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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

The presence of a blood-brain barrier (BBB) prevents the delivery of most drugs to the brain. This characteristic limitation poses a major challenge to effective pharmacological treatment for numerous neurodegenerative diseases, particularly Alzheimer's disease. Delivering small interfering RNA (siRNA) via nanoparticles represents a highly promising approach for treating Alzheimer's disease. Nevertheless, developing a safe and efficient siRNA delivery system remains challenging. To enhance brain targeting and therapeutic efficacy, we developed an siRNA nanocarrier system based on PAH-AM-PEG-ApoE (PAPA) nanoparticles (PAPA/siRNA NPs), which facilitates BBB penetration. In this study, an siRNA nanocarrier delivery system modified with ApoE peptide (PAPA/siRNA NPs) developed by our research team was employed to simultaneously encapsulate BACE1-siRNA and GSK3β-siRNA. The PAPA/siRNA NPs were prepared through self-assembly and electrostatic binding. The particle size distribution profile and zeta potential of the PAPA/siRNA NPs were analysed with dynamic light scattering, while its morphology was examined with transmission electron microscopy. For in vitro assessments, flow cytometry, confocal laser scanning microscopy, PCR, and Western blotting were employed to evaluate the cellular uptake, gene silencing capacity, and endosomal escape. The biodistribution was investigated by in vivo imaging technology, and the therapeutic effect on AD was verified in AD model mice. The prepared PAPA/siRNA NPs exhibited a regular spherical appearance with a uniform particle size distribution profile. In in vitro cell experiments, the PAPA/siRNA NPs demonstrated excellent cellular uptake ability and efficient endosomal escape. Meanwhile, the dual-loaded siRNA nanocarrier delivery system effectively inhibited the expression of GSK3β and BACE1 genes. In vivo experimental results showed that the siRNA could successfully cross the BBB and deliver to the brain. It not only significantly prolonged the half-life of siRNA but also greatly reduced the generation of pathological β-amyloid and phosphorylated microtubule-associated protein tau, showing excellent therapeutic effects in the treatment of AD. In this study, we successfully constructed a brain-targeted siRNA nanocarrier delivery system for double-gene knockdown. This system can efficiently overcome the obstacle of the BBB, markedly alleviating cognitive and memory deficits in AD mice. It paves the way for novel strategies in the clinical treatment of AD and is expected to bring new breakthroughs and changes to the conquest of this disease. Show less

Personality traits are associated with cognitive resilience to dementia-related neuropathology. This study examines whether personality traits are related to cognitive resilience to accelerated epigenetic aging. Participants were adults aged from 50 to 98 years (N = 2926, 58% female, Mean age = 68.72, SD = 9.57) from the Health and Retirement Study (HRS). Data on cognition and epigenetic aging measures (GrimAge and DunedinPoAM38) were obtained in 2016. Data on personality, demographic factors, and clinical, behavioral, and psychological covariates were obtained in 2014/2016. Cognitive resilience was defined as the residual from the regression of cognition on epigenetic aging measures. Controlling for demographic factors, linear regression analyses indicated that higher neuroticism was associated with worse-than-expected cognition relative to one's epigenetic aging for both GrimAge and DunedinPoAM38 epigenetic measures. Higher conscientiousness and openness were related to better-than-expected cognition relative to one's epigenetic aging across the two measures. Logistic regression further indicated that higher neuroticism was associated with a lower likelihood of cognitive resilience to accelerated epigenetic aging, whereas higher conscientiousness and openness were related to a higher likelihood of cognitive resilience. These associations were partially accounted for by disease burden, sleep quality, physical activity, smoking, depressive symptoms, childhood adversity, lifetime trauma, and APOE e4 status, and persisted when participants with cognitive impairment were excluded. There was little evidence that age or sex moderated the associations. The present study expands the literature on resilience from neuropathology to a broader systemic impact of aging to provide novel evidence that personality traits are associated with cognitive resilience to accelerated epigenetic aging. Show less

