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Postoperative delirium is the most common postoperative complication in older individuals. Genome-wide association studies (GWAS) can provide insights into how genetic factors influence postoperative risk. We examined the genetic architecture of postoperative delirium after major surgery and its relationship with related cognitive conditions (delirium of any type and Alzheimer's disease, including the APOE ε4 allele). A case-control GWAS was performed in the UK Biobank to identify genetic variants associated with postoperative delirium, adjusted for age, sex, genetic chip, and the first 10 principal components. These results were then used in genetic correlation and polygenic risk score analyses to investigate shared genetic risk between postoperative delirium and a) delirium of all causes, and b) Alzheimer's disease. The GWAS (1,016 cases, 139,148 controls) identified seven Single Nucleotide Polymorphisms (SNPs) that mapped to four genes (APOE, TOMM40, APOC1, and PVRL2); p < 5 x 10-8. Five SNPs remained significant after excluding pre-existing dementia, and two after excluding subsequent dementia. The lead SNP was rs429358, a missense variant of APOE. Genetic correlation and polygenic risk score analyses revealed evidence of shared genetic architecture and risk between postoperative delirium and Alzheimer's disease (rho 0.68, 95% CI [0.46, 0.81]; p < 0.001). After adjustment for age and sex, the APOE ε4 isoform had a dose-response effect on risk (odds ratios for one and two copies: 1.75, 95% CI [1.53, 2.0], and 4.19, 95% CI [3.25, 5.41], respectively; p < 0.001). The main limitations of the study include the reliance upon clinical coding for outcome definition and limited statistical power to detect small or modest genetic effects. We identified genetic variants associated with increased risk of postoperative delirium. We also found evidence of shared genetic liability with Alzheimer's disease via APOE, complementing recent large-scale studies in all-cause delirium. If validated, the findings have potential clinical applications, including preoperative risk stratification and early identification of pre-clinical Alzheimer's disease risk. Show less

This study investigated longitudinal plasma serotonin dynamics across the Alzheimer's disease (AD) continuum (cognitively normal [CN], mild cognitive impairment [MCI], and AD) to determine whether baseline serotonin and its 24-month change are associated with CSF amyloid-β (Aβ42), tau biomarkers, amyloid PET burden, structural brain integrity, and cognitive decline. Data from 959 ADNI participants (CN = 306, MCI = 421, AD = 232) with baseline and 24-month follow-up were analyzed. Measures included plasma serotonin, CSF biomarkers (Aβ42, total tau, p-tau181), florbetapir PET, MRI (hippocampal volume, cortical thickness), and cognitive tests (MMSE, ADAS-Cog 11, CDR-SB). Group differences were tested using ANOVA or Kruskal-Wallis, and associations were examined via partial correlations and mixed-effects models adjusted for age, sex, education, and APOE ε4, with FDR correction. The results revealed that baseline plasma serotonin levels showed a stepwise decline across the clinical continuum (CN > MCI > AD; p ≤ 0.05), consistent with progressive serotonergic dysregulation. In AD participants, higher baseline serotonin was significantly associated with less amyloid pathology and preserved brain structure, including higher CSF Aβ42 (β = 0.28, FDR p = 0.01), lower florbetapir PET SUVR (β = -0.31, FDR p = 0.02), and larger hippocampal volume (β = 0.33, FDR p = 0.02). Higher serotonin was also linked to better cognitive performance (MMSE: β = 0.22, FDR p = 0.02; ADAS-Cog 11: β = -0.24, FDR p = 0.02). Longitudinally, decreases in serotonin over 24 months in AD were associated with worsening amyloid burden (ΔPET SUVR: β = -0.29, FDR p = 0.02) and accelerated hippocampal atrophy (β = 0.32, FDR p = 0.01). Baseline serotonin predicted smaller 24-month declines in CSF Aβ42 (β = 0.28, FDR p = 0.01) and reduced hippocampal volume loss (β = 0.31, FDR p = 0.01). In CN and MCI groups, associations between serotonin and AD biomarkers or cognitive outcomes were not significant after FDR correction. On the whole, lower plasma serotonin levels are linked to amyloid pathology, hippocampal neurodegeneration, and cognitive decline in AD, supporting serotonin's potential as a stage-specific biomarker and mechanistic contributor to disease progression. Integrative longitudinal studies are needed to clarify causality and evaluate serotonergic pathways as therapeutic targets. Show less

