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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

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

The apolipoprotein E (APOE) ε4 allele represents the strongest genetic risk factor for Alzheimer's disease (AD), but its role in genetically diverse Latin American and Caribbean (LAC) populations is underexplored. We conducted a meta-analysis of 35 studies from 11 LAC countries, encompassing 3206 patients with AD and 5515 controls. The ε4 allele demonstrated significant association with increased AD risk (odds ratio [OR] = 3.25, 95% confidence interval [2.82-3.76]), while ε3 showed lower odds (0.42, [0.37-0.48]). Homozygous ε4/ε4 carriers had elevated risk (6.84, [5.09-9.19]), and heterozygous ε3/ε4 carriers showed moderate risk (2.59, [2.31-2.91]). Country-level analyses revealed variability, with Ecuador showing the highest OR for ε4/ε4 (13.29, [1.56-113.4]). These results confirm APOE ε4 as a major AD risk factor in LAC populations and highlight regional differences relevant to precision medicine. Show less

Alzheimer's disease (AD) is characterized by amyloid-β (Aβ) accumulation and brain atrophy; however, the assocation between plasma Aβ biomarkers and regional neurodegeneration remains unclear. We investigated whether plasma Aβ42, Aβ40, and the Aβ42/40 ratio are associated with temporal lobe atrophy measured using tensor-based morphometry (TBM) in cognitively healthy controls (HC) and participants with mild cognitive impairment (MCI). We analyzed longitudinal MRI and plasma biomarkers data from 29 participants from ADNI (HC = 14, MCI = 15) with imaging and blood samples available at baseline, 24 months, and 48 months. TBM Jacobian maps were summarized within temporal lobe regions of interest (ROIs). Associations between plasma Aβ measures and TBM-derived atrophy were examined with linear mixed-effects models, adjusting for age, sex, and APOE ε4 status, with false-discovery-rate correction. Participants with MCI showed greater temporal lobe atrophy compared with HC people, with significantly lower TBM values at follow-up. Plasma Aβ42, Aβ40, and Aβ42/40 levels showed no consistent or robust differences between diagnostic groups. After covariate adjustment and FDR correction, no plasma Aβ-TBM associations were significant at baseline or 24 months. At 48 months, positive associations were identified between Aβ42 and temporal lobe atrophy (measure 2) in HC participants (β = 0.70, p = 0.046) and between Aβ40 and measure 2 in participants with MCI (β = 0.60, p = 0.036). In contrast, a negative association was observed between the Aβ42/40 and temporal lobe atrophy (measure 2) in MCI group (β = -0.53, p = 0.049). TBM captured greater temporal lobe atrophy in participants with MCI compared with HC. Plasma amyloids showed only limited and inconsistent associations with temporal lobe atrophy over time. These findings suggest that plasma Aβ measures alone may not reliably reflect longitudinal regional neurodegeneration in early AD. Show less

The apolipoprotein E (APOE) ε4 allele is a risk factor for late-onset Alzheimer's disease; however, risk varies by sex and lifestyle. Regular physical activity is known to mitigate cognitive decline; whether the degree of benefit differs by APOE genotype, sex, and race remains unknown. Analyses utilized data from 2,985 participants in the Health, Aging, and Body Composition (HABC) cohort, comprising community-dwelling black and white older adults followed for 10 years. Cognitive performance was assessed multiple times across the 10 years using the Digit Symbol Substitution Test (DSST) for executive functions and processing speed and the Modified Mini-Mental State Examination (3MS) for global cognition. APOE genotypes were categorized into ε2, ε3, and ε4 groups. Annual self-reported walking time was used to quantify physical activity. Linear mixed models and latent growth curve modeling examined the interactions between APOE genotype, sex, and walking on cognitive trajectories with adjustments for race, study location, health score, age, education attained, and body mass index. APOE ε4 carriers demonstrated steeper declines in both DSST and 3MS scores compared to ε3 carriers, irrespective of sex (all β<-0.13, all p < 0.004). APOE ε2 was protective longitudinally for 3MS in females only (β = 0.15, p < 0.002). Walking showed the strongest protective effect in APOE ε4 carriers for females and males in the rate of change of DSST and 3MS scores (all β > 0.27, all p < 0.044). These findings underscore the importance of public messaging about the benefits of regular physical activity for retaining cognitive function especially for persons genetically at heightened risk. Show less

