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Aging and alcohol misuse independently alter monocyte (MO) and macrophage (MØ) function, leading to impaired antimicrobial responses. However, how alcohol misuse contributes to impaired MO/MØ function during aging remains unclear. We compared the transcriptomes of MOs and MØs from alcohol-modulated niches (liver, brain, and bone marrow [BM]) in young (3-month-old) and old (20-24-month-old) female C57BL/6N mice (n = 4-6 per group). Statistical significance was determined using two-way ANOVA. MO/MØ transcriptomes showed unique organ-specific responses to aging and alcohol. Aging elicited a common deregulation of pathogen-responsive pathways, while alcohol misuse commonly inhibited IFN signaling in the aged populations. Our studies on intercellular communication using ligand-receptor interactions revealed that BM MOs were the least communicative and liver MØs were the most communicative. Alcohol misuse specifically increased MO/MØ communication in aging. We also identified and validated specific pathways driving inter-organ MO/MØ crosstalk in alcohol misuse during aging, including APOE-TREM2 signaling from the liver to microglia and the NRXN2 and SPP1 pathways. Our results provide a unique insight into the heterogeneity of the MO/MØ transcriptome and define the inter-organ crosstalk between BM, liver, and brain during aging and alcohol misuse. Aging and alcohol misuse are linked to immune dysfunction, systemic inflammation, and altered innate immune responses. Here, we examined monocyte/macrophage responses in the liver, brain, and bone marrow of young and aged mice under alcohol exposure at the transcriptomic level. We observed that aging and alcohol predominantly elicited organ-specific changes in gene expression, with minimal overlap between the monocyte/macrophage populations across different tissues. However, aging commonly upregulated pathogen response pathways while alcohol misuse inhibited interferon signaling. We also assessed cell-cell communication by analyzing ligand-receptor expression in the different monocyte/macrophage populations and identified candidate molecules (APOE, TREM2, NRXN2, SPP1) from the top pathways guiding inter-organ signaling specifically in aging and alcohol misuse. Our findings have generated a unique repository and provide novel insights on how aging and alcohol impact tissue-specific monocytes/macrophages and their crosstalk. Show less

Atherosclerosis is a chronic vascular inflammatory disease caused by multiple factors. Anti-inflammatory treatment is an effective approach to treat atherosclerosis. Talin1 is a cell membrane-associated cytoskeletal protein that is widely expressed in mammals and plays essential roles in angiogenesis and endothelial cell barrier function. However, the role of Talin1 in atherosclerosis and the related mechanisms remains unclear. ApoE-KO mice were subjected to partial carotid artery ligation to establish an atherosclerosis model, and the expression of Talin1 in atherosclerotic plaques was verified in vivo. Human umbilical vein endothelial cells (HUVECs) and aortic endothelial cells (HAECs) were treated with tumour necrosis factor α (TNF-α) (10 ng/mL) and subjected to low oscillatory shear stress (OSS) (approximately ± 4 dyn/cm2) to establish cellular inflammation models. A lentivirus was used to regulate Talin1 expression in HUVECs and HAECs. Talin1 levels were increased in the serum of subjects with coronary heart disease (CHD) compared with those without CHD. We also found that Talin1 levels were increased in the serum of ApoE-KO mice in the operation group compared with the sham operation group. In addition, Talin1 expression was increased in endothelial cells in atherosclerotic plaques. In addition, neither TNF-α nor OSS promoted inflammation in endothelial cells with Talin1 knockdown. Moreover, we found that TNF-α and OSS could activate Piezo1 to mediate Ca²⁺ influx and subsequently activate Talin1 to regulate YAP and promote inflammation. The results of this study suggest that Talin1 plays a vital role in endothelial inflammation and may be a novel anti-inflammatory therapeutic target for atherosclerosis. Show less

Alzheimer's disease (AD) and dementia with Lewy bodies (DLB) are two of the most common neurodegenerative diseases in older adults, and both show well-documented sex-specific differences in terms of clinical presentation, prevalence, and progression trajectories. However, the underlying neurobiological substrates that underpin these differences are poorly understood. We conducted a literature search of PubMed for studies published between January 2000 and May 2025 examining sex differences in neuroimaging and biofluid markers of mild cognitive impairment (MCI), AD, and/or DLB. Eligible studies were required to include sex-stratified or sex-interaction analyses in human participants with clinically defined MCI (due to AD or DLB), AD, or DLB. Of a total of 261 articles imported for screening, 63 met inclusion criteria, comprising 50 cross-sectional and 13 longitudinal investigations across biofluid markers ( There is growing evidence that biological sex significantly influences the pathophysiology of AD and DLB as captured by Show less

