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Brain vascular aging is increasingly recognized as a critical therapeutic target for age-related cognitive decline. Oxidative stress, bioenergetic dysfunction, and molecular damage play central roles in the progression of vascular aging, contributing to cerebrovascular dysfunction and impaired cognitive function. While naturally occurring polyphenols such as resveratrol (RSV) have demonstrated potential in mitigating aging-related pathologies, their poor bioavailability and limited brain targeting efficiency significantly constrain their therapeutic impact. As a result, high doses or advanced drug delivery strategies are necessary to achieve meaningful physiological effects. We introduce a novel nanocarrier system designed to enhance RSV delivery to the cerebral endothelium by leveraging the natural formation of an apolipoprotein E (ApoE)-enriched protein corona around fusogenic liposomes (FL) Show less

Factors underlying discordant visual and quantitative amyloid beta-positron emission tomography (Aβ-PET) results and their clinical implications are not well understood. Participants from the 1Florida Alzheimer's Disease Research Center (1FLADRC) underwent Aβ-PET, blood draw, brain magnetic resonance imaging (MRI), and neuropsychological testing. We evaluated differences in demographics, apolipoprotein E ( We studied 386 participants (mean age ± SD: 70.7 ± 7.8, 55.2% female, 44.6% Hispanic White). Compared to V+/Q-, V-/Q+ had a higher frequency of Discordant Aβ-PET findings likely hold clinical significance and may reflect early stages of neuropathological progression. Groups with concordant/discordant visual-quantitative amyloid beta-positron emission tomography (Aβ-PET) results were compared.Visual-/quant+ were more likely than visual+/quant- to be apolipoprotein E ( Show less

Abdominal aortic aneurysms (AAAs) are characterized by ECM (extracellular matrix) degradation and chronic vascular inflammation, with macrophages playing a key role. The mechanisms regulating macrophage activation in AAA remain incompletely understood. Vascular macrophages express Olfr2 (olfactory receptor 2), a GPCR (G-protein-coupled receptor) implicated in inflammation, but its role in AAA development is unknown. We investigated the role of Olfr2 in AAA using PPE (porcine pancreatic elastase) infusion in Olfr2-deficient ( Microarray analysis revealed increased expression of the human Olfr2 regulates monocyte recruitment and macrophage-driven inflammation during AAA. Its genetic deletion or pharmacological inhibition protects against AAA, whereas receptor activation worsens the disease. Olfr2 represents a critical modulator of vascular inflammation and a potential therapeutic target in AAA. Show less

BackgroundThe Montreal Cognitive Assessment (MoCA) is widely used for cognitive screening. Despite numerous studies showing that MoCA scores are affected by demographic variables including age, education, and race, the instrument is typically evaluated using a raw score or simple one-point education correction in clinical practice.ObjectiveIn this study, we comprehensively evaluate the diagnostic accuracy of the MoCA in a large cohort of individuals being evaluated for mild cognitive impairment or dementia.MethodsWe used data from the National Alzheimer's Coordinating Center (NACC) database to examine diagnostic accuracy of the MoCA, using both raw scores and Z-scores subject to non-linear demographic correction. We present comprehensive accuracy statistics, concordance with Show less

BackgroundIdentifying genetic variants conferring resilience to Alzheimer's disease and related dementia (ADRD) may hold promise for developing therapeutics.ObjectiveTo determine genetic associations with being dementia-free at age 85 (DF85).MethodsWe examined genetic associations, using whole genome sequencing data, with DF85 in three Trans-Omics for Precision Medicine cohorts and the Alzheimer's Disease Sequencing Project Phenotype Harmonization Consortium. We tested common variants individually and aggregation of rare (MAF ≤ 1%) coding and non-coding variants in DF85 participants (n = 3657) against individuals who were not DF85 (n = 20,010). We verified associations using a stricter control set who developed dementia before age 85 (n = 5552).ResultsWe observed an association at Show less

BackgroundTau pathology begins to accumulate in the medial temporal lobe in many individuals in middle age. Some individuals develop amyloid pathology, more advanced tau pathology (Braak stage), and higher levels of CA1 hippocampal tau pathology in the context of Alzheimer's disease. Others never develop significant amyloid pathology; in these cases, hippocampal tau pathology can be CA2-predominant and tends not to accumulate past intermediate stages. But factors associated with the early formation of these tau patterns is unclear.ObjectiveThe objective of this study is to examine demographic, genetic ( 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

