📋 Browse Articles

Inflammation contributes to Alzheimer's disease (AD), but its stage-specific and amyloid-dependent patterns remain unclear. We analyzed 964 participants from the Bio-Hermes cohort (cognitively normal [CN] = 404, mild cognitive impairment [MCI] = 302, mild AD = 258). Plasma levels of 32 cytokines, neurofilament light chain (NfL) and glial fibrillary acidic protein (GFAP) were quantified alongside core AD biomarkers. Associations with cognition, amyloid, apolipoprotein E (APOE) ε4, and clinical outcomes were assessed using analysis of covariance, partial correlations, and regression models. Twenty-four cytokines, NfL, and GFAP differed across cognitive groups. Amyloid stratification revealed a core amyloid-independent profile (14 cytokines + NfL) and a broader amyloid-specific profile including GFAP, interleukin (IL)-1β, and IL-18, implicating microglial inflammasome and astrocytic activation. Stage-dependent patterns suggested inflammation may act as early driver, concurrent process, or late amplifier. Paradoxical associations (e.g., eotaxin-2, IL-2R with better memory) and APOE ε4-linked immune differences indicated context-dependent roles. This exploratory study reveals biologically plausible, inflammatory heterogeneity in AD and highlights plasma cytokine profiles as candidate biomarkers and therapeutic targets, warranting investigation. Show less

We investigate whether common circle of Willis (CoW) variants relate to cerebral blood flow (CBF) characteristics among aging adults. Vanderbilt Memory and Aging Project participants free of clinical stroke ( Show less

Based on the TCM theory of "phlegm-stasis intermingling", this study aims to investigate the mechanism of Danzha Tongmai Pills(DZTMW) in treating atherosclerosis(AS), focusing on elucidating its in vivo active components, metabolic regulatory effects in serum, hepatoprotective effects, and anti-inflammatory efficacy. An AS model was established in apolipoprotein E knockout(ApoE~(-/-)) mice, which were divided into a normal group, an model group, low/medium/high-dose DZTMW groups, and an atorvastatin positive control group. The normal group was fed a standard diet, while the other groups were fed a high-fat diet to induce AS lesions. During the intervention phase, the groups were administered corresponding drugs or an equal volume of solvent by gavage. A series of tests were conducted after continuous intervention. Ultra-performance liquid chromatography-quadrupole-time-of-flight mass spectrometry(UPLC-Q-TOF-MS) was used to identify the blood-entering components of DZTMW, and liquid chromatography-high-resolution mass spectrometry(LC-HRMS) was employed for non-targeted serum metabolomics analysis. Pearson correlation analysis was used to analyze the correlation between blood-entering components and differential metabolites. Levels of serum lipid [total cholesterol(TC), triglycerides(TG), low-density lipoprotein cholesterol(LDL-C), high-density lipoprotein cholesterol(HDL-C), and free fatty acids(FFA)] and liver function markers [alanine aminotransferase(ALT) and aspartate aminotransferase(AST)] were measured. Liver histopathology and lipid deposition were assessed by HE and oil red O staining, and serum levels of inflammatory factors [lipoprotein-associated phospholipase A2(LP-PLA2), high-sensitivity C-reactive protein(hs-CRP), interleukin-6(IL-6), tumor necrosis factor-alpha(TNF-α), and interleukin-1 beta(IL-1β)] were measured by enzyme-linked immunosorbent assay(ELISA). The results showed that 23 blood-entering components were identified from DZTMW, including three prototype compounds, 20 metabolites, and 142 differential metabolites of serum. Core blood-entering components such as hydroxyl asiatic acid M1 and neocryptotanshinone metabolite were highly/extremely correlated with differential metabolites like 5-hydroxytryptamine, lysophosphatidylcholine(P-18:1/0:0) and sphingomyelin(d18:1/15:0). DZTMW administration at various doses significantly reduced the serum levels of TC, TG, LDL-C, and FFA(P<0.01), increased the HDL-C level(P<0.01), decreased ALT and AST activities(P<0.05, P<0.01), alleviated hepatocyte steatosis and lipid droplet deposition, and down-regulated the expression of inflammatory factors in a dose-dependent manner(P<0.01). The effects of the high-dose DZTMW group were comparable to those of the atorvastatin group. In summary, DZTMW can effectively inhibit the progression of AS in ApoE~(-/-) mice. Its mechanism may involve the regulation of hepatic lipid metabolism by its in vivo active components to ameliorate the "phlegm-turbidity" pathology and reduce liver injury, and the inhibition of systemic inflammation to alleviate the "blood stasis" process. The study can provide a modern biological basis for the theory of "phlegm-stasis intermingling". Show less