Alzheimer's disease (AD) is characterized by inter-individual heterogeneity in brain degeneration, limiting diagnostic and prognostic precision. We present a novel framework integrating Morphometric Inverse Divergence (MIND) networks with hierarchical Bayesian large-scale population modeling to identify individual-level neuroanatomical deviations. MIND networks quantify similarity between brain regions using multivariate magnetic resonance imaging (MRI) features. A normative model of regional MIND values trained on UK Biobank (N = 35,133) was applied to the National Alzheimer's Coordinating Center cohort (N = 3,567). We examined brain deviations across clinical stages, apolipoprotein E (APOE) genotypes, mortality risk, and neuropathological burden. Negative deviations (reduced MIND) stratified disease stages (p < 0.01) and were concentrated in specific functional networks in AD. Greater negative deviations characterized APOE ε4 homozygotes and correlated with post mortem neuropathological severity (p = 0.032). Spatially, deviation patterns were associated with maps of neurotransmitter receptor density. This population neuroimaging modeling enables individualized brain mapping with direct utility for diagnosis, prognosis, and understanding of biological mechanisms. MIND networks were systematically integrated with normative modeling in AD. Negative deviations stratify clinical stages and correlate with neuropathology. Negative deviation count distinguishes APOE genotypes, highest in ε4 homozygotes. Deviations align with neurotransmitter maps. Individual brain maps enable precision medicine approaches in dementia. Show less

It is unclear whether the different Alzheimer's disease (AD) progression trajectories of apolipoprotein E (APOE) ɛ4 carriers is reflected by blood phosphorylated tau (p-tau) analytes. We assessed longitudinal trajectories in plasma p-tau181, 217, and 231, in amyloid beta-positive (A+) and negative (A-) APOE ɛ4 carriers (E+) or non-carriers (E-). We included 2039 participants from the observational Translational Biomarkers in Aging and Dementia (TRIAD) and Alzheimer's Disease Neuroimaging Initiative cohorts, categorized into 840 A-E-, 251 A-E+, 386 A+E4-, and 616 A+E4+. Longitudinal data were available for 1045 participants. In TRIAD, ALZpath p-tau217 (β = 0.45, p = 0.02) and p-tau217+ These findings suggest p-tau217 as a marker of faster progression in APOE ɛ4 carriers, highlighting its potential in disease stratification. Blood phosphorylated tau (p-tau)217 increases faster in apolipoprotein E (APOE) ɛ4 carriers with amyloid pathology. p-tau181 and p-tau231 do not increase faster in APOE ɛ4 carriers. APOE ɛ4 carriership does not change p-tau in individuals without amyloid pathology. Show less

Promising evidence indicates that treating hearing loss with hearing aids (HAs) could reduce dementia risk. We extend this evidence by investigating the effect of HAs on plasma biomarkers of Alzheimer's disease and related dementias (ADRD). We emulated two target trials using observational data from Australian participants of the ASPREE study. Eligible participants had self-reported hearing problems, no past HA use, and were dementia-free. HA prescriptions and frequency of HA use were measured by questionnaire. Phosphorylated-tau181 (pTau181), neurofilament light chain (NfL), glial fibrillary acidic protein (GFAP), and amyloid-β (Aβ) 42/40 were measured after approximately 6-8 years. We estimated the effect of new HA prescription (first target trial) and the frequency of HA use (second target trial) using targeted maximum likelihood estimation, with multiple imputation for missing data. Across imputed datasets, a median of 2842 eligible individuals were included (mean age 75 years, 48% female), with a median of 735 receiving a new HA prescription. Among survivors, the estimated mean differences comparing HA prescription and no HA prescription were 1.8 pg/mL (95% CI: -0.6, 4.1), 0.1 pg/mL (-7.8, 8.0), -2.2 pg/mL (-14.5, 10.1), and -0.7 (-2.6, 1.2) for the concentrations of pTau181, NfL, GFAP, and (Aβ42 × 1000)/Aβ40, respectively. Mean differences did not differ substantially across levels of potential baseline effect modifiers, including APOE-ε4 genotype and cognition. In community-dwelling older people with hearing loss and no dementia, we found minimal effects of HA prescription and frequency of HA use on plasma ADRD biomarkers after a 7-year follow-up. Show less