Coronary heart disease (CHD) is driven by endothelial dysfunction and chronic vascular inflammation. hsa-miR-2110 (miR-2110) has been associated with adverse cardiovascular outcomes, but its mechanistic role in CHD remains unclear. In this study, miR-2110 expression was quantified in peripheral blood from CHD patients and healthy controls. Functional effects were assessed in EA.hy926 endothelial cells following lentiviral overexpression of miR-2110. The target gene Show less

Inflammation plays a large role in the etiology of the late onset, sporadic form of Alzheimer's disease (AD), yet these critical factors are not adequately modeled in mice where inflammatory mechanisms often differ widely from primates. In contrast, aging rhesus macaques offer a powerful translational model for investigating how advancing age and inflammation initiate early-stage pathology in sporadic AD, and for evaluating preventive therapeutic strategies. Unlike rodents, macaques possess highly developed association cortices with magnified calcium signaling, human-like inflammatory responses, and are naturally homozygous for ApoE-ε4-factors that together contribute to the spontaneous emergence of tau and amyloid pathology alongside cognitive decline. Critically, macaques allow the detection of early, soluble forms of hyperphosphorylated tau (pTau), including pT217Tau, which rapidly dephosphorylates postmortem and is rarely observable in human brain tissue outside of biopsies. New findings reveal that soluble pTau is neurotoxic and capable of propagating pathology across cortical networks, with elevated pT217Tau in plasma. Growing evidence points to age-related inflammatory signaling as a key driver of calcium dysregulation, which in turn promotes tau hyperphosphorylation, amyloid-β (Aβ) accumulation, synapse loss and autophagic degeneration. Both GCPII (glutamate carboxypeptidase II) and kynurenic acid inflammatory signaling have expanded roles in the primate association cortices that contribute to cognitive deficits. Pharmacological interventions in aged macaques demonstrate that targeting inflammation and restoring calcium homeostasis can significantly reduce pTau pathology with minimal side effects-highlighting a promising path for early intervention in AD. Show less

To evaluate and compare the predictive value of eight dementia risk scores for late-life cognitive function and cognitive decline; ANU-ADRI, CAIDE, CogDrisk, LIBRA, LIBRA2, UKBDRS(-APOE), and a Lancet commission-based risk score. Using Norwegian Trøndelag Health Study (HUNT) data, we calculated risk scores from lifestyle and health data of 7221 dementia-free participants (mean age: 76.8 years, 54.1% female) collected in HUNT3 (2006-2008). Cognitive function was assessed using the Montreal Cognitive Assessment scale (MoCA) 11 years later in HUNT4 70+, and reassessed in 4716 participants 4 years thereafter. Associations between continuous risk scores or risk score tertiles, cognition and cognitive decline were examined using linear mixed-effects models. Logistic regression models were used to test associations between risk scores and a ≥ 3-point decline in MoCA scores. All risk scores were significantly associated with cognitive function and cognitive decline. Associations with cognitive function ranged from UKBDRS β Risk scores captured meaningful gradients in cognition and decline but offered limited discriminatory accuracy beyond demographics, supporting their use for prevention-oriented risk profiling rather than prediction. Show less

