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Apolipoprotein E (APOE) and Galectin-3 (Gal-3) are markers of activated microglia in neurodegenerative diseases of the central nervous system, whose targeting is protective in mouse models of glaucoma. In this study, we examined levels of APOE and Gal-3 in human aqueous humor (AH) and serum samples. Single-center, cross-sectional study. A total of 100 glaucoma and 110 control patients at Massachusetts Eye and Ear. We enrolled patients with various types and stages of glaucoma undergoing planned ophthalmic surgery as part of their routine care and compared them with patients without glaucoma undergoing phacoemulsification for age-related cataract. At the start of ophthalmic surgery, we collected AH and serum from 100 glaucoma and 110 control patients. APOE and Gal-3 levels were quantified by enzyme-linked immunosorbent assays. APOE and Gal-3 levels in AH and serum. APOE and Gal-3 levels were significantly elevated in the AH of glaucoma patients compared to controls (2.72 vs. 0.85 µg/ml, P < 0.0001 for APOE, and 2.89 vs. 1.45 ng/ml, P < 0.001 for Gal-3). A positive correlation was observed between AH APOE and Gal-3 levels in the glaucoma cohort (R = 0.44, P < 0.0001). While serum Gal-3 levels were similar between groups (25.5 vs. 25.7 ng/ml, P = 0.92), APOE levels were significantly elevated in the serum of glaucoma patients compared to controls (58.7 vs. 30.2 µg/ml, P < 0.0001). Serum APOE levels were not correlated with AH APOE levels in either the glaucoma or the control groups (both R ~ 0, P > 0.05) or dependent on APOE genotype. Our findings demonstrate that AH Gal-3 and APOE are elevated in patients with glaucoma. In contrast, only serum APOE was elevated in our glaucoma cohort, possibly reflecting the known dysregulation of lipid metabolism that occurs in this disease. Show less

Anti-amyloid monoclonal antibodies, including lecanemab and donanemab, are now available for the treatment of Alzheimer's disease (AD). Defining real-world patient eligibility and identifying barriers to access are critical for their effective implementation in routine clinical practice. Retrospective observational multicenter study of patients who underwent CSF AD biomarker testing at Lariboisière Hospital (Paris, France) from 2023 to 2024, assessing lecanemab eligibility using CLARITY AD trial criteria and the French Memory Clinic Federation appropriate use recommendations (AURs) following EMA authorization. From a source population of 3075 patients, 676 underwent CSF testing, and 356 had biomarker-confirmed AD; 315 patients with MRI, APOE status, and MMSE data available (mean age 73.2 ± 8.1 years; 47.8% female; median MMSE 22 [IQR 19-26]) were screened. Using CLARITY AD trial criteria, 90 patients (28.6%) were eligible; low MMSE scores and MRI findings were the most frequent exclusion criteria. French AURs reduced eligibility to 75 patients (23.8%), excluding patients with a CSF A + T - profile and APOE ε4 homozygotes. Eligibility did not differ by age group. Eligibility rates from the entire source population equated to only 2.9% of patients using the CLARITY AD criteria and 2.4% using the French AURs. At follow-up, 34.5% of initially eligible patients no longer met the MMSE eligibility criteria. In specialized settings, lecanemab eligibility remained limited, highlighting the need for early AD diagnosis and efficient screening pathways. Show less

Lipid abnormalities are emerging as key pathogenic mechanisms in neurodegenerative diseases, such as Alzheimer's disease, Parkinson's disease, and Lewy body dementia. Astrocytes in the brain provide apolipoprotein E (APOE) proteins and influence neuronal metabolism and health. Using live-cell imaging and objective neurite imaging techniques, we induced cellular lipid load (cholesterol and triglycerides) by inhibiting the lysosomal cholesterol transport protein NPC1 in human neuron-astrocyte cocultures and examined the effects of CRISPR-edited APOE3 and APOE4 human astrocytes on the rescue of dystrophic neurites, where axons and dendrites of nerve cells become disfigured. APOE3, but not APOE4 or APOE knockout, astrocytes prevented cholesterol- and lipid-induced neurite damage in APOE4 neurons. In the media of APOE3 neuron-astrocyte cocultures, high-density lipoprotein-like particles were larger and presumably more lipidated than those in equivalent APOE4 cocultures. This discovery highlights that living APOE3 astrocytes control key biological mechanisms by physiologically enhancing lipid cellular homeostasis and rescuing lipid-induced neurite structural abnormalities relevant to Alzheimer's disease and neurodegenerative diseases. Show less