This study established a hyperlipidemia model by feeding Sprague-Dawley rats a high-fat diet for 8 weeks. The rats were randomly assigned to the following groups: model group, atorvastatin calcium group(4.8 mg·kg~(-1)), low-, medium-, and high-dose Tanyu Tongzhi Optimization Decoction(TYTZD) groups(3.6, 7.2, and 14.4 g·kg~(-1)), and a normal diet control group. After 4 weeks of continuous administration, hematoxylin-eosin(HE) and oil red O staining were used to observe liver pathological changes and lipid infiltration. Automatic biochemical analyzer were performed to assess blood lipid profiles, coagulation function, and liver function. Transcriptomic and proteomic analyses were employed to identify differentially expressed genes(DEGs) and proteins(DEPs), followed by enrichment analysis. The MCODE algorithm was applied to classify DEGs and DEPs into modules, and network separation index(S₍AB)) was calculated to assess module separation, enabling construction of a gene-protein co-expression network for core target screening. The diagnostic accuracy of core targets was evaluated by area under the receiver operating characteristic(ROC) curve(AUC), and ELISA was used to measure core target expression. Western blot detected the expression of core pathway-related proteins in liver tissue. RESULTS:: demonstrated that TYTZD significantly improved dyslipidemia, coagulation dysfunction, liver injury, hepatic pathology, and lipid infiltration in hyperlipidemic rats. Transcriptomic analysis identified 571 DEGs significantly reversed by TYTZD, mainly enriched in inflammatory signaling pathways such as Toll-like receptor 4(TLR4)/nuclear factor-κB(NF-κB). Proteomic analysis identified 102 reversed DEPs, mainly involved in cholesterol metabolism pathways. Integrated analysis identified core targets including TLR4, tumor necrosis factor-α(TNF-α), integrin subunit alpha M(ITGAM), Toll-like receptor 2(TLR2), matrix metalloproteinase 9(MMP9), interleukin-1β(IL-1β), apolipoprotein E(APOE), and apolipoprotein C2(APOC2), all with AUC values greater than 0.70. ELISA showed that TYTZD intervention significantly downregulated MMP9, TNF-α, IL-1β, TLR2, ITGAM, and TLR4, and upregulated APOC2 and APOE. Western blot indicated that TYTZD reduced TLR4, p-NF-κB, and IL-1β protein expression in liver tissue. In conclusion, TYTZD may exert anti-hyperlipidemic effects through regulation of core targets such as ITGAM, TLR4, and APOC2, and by modulating the TLR4/NF-κB signaling pathway to intervene in inflammatory responses and cholesterol metabolism, thereby achieving multi-target, multi-pathway therapeutic effects against hyperlipidemia. Show less

Extracellular matrix (ECM) remodelling is critical in abdominal aortic aneurysm (AAA), a life-threatening condition lacking effective pharmacotherapy. However, key ECM components regulating vascular integrity and remodelling remain poorly understood. Transcriptome profiling and studies in human AAA and in aneurysms from two models susceptible to angiotensin II (Ang II)-induced AAA-apolipoprotein E knockout mice (ApoE Transcriptome profiling highlighted the relevance of the ECM-mediated pathway and the upregulation of THBS4 in human AAA. In a large cohort of patients and donors and in Ang II-infused ApoE We uncover the early and sustained induction of TSP4 in AAA and its protective role in limiting vascular inflammation and destructive remodelling. Modulation of TSP4-dependent pathways may represent a novel avenue to improve vascular stability in AAA. Show less

Euphorbia Lathyris L. Seed (ELLS) is a Traditional Chinese Medicine (TCM), which has long been used in China. This study was designed to reveal the synergistic mechanism of ELLS in the treatment of colorectal cancer (CRC) by using network pharmacology method and molecular docking. In addition, related in vitro experiments will be conducted to verify the efficacy of ELLS. ELLS related compounds were obtained from TCMSP database. Then active compounds were screened by ADME (absorption, distribution, metabolism, and excretion). Additionally, TCMSP, BATMAN-TCM, STITCH, Swiss Target Prediction and literatures were used to capture the relationships between drugs and targets. A compound-target (C-T) network was established by Cytoscape. Target genes related to CRC were acquired from GeneCards, TTD and OMIM databases. Correlations about compound-target-pathway (C-T-P) were visualized by Cytoscape. The protein-protein interaction (PPI) network was constructed by STRING. Gene survival analysis came from the GEPIA2. Gene Ontology (GO) analysis and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis were performed via metascape. Molecular docking analysis was constructed by the AutoDock Vina. And the efficacy of ELLS in combating CRC was verified using HCT116 and SW620 cells. A total of 12 active compounds and 173 associated targets of ELLS compounds were identified. Sixty-three common genes were obtained by matching 173 potential genes of ELLS with 1554 CRC related genes and PPI network screened out key targets, including AKT1, CASP3, ESR1, TNF, HSP90AA1. Five core compounds were beta-sitosterol, stigmasterol, euphol, Artemetin and lathyrol. Eight core targets were PRKACA, PRKCA, AR, BAX, GSK3B, NFKB1, RXRA and NCOA2 in the C-T-P network. KEGG pathway analysis indicated that ELLS effectively treated CRC through regulation of pathways in cancer, Epstein-Barr virus infection, thyroid hormone signaling pathway, bile secretion, and transcriptional misregulation in cancer. Gene survival analysis showed that 7 genes (APAF1, APOE, CASP3, HDAC2, NFKB1, PGR, and SNAI1) were significantly related in CRC patients’ survival and prognosis. Molecular docking results suggested that almost all of the core compound-targets had an excellent binding activity (affinity < − 5 kcal/mol). CCK8 results indicated that ELLS (20 µg/mL, 24-hour treatment) significantly inhibited the proliferation of HCT116 cells, while it had minimal impact on the viability of normal NCM460 cells under the same conditions (survival rate ≥ 80%). Key targets of ELLS could regulate multiple signaling pathways and biological process in treating CRC which provided a scientific basis for further elucidating the mechanism of molecules and screening drug targets. Show less