In this study, we investigated the intricate mechanisms underlying thrombin and Ang II-induced depletion of ABCA1. Under basal conditions, the COP9 signalosome interacts with ABCA1 as a whole complex rather than as individual subunits. In the presence of GPCR-agonists, thrombin or angiotensin II (Ang II), ABCA1 was phosphorylated and dissociated from COP9 signalosome, paving the way for its cullin3-mediated ubiquitination and degradation. Furthermore, forced expression of CSN5, the catalytic core subunit of the COP9 signalosome, inhibited thrombin or Ang II-induced ubiquitination and degradation of ABCA1, thereby restoring cholesterol efflux and suppressing foam cell formation. In addition, xanthine oxidase-dependent H Show less

Aging is the strongest risk factor for dementia; however, few studies have examined the association of biological aging with incident dementia. We analyzed 6069 cognitively unimpaired women (mean age = 70.0 ± 3.8 years) in the Women's Health Initiative Memory Study to examine the association of accelerated biological aging, measured with second and third-generation epigenetic clocks (AgeAccelPheno and AgeAccelGrim2, and DunedinPACE, respectively) with incident mild cognitive impairment (MCI) and probable dementia. Multivariable Cox proportional hazards models adjusted for age, education, race, ethnicity, smoking, hormone therapy regimen, physical activity, body mass index, and estimated white blood cell counts. For comparison, we also examined first-generation epigenetic clocks (AgeAccelHorvath; AgeAccelHannum). We evaluated effect modification by age, race/ethnicity, hormone therapy regimen, menopause type (natural vs. surgical), and APOE ε4 carriage. There were 1307 incident MCI or probable dementia events over a median follow-up of 9.3 (25th percentile = 6.1, 75th percentile = 16.1) years. The adjusted HRs (95% CI; p-value) for incident MCI/probable dementia per one-standard deviation increment were 1.07 (1.01-1.15; p = 0.03) for DunedinPACE, 1.11 (1.02-1.20; p = 0.01) for AgeAccelGrim2, and 1.01 (0.95-1.07; p = 0.74) for AgeAccelPheno. Only AgeAccelGrim2 remained significant under the Bonferroni-corrected threshold for significance (p < 0.02). Other epigenetic clocks were not associated with incident MCI/probable dementia. There was no effect modification in most subgroup analyses (p-interaction ≥ 0.05). In this cohort study of older women, accelerated biological aging measured by AgeAccelGrim2 was associated with higher risk of incident MCI/probable dementia. These findings provide evidence linking epigenetic biomarkers of biological aging with MCI and dementia development, independent of chronological age. Show less

The APOE-ε4 allele is the strongest genetic risk factor for late-onset Alzheimer's disease. However, APOE-ε4 is not deterministic, highlighting the need to identify additional genetic and environmental factors. APOE-ε4 has been linked to accelerated cognitive decline, so we sought to investigate genetic factors that modify APOE-ε4-associated cognitive decline. We conduct cross-ancestry APOE-ε4-stratified and interaction GWAS using harmonized cognitive data from 32,778 participants, including 29,354 non-Hispanic White and 3,424 non-Hispanic Black individuals. Our primary outcome is late-life cognition, measured using harmonized composite scores for memory, executive function, and language, modeled as continuous traits reflecting both normative cognitive aging and disease-related decline. We identify two genome-wide significant loci in APOE-ε4 carriers, reaching genome-wide significance for executive function. These loci also demonstrate nominal associations across the other domains, suggesting broad effects on cognition. In non-carriers, we identify a genome-wide significant association at ITGB8 restricted to executive function, and another locus associated with language. We further link these loci to SEMA6D, GRIN3A, and ITGB8 through expression and methylation databases. Post-GWAS analyses implicate additional genes including SLCO1A2, and DNAH11. Genetic correlation analyses reveal differences by APOE-ε4 status for immune-related traits, suggesting immune-related predispositions may exacerbate cognitive risk in APOE-ε4 carriers. Show less