Anti-amyloid antibody treatment for Alzheimer's disease is linked to Amyloid-Related Imaging Abnormalities (ARIA), including vasogenic edema (ARIA-E) and microhemorrhages (ARIA-H), especially in ApoE ε4/4 carriers. To investigate mechanisms underlying ARIA, we examined the binding and temporal vascular effects of immunization with 3D6, the precursor to the anti-amyloid antibody bapineuzumab, in two aged Alzheimer's disease amyloid mouse models. Acutely, 3D6 bound to cerebral amyloid angiopathy (CAA), resulting in C1q binding and classical complement activation. Weekly short-term immunization over 7 weeks resulted in elevated CAA- and plaque-associated complement deposition, red blood cell extravasation and microhemorrhages, and was accompanied by significant transcriptomic changes in genes related to complement, inflammation, vascular dysfunction, and endothelial lipid responses. Longer-term dosing over 13-15 weeks further increased complement deposition and was associated with blood-brain barrier disruption, MMP-9 upregulation, and microhemorrhages, accompanied by reduced amyloid burden and modest CAA clearance. C3 levels correlated with microhemorrhage severity. Perivascular macrophages co-localized with complement-decorated CAA in 3D6-treated mice. These findings implicate complement activation as an early key driver of ARIA and suggest that therapeutic targeting of complement may reduce ARIA risk. Show less

Triggering receptor expressed on myeloid cells 2 (TREM2) is a microglial immune receptor genetically and functionally linked to Alzheimer's disease (AD). VG-3927, the first clinical-stage small-molecule TREM2 agonist, has been proposed to function as a transmembrane molecular glue and positive allosteric modulator (PAM). Whether it directly engages the extracellular ligand-recognition surface of TREM2 remains unknown. Here, we used a deep learning-based blind docking algorithm to map potential VG-3927 binding sites across TREM2 and identified a binding site within the ectodomain hydrophobic groove, a ligand-recognition surface previously implicated in Aβ and apoE binding. Microscale thermophoresis (MST) confirmed direct interaction of VG-3927 with TREM2 under optimized PEG-400 buffer conditions and independently demonstrated binding of Aβ Show less

While a growing body of literature suggests a role for infections in Alzheimer's disease (AD), microbial contributions to AD remains a contentious topic, in part due to challenges in reconciling the positive evidence with studies reporting null findings. Here, we examine the evidence that argues against a role for infections in AD, while offering mechanistic hypotheses that may account for both the negative and positive findings, including dysregulated host immunity and gene-environment interactions of AD-associated genes. Show less

Accurate prediction of progression from mild cognitive impairment (MCI) to Alzheimer's disease (AD) is critical for early intervention. Many existing models lack the ability to capture the nonlinear nature of cognitive decline and individual heterogeneity. This study employed a semi‑parametric joint model to analyze longitudinal cognitive trajectories and identify robust predictors of conversion. Data from 596 participants (184 AD converters, 412 stable MCI) were obtained from the Alzheimer's Disease Neuroimaging Initiative (ADNI). Longitudinal assessments included ADAS‑Cog13, ADAS‑Cog11, CDR‑SB, FAQ, RAVLT‑IR, RAVLT‑L, and MMSE. A semi‑parametric joint model combining B‑splines for the longitudinal process with a Cox survival submodel was fitted for each cognitive measure. Model performance was evaluated using AIC, BIC, intraclass correlation coefficient (ICC), time‑dependent C‑index, dynamic AUC, and calibration curves. Subgroup analyses were conducted by APOE‑ε4 carrier status. In multivariable joint models, APOE‑ε4 carriage was a consistent risk factor (HR range: 1.38-1.77). Higher scores on ADAS‑Cog13 (HR = 3.71 per SD), ADAS‑Cog11 (HR = 2.71), CDR‑SB (HR = 3.79), and FAQ (HR = 2.85) increased the hazard of conversion, whereas higher scores on RAVLT‑IR (HR = 0.23), RAVLT‑L (HR = 0.14), and MMSE (HR = 0.53) were protective. All models showed high ICCs (0.94-0.98) and moderate‑to‑good predictive accuracy over 2, 5, and 8 year horizons (C‑index: 0.585-0.668). CDR‑SB and FAQ exhibited the strongest effect sizes and clearest dose‑dependent trajectories across APOE‑ε4 subgroups. Calibration curves demonstrated good agreement between predicted and observed survival. The semi‑parametric joint model effectively captures nonlinear cognitive‑functional decline and provides validated predictions of AD risk. APOE‑ε4 genotype combined with longitudinal monitoring of CDR‑SB and FAQ offers a robust framework for stratifying progression risk in clinical MCI management. Show less