Alzheimer's disease (AD) is the leading cause of dementia worldwide, with substantial unmet clinical needs. The apolipoprotein E4 (APOE4) allele is the strongest genetic risk factor for late onset AD, with each copy increasing risk approximately two- to three-fold, and homozygous carriers facing up to a 10- to 15-fold higher risk compared to APOE3 carriers. APOE4 contributes to diverse pathogenic mechanisms including lipid dysregulation, neuroinflammation, synaptic dysfunction, and vascular compromise. The precise, allele-specific correction of APOE4 therefore holds transformative therapeutic potential. CRISPR-based genome editing technologies, including nuclease disruption, base editing, and prime editing, offer unprecedented opportunities to directly modify APOE4 at its genomic source. Here, we review mechanistic underpinnings of APOE4 pathology, summarize current gene editing platforms for APOE4 correction, evaluate relevant in vitro and in vivo model systems, and assess delivery strategies with an emphasis on nanoparticle and exosome based approaches. We highlight recent breakthroughs in exosome mediated APOE4 editing while addressing ongoing technical hurdles in allele specificity and translational barriers such as Cas nuclease immunogenicity, limited delivery efficiency across the blood brain barrier (BBB), and concerns over long term genomic safety. This review concludes that overcoming BBB constraints remains the most significant challenge for clinical translation, and that innovations in exosome and nanoparticle based delivery platforms represent the most promising strategies for advancing CRISPR therapeutics for AD. Show less

Non-alcoholic fatty liver disease and atherosclerosis may share a common pathogenesis involving chronic IL-1β-induced inflammation. We aimed to evaluate the efficacy of diacerein, an IL-1 pathway inhibitor, in improving liver fibrosis, steatosis, and atherosclerosis in apolipoprotein E-knockout (apoE k/o) mice. ApoE k/o mice fed a high-fat diet (HFD) were divided into three groups based on diacerein dosage. Liver fat accumulation and fibrosis severity were compared across groups, along with changes in the expression of genes related to lipid metabolism and fibrosis. Atherosclerotic burden in the aorta was evaluated via en face analysis, and the related signaling pathway was verified in vitro. Diacerein treatment reduced the amount of collagen fibers and fat accumulation in the liver in a dose-dependent manner as well as fibrosis-related gene expression. Atherosclerotic plaque burden in the aorta showed a decreasing trend with diacerein treatment, accompanied by reduced expression of pro-inflammatory cytokines, including TNF-α. Diacerein treatment ameliorated liver steatosis/fibrosis and showed beneficial effects on atherosclerosis-related mechanisms in HFD-fed apoE k/o mice. Given its dual anti-inflammatory and anti-fibrotic actions, diacerein represents a promising therapeutic candidate for metabolic disorders characterized by chronic inflammation. KEY MESSAGES: We analyzed the effects of diacerein on liver fibrosis, steatosis, and atherosclerosis in apolipoprotein E knockout (apoE k/o) mice. Diacerein reduced fat accumulation in the liver and collagen fibers in the liver. It decreased the expression of genes related to fibrosis and the burden of atherosclerotic plaque in the aorta. The expression of pro-inflammatory cytokines was reduced. Treatment of apoE knockout mice fed an HFD with diacerein effectively ameliorated liver steatosis/fibrosis and atherosclerosis. Show less

The We employed a multi-omics approach, combining snRNA-seq and locus-specific epigenetic analysis, alongside microglia-specific gene manipulation in ApoE-targeted replacement (TR) mice. Primary microglia were challenged with cholesterol to simulate lipid overload conditions. In mid-life ApoE4-TR mice, microglia within the dentate gyrus developed pronounced lipid droplet accumulation, concurrent with impaired Aβ clearance and a pro-inflammatory shift. snRNA-seq unveiled a unique microglial cluster in ApoE4 mice, enriched for lipid-metabolism genes and marked by the pronounced downregulation of the hub gene Asxl1. Mechanistically, ApoE4 attenuated the Asxl1–LXRα interaction, leading to reduced H3K4me3 occupancy at promoters of lipid-efflux genes such as Abca1. Crucially, CRISPR-mediated, microglia-specific overexpression of Asxl1 restored H3K4me3 levels, normalized cholesterol efflux, and rescued Aβ phagocytic deficits in vivo. Our findings define an epigenetic pathway whereby ApoE4 drives microglial dysfunction via the Asxl1–LXRα–H3K4me3 axis, fostering the LDAM phenotype. Enhancing Asxl1 function presents a promising therapeutic avenue for countering ApoE4-mediated pathogenesis in AD. The online version contains supplementary material available at 10.1186/s12974-026-03740-3. Show less

