCQ reduces aortic atherosclerosis in ApoE Show less

Dementia with Lewy bodies (DLB) frequently coexists with cerebrovascular injury and Alzheimer's-related pathology, yet accessible in vivo markers of these processes remain limited. The retinal microvasculature shares structural and physiological characteristics with cerebral small vessels and may provide a non-invasive window into neurovascular and neurodegenerative pathology. In this cross-sectional study, 32 individuals with DLB and 31 age-matched cognitively unimpaired controls (CU) underwent swept-source optical coherence tomography angiography (OCTA), brain MRI, and plasma biomarker assessment. Retinal vessel densities of the superficial vascular complex (SVC), deep vascular complex (DVC), and choriocapillaris (CC) were quantified. Plasma amyloid-β, phosphorylated tau-217 (p-tau217), and glial fibrillary acidic protein were measured. Cerebral small vessel disease (SVD) burden and white matter hyperintensity (WMH) volumes were derived from MRI. Associations with cognition and mediation by WMH burden were evaluated using generalized estimating equations and bootstrapped mediation analyses. Compared with CU, individuals with DLB exhibited significantly reduced SVC, DVC, and CC vessel densities (all p < 0.001). Lower retinal vessel densities were associated with higher plasma amyloid burden and elevated p-tau217, as well as greater SVD burden and periventricular WMH volume. APOE ε4 carriers demonstrated more pronounced retinal microvascular impairment, higher WMH burden, and elevated p-tau217 levels than non-carriers. Reduced SVC density was associated with worse global cognition, and this relationship was partially mediated by periventricular WMH volume. Retinal microvascular impairment measured by OCTA is closely linked to Alzheimer's-related plasma biomarkers, SVD, and cognitive decline in DLB. These findings support retinal OCTA as a scalable, non-invasive biomarker reflecting convergent neurodegenerative and vascular pathology in DLB. Show less

Clusterin, a multifunctional glycoprotein involved in proteostasis, amyloid-β clearance, and neuroinflammation, has been proposed as a biomarker in Alzheimer's disease (AD), but its stage-specific links to brain structure, tau pathology, and cognition remain unclear. This study evaluated plasma clusterin across the AD spectrum, its associations with brain volumes and CSF tau/p-tau, and whether structural brain measures mediate its cognitive effects. Data from 333 participants (CN = 38, MCI = 207, AD = 88) were analyzed using FDR-corrected regression, Pearson correlations, and mediation analyses, adjusting for demographic factors and APOE ɛ4 status. Results showed that plasma clusterin was highest in mild cognitive impairment (MCI) compared to cognitively normal (CN) and AD, suggesting a peak during early neurodegeneration. In CN participants, higher clusterin was associated with lower whole-brain volume, but it was not significantly related to hippocampal volumes or tau/p-tau. In MCI, clusterin was modestly associated with reduced whole-brain volume and elevated CSF tau, while associations with hippocampal volumes and p-tau were nonsignificant. In AD, higher clusterin was significantly associated with smaller left and right hippocampal volumes, with a trend toward lower whole-brain volume; no significant associations with tau or p-tau were observed. Based on the mediation analysis, in CN participants, no significant mediation effects of brain volumes were observed between plasma clusterin and cognitive function. In the MCI group, higher plasma clusterin was associated with lower whole-brain volume, and this volumetric measure showed significant indirect effects linking plasma clusterin to cognitive performance, consistent with indirect-only (full mediation) patterns. This suggests an indirect association whereby higher clusterin may be linked to poorer cognitive function through its association with reduced global brain volume. Likewise, in the AD group, higher clusterin levels were associated with lower whole-brain and right hippocampal volumes. Both measures significantly mediated the relationship between clusterin and cognitive performance, indicating that higher clusterin may be linked to poorer cognitive function through its association with reductions in global and region-specific brain volumes. Future studies should clarify the temporal and mechanistic pathways linking clusterin to neurodegeneration to determine its value as a biomarker and therapeutic target. Show less