Atherosclerosis is a chronic inflammatory condition marked by the deposition of lipids within the arterial wall and the infiltration of inflammatory cells, culminating in the development of atherosclerotic plaques. Ubiquitin-specific protease 18, USP18, a specific deubiquitinating enzyme, has been demonstrated to exert protective effects on the cardiovascular system. Pathological studies were performed utilizing human coronary arteries obtained from the Forensic Medical Examination Center of Guizhou Medical University, in conjunction with the aorta from experimental ApoE knockout mice. The ApoE knockout mice underwent intervention with adenovirus carrying USP18-RNAi and a control adenovirus containing hU6-MCS-CMV-EGFP, after which pathological analyses were conducted. In vitro, THP-1 cells, induced with phorbol ester, were subjected to treatment with si-USP18 or si-NC, followed by exposure to oxidized low-density lipoprotein. The expression levels of USP18 and proteins associated with the TAK1/NF-κB signaling pathway, as well as the interaction between USP18 and TAK1, were assessed using Western blotting, RT-PCR, and immunofluorescence techniques.The interaction between USP18 and TAK1 was confirmed using molecular docking techniques, co-immunoprecipitation assays, and immunofluorescence analysis. The purpose of this study is to explore the role of USP18 on atherosclerosis and the underlying mechanism. The expression of USP18 is elevated in early-stage human coronary atherosclerotic plaques but decreases in advanced lesions. Treatment of macrophages derived from THP-1 cells and bone marrow-derived macrophages (BMDMs) with lipopolysaccharide (LPS) results in reduced USP18 expression. In ApoE USP18 modulates TAK1 to suppress the activation of the NF-κB signaling pathway in macrophages, consequently exerting an anti-atherosclerotic effect and offering a potential therapeutic strategy for atherosclerosis treatment. Show less

Atherosclerosis is a common vascular disease that poses a serious threat to global health. However, the mechanism underlying the pathogenesis and progression of atherosclerosis remains elusive. We analysed the expression of deubiquitinating enzymes in human atherosclerotic lesions and found that USP25 was significantly downregulated. The role of USP25 in atherosclerosis was validated in mouse models with an ApoE USP25 was predominantly expressed in macrophages in atherosclerotic lesions, and ablation of macrophagic USP25 significantly exacerbated atherosclerosis in ApoE This study elucidated the function and molecular mechanism of USP25 in atherosclerosis, identifying USP25 as a beneficial regulator for this disease. This work was supported by the Natural Science Foundation of Zhejiang Province (LZ24H090003 to X.W. and LTGY23H090001 to W.W.), the National Natural Science Foundation of China (82150710557 and 82293642 to W.S.; 81971143 to X.W., and 82271347 to G.W.), and Wenzhou Municipal Science and Technology Bureau (Y2021094 to J.H.). Show less

To investigate the distribution of the apolipoprotein E (ApoE) and solute carrier organic anion transporter family member 1B1 (SLCO1B1) polymorphisms in dyslipidemia patients and their impact on statin efficacy and safety. A retrospective analysis was conducted on dyslipidemic inpatients (April 2024-March 2025) who received statin therapy and genetic testing for SLCO1B1 (rs4149056) and ApoE (rs429358 and rs7412), to analyze the association of genotypes with lipid levels and safety indicators. The final analysis included 238 hospitalized patients with dyslipidemia (156 males and 82 females) who met the inclusion criteria. The study population had a mean age of 60.61 ± 0.91 years (mean ± SEM). The allele frequencies for both ApoE and SLCO1B1 polymorphisms were in Hardy-Weinberg equilibrium (P > 0.05). Analysis of statin efficacy revealed a significant association between ApoE genotype and atorvastatin response: E3 carriers demonstrated higher low-density lipoprotein cholesterol levels posttreatment compared to E2 carriers (2.85 ± 1.00 mmol/l vs. 2.28 ± 0.96 mmol/l, P = 0.026). However, no such association was found in patients administered rosuvastatin. For safety outcomes, comparisons of creatine kinase and alanine aminotransferase levels between carriers of the SLCO1B1 TC and TT genotypes showed no statistically significant differences. APOE polymorphisms influence statin efficacy. The E2 genotype is associated with better atorvastatin efficacy in lipid management. At low-to-moderate doses, the SLCO1B1 TC genotype did not increase safety risk, supporting its clinical safety. Show less

The APOE gene, which encodes Apolipoprotein E (ApoE), is the strongest genetic risk locus for Alzheimer's disease (AD). A substantial fraction of AD risk genes converges on pathways controlling lipid metabolism and immune regulation, in which microglia serve as a central integrative hub in the brain. Although microglial phenotypes linked to different APOE genotypes have been extensively characterised, the fundamental question of how ApoE shapes the core functions of human microglia remains unresolved. Here, we generated APOE knockout (KO) microglia from AD patient-derived induced pluripotent stem cells (iPSCs) and characterised their cellular and molecular phenotypes. Ablation of APOE resulted in marked lipid droplet accumulation and increased NLRP3 inflammasome activation. Transcriptomic analysis further revealed downregulation of cell cycle-related pathways, accompanied by enrichment of an oxidative stress-associated pathway. Consistent with these transcriptomic signatures, APOE KO microglia exhibited elevated intracellular reactive oxygen species (ROS) levels and a marked reduction in proliferative capacity. Given the importance of microglial proliferation for maintaining immune homeostasis in the brain, our findings highlight ApoE as being an important regulator of this process, with potential consequences for the pathogenesis of neurodegenerative disorders. Show less