Coronary restenosis remains a major challenge following percutaneous coronary intervention (PCI), necessitating the development of effective stent-eluting drugs. Previous studies indicate that scutellarin protects vascular endothelial cells and exhibits anti-thrombotic and anti-platelet effects. Notably, our prior research demonstrated that scutellarin specifically counteracts oxidative stress-driven endothelial dysfunction, a key initiating event in restenosis. This combined evidence strongly suggests its potential against in-stent restenosis (ISR). Therefore, this study explores the efficacy of scutellarin in preventing ISR after PCI. We investigated scutellarin, derived from Erigeron breviscapus, for its potential to prevent ISR following PCI. The efficacy and mechanism of scutellarin were evaluated using both in vivo and in vitro models. An experimental atherosclerosis model was established in APOE In APOE This study establishes the efficacy of scutellarin in mitigating ISR using two complementary in vivo models. Scutellarin-eluting stents in atherosclerotic minipigs overcome translational barriers through full interventional simulation. Furthermore, scutellarin inhibits VSMCs proliferation, migration and promotes autophagy-coordinated apoptosis by the coordinated downregulation of both the Pl3K/AKT and lKKs/NF-κB cascades.These findings highlight scutellarin as a promising candidate for next-generation bioactive stent coatings, bridging phytopharmacology and precision interventional cardiology. Show less

Cardiovascular disease is one of the diseases with the highest global incidence and mortality rates, and atherosclerosis is its basic cause. Endothelial dysfunction induced by risk factors such as lipid oxidation or inflammatory stimulation is a critical stage in the development of atherosclerosis, with endothelial oxidative stress and apoptosis serving as important pathological bases. Rosuvastatin influences the occurrence of atherosclerosis by regulating lipid levels. In this study, we investigated the effects of rosuvastatin on ox-LDL-induced endothelial cell injury and atherosclerosis. The results showed that intragastric administration of rosuvastatin inhibited high-fat diet (HFD)-induced changes in the aortic plaque area and aortic root lipid deposition in mice. In addition, rosuvastatin reduced mouse body weight and decreased the plasma levels of low-density lipoprotein (LDL) and total cholesterol (TC). The in vitro results demonstrated that rosuvastatin suppressed ox-LDL-induced endothelial oxidative stress, promoted the expression of nitric oxide (NO) and endothelial nitric oxide synthase (eNOS), and reduced intracellular reactive oxygen species (ROS) production. Additionally, rosuvastatin protected against ox-LDL-induced endothelial apoptosis by increasing Bcl-2 expression and decreasing Bax expression. Mechanistically, rosuvastatin inhibited the activation of the NF-κB signaling pathway induced by ox-LDL and suppressed the phosphorylation of P65, thereby reducing the expression of molecules related to oxidative stress and apoptosis. In conclusion, this study suggests that rosuvastatin may attenuate atherosclerosis by inhibiting endothelial oxidative stress and apoptosis, which provides a theoretical basis for the prevention and treatment of atherosclerosis. Show less

Genetic polymorphisms can modulate susceptibility to mercury (Hg) toxicity by altering metabolic and detoxification pathways. This review evaluated the association between genetic variants, Hg exposure, and obstetric outcomes. A systematic search of Scopus, PubMed and ScienceDirect through May 2025 identified 12 eligible studies ( Show less