Machine learning enables scalable quantification of neuropathology, offering deeper phenotyping of Alzheimer's disease (AD). In this validation study, we quantified amyloid-beta (Aβ) deposits, evaluating multiple brain regions across institutions, and evaluated associations with clinical, demographic, and genetic factors in persons pathologically diagnosed with AD. All linear models were adjusted for sex, age of death, ethnicity, and center. We analyzed densities (#/mm2) of cored plaques, diffuse plaques, and cerebral amyloid angiopathy (CAA) in 273 individuals from 3 Alzheimer's Disease Research Centers. Formalin-fixed paraffin-embedded sections of frontal, temporal, and parietal cortices were immunostained and digitized, generating 799 whole-slide images (WSIs). Following log transformation, mixed-effects modeling revealed the parietal cortex had the highest cored plaque densities (P < .001); the temporal cortex had the highest diffuse plaque (P < .001); CAA showed no regional differences. Wilcoxon rank-sum test, and covariates adjusted linear models showed ApoE ε4- status was associated with higher cored plaque densities in the temporal lobe (P = .04). ApoE ε4+ status was associated with diffuse plaques in the temporal lobe (P = .001), and CAA in the frontal lobe (P = .004). These findings provide further validation and provide exploratory associations advancing deeper phenotyping of AD. Show less

Synaptic formation impairment is closely correlated with cognitive impairment in Alzheimer's disease (AD), yet the underlying mechanisms remain incompletely understood. Emerging evidence indicates that extracellular vesicles (EVs), critical mediators of intercellular communication, are implicated in the progression of AD. However, the specific mechanisms through which neuron-derived EVs contribute to synaptic formation impairment in AD remain unexplored. In this study, we characterized EVs derived from primary neurons of APP/PS1 transgenic mice (APPNEVs) and investigated their impact on synapse formation. Transmission electron microscopy, nanoparticle flow cytometry, and immunoblotting confirmed that APPNEVs and WT neuron-derived EVs (WTNEVs) had similar morphology, size, and canonical small EVs markers. We further revealed that APPNEVs significantly impaired neuronal synapse formation by downregulating synaptic proteins PSD95 and Synaptophysin (SYP), reducing total synapse number, and shifting synapse morphology toward immature states. Proteomic profiling via mass spectrometry identified APOE as a key upregulated protein in APPNEVs. Pharmacological inhibition of APOE with EZ-482 effectively prevented APPNEV-induced synaptic formation impairment, APPNEV-mediated downregulation of synaptic proteins, and the APPNEV-induced decrease in synaptic maturity. Mechanistically, APPNEVs suppressed Rac1-N-WASP-Arp2/3-mediated filament actin polymerization, a critical pathway for synaptic spine formation, which was prevented by APOE inhibition. In vivo stereotactic injection of APPNEVs into the hippocampus of WT mice further validated their detrimental effects on synaptic integrity, which were prevented by EZ-482 treatment. Collectively, these findings demonstrate that APPNEVs mediate synaptic damage via carrying APOE, providing novel insights into EV-mediated neurodegeneration in AD and highlighting APOE as a potential therapeutic target for preserving synaptic formation. Show less

Antihypertensive medications (AHMs) may modulate Alzheimer's disease (AD) pathogenesis via cerebrovascular or neuroinflammatory pathways, yet evidence remains conflicting. This study investigated causal associations between AHM use and AD risk, focusing on drug classes, blood pressure status, and apolipoprotein E epsilon 4 (APOE ε4) effects. We integrated genetic causal inference with longitudinal survival analyses in a dual-evidence framework. Mendelian randomization (MR) was used to estimate class-specific causal effects at the population level. To examine effect modification by genetic and clinical factors, we analyzed 532 cognitively normal or mildly impaired older adults in ADNI with baseline assessments, with time-to-AD conversion modeled using Cox regression stratified by hypertension history and APOE ε4 status. Overall antihypertensive use showed no significant association with AD risk in hypertensive individuals (HR = 0.71) or APOE ε4 carriers (HR = 0.72). However, ARBs demonstrated protective associations in APOE ε4 carriers (HR = 0.32, 95% CI: 0.12-0.86). MR analysis supported causal protective effects for angiotensin II receptor blockers (ARBs, OR = 0.94, 95% CI: 0.89-0.98), calcium channel blockers (CCBs, OR = 0.93, 95% CI: 0.90-0.97), and beta-blockers (BBs, OR = 0.92, 95% CI: 0.86-0.98), whereas ACEIs lacked MR support and thiazide diuretics showed no benefit. Our findings reveal class-specific antihypertensive effects on AD risk. ARBs demonstrated the strongest protection, particularly in APOE ε4 carriers, while BBs and CCBs showed neuroprotective benefits. Results suggest AD prevention involves mechanisms beyond blood pressure reduction alone, supporting precision medicine with genotype-guided antihypertensive selection for genetically vulnerable individuals. Show less