Decline in pulmonary function (PF) and respiratory muscle strength (RMS) is influenced by environmental and genetic factors and is inconsistently linked to cognitive outcomes. This study explores the associations between PF, RMS, and cognitive function among community-dwelling older adults in China, analyzing interactions with APOE Ɛ4 and the mediating effect of serum total bilirubin. About 1,081 Hubei Memory and Aging Cohort (HMACS) participants underwent PF (PEF, FEV1 and FVC), RMS (MIP and MEP) assessment, cognitive tests, APOE genotyping, and bilirubin measurement. Multivariate logistic regression and general linear regression were used to analyze associations. Among 1,081 participants (mean age 70.52 ± 5.55 years), 26.1% had cognitive impairment. Lower PF and RMS scores were associated with cognitive impairment. Higher comprehensive PF (c-PF) and RMS indices protected against cognitive impairment (eg, c-PF: OR = 0.482-0.609, PF (especially PEF) and RMS (especially MEP) indices are significantly associated with cognitive function and impairment in older adults, independent of APOE Ɛ4 status. These findings provide biomarkers for assessing cognitive health risk and a basis for interventions targeting PF and RMS to preserve cognitive function. Show less

Tripartite motif-containing protein 21 (TRIM21), an E3 ubiquitin ligase of the TRIM superfamily, modulates critical cellular processes including ubiquitination, autophagy, and oxidative stress response. Accumulating evidence highlights its context-dependent regulatory roles in hepatocellular carcinoma (HCC)-the most prevalent primary liver malignancy with high mortality and limited therapeutic efficacy. This review systematically summarizes the core mechanisms by which TRIM21 orchestrates HCC progression: ① Autophagy regulation: TRIM21 modulates HCC autophagy via multiple axes, including CCR4-NOT complex (TNKS1BP1/CNOT4)-mediated substrate ubiquitination, ATG14-dependent autophagosome initiation, and RETREG1-driven reticulophagy, with context-dependent effects on tumor proliferation. ② Drug resistance: TRIM21 enhances oxaliplatin sensitivity by ubiquitinating and degrading G6PD (the rate-limiting enzyme of the pentose phosphate pathway), while its role in sorafenib resistance involves dual pathways-the MST1/YAP axis and the ApoE/cholesterol/PI3K-AKT cascade. ③ Metastasis suppression: TRIM21 restricts HCC invasion and metastasis by ubiquitinating key oncoproteins, preserving epithelial integrity and inhibiting mesenchymal transition. ④ Reactive oxygen species (ROS) balance: TRIM21 regulates oxidative stress in HCC via the SQSTM1/p62-Keap1-NRF2 axis, coordinating with HIF1α to modulate antioxidant responses and tumor cell survival. Additionally, we discuss the regulatory significance of TRIM21 in HCC associated with hepatitis B virus (HBV) infection (via HBx/DNA polymerase ubiquitination) and nonalcoholic steatohepatitis (NASH) (via suppressing lipogenic enzymes to reduce steatosis-driven carcinogenesis). This review provides a theoretical basis for TRIM21 as a potential diagnostic marker and therapeutic target for HCC. Show less

Aortic dissection is a life-threatening cardiovascular disease whose complex cellular pathophysiology is studied using various mouse models. To systematically evaluate their fidelity, we performed cross-species single-cell RNA sequencing, integrating data from human aortic dissection with five mouse models (BAPN, Ang-II, Ang-II apoE Show less

Apolipoprotein E (APOE) regulates lipid metabolism and neuronal repair, yet its alleles show contrasting effects on hemorrhagic stroke (HS) risk. While some variants increase susceptibility, others appear protective, leading to inconsistent findings. This meta-analysis systematically evaluates the APOE-HS association to clarify its role in stroke pathophysiology. A comprehensive literature search was conducted across multiple databases up to January 31, 2025, using the keywords: ("Apolipoprotein E" OR "APOE" OR "APOE genotype") AND ("Single Nucleotide Polymorphisms" OR "SNP") AND ("Hemorrhagic stroke" OR "HS" OR "Intracerebral Hemorrhage" OR "ICH"). The APOE ε3/ε3 genotype served as the reference genotype in all studies, and only those studies with ε3/ε3 genotype were included in the analysis. Pooled odds ratios (ORs) and 95% confidence intervals (CIs) were calculated, and statistical analyses were performed using STATA version 13.0 (StataCorp LLC, College Station, Texas, United States). A total of 24 studies comprising 8,269 HS patients and 26,321 controls were included. Meta-analysis revealed a significant association of APOE ε2/ε2 (OR = 1.93, 95% CI = 1.32-2.81), ε4/ε4 (OR = 1.60, 95% CI = 1.21-2.13), ε2/ε4 (OR = 1.81, 95% CI = 1.34-2.44), ε2 (OR = 1.23, 95% CI = 1.12-1.35), and ε4 (OR = 1.31, 95% CI = 1.14-1.51) with an increased risk of HS. Our findings suggest that APOE ε2/ε2, ε2/ε4, ε2, and ε4/ε4 genotypes and the ε4 allele are associated with an elevated risk of HS. These results highlight the potential role of APOE genotypes in HS susceptibility and warrant further investigation. Show less