Allostatic load (AL), an index of cumulative physiological dysregulation from chronic stress, may contribute to Alzheimer's disease (AD) pathophysiology by accelerating brain aging. Higher AL has been associated with AD-related biomarkers, suggesting a mechanistic connection. Lifestyle factors influence both AL and AD vulnerability, but their moderating role in AL-AD biomarker associations remains unclear. We included 111 cognitively unimpaired older adults from the baseline visit of the Age-Well trial. AL was computed as a composite score of 18 biomarkers spanning neuroendocrine, immune, metabolic, cardiovascular-respiratory, and anthropometric systems. Plasma biomarkers included amyloid beta (Aβ)42, Aβ40, phosphorylated-tau (p-tau231), glial fibrillary acidic protein (GFAP), and neurofilament light chain (NfL). Physical activity, Mediterranean diet adherence, and cognitive activity were assessed using validated questionnaires. Multiple linear regressions tested associations between AL and (1) AD-related biomarkers and (2) lifestyle factors, as well as their interactions, controlling for age, sex, education, apolipoprotein E ε4 (APOE ε4) status, and glomerular filtration rate (GFR). Higher AL was associated with higher Aβ42/Aβ40 ratio ( Regular physical activity was associated with a weaker relationship between AL and early AD-related biomarkers in this cross-sectional sample. Longitudinal studies should confirm whether maintaining physical activity attenuates stress-related physiological dysregulation and reduces AD vulnerability. Show less

Sacubitril/valsartan (LCZ696), an angiotensin receptor neprilysin inhibitor (ARNI), simultaneously inhibits neprilysin and the renin-angiotensin-aldosterone system, but its effects on diet-induced vascular inflammation and atherosclerosis are unclear. LCZ696 (100 mg/kg/day), valsartan (50 mg/kg/day) or hydralazine (10 mg/kg/day) was orally administered to apolipoprotein E-deficient (ApoE-/-) mice for 20 weeks. En-face Sudan IV staining of the aortic arch, quantitative reverse transcription polymerase chain reaction (RT-PCR) of abdominal aorta. There were no differences in metabolic parameters between the groups. Valsartan or LCZ696 significantly reduced the progression of atherosclerotic lesions compared to the hydralazine group, as determined by Enface Sudan IV staining of the aortic arch (p<0.05). In the abdominal aorta, valsartan or LCZ696 treatment reduced mRNA expression of inflammatory molecules. However, no significant difference was observed between the valsartan group and the LCZ696 group regarding these atherosclerotic changes and vascular inflammation. LCZ696 reduced the progression of diet-induced atherosclerotic plaques and vascular inflammation compared with hydralazine in ApoE-/- mice, but showed no difference compared with the valsartan group. J. Med. Invest. 73 : 116-120, February, 2026. Show less

Most existing transcriptome wide association studies (TWASs) of Alzheimer's Disease (AD) dementia only use bulk RNA-seq data and a single statistical method. Here, we utilize an omnibus TWAS (TWAS-O) pipeline that leverages multiple complementary statistical methods to integrate the snRNA-seq dataset (n = 415) of the dorsolateral prefrontal cortex (DLPFC) and the latest GWAS data of AD dementia. We fine-map TWAS risk genes by gene-based conditional analysis and conducted validation analyses by the analogous omnibus proteome-wide association studies (PWAS-O) using bulk proteomics data of DLPFC (n = 716). We identify 223 unique cell-type-aware TWAS risk genes from 350 associations across six major brain cell-types, including 91 fine-mapped independent associations, 11 of which are novel. By PWAS-O, we identify 21 significant PWAS risk genes, including 13 independent associations, which validated 31.9% independent cell-type-aware TWAS associations. By protein-protein interaction network analyses, our novel cell-type-aware TWAS findings are linked to established AD risk genes such as APOE, BIN1, and MAPT. Show less