Blood-based biomarkers could improve the precision of Alzheimer's disease (AD) clinical diagnosis and expand access to targeted treatments. Therefore, we evaluated the diagnostic accuracy of plasma Elecsys p-tau217 (Roche) and compared it with Elecsys p-tau181 (Roche) and Lumipulse p-tau217 (Fujirebio). We also assessed the added value of APOE-ε4 carrier status, plasma Aβ42 and Aβ42/40 in a memory-clinic cohort and evaluated associations with longitudinal cognition. A total of 187 patients from the Cognitive Centre Ghent University (CCUG) biobank, classified as AD (n = 103) or non-AD cognitive disorders (n = 84) based on CSF biomarkers (CSF Aβ42/40 ratio, total tau and p-tau181), were included. Plasma Elecsys p-tau181, p-tau217, and APOE-ε4 were measured on the Roche cobas Elecsys plasma p-tau217 showed high discriminative performance for AD versus non-AD (AUC 0.939), comparable to Lumipulse p-tau217 (AUC 0.950; p = 0.485). Elecsys p-tau181 performed lower than Elecsys p-tau217 (AUC 0.903; p = 0.043). Using a two-cut-off strategy, the intermediate proportion was 19.9% for Elecsys p-tau217, 11.9% for Lumipulse p-tau217, and 33.2% for Elecsys p-tau181. Adding APOE-ε4 to Elecsys p-tau217 improved discriminative performance (AUC 0.970, p = 0.02) and reduced intermediates to 11.0%. Adjustment for Aβ42 on the Fujirebio platform did not significantly increase the AUC (0.950 vs. 0.957; p = 0.322) and modestly reduced intermediate classifications (11.9% to 10.0%). Higher baseline Elecsys p-tau217 was associated with lower baseline MoCA and a trend towards faster MoCA decline (p = 0.07). Age, sex, renal function, Fazekas score, and CAA were not significantly associated with Elecsys p-tau217 concentrations. Plasma Elecsys p-tau217 measured on an automated high-throughput platform shows excellent diagnostic accuracy for AD. Incorporating APOE-ε4 further improves classification, while Aβ42 adjustment had only limited additional impact. Baseline p-tau217 also reflects cognitive severity and may relate to subsequent cognitive decline in the memory-clinic setting. Show less

Heterozygous familial hypercholesterolemia (FH), a monogenic cause for premature coronary artery disease (CAD) is often underdiagnosed. In individuals who meet the FH diagnostic criteria and lack pathogenic variants, polygenic factors are recognized as potential contributors. This study aimed to characterize the spectrum of genetic variants and determine the low-density lipoprotein polygenic risk score (LDL-PRS) among clinically diagnosed FH participants from South India. We recruited 116 unrelated participants with a pretreatment LDL- C concentration ≥ 190 mg/dl and a DLCN (Dutch Lipid Clinic Network) score ≥ 3. Targeted next-generation sequencing (NGS) of 23 lipid related genes and 12-SNP (Single nucleotide polymorphism) genotyping were performed. NGS identified 39 variants including 13 pathogenic and 26 variants of unknown significance (VUS) some of which were in non-classical genes: ABCG5, ABCG8, APOE, PPP1R17, SREBF2. Pathogenic variants were detected in 66.7% of those with definite FH,19.7% in probable FH and 2.7% in possible FH. Overall,66% were variant negative. Among variant negative (FH/V-) participants, 64% demonstrated high LDL-PRS, whereas 70% of variant positive participants also exhibited elevated scores; suggesting a contributory role of polygenic factors across both groups. Additionally, the observation that variant positive individuals with high LDL-PRS have an increased risk of coronary artery disease (CAD) adds important nuance to risk stratification within genetically confirmed FH patients. Confirmation of diagnosis by genetic testing is essential for the diagnosis of FH. Although LDL-PRS may offer little benefit in variant negative cases and improve CAD risk prediction in variant positive individuals, large scale studies are essential to validate its clinical utility and assess whether inclusion of additional LDL- raising SNPs could enhance the detection of polygenic FH in the Indian population. Show less

Amyloid related imaging abnormalities (ARIA) are the most significant risk associated with the use of anti-amyloid monoclonal antibodies (MAB) for Alzheimer's disease (AD). Currently, the presence of the APOE ε4 allele is the best predictor for the development of ARIA. However, the degree of baseline memory impairment has not been fully explored as a risk factor for ARIA. Here, we examined MAB outcomes in a memory clinic population and compared patients with AD who developed ARIA to a case-matched group who did not develop ARIA. Participants who developed ARIA had greater numbers of recall intrusions and false positives, both markers for memory consolidation, at baseline than those who did not develop ARIA. We also observed greater baseline hippocampal and supplementary motor cortical atrophy with ARIA. These differences remained when controlling for the APOE ε4 allele and the presence of pretreatment microhemorrhages. Further investigation of memory impairment and associated brain atrophy is warranted to understand ARIA risk and MAB outcomes in AD. Show less