Aortic aneurysms are age-linked aortic dilations that progress silently and carry high mortality rates following rupture. Immune cells are recognized drivers of aneurysm pathogenesis. Clonal hematopoiesis is an age-related expansion of somatically mutated hematopoietic stem cells that reshapes immune function and contributes to diverse age-associated diseases. However, its contribution to aneurysm pathogenesis remains unclear. In this study, targeted ultradeep sequencing of patient specimens revealed a high prevalence of clonal hematopoiesis-associated mutations that correlated with faster aneurysm expansion. Thus, we modeled clonal hematopoiesis by competitively transplanting ten-eleven translocation 2-deficient (Tet2-deficient) bone marrow into apoliprotein E-KO (Apoe-KO) mice and induced aneurysms with angiotensin II. Mice with Tet2 clonal hematopoiesis developed significantly greater aortic dilation than did controls. Interestingly, Tet2-deficient macrophages adopted an acid phosphatase 5, tartrate resistant (ACP5+), osteoclast-like state and produced more matrix metalloproteinase 9 (MMP9). Both genetic and pharmacological inhibition of osteoclast-like differentiation suppressed the Tet2-mediated aneurysmal growth in vivo. Thus, Tet2-driven clonal hematopoiesis accelerated aortic aneurysm progression through MMP9-producing, osteoclast-like macrophages and therefore represents a tractable therapeutic axis. Show less

Subjective cognitive complaints (SCC) can precede cognitive decline and are associated with demographic, exposure, lifestyle, and psychological factors. Prevalences of SCC and their correlates in individuals with repetitive head impacts (RHI) are poorly understood. This study characterized SCC in former elite American football players by frequency, mood and behavioral correlates, concordance with informant reports, and associations with neuropsychological test performance, cerebrospinal fluid (CSF), and magnetic resonance imaging (MRI) markers of neurodegeneration. Former American football players ( Rates of SCC ranged from 43 to 77% depending on the domain. Symptoms of depression, impulsivity, and anxiety were strongly associated with SCC. Self- and informant-reported SCC showed moderate inter-rater agreement. Adjusting for age, race, education, SCC are strongly associated with neuropsychiatric factors in former American football players. SCC may also be a marker of cognitive decline and neurodegeneration. Show less

Associations of Alzheimer's disease biomarker progression with cognitive decline are important to inform patient prognosis. Of particular interest is how newly available plasma biomarkers evolve relative to cognitive decline. The goals of this work are to measure how much earlier vs later an individual's progression on plasma and PET Alzheimer's disease biomarkers is associated with earlier vs later cognitive progression and to estimate the average timeline of progression of these processes in the population. In this cohort study of 2369 Mayo Clinic Study of Aging (MCSA) and 1591 Alzheimer's Disease Neuroimaging Initiative (ADNI) participants, we fit non-linear mixed effects models to estimate how much earlier vs later each individual progresses on plasma p-tau217, amyloid PET, tau PET, and auditory verbal learning test (AVLT) sum of trials relative to the population mean (individual adjustment), the associations of these individual adjustments among biomarker pairs, and how covariates affect the timing of biomarker progression. The association of individual adjustments implies mechanistic associations and the amount of variability in cognitive decline accounted for by each biomarker. By applying cutpoints, we also estimated the relative timing that these biomarkers become abnormal in the population. Associations of individual adjustments were moderate between all biomarkers and AVLT (R=0.38-0.47) in the MCSA and stronger (R=0.74-0.81) in ADNI; plasma p-tau217 accounted for 16% of the variability in timing of AVLT decline in the MCSA and 64% in ADNI. APOE ɛ4 carriership was associated with earlier biomarker progression. AVLT became abnormal after the biomarkers up to age 90, after which AVLT was estimated to become abnormal prior to tau biomarkers. The association of the timing of plasma and PET AD biomarker progression with cognitive decline was modest in the MCSA population-based sample and stronger in the Alzheimer's disease-enriched ADNI cohort. The timing of plasma p-tau217 progression explained a similar degree of variability in AVLT progression as amyloid PET, supporting its utility as a marker of disease progression. The estimated temporal ordering of biomarkers and cognitive abnormality was as anticipated (amyloid, tau, cognition) up to the age of 90, beyond which AVLT was estimated to become abnormal prior to tau biomarkers, likely related to the effects of non-Alzheimer's disease co-pathologies. Show less

A deep multi-omic analysis of post mortem human brains has identified a new co-expression protein network - Module 42 (M42), strongly corelated with Alzheimer's disease (AD) pathology. M42 comprises 32 transmembrane and extracellular matrix (ECM)-associated proteins, including the amyloid precursor protein (APP) and apolipoprotein E (apoE), and its members have been implicated in amyloid beta (Aβ) pathology. We systematically evaluated the Aβ-independent effects of M42 on immune function in vitro. Recombinant M42 proteins were expressed and purified. Their effects on phagocytosis, intracellular signaling, and cell viability were assessed in human induced pluripotent stem cell-derived macrophages. Treatment with Midkine (MDK) reduced phagocytosis, while treatment with the ectodomain of Transmembrane protein with EGF-like and two follistatin-like domains 2 (TMEFF2) had the opposite effect. Both proteins promoted intracellular Ca Our results suggest an additional role for M42 in AD via regulating immune functions. We tested M42 proteins for their effects on immune functions in vitro. Five proteins altered phagocytosis, and seven altered Ca Show less