Atherosclerosis is the inflammatory consequence of lipid accumulation with plaque formation in the vascular intima and is a common condition to develop into various cardiovascular diseases. Current therapies do not always lead to satisfactory treatment outcomes. Enterolactone, a mammalian lignan produced by bacterial transformation from plant lignans, has a preventive effect against cardiovascular disease. However, its effect on atherosclerosis and the underlying mechanism of action remain unclear. To explore the therapeutic effect of ENL on atherosclerosis and elucidate the underlying mechanism. We established a model of atherosclerosis on ApoE-/- C57BL/6 mice by high fat diet. The aortic root was collected and sectioned to assess arterial plaque area, collagen fibrillar proliferation, and lipid content. RT-qPCR was used to determine the inflammatory response in the artery of mice. The serum from mice was isolated to measure lipid levels, and the fecal microbiota was analyzed by 16S rDNA. H In the animals, enterolactone significantly improved lipid metabolism, attenuated ferroptosis occurring in the intima, facilitated the antioxidant mechanisms, and promoted healing of the endothelial lesions, by interacting with Nrf2. Of great importance, enterolactone massively altered the gut microbiota toward a curative outcome by elevating the abundance of beneficial bacteria, such as the SCFA-producing taxa. Additionally, ENL suppresses lipid peroxidation and inflammatory activation in HUVECs by regulating the Keap1/Nrf2/GPX4 pathway, and knocking down Nrf2 attenuates the treatment effect of ENL. Enterolactone effectively resolves intimal inflammation and redresses atherosclerosis by ameliorating the gut microbiome and modulating lipid metabolism via the Keap1/Nrf2/GPX4 pathway. 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

Plasma phosphorylated tau217 (p-tau217) is a promising biomarker for Alzheimer's disease (AD) risk detection. Its relationship with brain microstructure and cognitive impairment remains unclear. Multi-component T2-relaxometry is an MRI technique sensitive to myelin content, axonal degeneration, and neuroinflammation. A total of 229 participants classified by p-tau217 levels into p-tau217- ( The p-tau217+ participants showed poorer cognition, increases in FQFWF and TWC, and reductions in IEWF and T2 High p-tau217 level associates with brain microstructure alterations and poorer cognition, supporting it as a biomarker of AD-related neuropathology and the utility of T2-relaxometry for detecting tissue integrity. 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

Caloric restriction (CR) improves metabolic health and reduces the risk of aging-related vascular diseases. However, the systematic metabolic reprogramming associated with CR remains unclear. To address this, we performed multi-tissue metabolomic profiling (liver, heart, and serum) in apolipoprotein E-deficient (ApoE-/-) mice subjected to CR. Metabolomic analyses of the multiple tissues revealed that glycerophospholipid metabolism pathway was consistently modulated by CR. To explore its relevance in vascular diseases, we performed serum metabolomic profiling in an abdominal aortic aneurysm (AAA) model induced by angiotensin Ⅱ (AngⅡ) infusion in ApoE-/- mice. The level of lysophosphatidylethanolamine (LPE) (16:0/0:0), a metabolite in the glycerophospholipid metabolism pathway, was elevated during AAA progression and significantly reduced by CR intervention, suggesting its potential as a vascular disease risk factor. Notably, glycerophospholipid metabolism and LPE (16:0) were significantly associated with vascular diseases and aging-related indicators in human multi-omics data, including public transcriptomic and lipidomic, and our serum multi-omics profiling of 76 healthy aged individuals. Collectively, our findings establish glycerophospholipid metabolism and LPE (16:0) as systemic signatures of CR with diagnostic potential. They highlight a crucial link between systemic metabolism and vascular remodeling and remodeling-associated vascular diseases, while also functioning as indicators of systemic aging. Show less

To observe the effect of moxibustion on the lipid metabolism, aortic arch and mitochondrial structure, PTEN-induced kinase 1 (PINK1)/Parkin signaling pathway, and the expressions of apoptosis-related proteins in atherosclerotic (AS) mice, so as to explore its potential mechanisms underlying prevention and treatment of AS. Ten C57BL/6J mice were fed with normal chow and used as the control group. Thirty ApoE Compared with the control group, the contents of serum TC, TG and LDL-C, expression levels of PINK1, Parkin, Bax and Caspase3 protein, and the immunoactivity of Parkin and Cyt C were significantly increased ( Moxibustion can improve the lipid metabolism level, relieve pathological injury of the thoracic aorta, restore mitochondrial structure and function in ApoE Show less