Patients with chronic kidney disease (CKD) are at a significantly increased risk of developing Alzheimer's disease (AD) and cognitive dysfunction compared to the general population. While recombinant human erythropoietin (rHuEPO) is commonly used to treat anemia in CKD, emerging evidence indicates that it also possesses neuroprotective properties. This study aimed to evaluate the therapeutic impact of rHuEPO on platelet expression of amyloid precursor protein (APP) proteolytic fragments, apolipoprotein E (ApoE), glycogen synthase kinase 3β (GSK3β), total Tau, and phosphorylated Tau species (P-Tau181, P-Tau217, and P-Tau231), along with plasma levels of APP cleaving enzymes, P-Tau217, P-Tau231, inflammatory cytokines, and cholinergic markers in CKD patients with cognitive dysfunction. A total of 60 CKD patients were enrolled, including 30 without cognitive dysfunction and 30 with cognitive dysfunction, as determined by neuropsychological assessment. Platelet protein expression levels of total Tau, P-Tau181, P-Tau217, P-Tau231, and ApoE were analyzed using Western blotting. Gene expression levels of APP-cleaving enzymes, ApoE, GSK3β, and MAPT in platelets were assessed by RT-PCR. Plasma concentrations of APP-cleaving enzymes, inflammatory cytokines, cholinergic markers, P Tau217, and P-Tau231 were quantified. Results were compared with healthy controls, normocytic normochromic anemia, and AD. CKD patients with cognitive dysfunction showed significant alterations in the expression of platelet proteins (total Tau, P-Tau181, P Tau217, P-Tau231, and ApoE) and related genes (APP cleaving enzymes, ApoE, GSK3β, and MAPT), resembling the molecular profile observed in AD. Additionally, plasma levels of APP cleaving enzymes, inflammatory cytokines, cholinergic markers, and phosphorylated Tau species (P-Tau217 and P-Tau231) were significantly altered in these patients. Notably, after 6 months of rHuEPO therapy, these biomarkers showed marked improvement in CKD patients with cognitive dysfunction. These findings suggest that rHuEPO may offer therapeutic benefits beyond anemia correction, potentially serving as a supportive treatment for cognitive dysfunction in CKD by modulating AD-related peripheral biomarkers. Show less

The proteasome is a major intracellular protease complex, but the significance of circulating proteasome activity in Alzheimer’s disease (AD) is not well established. Because APOE ε4 is the strongest genetic risk factor for AD, we examined whether plasma proteasome activity is associated with AD-related pathology, neurodegeneration, and cognitive decline, focusing on APOE ε4 carriers. In this observational study, participants were classified as cognitively normal (CN), mild cognitive impairment (MCI), and dementia. All underwent 3.0-T MRI, [ A total of 148 individuals were included (58 CN, 39 MCI, 38 AD dementia, and 13 other dementia). Significant associations appeared only in APOE ε4 carriers ( Downregulated proteasome activity is strongly associated with amyloid burden, early tau accumulation, hippocampal atrophy, and cognitive impairment only in APOE ε4 carriers. These findings suggest that plasma proteasome activity may serve as a noninvasive marker of AD-related vulnerability in genetically at-risk individuals. Further studies are needed to clarify whether proteasome activity contributes to or results from amyloid and tau aggregation. KCT0005428. Registered September 24, 2020. Study subjects included in this analysis were those recruited from November 2018 onwards (retrospectively registered). The online version contains supplementary material available at 10.1186/s13195-026-01994-w. Show less

Dementia comprises a spectrum of neurodegenerative disorders marked by progressive cognitive and behavioural decline, with Alzheimer’s disease (AD) being the most prevalent form. While several genetic factors have been implicated in AD pathogenesis, a significant portion of heritability remains unexplained. One potential contributor to this “missing heritability” is structural variation within non-coding regions, such as variable-number tandem repeats (VNTRs). This study investigated the 40-bp VNTR located in the 3’ untranslated region of the A cohort of 799 elderly individuals from Central Italy, including AD, mild cognitive impairment (MCI), mixed dementia, and control subjects, was genotyped for the No significant association was observed between These findings suggest that while the The online version contains supplementary material available at 10.1186/s12920-026-02341-6. Show less