Vascular smooth muscle cell (VSMC) phenotype switching plays a significant role in the pathogenesis of atherosclerosis (AS). However, the subtypes of VSMC transdifferentiation and their impact on AS progression and atherosclerotic plaque instability remains unclear. We reanalysed scRNA-seq datasets of GSE155513 and GSE253903 and performed single-sample gene set enrichment analysis (ssGSEA) in three transcriptome datasets from unstable plaques to determine the major subtypes contributing the most to plaque instability. Using high-dimensional weighted gene co-expression network analysis (hdWGCNA), we identified hub genes in macrophage (MP)-like smooth muscle cells (SMCs) of unstable plaques. We conducted cell communication analysis according to tensin1 (TNS1) gene levels in VSMCs. TNS1 expression was analysed in human AS plaques. Finally, an AS model was established in VSMC-specific Tns1 knockout ApoE MP-like SMC was identified as the key subtype for plaque instability. hdWGCNA analysis for MP-like SMC identified blue module as the key gene module involved in unstable plaques. Decreased TNS1 expression in VSMCs was positively correlated with the down-regulation of contractile VSMC marker genes, SRF and MYCOD genes, negatively correlated with the up-regulation of CD68 and KLF4 genes, and activated VCAM, PDGF, THBS and CXCL signalling pathways. TNS1 mRNA expression levels were lower in human atherosclerotic arteries than in healthy arteries, and even lower in unstable plaques than in early and stable plaques. TNS1 protein levels in VSMCs were lower in human atherosclerotic plaques than in healthy arteries, and even lower in advanced plaques than in early plaques. VSMC-specific Tns1 gene deficiency aggravated AS progression and enhanced plaque instability with increased MP-like SMC transdifferentiation. The reduction of TNS1 gene in VSMCs might drive contractile VSMC transdifferentiation into MP-like SMC, the major subtype contributing to plaque instability. In vivo experimental results confirmed the role of Tns1 gene in contractile VSMC transdifferentiation into MP-like SMC and plaque instability. Show less

Myokines and cytokines are signaling proteins released by skeletal muscle cells during exercise that act as messengers, influencing the function of various organs, including the brain. We examined whether a single bout of walking exercise induces distinct changes in plasma myokine and cytokine concentrations in older adults with and without mild cognitive impairment (MCI). In 146 older adults characterized based on the Montreal Cognitive Assessment (MoCA) scores in non-MCI (MoCA score ≥26, n = 55) vs MCI (MoCA score <26, n = 91), we measured cognitive performance by battery, body composition by DXA, and functional performance by 6 min walk test (6MWT) distance. In addition, plasma myokine and cytokine concentrations were assessed before and immediately after 6MWT by MILLIPLEX® Human Myokine Magnetic Bead Panel (HMYOMAG-56K) and Immunology Multiplex Assay (HCYTA-60K-PXBK38) using Luminex® 200™ and MagPix system. Analysis was performed by GLMM to test the effects of group (Non-MCI vs MCI) and walking exercise. The MCI group had worse cognitive performance on trail-making test, stroop color word test (SCWT), phonemic and semantic fluency test, digit span backward, and the Rey auditory verbal learning test (AVLT) delayed memory (all P < 0.02). Body weight, BMI, lean mass, and (visceral) fat mass were comparable between non-MCI and MCI groups. There was a trend toward significantly lower 6MWT distance in the MCI (P = 0.067). We found lower baseline GM-csF concentration (P = 0.006) and a smaller increase in BDNF, FABP-3, and Osteocrin concentration in response to 6MWT in the MCI, even after adjustment for age and 6MWT distance (P < 0.003). Lower BDNF response to exercise was further associated with advancing age and worse cognitive function (MoCA, SCWT) (P < 0.04), but not with changes in lifestyle (habitual physical activity or dietary intake). We observed 6MWT-induced increases for the other myokines (apelin, BDNF, EPO, osteonectin, IL-15, myostatin, FABP-3, FSTL-1, IL-6, FGF-21, and osteocrin), and nearly all cytokines were independent of the group studied (all P < 0.02). A single bout of 6-minute walking exercise elicits a suppressed increase in BDNF, FABP-3, and Osteocrin in individuals with MCI, with a particularly blunted BDNF response in those who are older and more cognitively impaired. Whether disturbances in muscle-brain crosstalk, mediated by suppressed exercise induced BDNF response, contribute to cognitive decline in older adults warrants further investigation. Show less

The brain is vulnerable to DNA damage and cardiometabolic risk. Yet, whether genetic variation in DNA repair interacts with cardiometabolic factors to explain cognitive variability remains unclear. Participants (n = 376,533) of white-British ancestry from the UK biobank with cognitive, neuroimaging, and whole-exome sequencing data were included. Six cognitive outcomes were assessed: fluid intelligence (FIQ), symbol-digit matching task (SDMT), visual matching (MATCH), trail making (TRAIL1 and TRAIL2), and prospective memory (PMEM). Seven brain regions of interest were assessed: total brain (TBV), grey matter (GMV), left and right white matter (LWM/RWM), left and right hippocampi (LHC/RHC), and white matter hyperintensities (WMH) volumes. A total of 3487 genetic variants across 39 DNA repair genes were tested. SNP and gene/gene-set level associations were tested using regression models adjusted for age, sex, APOE ε4, ancestry, and outcome-specific covariates. Genetic interactions with a multidimensional cardiometabolic risk index (CMRI), encompassing established risk factors, were assessed. We detected 107 genetic variants (mostly extremely rare) across 36 DNA repair genes associated at Bonferroni-significance (p ≤ 1.4 × 10 Show less