Diabetic foot ulcers (DFU) are a severe complication of diabetes. Although dysregulated M2 macrophage polarization is recognized as a key driver of chronic inflammation in DFU, the molecular checkpoints that can be therapeutically targeted to restore M2 bias remain poorly defined. Here, we aimed to determine whether the RNA-binding protein TAF15 acts as a post-transcriptional stabilizer of the M2-promoting CEBPB/APOE/PTX3 axis, thereby accelerating DFU healing. First, we confirmed that APOE positively regulates PTX3, which supports M2 polarization and the proliferation and migration of HDF. CEBPB transcriptionally activated APOE and promoted M2 macrophage polarization. TAF15 stabilized CEBPB mRNA and affected HDF cell proliferation and migration by promoting M2 macrophage polarization. Additionally, TAF15 overexpression partially counteracted the disruption of M2 macrophage polarization caused by APOE silencing and facilitated DFU wound healing. Collectively, our findings establish TAF15-driven stabilization of CEBPB mRNA as a target point that sequentially activates APOE/PTX3 signaling to enforce M2 polarization and accelerate DFU closure. This study provides a preclinical rationale for the development of TAF15-targeted oligonucleotides or small-molecule strategies to reprogram wound macrophages and improve DFU outcomes in patients with diabetes. Show less

There is limited research on the long-term associations of plasma phosphorylated tau 217 (p-tau217) with mild cognitive impairment (MCI) and dementia. No study has evaluated whether such associations vary by race or hormone therapy (HT) use. To examine associations of baseline plasma p-tau217 with incident MCI and dementia and determine whether associations vary by age, race, APOE ε4 carrier status, or HT use. This cohort study examined women recruited from 39 US clinical sites between 1996 and 1999 into the Women's Health Initiative Memory Study who were randomized to either estrogen alone vs placebo or estrogen plus progestin vs placebo. Women were assessed for up to 25 years through 2021. Baseline plasma p-tau217 was measured in 2024 and analyzed between February and August 2025. Women aged 65 to 79 years who were cognitively unimpaired at baseline were included for this analysis. Plasma p-tau217, quantified using the ALZpath Simoa assay. The primary outcome was the combined end point of incident MCI or probable dementia. Secondary outcomes included MCI and dementia examined separately. Cause-specific hazard ratios (HRs) and 95% CIs for the association of p-tau217 with MCI or dementia were estimated using Cox proportional hazards regression models. Among 2766 participants (mean [SD] age, 69.9 [3.8] years; 486 [17.9%] Black, 196 [7.1%] Hispanic, and 2007 [73.9%] White), 1311 developed the combined end point of MCI or dementia (849 participants with MCI and 752 participants with dementia). Every 1-SD increase in log2-transformed p-tau217 was associated with incident MCI or dementia (HR, 2.43; 95% CI, 2.18-2.71) and each individual outcome (MCI: HR, 1.94; 95% CI, 1.72-2.20; dementia: HR, 3.17; 95% CI, 2.79-3.61). Associations of p-tau217 with dementia were larger in magnitude for women randomized to estrogen plus progestin (HR, 4.18; 95% CI, 3.41-5.13) vs placebo (HR, 3.07; 95% CI, 2.41-3.91) (P for interaction = .04) but did not significantly vary by estrogen alone vs placebo. P-tau217 associations with MCI or dementia were larger in magnitude for women older than 70 years (P for interaction = .04), APOE ε4 carriers (P for interaction = .02), and White women compared with Black women (P for interaction < .001). However, the combination of p-tau217 and age performed similarly in White women (area under the curve = 72.0%; 95% CI, 70.3%-73.6%) and Black women (area under the curve = 70.4%; 95% CI, 64.0%-78.0%). P-tau217 was not associated with incident MCI in Black women. In this cohort study of cognitively unimpaired older women, p-tau217 was associated with incident MCI or dementia up to 25 years later. These findings suggest that age, race, APOE ε4, and HT use should be considered when examining associations of p-tau217 with cognitive outcomes. Show less

Cognitive impairment is common after transient ischemic attack (TIA) and stroke, but contemporary population-representative estimates of dementia risk after stroke are scarce, particularly in view of stroke severity and competing risk of mortality. We included individuals from the population-based Rotterdam Study with first-ever covert brain infarction (n=630), TIA (n=547), minor stroke (National Institutes of Health Stroke Scale score <4; n=392), or major stroke (National Institutes of Health Stroke Scale score ≥4; n=493) between 2002 and 2018, and matched those 1:3 to reference participants on age and sex. We determined 10-year dementia risks by event severity, comparing cause-specific and subdistribution hazards models to account for competing risk of death, and explored prognostic indicators of dementia after TIA and stroke. Of 1431 patients with first-ever TIA or stroke (mean age 75.2 years, 58.3% women), 161 had pre-event dementia and 205 developed dementia during a median follow-up of 6.1 years. After 10 years, 59.4% of patients had died, with highest risk in the first months after major stroke. Compared with reference participants, dementia risk was increased after minor (cause-specific hazard ratio [HR], 1.60 [95% CI, 1.21-2.12]) and major stroke (HR, 1.72 [95% CI, 1.29-2.30]), but not TIA (HR, 0.97 [95% CI, 0.76-1.23]). Among those with covert brain infarction, dementia risk was between that of TIA and minor stroke (HR, 1.34 [95% CI, 0.98-1.83]). Accounting for mortality, 10-year dementia risk ranged from 14% (95% CI, 12%-19%) after TIA to 21% (95% CI, 16%-25%) after minor stroke and 16% (95% CI, 12%-20%) after major stroke. These risks were substantially higher in the Kaplan-Meier-estimations for minor stroke (33%) and major stroke (40%). Prognostic indicators for dementia after TIA and stroke included higher age, less education, premorbid cognition, Dementia risk is elevated after stroke, and to a lesser extent covert brain infarction, but not after TIA. Excess risk extends to long-term follow-up for minor stroke, whereas competing risk of death attenuates risk after major stroke. Clinical and imaging indicators hold potential for personalized estimation of dementia risk. Show less