Oxidised 1-palmitoyl-2-arachidonoyl-sn-glycero-3-phosphorylcholine (oxPAPC), dendritic cells (DCs), and long non-coding RNAs (lncRNAs) play crucial roles in atherosclerosis (AS). This study aimed to determine whether oxPAPC-induced DC-derived lncRNAs contribute to AS and to elucidate the underlying regulatory mechanisms. DCs were treated with increasing oxPAPC concentrations to assess transcriptomic changes. RNA sequencing was used to identify differential expression of lncRNAs. ChIP-Seq and RNA pull-down assays were used to assess direct binding between lncRNA CYP1B1-AS1 and NFATC2. The association between CYP1B1-AS1 and CYP1B1 was assessed using Pearson's correlation analysis. Elevated serum oxPAPC levels were confirmed in patients with coronary heart disease. In vitro, sustained oxPAPC stimulation activated the TLR4-MD2 pathway in DCs. CYP1B1-AS1 was identified as the key oxPAPC-induced DC-derived lncRNA, with Gm33055 as its murine homologue. RNA sequencing revealed oxPAPC-driven alterations in DC chemotaxis, differentiation, and lymphocyte activation. Analysis of human atherosclerotic plaque-derived DCs showed significant CYP1B1-AS1 upregulation. Gm33055 enhanced Cyp1b1 expression in murine DCs. Mechanistically, oxPAPC promoted NFATC2 nuclear translocation. NFATC2 binds to the CYP1B1-AS1 promoter, whereas CYP1B1-AS1 directly interacts with NFATC2, forming a positive regulatory loop. Adoptive transfer of m-CYP1B1-AS1-expressing DCs into Apoe Show less

Alzheimer's disease (AD), particularly its sporadic form (SAD, 95 % AD patients), is strongly associated with the apolipoprotein E4 (ApoE4) genotype and characterized by oxidative stress, iron dysregulation, and increased susceptibility to ferroptosis. Lithium, a well-established neuroprotective agent, has shown potential to mitigate several pathological mechanisms in AD, including ferroptosis. This study investigates the therapeutic potential of lithium chloride in human induced pluripotent stem cells (iPSCs) derived from a SAD patient with ApoE4/E4 genotype and compared effects with those of isogenic gene-edited ApoE3/E3 control. Lithium treatment significantly improved cell viability in ApoE4/E4 iPSCs. It also reversed key ferroptosis phenotypes, including elevated cytosolic Fe Show less

Atherosclerotic cardiovascular disease is a leading cause of morbidity and mortality worldwide, and an urgent need exists to discover new therapeutic strategies. Isolinderalactone (ISO) is a sesquiterpene compound derived from the Lindera aggregata root with significant anti-inflammatory effects. Given that atherosclerosis (AS) is a chronic inflammatory condition, the efficacy and mechanism of ISO on atherosclerotic disease are still unclear. The study aims to evaluate the therapeutic potential of ISO as an NLRP3 inhibitor in the management of AS. For in vivo study, ApoE Our data show that ISO reduced atherosclerotic plaque formation by inhibiting NLRP3 inflammasome activation and inflammatory responses. Network pharmacology analyses showed that ISO might alleviate AS by suppressing the NOD-like receptor (NLR) pathway, leading to reduced inflammatory mediators. ISO dose-dependently suppressed IL-1β secretion through inhibiting NLRP3 inflammasome activation, displaying an IC Collectively, ISO emerges as a novel NLRP3 inhibitor and a potential therapeutic candidate for atherosclerotic disease. Show less