Alzheimer's disease (AD) is frequently complicated by vascular co-morbidities. However, the specific mechanistic pathways by which vascular lesions interact with genetic susceptibility to accelerate cognitive decline remain unclear. This study investigated whether cerebral amyloid angiopathy (CAA) and cortical microinfarcts mediate the impact of AD pathology on cognition and evaluated the modifying role of APOE genotype. We conducted a retrospective clinico-pathological study using the National Alzheimer's Coordinating Center (NACC) database. The cohort included autopsy-confirmed participants aged 50 and older. Structural Equation Modeling (SEM) was employed to quantify the pathways linking AD pathology (Thal phase) to CAA severity, microinfarcts, and cognitive performance (CDR-Sum of Boxes). We further assessed the cumulative burden of pathology by comparing "Pure AD" cases against those with a "Triple Hit" of AD, CAA, and microvascular injury. SEM analysis identified a significant statistical mediation pathway wherein parenchymal amyloid is strongly associated with CAA, which correlates with an increased risk of microinfarcts and subsequent cognitive dysfunction. We observed a significant gene-pathology interaction: APOE ε4 carriers demonstrated a steeper trajectory of cognitive decline for a given severity of CAA compared to non-carriers. Furthermore, the "Triple Hit" group exhibited significantly worse cognitive impairment than the "Pure AD" group (P < 0.001), independent of age and education. Vascular pathology is a critical mediator of cognitive failure in AD, particularly in APOE ε4 carriers. The concurrent "Triple Hit" of proteinopathy and vasculopathy is associated with a profound failure of cognitive reserve, likely reflecting a more advanced global disease state. These findings highlight the urgent need to target vascular resilience as a disease-modifying strategy in Alzheimer's disease. Show less

Klotho is a longevity-associated protein with established neuroprotective properties. However, it is unclear how plasma klotho levels relate to Alzheimer's disease (AD) pathologies and cognitive performance. In this study, we examined the associations between plasma klotho levels and plasma biomarkers, as well as amyloid beta (Aβ) positron emission tomography (PET), tau PET, neurodegeneration, and cognition, in 354 older adults. Stratified association, interaction, and mediation analyses were conducted to elucidate apolipoprotein E (APOE) ε4-dependent relationships and potential underlying pathways. Higher plasma klotho levels were associated with lower AD-related biomarkers and cognitive decline in APOE ε4 carriers. Plasma klotho and APOE ε4 exhibited significant or marginal interactions with less abnormal changes in plasma phosphorylated tau217, glial fibrillary acidic protein, neurofilament light chain, Aβ PET, and cognition. These AD-related biomarkers mediated the protective effect of plasma klotho on cognitive function in APOE ε4 carriers. This study suggests that plasma klotho is an APOE ε4-dependent protective factor, which may attenuate AD-related pathology and improve cognitive performance. Show less

Lecanemab binds "protofibrils," which are poorly characterized in human brain. It is unknown why lecanemab caused fewer amyloid-related imaging abnormalities (ARIAs) than other antibodies in trials. The apolipoprotein E (APOE) ε4 allele increases ARIA risk through unknown mechanisms. Equilibrium binding constants (K Lecanemab and aducanumab had indistinguishable preference for "protofibrils." Antibody preference for plaque-enriched versus CAA-enriched Aβ did not differ in soluble extracts or by IF staining but differed slightly in insoluble extracts. The APOE ε4 allele was associated with more soluble antibody-accessible Aβ. Lecanemab's binding target is similar to other antibodies'. Differences in antibody preference for plaque versus CAA Aβ may not explain differences in ARIA with edema rates. Show less

Alzheimer's disease prediction using genomic data remains challenging due to the high dimensionality of whole-genome sequencing data and the complex relationships between genetic variants. We developed DuAL-Net (Dual Approach Local-global Network), a hybrid framework that integrates local genomic window analysis with global annotation-based modeling to prioritize disease-associated single-nucleotide polymorphisms (SNPs). As a proof of concept, we applied DuAL-Net to 14,094 SNPs within the Show less