Cerebrospinal fluid amyloid beta 42, total tau, and phosphorylated tau 181 are well accepted markers of Alzheimer's disease. These biomarkers better reflect disease pathogenesis compared to clinical diagnosis. Here, we perform a genome wide association study meta-analysis including 18,948 individuals of European ancestry and identify 12 genome-wide significant loci across all three biomarkers, eight of them novel. We replicate the association of biomarkers with APOE, CR1, GMNC/CCDC50 and C16orf95/MAP1LC3B. Novel loci include BIN1 for amyloid beta and GNA12, MS4A6A, SLCO1A2 with both total tau and phosphorylated tau 181, as well as additional loci on chr. 8, near ANGPT1 and chr. 9 near SMARCA2. We also demonstrate that these variants have significant association with Alzheimer's disease risk, disease progression and/or brain amyloidosis. The associated genes are implicated in lipid metabolism independent of APOE, coupled with autophagy and brain volume regulation driven by total tau and phosphorylated tau 181 dysregulation. Show less

Abdominal aortic aneurysm (AAA) is a fatal disease characterized by vascular wall inflammation and matrix remodeling. The inflammatory phenotypic transformation of smooth muscle cells (SMCs) holds a pivotal role in AAA pathogenesis. As an inflammatory regulator, whether FBJ osteosarcoma oncogene B (Fosb) participates in AAA progression by driving SMC phenotypic switching remains unclear. Using the scRNA-seq data from AAA patients, we identified Fosb as a key driver of SMC phenotypic switching through cell clustering annotation, differential gene screening, functional enrichment, and pseudo-time trajectory analysis. An in vitro AAA cell model was established using Ang-II-stimulated T/G HA-VSMC cells. Fosb expression was assessed by qRT-PCR and western blot (WB). AAA cell models with Fosb knockdown or overexpression were constructed to investigate the effects of Fosb on T/G HA-VSMC cell proliferation, apoptosis, migration, invasion, contractile marker protein expression, and inflammatory cytokine secretion via WB, CCK8, Transwell, flow cytometry, and ELISA. Furthermore, WB was applied in detecting ferroptosis and NF-κB signaling pathway protein expression. Kits were employed for the determination of MDA, GSH, and Fe Fosb Fosb drives SMC ferroptosis and inflammatory phenotypic switching, via NF-κB pathway activation, thereby reinforcing AAA progression. Targeting Fosb or the ferroptosis pathway may provide new therapeutic strategies for AAA treatment. Show less

Vascular smooth muscle cell (VSMC)-derived foam cells critically drive atherosclerotic plaque progression, yet their regulatory mechanisms remain incompletely understood. This study aimed to elucidate the pathophysiological role of the VSMC-enriched factor axin interactor, dorsalization-associated (AIDA) in this process and evaluate its therapeutic potential. We utilized VSMC-specific AIDA knockout in male ApoE Show less

Apolipoprotein (apo) E is the major cholesterol carrier in the central nervous system (CNS); however, the clinical relevance of its cysteine-thiol redox status in cerebrospinal fluid (CSF) remains unclear. We investigated whether CSF apoE redox indices (redox-IDX-apoE) reflect cholesterol transport efficiency and disease-specific pathologies. We quantified reduced (red), reversibly oxidized (roxi), and irreversibly oxidized (oxi) apoE in CSF and serum using a maleimide-based band-shift assay. We analyzed relationships between redox-IDX-apoE, CSF cholesterol (TC) level, and the TC/apoE ratio (inverse transport efficiency) in patients with apoE3/E3 and identified transport determinants using isometric log-ratio (ILR) regression. Significant but only moderate correlations between CSF and serum indices suggested distinct redox behavior in the two compartments. ApoE3/E4 carriers exhibited higher oxi-apoE, reflecting reduced buffering capacity. In apoE3/E3 CSF, aging increased roxi/total and decreased red/roxi, suggesting a shift toward oxidized forms. CSF TC level positively correlated with roxi-related indices. Conversely, the TC/apoE ratio negatively correlated with red/roxi, indicating that red-apoE supports higher efficiency. ILR analysis confirmed that maintaining the reduced monomeric state, rather than the reversibly oxidized form, was independently associated with improved transport efficiency. Diagnostic groups exhibited distinct signatures: neurodegenerative disorders showed elevated irreversible oxidation, whereas neuroimmunological and infectious conditions exhibited profiles suggestive of reversible and acute oxidation, respectively. The CSF apoE redox status links local redox balance to cholesterol handling and reflects CNS pathophysiology. Maintaining reduced cysteine-thiol appears important for functional capacity, whereas a shift toward oxidation reflects a trade-off between buffering ability and transport efficiency. These indices may serve as potential biomarkers. 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