Cardiovascular disease (CVD) risk is elevated among people living with HIV (PLWH), particularly those receiving antiretroviral therapy (ART). This study aimed to examine associations between single-nucleotide polymorphisms (SNPs) in lipoprotein-related genes and CVD risk among PLWH undergoing ART. Blood samples from 337 PLWH at Chung Shan Medical University Hospital were analyzed, including 238 individuals who switched ART and 99 who continued their regimen. Genotyping of four SNPs-namely, ATP binding cassette B1 ( The cohort was predominantly male 95.6% (322/337), with a mean age of 34.6 years. Metabolic abnormalities were common, and 16.0% (54/337) of participants on ART were classified as high-risk for CVD. Among the SNPs analyzed, SNPs in Show less

Alzheimer’s disease (AD) is a progressive neurodegenerative disorder thought to result from complex interactions between genetic and environmental risk factors. The APOE-ε4 allele is the strongest genetic contributor to late-onset AD, while a Western diet - high in saturated fats and refined sugars - is a major lifestyle-related risk factor associated with AD progression. However, how these two factors interact at an early stage of the disease remains unclear. In this study, we examined their combined impact on hippocampal synaptic transmission and plasticity in an AD mouse model and evaluated whether supplementation with d-serine, the key NMDAR co-agonist, could reverse the resulting deficits. To assess the combined effects of genetic and dietary risk factors on synaptic function, we crossed APP/PS1 mice with APOE-ε4 KI mice and generated four mouse lines: wild-type, APP/PS1, APOE-ε4, and APP/PS1/APOE-ε4. Hippocampal synaptic transmission and plasticity, NMDAR function and d- and l-serine levels were evaluated using a combination of electrophysiological recordings, pharmacological interventions and capillary electrophoresis in brain slices, under either control or Western diet conditions. A significant impairment of both basal excitatory synaptic transmission and long-term potentiation (LTP) was detected in APP/PS1 mice by 9 months of age. These deficits were significantly more pronounced in APP/PS1/APOE-ε4 mice. Notably, Western diet accelerated these impairments, with significant deficits already present at 7 months in both APOE-ε4 and APP/PS1/APOE-ε4 mice. Mechanistically, these impairments were associated with reduced d-serine availability and NMDAR hypofunction at CA3-CA1 synapses. This study provides direct evidence of a specific and synergistic interaction between the APOE-ε4 genotype and Western diet in advancing and exacerbating hippocampal synaptic dysfunction in an AD mouse model. These findings highlight d-serine/NMDAR signaling as a key mechanistic pathway through which genetic and environmental risk factors converge in early AD, and underscore the potential of targeting astrocytic d-serine biosynthetic pathways as a promising therapeutic strategy for APOE-ε4 carriers at risk for late-onset AD. Not applicable. The online version contains supplementary material available at 10.1186/s13195-026-01992-y. Show less