Apolipoprotein E (ApoE), reelin, and several other proteins bind ApoE-receptor 2 (apoER2), distinguished from other members of its receptor family by signal transduction which enhances the activity of N-methyl D-aspartate (NMDA) receptors. Evidence indicates that this signal transduction depends upon apoER2 forming dimers or other high-order clusters. It seems noteworthy therefore that protein products of major We examined calcium fluxes via the NMDA receptor in neurons derived from the NTera2 cell line in response to conditioned medium from human astrocytes differing in Reelin, fibrillar Aβ, ApoE3, and conditioned medium from These findings suggest a comprehensive hypothesis for the pathogenesis of AD whereby the common factor in development of disease is antagonism of apoER2, likely to include agents that cannot promote the receptor's dimerization yet competitively inhibit those ligands that can cause dimerization. Show less

White matter (WM) is a key substrate for interregional neural communication and cognitive function but the role of WM glucose metabolism in cognitive aging has been understudied. Using multimodal neuroimaging (MRI, FDG-PET, amyloid-PET) from 3142 participants (15,287 visits) across two studies, we examined the contribution of WM to cognition and identified divergent WM signatures. Higher glucose metabolism in expected WM (EWM; corpus callosum and cingulum) was associated with better cognition, whereas increased metabolism in atypical WM (AWM; corona radiata) was linked to worse cognition, indicating a compensatory mechanism. EWM metabolism declined with aging, Alzheimer's disease (AD) progression (amyloid-β and APOE-ε4 carrier), and white matter hyperintensities, while AWM metabolism increased with aging and vascular risk but was partially weakened by AD neuropathology. Longitudinally, higher EWM and lower AWM metabolism predicted slower cognitive decline. Divergent WM metabolic patterns shed light on the dynamic role of WM in maintaining cognitive function. This study emphasizes the complementary information provided by WM metabolism for predicting future cognitive decline and identifying cognitive resilience. Show less

Lewy body dementia (LBD) is a complex neurodegenerative disorder marked by α-synuclein aggregation and dual impairment of cognitive and motor function.While genome-wide association studies have identified risk loci, the cellular mechanisms linking genetic variation to disease susceptibility remain largely unexplored. We performed single-cell transcriptome-wide Mendelian randomization using brain cell-type-specific eQTLs across eight major cell types. Genetic associations were evaluated using inverse-variance weighted models, followed by Bayesian colocalization analysis. Replication was performed in independent stratified LBD cohorts based on APOE ε4 carrier status. Phenome-wide association analysis was included as a supplementary, descriptive assessment of cross-trait associations. Expression of ANKRD65 in excitatory neurons was significantly associated with reduced LBD risk (odds ratio = 0.65, 95 % CI: 0.52-0.81, p = 0.00013). This association passed a false discovery rate of 0.1 and showed strong evidence of colocalization (posterior probability = 0.93). Effect direction was consistent across APOE ε4+ and ε4- LBD subgroups in independent cohorts. No genome-wide significant associations were observed with non-neurological traits in the phenome-wide analysis. Our findings identify a genetically supported, cell-type-resolved association between ANKRD65 expression in excitatory neurons and LBD risk. This study demonstrates the value of integrating cell-resolved transcriptomic regulation with genetic inference to pinpoint functionally relevant targets in neurodegenerative diseases. Show less

The apolipoprotein E (APOE) ε4 allele increases Alzheimer disease risk. Understanding genotype-specific dietary needs could inform more personalized prevention strategies. To test the hypothesis that higher meat consumption may be associated with cognitive health benefits in individuals with APOE genotypes ε3/ε4 and ε4/ε4 (APOE34/44) and to examine whether this association differs from that in other genotypes. This population-based cohort study used panel data analyses conducted in January 2025 to January 2026 over 15 years of follow-up in the Swedish National Study on Aging and Care-Kungsholmen (SNAC-K), using strategies aligned with causal inference principles. Recruitment was done in 2001 to 2004 among adults without dementia aged 60 years or older. The primary exposure was total meat consumption in grams per total kilocalories assessed via validated food frequency questionnaires. The secondary exposure was the ratio of processed to total meat. Global cognitive trajectory, measured as change in z score per 10 years, was analyzed by linear regression. Incident dementia was analyzed using Fine and Gray subdistribution hazard ratios (sHRs), treating nondementia death as a competing risk. Among 2157 older adults without dementia (mean [SD] age 71.2 [9.2] years; 1337 female [62.0%]), 1680 participants had longitudinal cognition data and 569 participants (26.4%) had APOE34/44 genotypes. During follow-up, 296 participants developed dementia and 690 died without dementia. Among participants with APOE34/44 genotypes, higher total meat consumption (top vs bottom quintile) was associated with better cognitive trajectories (β = 0.32; 95% CI, 0.07 to 0.56; P = .01) and reduced dementia risk (sHR, 0.45; 95% CI, 0.21 to 0.95; P = .04). No associations were found in participants with APOE22/23/24/33 genotypes (cognitive trajectory: β = -0.11; 95% CI, -0.27 to 0.06; P = .20; dementia: sHR, 0.95; 95% CI, 0.57 to 1.61; P = .86). P values for APOE interaction were .004 for cognition and .10 for dementia. In the top quintile of meat consumption, dementia risk and cognitive decline were similar between APOE strata. A higher ratio of processed to total meat was unfavorably associated with dementia (sHR, 1.14; 95% CI, 1.01 to 1.29; P = .04), showing no APOE interaction and no substantial difference between unprocessed red meat and poultry. Post hoc analyses suggested concordant APOE interaction for all-cause mortality (unprocessed meat exposure, APOE34/44: HR, 0.85; 95% CI, 0.73 to 0.99; P = 0.04; P for interaction = .03). In this study, higher meat consumption was associated with better cognitive trajectories and lower dementia risk among individuals with APOE34/44 genotypes. The expected cognitive disadvantage among individuals with APOE34/44 genotypes was not observed at high meat consumption, suggesting clinical and public health relevance. Show less