BackgroundDementia represents a major global health challenge, particularly in low- and middle-income countries (LMICs). Morocco, facing rapid population ageing, lacks integrated epidemiological and translational research on Alzheimer's disease (AD) and related disorders.ObjectiveThis study aims to map Moroccan dementia studies and identify national advances and research gaps.MethodsFollowing PRISMA-ScR guidelines, a literature search was conducted in PubMed, Scopus, MEDLINE, and Web of Science covering the period 2000-2025. Studies including Moroccan samples and addressing dementia or AD in epidemiology, diagnostics, genetics, or therapy were retained. Thirty papers met criteria. Data were summarized narratively and organized in four thematic tables.ResultsMoroccan research spans four main pillars: (1) early-onset and clinical features; (2) validated cognitive assessment tools adapted to Arabic and Tamazight; (3) discovery of distinct APP, PSEN, and APOE mutations; and (4) emerging pharmacological and non-pharmacological interventions.ConclusionsThough still limited, Moroccan dementia research demonstrates scientific maturity and regional relevance. Establishing national registries, biobanks, and culturally tailored interventions will strengthen Africa's contribution to global neurodegenerative research. Show less

A priority in aging and dementia research is to integrate sex (biological attribute) and gender (sociocultural/behavioural characteristics) in theories, designs, analyses, and intervention protocols. We recently reported a data-mining procedure for operationalizing empirically-derived composite gender variables in archival databases. The present study extends the prior cross-sectional approach by examining sex and gender as separate and interactive predictors of longitudinal data-driven memory trajectory classes. Participants (N = 746) contributed baseline data for binary sex (female/male), education (years), and empirically-derived composite variables representing complementary gender facets. These facets included Manual Tasks and Physical Activities; Social and Household Management; Leisure, Socializing, and Travel; Cognitive Activity and Brain Games; Health Perceptions and Practices; and Subjective Memory Beliefs. We integrated these into a longitudinal episodic memory trajectory distribution spanning 42 years (53-95) of aging. Data-driven latent class growth analysis (LCGA) on the trajectory distribution identified discriminable classes. Using the R3STEP approach, we separately tested sex, gender facets, and education as predictors of membership in the higher (healthier) trajectory classes relative to the lowest (benchmark) class. We then included interaction terms to test for sex moderation of gender effects. Finally, we identified all genotyped participants and tested whether sex and gender effects were moderated by Apolipoprotein E (APOE). LCGA revealed three memory classes: High-Stable (highest level/relatively stable), Moderate/Normal-Declining (average level/moderate decline), and Low-Declining (lowest level/steepest decline). Several variables separately predicted High-Stable membership. For sex, females were more likely than males to belong to this class. For gender, (a) higher scores for Social and Household Management, Cognitive Activity and Brain Games, and Subjective Memory Beliefs predicted High-Stable membership; and (b) higher scores for Manual Tasks and Physical Activities and Health Perceptions and Practices decreased the likelihood of High-Stable membership (relative to Low-Declining). Moderate/Normal-Declining membership was predicted by Social and Household Management (higher). For education, more years predicted High-Stable membership. Moderation analyses indicated that gender effects were consistent across both sexes and APOE carrier status. Data-driven analyses show that biological sex and measurable facets of gender differentially contribute to memory trajectory patterns over a 42-year span of cognitively unimpaired aging. Show less

Retinal detachment (RD) is a prevalent ocular disorder that leads to photoreceptor death and irreversible visual impairment. Following RD, microglia—the resident immune cells of the retina—become activated and participate in regulating inflammatory responses and tissue repair processes. A distinct microglial subtype, disease-associated microglia (DAM) emerges in stressed neuronal microenvironments. However, its specific contribution to photoreceptor degeneration remains poorly understood. Apolipoprotein E (ApoE), a major lipoprotein predominantly expressed in brain and ocular myeloid cells, has been implicated in modulating neurodegeneration within the central nervous system through influencing DAM activation. In this study, we employed an experimental mouse model of RD and observed upregulation of ApoE and DAM-related markers at three days following RD induction. Genetic deletion of ApoE significantly attenuated photoreceptor loss and suppressed neuroinflammatory responses after RD, accompanied by reduced DAM activation. Furthermore, modulation of the ApoE-Galectin-3 axis reduced TUNEL-positive cells and inhibited TLR4-dependent inflammatory cascades post-RD. Using humanized ApoE allele mice, we further elucidated that the ApoE4 isoform significantly downregulated DAM-associated markers (including Galectin-3, Spp-1 and Gpnmb), promoted photoreceptor survival, and attenuated retinal inflammation. In contrast, ApoE2 and ApoE3 conferred no protection benefit compared to wild-type mice after RD. Our findings indicate that ApoE-mediated DAM activation exacerbates photoreceptor degeneration after RD insult. Both ApoE deficiency and ApoE4 expression potentially mitigated RD-induced photoreceptor death and ameliorated neuroinflammatory pathways via suppression of DAM activation. Collectively, our study highlights ApoE4 as a promising therapeutic target for modulating microglial cells to promote neuronal survival in photoreceptor degeneration conditions. The online version contains supplementary material available at 10.1186/s12974-026-03762-x. Show less