Diabetes accelerates atherosclerosis by driving persistent vascular inflammation. MicroRNA-155 (miR-155) is a post-transcriptional regulator of inflammatory genes, while suppressor of cytokine signaling 1 (Socs1) limits Janus kinase (JAK)/signal transducer and activator of transcription (STAT)-mediated cytokine responses. We explored how the imbalance between miR-155-5p and Socs1 contributes to atherosclerotic plaque progression in diabetes. Apolipoprotein E knockout (ApoE-/-) mice were studied in two settings: age-dependent atherosclerosis progression under non-diabetic conditions, and streptozotocin-induced diabetes to model accelerated atherosclerosis. Diabetic mice received a miR-155-5p inhibitor, a Socs1-expressing adenovirus, or respective controls. Lesion size, composition, and gene expression were analyzed. Cultured vascular smooth muscle cells (VSMCs) and macrophages were transfected with miR-155-5p mimic/inhibitor and Socs1 siRNA/plasmid to assess inflammatory responses, phenotypes, and efferocytosis under diabetic-like conditions. During atherosclerosis progression, vascular miR-155-5p inversely correlated with Socs1 and positively with lesion size, while Socs1 correlated negatively with plaque burden. In diabetic mice, miR-155-5p inhibition reduced lesion area, lipid/collagen and macrophage/VSMC ratios, pro-inflammatory cytokines, M1 macrophages and synthetic VSMC markers, while increasing Socs1, M2 and contractile VSMC genes. Socs1 gene transfer reproduced these effects by reducing miR-155-5p and Stat1 expression, and lesion size. In vitro, miR-155-5p mimic suppressed Socs1, activated STAT1 and inflammatory phenotypes in macrophages and VSMCs, whereas miR-155-5p inhibition had opposite effects. Socs1 silencing amplified inflammation, and its overexpression counteracted miR-155-5p actions. Moreover, miR-155-5p inhibition reduced soluble Mer receptor tyrosine kinase (MerTK) in plaques and macrophages, indicating improved efferocytosis, whereas the mimic promoted macrophage MerTK shedding and impaired apoptotic cell clearance. Reciprocal regulation between miR-155-5p and Socs1 influences vascular inflammation, phenotypic changes, and defective efferocytosis in a diabetic context. Targeting this axis may restore resolution mechanisms and enhance plaque stability in diabetes-associated vascular disease. The online version contains supplementary material available at 10.1186/s12933-026-03121-3. Show less

Investigating the genetic underpinnings of functional brain connectivity is essential to understand how genetic variation influences brain health and disease. Here, a mass-univariate approach was adopted to study the genetic architecture of functional brain circuitry (N Show less

Cognitive impairment varies across sporadic Parkinson's disease (PD) and the common genetic subtypes glucocerebrosidase (GBA1) and leucine-rich repeat kinase 2 (LRRK2) PD and is influenced by Apolipoprotein E (APOE) polymorphisms and Alzheimer's disease (AD) co-pathology. However, the effects of APOE genotype, Aβ42 and tau on cognitive decline across these PD subtypes remain unclear. Using pooled longitudinal data across the PPMI and CPP cohorts, we examined the effects of APOE genotype and cerebrospinal fluid (CSF) Aβ42 and tau on cognitive decline across sporadic PD, GBA1-PD, LRRK2-PD, and healthy control (HC) subjects. Whereas in sporadic PD the APOE ε4 allele was associated with faster cognitive decline than APOE ε3 or ε2 alleles, no APOE effect was observed in GBA1-PD or LRRK2-PD. While lower baseline CSF Aβ42 was linked to faster cognitive decline in all groups, higher baseline CSF pTau was associated with faster decline in sporadic PD and LRRK2-PD but not in GBA1-PD. These findings underscore differential vulnerabilities to APOE genotype and AD-related biomarkers among PD subtypes, a critical consideration for clinical trials targeting cognitive decline in PD. Show less

What social repercussions do older adults expect to experience if they learn they are at heightened genetic risk for Alzheimer's disease (AD)? We compared these individuals' hypothetical expectations to the actual experiences of AD stigma reported by those who knew their apolipoprotein E ( Show less