Spinocerebellar Ataxia Type 3 (SCA3) is an autosomal dominant neurodegenerative Polyglutamine (polyQ) disease, caused by a cytosine-adenine-guanine (CAG) repeat expansion in the ATXN3 gene, resulting in an expanded polyQ tract in the Ataxin-3 protein. Although the principal genetic determinant of the age at onset (AAO) in polyQ diseases is the expanded CAG repeat length, variability in AAO has been explained only partly, suggesting the existence of additional genetic modifiers. Apolipoprotein E (APOE) haplotypes are associated with the risk of numerous, especially degenerative, diseases. Investigations of a potential role of APOE haplotypes in AAO variability of SCA3 have resulted in partly conflicting outcomes, with current evidence lacking power and patient diversity. To further clarify a potential modifying effect of APOE haplotypes on the AAO in SCA3, over 800 SCA3 patients from different origins were enrolled in the present study. While we did not find an association of common APOE haplotypes or singular APOE alleles with AAO in SCA3, rare ε4 homozygosity was linked to an earlier AAO in individuals from Brazil, with a mean disease onset six years earlier than carriers of other APOE haplotypes. Our study thus provides initial evidence for a relevant impact of ε4 homozygosity on disease onset in SCA3 and provides evidence supporting an allele-dosage effect of APOE ε4 in polyQ diseases. Show less

Endothelial cell (EC) senescence is intimately linked to the development and progression of atherosclerosis. The FGFR2 (fibroblast growth factor receptor 2) signaling is crucial in regulating the phenotype of ECs. Recent studies have revealed that cell phenotype-specific alternative splicing of FGFR2 premRNA (precursor mRNA) results in the mutually exclusive inclusion of either exon IIIb or IIIc, leading to critical differences in receptor function. This study aimed to investigate the role of FGFR2 alternative splicing in EC senescence and atherosclerosis development, and to elucidate the underlying mechanisms. Clinical samples and animal models were used to assess the association between FGFR2-IIIc isoform expression and EC senescence as well as atherosclerotic plaque formation. The mechanisms underlying FGFR2-IIIc-induced EC senescence were elucidated through a combination of in vivo and in vitro investigations. In addition, genetically engineered mice with endothelial-specific overexpression or knockdown of FGFR2-IIIc were utilized to investigate the impact of FGFR2-IIIc on vascular endothelial senescence and the progression of atherosclerosis. Elevated expression of the FGFR2-IIIc isoform was detected in clinical samples and animal models of aging and atherosclerosis, where it correlated with both EC senescence and atherosclerotic plaque formation. Mechanistically, the alternative splicing-mediated switch from FGFR2-IIIb to FGFR2-IIIc established an FGF2-FGFR2-IIIc autocrine feedback loop, which drove ECs toward a senescence-associated secretory phenotype via the PKC (protein kinase C) ε/STAT3 (signal transducer and activator of transcription) pathway. Senescence-inducing stimuli promoted the binding of the splicing factor hnRNP H1 (heterogeneous nuclear ribonucleoprotein H1) to exon IIIb of the This study reveals that FGFR2 splicing mediated by hnRNP H1 promotes EC senescence and atherosclerosis via an FGF2-FGFR2-IIIc autocrine loop. These findings identify FGFR2-IIIc as a potential therapeutic target for age-related atherosclerosis. Show less

Diabetes mellitus (DM) is hypothesized to increase the risk of Alzheimer's disease (AD). However, existing studies have yielded conflicting results, with some demonstrating a significant association between DM and AD risk while others have not. Therefore, this meta-analysis aimed to systematically evaluate the association between DM and AD risk. Comprehensive searches were conducted in PubMed, Web of Science, and Embase databases to identify cohort or case-control studies investigating the association between DM and AD risk. All eligible studies published before October 2025 were included. The Newcastle-Ottawa Scale (NOS) was used to assess the risk of bias. Hazard ratio (HR) and 95% confidence interval (CI) were pooled as the effect size for meta-analysis. Heterogeneity among studies was evaluated using Cochran's A total of 11 studies involving 3,393,545 participants were included. A meta-analysis revealed that DM was significantly associated with an increased risk of AD (HR = 1.36, 95% CI (1.19, 1.55), This meta-analysis provides compelling evidence that DM is an independent risk factor for AD, offering important implications for clinical practice and future research. However, due to the methodological limitations of this study, the results should be interpreted with caution. Large-scale, high-quality prospective cohort studies are needed to fully investigate the relationship between DM and AD risk. https://www.crd.york.ac.uk/prospero/, identifier CRD420251159844. Show less