The genetic and clinical factors influencing the rate of brain structure change in cognitive decline remain poorly understood. This study aimed to identify genetic variants and risk factors contributing to these changes and explore potential causal relationships. We analyzed data from 2036 individuals across three longitudinal cohorts to assess change rates in 17 brain regions associated with cognitive decline. Genome-wide association studies (GWASs) were followed by phenome-wide association studies (PheWASs), Mendelian randomization (MR), and independent replication. We identified loci associated with brain structure change, including known Alzheimer's disease genes (apolipoprotein E, APOC1) and novel signals (BEAN1, SDHC). PheWAS and MR analyses in large biobanks suggested potential causal links between brain atrophy and anemia-related traits as well as type 2 diabetes. Our findings highlight genetic contributors and clinical traits associated with brain structure change in cognitive decline. Larger studies with broader cognitive assessments are needed to validate these findings. Show less

This study aimed to investigate the potential health hazards and molecular mechanisms of nanoplastic (NP) pollutants. Polystyrene nanoplastics (PS-NPs), which are prevalent in the environment and can enter the human body, have been closely associated with the risk of cardiovascular diseases, yet their impact on cholesterol metabolism remains unclear. In this study, proteomic analysis revealed that PS-NPs specifically adsorbed 1 676 proteins following their interaction with macrophages. Bioinformatic analysis indicated that these adsorbed proteins were significantly enriched in the cholesterol metabolism pathway, with apolipoprotein E (APOE) being the most prominently adsorbed. Further molecular docking and molecular dynamics simulations demonstrated that polystyrene molecules could inhibit the interaction between APOE and cholesterol by competitively binding to key amino acid residues (e.g., LEU-202 and TRP-228) of APOE. Cell experiments confirmed that exposure to 100 μg/mL PS-NPs for 24 h significantly induced lipid accumulation in macrophages. This study reveals, from a molecular interaction perspective, a novel mechanism by which PS-NPs disrupt lipid metabolism by interfering with APOE function. It provides key evidence for elucidating the toxicological mechanism through which PS-NPs promote atherosclerosis and holds significant scientific importance for assessing their health risks. 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

Epidemiological studies have consistently shown that chronic kidney disease is associated with increased Alzheimer disease risk. However, the underlying genetic architecture connecting these two conditions remains largely unexplored beyond genome-wide correlation analyses. Here, we conducted the first comprehensive, multi-ancestry, large-scale genetic investigation to identify shared genetic components between kidney function and Alzheimer disease. We leveraged large-scale genome-wide association study summary statistics for estimated glomerular filtration rate (N≈1.5 million European, N≈145,000 African ancestry) and late-onset Alzheimer disease (N=63,926 and N=398,058 in two European cohorts; N=9,168 in African ancestry) corrected for competing risk bias. We deployed a novel analytical framework integrating linkage disequilibrium score regression and polygenic risk score analysis, local analysis of [co]variant association, conjunctional false discovery rate analysis with Bayesian colocalization and fine-mapping, and bidirectional cis-Mendelian randomization to identify vertical pleiotropy. Despite the absence of genome-wide genetic correlation (r Show less

Non-alcoholic fatty liver disease (NAFLD) is a prevalent liver disorder driven by metabolic dysregulation and chronic inflammation, for which targeted pharmacotherapies remain limited. Rutin, a bioactive flavonoid from Sophora japonica and Fagopyrum esculentum, possesses notable anti-inflammatory and antioxidant properties. This study explored its pharmacological effects and underlying mechanism in NAFLD using a combination of in vivo and in vitro approaches. We found that rutin administration markedly attenuated hepatic steatosis, reduced oxidative stress, restored mitochondrial function, and improved liver injury markers, including alanine aminotransferase (ALT) and aspartate aminotransferase (AST), in both high-fat diet (HFD)-fed ApoE Show less