Sex and racial or ancestral disparities in Alzheimer disease remain incompletely understood; autopsy studies that examine amyloid, tau, and genetic factors are scarce. To test whether neuritic plaque burden and cognitive outcomes differ by sex and whether sex modifies the effects of apolipoprotein E ε4 (APOEε4), informant-reported race, and African ancestry. This was a cross-sectional study using postmortem neuropathological data from the Biobank for Aging Studies, University of São Paulo, São Paulo, Brazil. A total of 2268 autopsies from a population-based, diverse clinicopathological sample were collected between April 2004 and March 2025. Sex, informant-reported race (Black, White), African ancestry proportion, and APOEε4 carrier status. Neuritic plaque burden (Consortium to Establish a Registry for Alzheimer's Disease [CERAD] score), and cognitive function (Clinical Dementia Rating-Sum of Boxes [CDR-SB]). Ordinal logistic regression examined association of sex with CERAD scores and 2- and 3-way interactions among sex, race, ancestry, and APOEε4; adjusting for age, education, vascular factors, and Braak stages. Linear models related pathology to CDR-SB, adding copathologies. The analysis included 2268 autopsies (median [IQR] age, 74.8 [63.8-83.3] years; 1152 [51% male] and 1116 [49%] female; 802 [35%] Black and 1466 [65%] White; other race groups not included owing to small numbers); female individuals were older than male individuals and more likely to exhibit cognitive impairment (CDR global score ≥0.5). Female individuals had higher plaque burden than male individuals (unadjusted odds ratio [OR], 1.97; 95% CI, 1.67-2.29; P < .001), and this association remained significant in adjusted models for sociodemographic and vascular factors and APOEε4 status (adjusted OR, 1.65; 95% CI, 1.33-2.20; P < .001). APOEε4 carriers of both sexes had an approximately 4-fold greater odds of plaques. Significant 2-way interactions were found between sex, APOEε4 status, race, and ancestry on CERAD scores. Black noncarriers (OR, 0.47; 95% CI, 0.34-0.67) and noncarriers of African ancestry (OR, 0.57; 95% CI, 0.43-0.76) were least likely to have high plaque burden, whereas this protection was weakened in ε4 carriers. No significant 3-way interaction was detected. Among individuals with a CERAD score of 2 or higher, female individuals were more likely than male individuals to reach Braak stage V-VI than male individuals (probability ratio, 1.25; 95% CI, 1.13-1.38; P = .002). Adding Braak stage to multivariable models attenuated the female-male difference in plaques and interaction of sex and plaque on CDR-SB was no longer significant. The findings indicate that female sex, APOEε4, and both race and African ancestry were jointly associated with amyloid in this study population. Excess amyloid among women may partly explain their greater tau burden and steeper cognitive decline. These findings highlight the importance of incorporating sex, race, and ancestry into biomarker thresholds, risk stratification, and the design of preventive or disease-modifying trials for Alzheimer disease. Show less

With a rapidly aging population living with HIV that may face a double-hit of neuroHIV and Alzheimer's disease, the objective of this meta-analysis was to evaluate the impact of ε4 on cognitive performance in adults with HIV. The primary literature search was conducted with PubMed and other databases on studies published between 1997 and 2025. Searches were conducted from inception until June 2025. Out of 289 initial studies, 17 were identified for inclusion meeting pre-defined criteria. Data extraction was performed by two independent observers and followed established guidelines (PRISMA). Pooled data included a total of 2610 adults with HIV, including 765 ε4 carriers (age 45.3 ± 8.1 years, 62.1% male) and 1845 non-carriers (age 44.7 ± 9.2, 67.5% male). There was no significant difference between ε4 carriers and non-carriers in diagnosis of neurocognitive impairment (OR = 1.10, 95% CI 0.8 to 1.5 p = .563), nor in performance of any of the examined cognitive domains (Hedges gs<0.2, ps > 0.17). Meta-regression analysis suggested that less education was associated with increased risk of neurocognitive impairment in carriers (p = .0143). After controlling for the potential bias from "overrepresented" cohorts that appeared in multiple publications, this meta-analysis found no significant effects of ε4 on neurocognitive performance or impairment in adults with HIV, despite a weak and non-significant trend of low performance in memory and executive function in ε4 carriers. Factors such as a relatively young age may contribute to the null findings. Future studies with relatively older cohorts and more sensitive/interdisciplinary approaches are needed. Show less

Abdominal aortic aneurysm (AAA) has high mortality and enhanced oxidative stress; autophagy inhibition accelerates its formation. Nicotinamide adenine dinucleotide phosphate hydrogen (NADPH) oxidase 2 (NOX2) is responsible for generating reactive oxygen species (ROS). The aim is to clarify the mechanism of NOX2-mediated autophagy in AAA. Subcutaneous angiotensin II (AngII) infusion in ApoE Show less

Using longitudinal data from multiple cohorts, we evaluated plasma P-tau217 as a predictor of when cognitive impairment occurs in AD. P-tau217 concentrations were analyzed as continuous and binary variables using cohort-specific biomarker positivity thresholds. Association of plasma P-tau217 with prevalent and incident cognitive impairment were assessed using logistic regression and Cox models, stratified by Elevated P-tau217 levels were significantly associated with the onset of cognitive impairment. Among Plasma P-tau217 levels and the presence Show less