Patients with traumatic brain injury (TBI) and Glasgow Coma Scale scores of 13-15 (historically called mild TBI [mTBI]) commonly experience changes in cognitive functioning, including processing speed, memory, and executive functioning. In a prospective sample ( Show less

The pathological environment of atherosclerosis (AS) is characterized by hyperlipidemia and chronic inflammation, which cause increased heterogeneity among vascular smooth muscle cells (VSMCs). Owing to its lipid-regulating and anti-inflammatory effects, paeoniflorin (Pae) inhibits VSMC phenotypic transformation, making it a promising candidate for AS treatment. Mouse aortic VSMCs were treated with oxidized low-density lipoprotein (ox-LDL) and Pae, and the effects on cell phenotype were examined. An AS model was established by feeding ApoE Pae reversed weight gain and elevated TG levels in the AS model. Oil Red O staining showed that Pae inhibited VSMC-derived foam cell formation in vitro and reduced aortic sinus plaque area, aortic wall lipid deposition, and hepatic steatosis in the AS model. Immunofluorescence staining of the aortic sinus revealed that Pae mitigated α-SMA overexpression and reversed ATP-binding cassette transporter A1 (ABCA1) downregulation. Western blotting analysis revealed that Pae inhibited ERK1/2 and p65 phosphorylation, curbed MMP2 overexpression, and restored downregulated ABCA1 expression. Cell Counting Kit-8, 5-ethynyl-2'-deoxyuridine staining, and wound healing assays demonstrated that Pae inhibited ox-LDL-induced VSMC proliferation and migration. Additionally, Pae significantly inhibited the expression of the inflammatory factors IL-6 and MCP-1 both in vivo and in vitro. Pae may treat AS by inhibiting VSMC phenotypic transformation. Show less

Lecanemab is a monoclonal antibody targeting amyloid-beta protofibrils, indicated for patients with mild cognitive impairment (MCI) and mild dementia due to Alzheimer's disease. This study reports interim findings of an ongoing, multicenter, prospective, observational post-marketing study for all patients treated with lecanemab in routine clinical practice in Japan, focusing on amyloid-related imaging abnormalities (ARIAs) and infusion-related reactions primarily observed during up to 28 weeks after treatment initiation. Patients treated with lecanemab at any medical institutions across Japan are included in the study. Data are collected using an electronic data capture system via standardized case report forms (CRFs). Study items included the incidence of ARIA, ARIA-edema or effusion (-E), ARIA-hemorrhage (-H: cerebral microhemorrhages, superficial siderosis, and macrohemorrhage), and infusion-related reactions, reported as adverse drug reactions. As of July 5, 2025, CRFs from 2675 patients were collected, of whom 2672 had data available for the interim analysis. The median age was 76.0 years, and 62.6 % (1672/2672) of patients were diagnosed with MCI. At Week 28, 7.3 % (195/2672) of patients discontinued treatment, with a mean treatment duration of 189.6 ± 34.4 days. Among 2634 patients confirmed to have undergone MRI scans after treatment initiation, ARIA was observed in 7.1 % (188/2634) of patients, ARIA-E in 3.0 % (78/2634), and ARIA-H in 5.2 % (137/2634). Serious ARIA-H (macrohemorrhage) occurred in two patients (0.1 %). Infusion-related reactions were observed in 17.0 % (455/2672), including 0.7 % (18/2672) serious cases. The proportion of patients who experienced ARIA was highest in patients with apolipoprotein E (APOE) ε4 homozygotes. This interim analysis represents one of the largest real-world lecanemab cohorts reported globally to date. Although absolute rates are not directly comparable with those from clinical trials, the trends in ARIA distributions across APOE genotypes and infusion-related reactions were comparable to those observed in clinical trials. Show less