Near-infrared (NIR)-II fluorescence imaging at 1000-1700 nm is widely used for deep-tissue visualisation and disease theranostics in the brain, with NIR-II theranostics greatly improving imaging resolution, imaging depth, and therapeutic efficacy. However, the extreme lack of molecular design in NIR-II fluorophores has slowed the discovery of bright candidates and restricted their efficacious application in brain theranostics. Here, we develop a covalent bond locking (CBL) strategy that enables the feasible design of bright NIR-II fluorophores by effectively restricting the twisted intramolecular charge transfer state. These spirofluorophores incorporate terminally spiro-donor groups, which leads to a higher molar extinction coefficient and improved quantum yield than non-spirofluorophores do. With bright and stable NIR-II fluorescence advantages, we demonstrate that CBL nanoparticles (NPs) of spirofluorophores achieve multiscale high-resolution NIR-II angiography via one-photon fluorescence and two-photon fluorescence bioimaging simultaneously. With apolipoprotein E (ApoE) modification, CBL@ApoE NPs achieve enhanced blood-brain barrier permeability, facilitating superior brain glioma theranostics. This work proposes a CBL strategy to engineer highly bright NIR-II fluorescent fluorophores, providing a reliable nanoplatform for deep brain theranostics that can be effectively delivered across biological barriers to target brain tumors. Show less

In forensic pathology, accurately estimating the time since injury is essential. Current histological and imaging approaches commonly miss subtle temporal changes, especially in deaths occurring within hours of injury. This review discusses the timing of neuroinflammation after traumatic brain injury and emphasizes possible markers for estimating the time of injury in forensic cases. Promising markers include microglial activation (allograft inflammatory factor 1 and transmembrane protein 119, detectable within 10 min to 2 h), β-amyloid precursor protein accumulation (20-35 min), high-mobility group box 1 translocation (2-6 h), cytokine fluctuations (IL-1β and TNF-α peak between 4 and 24 h, IL-6 shows delayed, extended elevation), sequential leukocyte infiltration (neutrophils from 2 to 48 h, lymphocytes after 3-5 days), blood-brain barrier breakdown markers such as fibrinogen and IgG leakage, loss of tight junction proteins (2-3 h), matrix metalloproteinase-9 activity (peaking at 24-48 h), and reactive astrocytosis with increased glial fibrillary acidic protein levels (from 12 to 24 h onward). The association between injury severity and inflammation is influenced by factors such as age, genetics (e.g., APOE ε4), coexisting conditions, and preexisting inflammation, which reduce the reliability of individual markers. A multiparametric approach may offer the best prospects to improve the accuracy of post-traumatic and post-mortem interval assessment in medicolegal cases. Show less

Traffic-related air pollution (TRAP) is known to contribute to oxidative stress in the central nervous system (CNS) and has been linked to increased risk of Alzheimer's disease (AD). Alterations in the renin-angiotensin system (RAS), specifically increased angiotensin II (Ang II) signaling via the angiotensin II type 1 (AT Show less

Atherosclerosis is characterized by chronic vascular inflammation involving endothelial dysfunction and macrophage-mediated inflammatory responses. However, the molecular mechanisms linking these processes remain incompletely understood. This study investigates the role of interleukin-32γ (IL-32γ) in mediating endothelial-macrophage interactions during atherosclerosis progression. IL-32 isoform expression was analyzed in peripheral blood samples from atherosclerosis patients and healthy controls. Human endothelial cells were treated with oxidized low-density lipoprotein (Ox-LDL) with or without NF-κB inhibitor. Endothelial-macrophage interactions were studied using Transwell co-culture systems with THP-1-derived macrophages. Macrophage polarization was assessed by flow cytometry, qRT-PCR, and ELISA. The direct effects of IL-32γ were evaluated using recombinant protein with or without p38 MAPK inhibitor. In vivo studies employed ApoE-/- mice fed a Western diet and administered with IL-32γ alone or with p38 inhibitor. IL-32γ was significantly upregulated in atherosclerosis patients. Ox-LDL induced IL-32γ expression in endothelial cells through NF-κB activation, concurrent with endothelial dysfunction. Ox-LDL-treated endothelial cells promoted M1 macrophage polarization and migration, effects attenuated by either NF-κB inhibition or IL-32γ neutralization. Treatment with recombinant IL-32γ induced M1 polarization through p38 MAPK signaling. In ApoE-/- mouse model, IL-32γ administration accelerated atherosclerotic plaque formation and macrophage infiltration, while p38 inhibition reversed these effects. IL-32γ serves as a crucial mediator between Ox-LDL-induced endothelial dysfunction and macrophage-mediated inflammatory responses in atherosclerosis. Endothelial-derived IL-32γ promotes M1 macrophage polarization through p38 MAPK signaling, accelerating disease progression. These findings identify IL-32γ as a potential therapeutic target for atherosclerotic cardiovascular disease. Show less