Hydroxychloroquine (HCQ) has been associated with lower incidence of cardiovascular events in patients with autoimmune diseases and atherosclerosis progression in mouse models. Our study aimed at investigating the effect of HCQ on autophagy and neutrophil extracellular trap (NET) formation in aortas of ApoE-/- mice. ApoE-/- mice were treated with 10 mg/kg/day HCQ for 16 weeks. The aortas were examined histologically, while immunofluorescence staining and confocal microscopy were performed to identify the co-localization of myeloperoxidase (MPO) with DNA or microtubule-associated protein 1A/1B-light chain 3B (LC3B) as markers of NET formation and autophagy, respectively. Among 52 ApoE-/- mice (30 male, 22 female), HCQ was administered in 15 male and 12 female mice. HCQ was associated with a significant reduction of the mean (±SD) surface of the atherosclerotic plaque compared to controls (HCQ-treated vs. control, 0.04 ± 0.01 mm2 vs. 0.08 ± 0.04 mm2, p < 0.01 and 0.06 ± 0.04 mm2 vs. 0.15 ± 0.09 mm2, p = 0.012, for male and female, respectively). This reduction was associated with a significant attenuation in the mean fluorescence intensity of MPO and LC3B expression in the atherosclerotic plaque of HCQ-treated mice (p = 0.03 and p = 0.01, respectively). In line with these findings, HCQ significantly reduced the proportion of MPO+ and LC3B+ cells within the atherosclerotic lesions. HCQ administration in ApoE-/- mice may mitigate the progression of atherosclerotic plaque, by inhibiting autophagy and NET formation. Show less

White matter hyperintensities (WMH) in patients with cerebrovascular risk factors (CVRF), are often linked to cerebral vascular changes, but can be caused by genetic variants selectively targeting white matter. In addition, WMH can be present in neurodegenerative disorders such as frontotemporal lobar degeneration (FTLD) and are linked to some FTLD genetic variants. This study aims to investigate WMH burden in patients with behavioral variant frontotemporal dementia (bvFTD) and semantic variant primary progressive aphasia (svPPA) versus controls and to evaluates the influence of CVRF. This cross-sectional retrospective analysis examined individuals meeting research diagnostic criteria for bvFTD and svPPA with high-quality structural MRI at the UCSF Memory and Aging Center between September 2008 and December 2021. WMH burden and spatial distribution were assessed by disease group compared to age- and sex-matched controls and associations with CVRF evaluated. We included 109 individuals with bvFTD [mean age (SD) 62.9 (8.6), 40% female], 47 with svPPA [mean (SD) age 65.4 (7.5), 51% female], and matched controls. After adjusting for age, bvFTD and svPPA are associated with elevated WMH burden independent of CVRF. In bvFTD, WMH are primarily distributed within the frontal lobes, while svPPA shows widespread distribution across lobes. Study limitations include its retrospective, single-center design and limited power for genetic subgroup analyses. Show less

Despite substantial advances in Parkinson's disease genomics, Latin American populations remain underrepresented in global genetic studies, limiting the generalizability of risk estimates and biological inference. Mexico, characterized by complex admixture patterns, represents a critical setting for evaluating population-level genetic variation associated with Parkinson's disease. Following PRISMA 2020 guidelines, we systematically reviewed original studies published between 2004 and February 2025 that investigated genetic variants or gene-expression profiles in clinically diagnosed Parkinson's disease among individuals recruited in Mexico. Twenty-four studies (7,048 participants; 3,367 patients and 3,781 controls) met the inclusion criteria. Variant nomenclature was harmonized using HGNC and dbSNP identifiers. Study quality was appraised using the Q-Genie instrument, and effect estimates were standardized where feasible. Functional interpretation incorporated Gene Ontology, WikiPathways, and network-based analyses. Across the included literature, 27 genes and 71 distinct genetic variants were examined. Eight loci- This systematic review provides the first quality-assessed synthesis of genetic studies of Parkinson's disease conducted in Mexico. The available evidence supports the involvement of established Parkinson's disease-related molecular pathways while underscoring substantial methodological heterogeneity and limited ancestry-aware analyses. Larger, well-powered genome-wide and multi-omic studies incorporating explicit ancestry modeling are required to refine genetic risk architecture and improve the interpretability of Parkinson's disease genomics in Mexican populations. Show less