This study examined the effects of APOE gene polymorphisms on body composition changes following high-intensity interval training (HIIT) in non-athletic Han Chinese university students from plain regions and identified genetic loci associated with HIIT sensitivity. A total of 236 Han Chinese undergraduates from non-physical education majors completed a 12-week HIIT program (three sessions/week). Body composition was assessed before and after the intervention. Genomic DNA from white blood cells was genotyped using Illumina chips. Single nucleotide polymorphism (SNP) quality control and association analyses with body composition indices were performed using PLINK (v1.09) and SPSS 25.0, applying linear regression and ANOVA with least significant difference (LSD) (1) Of 22 initial APOE SNPs, five passed quality control; the rs405509 locus was associated with HIIT-induced changes in body composition. (2) The GG genotype at rs405509 was associated with higher baseline BMI overall and with higher baseline weight, BMI, and waist-to-hip ratio in females than the TT genotype. (3) After training, GG carriers showed greater reductions in overall body fat than GT/TT carriers ( The rs405509 locus of the APOE gene is associated with body composition responses to HIIT, and female GG carriers show heightened responsiveness. Show less

The disruption of key mechanisms involved in amyloid beta (Aβ) clearance during the early stages of dementia may contribute to the progression of cognitive decline toward irreversible brain damage. In this study, we investigated multiple immune-related pathways implicated in the management and clearance of Aβ within circulating extracellular vesicles (cEVs) and serum from individuals with subjective cognitive decline (SCD) who later progressed to mild cognitive impairment (MCI). A cytokine panel and the levels of Aβ In SCD patients, the concentrations of Aβ Our findings support the potential value of integrating serum M-CSF levels with RAVLT performance and cEVs Aβ Show less

The choroid plexus (CP), known for producing cerebrospinal fluid, is increasingly implicated in the pathogenesis of Alzheimer's disease (AD). Neuroimaging studies document structural CP alterations in aging and AD. One such alteration, calcium deposition, increases with age and is typically considered benign, though the mechanism and clinical significance of CP calcification remain uncertain. Given established association between peripheral vascular calcification and cardiovascular risk, we hypothesized that the volume of calcium within CP would correlate with systemic cardiovascular health. Based on prior findings of APOEε4-specific associations between CP calcium and neurodegeneration, participants were stratified by APOEε4 status, a strong genetic risk factor for AD also implicated in cardiovascular disease. In this retrospective analysis of 105 adults (mean age 58.9 years; 39 APOEε4+), we examined whether CP calcium correlates with cardiovascular risk in cognitively normal adults. CP calcium was quantified using a previously validated MRI-CT method. Spearman correlations assessed the association of CP calcium and Framingham Cardiovascular Risk Score (FCRS), as well as individual cardiovascular risk factors. Overall, CP calcium was not associated with FCRS. Among APOEε4- subjects, CP calcium correlated positively with FCRS ( Show less

Blood-based biomarkers are increasingly used to characterize Alzheimer's disease (AD)-related pathology, yet substantial heterogeneity exists in how biomarker burden relates to cognitive performance. Grip strength, a marker of frailty and functional reserve, may modify this relationship. We conducted a cross-sectional analysis of 348 participants from the Aging Adult Brain Connectome (AABC) study. Global cognition was assessed using the Preclinical Alzheimer Cognitive Composite (PACC). Plasma biomarkers included phosphorylated tau-217 (pTau Show less

This study evaluates plasma-based proteomic profiles for predicting amyloid positivity in adults with Down syndrome (DS) and examines the impact of apolipoprotein E ε4 (APOE ε4) on test performance. Cross-sectional data from 290 adults with DS were analyzed using single molecule array (SIMOA) technology to measure plasma amyloid beta (Aβ)42, Aβ40, neurofilament light chain (NfL), glial fibrillary acidic protein (GFAP), tau phosphorylated at threonine 181, and total tau. Amyloid burden was quantified using Pittsburgh Compound B and (18)F-florbetapir Aβ positron emission tomography. Support vector machine analyses were conducted with biomarkers as predictors and age, sex, and APOE ε4 carrier status as covariates. Age, GFAP, and NfL contributed the most to the model performance. The proteomic profile achieved an area under the curve (AUC) of 96% in models with and without APOE ε4. These findings suggest that plasma proteomic biomarkers can effectively identify amyloid positivity in adults with DS and may support clinical triage, monitoring, and selection for clinical trials, independent of APOE ε4 status. Show less

Genetic polymorphisms in cardiovascular disease (CVD) susceptibility across different ethnic groups is highly imperetive. Therefore, it is of interest to investigate the role of genetic polymorphisms in cardiovascular disease (CVD) susceptibility across different ethnic groups. Participants were tested for variations in LDLR, APOE and LPL genes and their association with cardiovascular risk factors such as cholesterol levels and blood pressure was examined. Data shows ethnic differences in the prevalence of these polymorphisms, suggesting that genetic factors contribute to CVD risk in a population-specific manner. Thus, we show the need for personalized cardiovascular risk assessment strategies. The ethnic-specific distribution of genetic polymorphisms (LDLR, APOE and LPL) linked to cardiovascular disease susceptibility, highlighting the need for personalized cardiovascular risk assessment strategies based on genetic and ethnic factors is highlighted. Show less