Given the complexity of dementia, the inconsistent evidence on statins and dementia highlights the need for robust methods to assess heterogeneous treatment effects (HTEs). We emulated a target trial using UK Biobank comparing statin initiators and non-initiators aged ≥55 years. Marginal structural models were fitted to estimate 5-year adjusted risk difference (aRD). We used iterative causal forest, a causal machine learning subgrouping algorithm, to identify subgroups with HTEs. Among 18,366 participants, the overall aRD for all-cause dementia was -1.0‰ (95% CI: -4.2‰ to 2.3‰). We identified subgroups by polygenic risk score for Alzheimer's disease (AD) excluding apolipoprotein E (APOE) genotype ("non-APOE PRS"). Participants with high non-APOE PRS showed cognitive benefit (all-cause dementia: aRD -5.9‰, 95% CI: -8.1‰ to 1.2‰; AD: aRD -5.0‰, 95% CI: -8.2‰ to -0.2‰). Participants with high non-APOE PRS may benefit from statins, suggesting genetic susceptibility beyond APOE could modify statins' cognitive effects. Show less

Benzo[a]pyrene (BaP), a pervasive environmental pollutant, has been implicated in cardiovascular injury, yet its mechanistic contribution to atherosclerosis remains unclear. Here, we combined network toxicology, RNA-seq profiling, molecular simulations, and cellular validation to elucidate BaP-driven vascular effects. Integration of BaP-associated targets with atherosclerosis gene sets identified SPP1 as a key hub. Transcriptomic analysis of aortas from BaP-treated ApoE Show less

Lipid-lowering therapy is a cornerstone in the treatment of atherosclerotic cardiovascular diseases. Although some lipid-lowering drugs have demonstrated positive effects in patients with atherosclerotic cardiovascular diseases, their effects are limited in those with homozygous familial hypercholesterolemia. It is essential to seek new lipid-lowering targets. YAP (Yes-associated protein) may be involved in lipid metabolism in the liver; therefore, we investigated the function of hepatocyte YAP in hyperlipidemia and atherosclerosis. Hyperlipidemia models were generated in apoE knockout (apoE High-cholesterol diet-fed apoE Taken together, our findings revealed a novel role for the YAP-TEAD4-ANGPTL3 axis in lipid metabolism independent of LDLR. Inhibition of hepatocyte YAP may be an effective lipid-lowering strategy for homozygous familial hypercholesterolemia. Show less

Breast cancer is the most common form of cancer among women worldwide, and the rates of both new cases and deaths have increased over the past two decades. The aim of the study was to identify and validate molecular pathways that could potentially be targeted for therapeutic interventions. The bioinformatics resource WebGestalt was used to determine the functional annotation of the Gene Ontology, as well as enrichment analysis of Reactome and KEGG pathways in 2023-2024. GeneMANIA, a server for assessing protein-gene interactions, co-localization, pathways, co-expression, and protein-domain similarity of target genes and their interacting genes, was evaluated via this web tool. GEO was also used to determine mRNA expression levels in BRCA individuals. R packages were used to screen for differentially expressed genes for both datasets. On the other hand, the open cancer resources GENT2 TNMPlot, UCSCXena, ENCORI platform, BioXpress, OncoDB, OncoMX, and GEPIA2 were used to measure the differential expression of mRNAs in BRCA patients. Among the genes analyzed, matrix metalloproteinase-9 ( The results predict that the hub genes correlated with angiogenesis may serve as potential therapeutic targets or could be biomarkers for breast cancer. Show less