Aortic valve calcification increases leaflet stiffness and contributes to the development of calcific aortic valve disease. The molecular and cellular mechanisms underlying calcification remain unclear. Here, we aimed to investigate the role of PRMT3 (protein arginine methyltransferase 3) in valvular calcification and calcific aortic valve disease progression. Both aortic valve leaflets and valvular interstitial cells from patients were used to evaluate the expression pattern and investigate the underlying mechanism of PRMT3 in calcific aortic valve disease pathogenesis. High-cholesterol diet-fed Apoe (apolipoprotein E)-deficient ( We found that PRMT3 expression was significantly upregulated during aortic valve calcification. RUNX2 (runt-related transcription factor 2) recruited P300 to promote PRMT3 expression through histone H3 lysine 27 acetylation. Moreover, We identify a previously unrecognized posttranslational mechanism regulating PCSK9 stability in valve interstitial cells during calcific aortic valve disease and establish a link between PRMT3-mediated arginine methylation and valve-specific lipid-osteogenic coupling. Show less

Atherosclerotic plaque destabilization during acute infections such as pneumonia represents a critical clinical challenge, yet the underlying molecular dynamics remain poorly characterized. This study introduces a furin-responsive photoacoustic/fluorescence dual-modal probe (FRP) to investigate intraplaque furin activity in ApoE Show less

Exercise training improves endothelial function and reduces vascular inflammation. However, whether aerobic exercise training-induced secretion of irisin, a myokine cleaved from fibronectin type III domain-containing protein 5 ( Show less

Pyroptosis, apoptosis and necroptosis (PANoptosis) simultaneously occur and are extensively cross-linked in infectious and inflammatory diseases. However, the co-existence and regulation of macrophage pyroptosis, apoptosis and necroptosis in atherosclerosis have not yet been investigated. Atherosclerotic specimens from human lower extremity amputation and carotid endarterectomy were analysed. Ox-LDL-induced macrophages and high-fat diet (HFD)-fed ApoE A substantial content of inflammatory factors, the activation of NLRP3/GSDMD/CASP3/CASP8/RIPK3/pMLKL, and the upregulation of galectin-3 were detected in advanced human and mouse atherosclerotic lesions. Galectin-3 was predominantly expressed in atherosclerotic macrophages, and Galectin-3-positive macrophages were mainly distributed in the atherosclerotic core in comparison with the proximal adjacent artery. Ox-LDL induced apoptosis, pyroptosis and necroptosis in macrophages, as evidenced by the activation of NLRP3/GSDMD/CASP3/CASP8/RIPK3/pMLKL and the secretion of proinflammatory cytokines. Galectin-3 interacted with NLRP3. Genetic knockdown of galectin-3 alleviated ox-LDL-induced activation of inflammatory cell death, which was pronouncedly abrogated by NLRP3 agonist nigericin. Genetic galectin-3 deficiency attenuated, and conversely nigericin exacerbated macrophage death, vascular inflammation and atherosclerosis in HFD-fed ApoE Macrophage-derived galectin-3 contributed to pyroptosis, apoptosis and necroptosis in concert, promoted vascular inflammation and atherosclerosis through the upregulation of TLR4/MyD88/NF-κB/NLRP3 pathway. Pyroptosis, apoptosis, and necroptosis of macrophages occur concurrently in atherosclerosis. Galectin-3 and NLRP3 expression levels are elevated in both human and murine atherosclerotic lesions. Galectin-3 is predominantly expressed in macrophages within atherosclerotic plaques.Galectin-3 interacts with NLRP3, activates TLR4/MyD88/NF- Show less

Atherosclerosis (AS) is a chronic inflammatory disease that constitutes the primary pathological basis of cardiovascular disorders. Although the natural isoflavone C-glycoside puerarin (PU) has demonstrated promising anti-atherosclerotic effects, its underlying molecular mechanisms remain incompletely elucidated. In this study, we aimed to systematically characterize the pharmacological actions and mechanistic basis of PU in AS by integrating network pharmacology analyses with experimental validation. Potential targets of PU were identified by integrating network pharmacology databases and intersecting them with AS-related genes. Protein-protein interaction analysis, functional enrichment, and machine-learning-based screening were subsequently performed to identify key regulatory targets. Molecular docking and molecular dynamics simulations were then conducted to evaluate the feasibility and stability of PU-target interactions. In addition, single-cell transcriptomic and immune infiltration analyses were used to determine the cellular localization and inflammatory relevance of the core targets. Finally, a high-fat diet (HFD)-induced ApoE This integrative analysis identified 56 potential PU-AS-related targets, among which TNF, NFKBIA, STAT3, SRC, and PTGS2 emerged as central hub genes. Notably, TNF was consistently highlighted as a key regulatory target across differential expression analysis, molecular docking, and molecular dynamics simulations. Single-cell transcriptomic and immune infiltration analyses further revealed that TNF was predominantly expressed in macrophages and related immune cell subsets. Experimental validation demonstrated that PU treatment significantly attenuated inflammatory responses, reduced aortic plaque burden, enhanced plaque stability, and suppressed macrophage infiltration in HFD-induced ApoE PU ameliorates atherogenesis by suppressing TNF-NF-κB-mediated inflammatory responses. These findings identify the TNF-NF-κB axis as a key mechanistic pathway underlying the anti-atherosclerotic effects of PU and support its potential as a natural product-based therapeutic strategy for cardiovascular disease. Show less