Aging is asynchronous across cells and organs, but whether plasma proteins can capture cell type-specific aging and predict disease and mortality remains unknown. We developed machine learning models to estimate the biological age of more than 40 distinct cell types-spanning neuronal, immune, glial, endocrine, epithelial, and musculoskeletal origins-using over 7,000 plasma proteins measured in 60,000 individuals across three cohorts, comprising the largest human plasma proteomics aging study to date. Individuals showed heterogeneous aging profiles, with 20-25% exhibiting accelerated aging in a single cell type and 1-3% across ten or more cell types. APOE genotype showed antagonistic aging effects in different cell types: APOE4 carriers exhibited older astrocytes but younger macrophages, while APOE2 carriers showed the inverse. Cellular aging signatures were uniquely associated with disease status and predicted incident disease and mortality over 15 years of follow-up. Amyotrophic lateral sclerosis (ALS) showed the strongest association with skeletal myocyte aging (hazard ratio = 12.7 for extreme accelerated versus youthful aging). In Alzheimer's disease (AD), prevalent cases showed accelerated aging across multiple neural and peripheral cell types, with extreme astrocyte aging conferring AD risk comparable to APOE4 carrier status. Moreover, extreme astrocyte aging increased AD risk in APOE4/4 carriers threefold, while youthful astrocytes strikingly reduced risk. Beyond neurodegeneration, respiratory cell aging identified smokers at 58% higher lung cancer risk, and myeloid aging identified normoglycemic individuals at higher diabetes risk. Both specific cellular vulnerabilities and cumulative aging burden influenced survival, wherein youthful immune or neuronal profiles were protective. A polycellular aging risk score provided robust mortality risk stratification across platforms and cohorts. These findings establish a framework for quantifying biological aging at the cellular resolution using plasma proteomics, revealing heterogeneity in aging trajectories and their impact on disease susceptibility and resilience. Show less

Alzheimer's disease (AD) is the most widespread neurodegenerative disease, strongly linked to amyloid depositions in the brain consisting of amyloid β (Aβ) peptides. The likelihood of developing late-onset Alzheimer's disease (LOAD) is influenced by the specific isoforms of apolipoprotein E (ApoE), with ApoE4 being the strongest known genetic risk factor for LOAD. Strong evidence suggests that ApoE impacts AD by modulating Aβ aggregation and clearance, although the precise molecular mechanisms remain incompletely understood. Microscale thermophoresis (MST) is a powerful technique for characterizing molecular interactions in solution, which has been used to determine various binding constants, although not the binding of ApoE to Aβ peptides. MST results show that ApoE isoforms bind Aβ1-40 and Aβ1-42 with low micromolar affinity. For Aβ1-42, ApoE3 shows the strongest binding ( Show less

The selective cholesteryl ester transfer protein (CETP) inhibitor obicetrapib is in clinical evaluation for dyslipidemia and cardiovascular risk reduction. This study investigated how obicetrapib alone and with ezetimibe reduces non-HDL-C, affects atherosclerotic lesion progression, and regression when added to background atorvastatin intervention. APOE∗3-Leiden.CETP mice received a Western-type diet (WTD) or this diet supplemented with obicetrapib, ezetimibe, or both. After 8 weeks, all interventions reduced non-HDL-C levels (obicetrapib: -53%; ezetimibe: -19%; combination: -75%). Obicetrapib mono and combination treatment blocked CETP activity (-99% and -98%), thereby increasing HDL-C levels (+286% and +256%). Very low-density lipoprotein (VLDL) cholesterol production was not affected, while obicetrapib and the combination with ezetimibe increased VLDL clearance (plasma half-life [ Show less

Biomarker-based Alzheimer's disease (AD) diagnosis has shifted clinical practice from syndromic, dementia-stage diagnosis to a biologically defined framework anchored in amyloid positron emission tomography (PET) and cerebrospinal fluid (CSF) assays. However, binary amyloid/tau status does not capture disease complexity, stage, and the impact of co-existing neuropathologies. Here, we review in vivo human PET-fluid biomarker studies in AD and related neurological disorders. We highlight how PET readouts of aggregated pathology and fluid biomarkers reflect related yet non-identical processes, and what relevant insights for staging and prognosis can be derived from it. We review recent efforts to infer tau stage from plasma and CSF markers, emphasizing stage-dependent relationships between soluble p-tau, amyloid burden, and tau-PET signal, and associated limitations that are partly driven by the lack of standardized tau PET staging methods. Finally, we examine how co-pathologies and biological modifiers - including age, APOE ε4, sex, and neuroinflammatory states - shape PET-fluid coupling and contribute to disease course. The reviewed evidence supports a complementary, multimodal biomarker approach that integrates PET with CSF and plasma measures. To maximize insights from multimodal signals, harmonized integration frameworks - supported by neuropathology-anchored and real-world validation and explicitly accounting for modifiers such as age, sex, and APOE ε4 - will be essential. Show less