To investigate the correlation between thyroid hormone levels and cognitive dysfunction in older patients with subclinical hypothyroidism (SCH). A retrospective matched case-control study (1:2 ratio) was conducted, enrolling 420 participants aged ≥ 60 years (140 SCH cases, 280 euthyroid controls) matched by gender, age (± 5 years) and education level. Thyroid function parameters, including thyroid-stimulating hormone (TSH), free triiodothyronine (FT3), free thyroxine (FT4), thyroid peroxidase antibody (TPOAb), and thyroglobulin antibody (TgAb), and cognitive performance assessed via the Mini-Mental State Examination (MMSE), Montreal Cognitive Assessment (MoCA), Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-Cog), Auditory Verbal Learning Test (AVLT), Trail Making Test (TMT), and Stroop Color and Word Test (Stroop Test) were measured. The SCH patients had TSH levels consistent with the grouping criteria (TSH > 4.2 mIU/L), higher thyroid autoantibody positivity, and poorer cognitive performance across all domains (all P < 0.001). A dose-response relationship was observed between increasing TSH levels and worsening cognitive function. Multivariate logistic regression identified TSH (odds ratio, OR = 1.19), FT3 (OR = 0.68), age, education and APOE ε4 carrier status as independent predictors of cognitive impairment (ROC AUC = 0.786). Stratified analyses showed stronger associations in females and those aged < 75 years, whereas the significance of the correlation between TSH and cognitive impairment was lost in patients aged ≥ 75 years. Sensitivity analyses confirmed the robustness of the findings. The SCH is independently associated with cognitive dysfunction in older people, with thyroid hormones playing a critical role. The findings suggest potential clinical implications for thyroid function monitoring and cognitive protection in this population. Show less

Atherosclerosis (AS), a chronic inflammatory disorder initiated by vascular endothelial dysfunction (ED), is prominently triggered by hemodynamic low-shear stress (LSS). Interferon regulatory factor 6 (IRF6) is a transcription factor that regulates the inflammatory response following injury. In this work, the LSS-induced AS model was induced by the partial ligation of the left carotid artery in high-fat diet-fed ApoE Show less

Psychosis in Alzheimer's disease (AD), including hallucinations and delusions, affects up to 50% of patients and is linked to faster cognitive decline. Delusions can occur across AD, with persecutory delusions early and misidentification delusions late, while hallucinations emerge in advanced stages and predict greater cognitive and functional decline. The APOE4 allele is the strongest genetic risk factor for late-onset AD, although its influence on neuropsychiatric symptoms, including psychosis, remains unclear. This study examined the interaction between APOE4 status, sex, EHT use, and psychosis symptoms in AD using data from participants in the National Alzheimer's Coordinating Center Uniform Data Set. Generalized Additive Models assessed nonlinear associations between predictors and psychosis outcomes, including the presence of delusions, hallucinations, and their visual and auditory subtypes. Analyses were stratified by sex (males: n = 13,841, females: n = 15,354). Predictor variables included APOE4 status, current use of estrogen hormone therapy (EHT) in females. Due to limited data availability, CSF biomarkers (Aβ1-42, p-tau181, t-tau) could not be included in the main models and were instead examined in a secondary sub analysis. APOE4 homozygosity was associated with significantly greater odds of delusions in the past month in both males and females, with a stronger effect in females (p<0.05). In females only, APOE4 homozygosity was significantly associated with hallucinations, with no effect in males (p<0.05). EHT was associated with lower risk of hallucinations in females (p<0.05). These findings underscore sex-specific genetic and biological contributors to psychosis in AD and support sex-stratified approaches to understanding and addressing psychosis symptoms in clinical settings. Show less

Atherosclerosis is respectively correlated with interleukin-6/interleukin-6 receptor (IL6/IL6R) mediated inflammation signaling and macrophages ferroptosis. Nonetheless, the underlying mechanism of IL6/IL6R signaling mediated macrophages ferroptosis in atherosclerosis remains unknown. This study aims to investigate whether IL6/IL6R signaling mediated macrophages ferroptosis through mitochondrial fragmentation and mitophagy impairment. Two human atherosclerotic transcriptomic datasets were used to conduct bioinformatic analysis. In vitro, counting kit-8 (CCK-8) assays, flow cytometry, immunofluorescence staining, malondialdehyde (MDA) and glutathione (GSH) assay kits were employed to evaluate reactive oxygen species (ROS) levels and macrophages ferroptosis. Transmission electron microscopy (TEM), laser confocal microscope and seahorse experiments were used to evaluate changes of mitochondrial morphology and mitochondrial function. Western blotting (WB) was used to quantify key markers of mitophagy and ferroptosis. In vivo, histological stainings and WB were used to determine the effects of IL6R deficiency on atherosclerosis, mitophagy and ferroptosis. Integrated bioinformatic analysis revealed that the IL6 expression could stratify early and advanced plaques. IL6 induced macrophages ferroptosis by increasing ROS and MDA levels, depleting GSH level, promoting lipid peroxidation and suppressing glutathione peroxidase 4 (GPX4) expression. Dynamin-related protein 1 (Drp1) mediated excessive mitochondrial fragmentation in IL6-induced macrophages, resulting in more shortened mitochondria, impaired oxidative phosphorylation (OXPHOS) and ROS accumulation. Activation of mitophagy, the process of mitochondrial fragmentation clearance, could increase GPX4 expression and attenuate the lipid peroxidation level in IL6 induced macrophages. Aggravation of ferroptosis further compromised mitophagy-related proteins expression. Targeting IL6R signaling attenuated atherosclerotic burden in ApoE [Image: see text] The online version contains supplementary material available at 10.1007/s10753-025-02359-5. Show less