Evaluating prognostic performance of Alzheimer's biomarkers, multi-modal physiological measures, and clinical history in asymptomatic individuals versus established risk factors in asymptomatic individuals is can inform efficient screening strategies. To determine and compare the prognostic performance of amyloid biomarkers, multi-modal physiological measures, and clinical/modifiable risk factors We used clinical trials (A4/LEARN), longitudinal cohorts (ADNI, AIBL, HABS, NACC, OASIS), and the UK Biobank spanning 2004-2025 (median follow-up time range: 1.8-13.72 years) in time-varying survival and binary classification analyses. Settings included a United States clinical trial, longitudinal cohort studies spread across medical centers in the United States and Australia, and the volunteer-based UK Biobank. Patients were cognitively asymptomatic and age 65+ at baseline, and potentially progressed to either clinical impairment, clinical AD diagnosis, or incurred AD ICD-codes. Patients were volunteer or convenience samples. PTau-217, amyloid-PET, CSF markers (AB1-42, pTau-181, total-Tau), plasma proteomics, multi-modal brain-imaging, and cognitive tests were evaluated as predictors, along with demographics (age, sex, education), APOE genotype, and modifiable risk factors in the 2024 Lancet report PTau-217 and amyloid-PET from A4/LEARN were used to predict clinical impairment (CDR score of 0.5+ on two consecutive visits). PTau-217, amyloid-PET imaging across five cohorts, and CSF markers were used to predict clinical AD diagnosis. Plasma proteomics, multimodal neuroimaging, and cognitive assessments from the UK Biobank were used to predict AD ICD-codes. Sample-sizes ranged from 356-28,533 (31-519 cases; female percentages: 48.45-67.39). Models of demographics, APOE genotype, and risk-factors as predictors did not show statistically significant differences in time-dependent area under the receiver operating characteristic curve (AUROC) compared to separate models using amyloid biomarkers. Predicting cognitive impairment in A4/LEARN, pTau-217 improved AUROC by 0.045-0.084 (best: 0.616 (CI: 0.51-0.723) vs. 0.7 (CI: 0.609-0.793)). Amyloid-PET improved AD prediction (maximum AUROC increase 0.074; 0.561 (CI: 0.468-0.653) vs. 0.635 (CI: 0.537-0.733)), and CSF biomarkers showed slightly larger gains (maximum AUROC increase 0.127; 0.627 (CI: 0.438-0.816) vs. 0.754 (CI: 0.577-0.931)). In UK Biobank analyses, mean AUROC improvements were minor across proteomics (0.044), neuroimaging (0.143, with 99.8%/0.2% class-balance), and cognitive tests (0.064). In cognitively asymptomatic populations, biomarkers offer limited advantage over demographics, APOE genotype, and modifiable risk factors, supporting their importance in early AD screening strategies. Show less

Association studies have linked many genetic variants to a variety of phenotypes but understanding the biological mechanisms underlying these signals remains a major challenge. Since genes operate within complex networks, statistical interactions between genetic mutations that reflect biological pathways are expected to exist. However, their discovery has been hampered by the vast search space of variant combinations and the multiplicatively small expected effect sizes of interactions. To increase power, we created a test for interaction between single-nucleotide polymorphisms (SNPs) and Show less

Type 2 diabetes (T2D) is associated with cognitive decline, but the role of We analyzed 883 Brazilian adults with T2D (median age 68 years) from primary care, excluding those with dementia. Cognitive function was assessed using Mini-Mental State Examination (MMSE), and Show less

APOE is the greatest genetic risk factor for late-onset Alzheimer's disease (AD). In humans, APOE has three isoforms: APOE2 (E2), APOE3 (E3), and APOE4 (E4); E4 increases AD risk, while E3 is neutral and E2 decreases risk. In the brain, APOE is predominantly produced by astrocytes, where it binds lipids to form HDL-like particles, and plays a central role in lipid homeostasis, Aβ clearance, and neuroimmune modulation. Its lipidation state is critical for function, with E4 being poorly lipidated compared to E2 and E3, contributing to the pathogenic effects of E4 while also offering a potential therapeutic target. We have previously demonstrated that the HDL-mimetic peptide 4F increases APOE secretion and lipidation in wild-type mouse astrocytes and counteracts the inhibitory effects of Aβ42. Here, we assessed the ability of 4F to mitigate E4-associated dysfunction using primary astrocytes from humanized E3 and E4 knock-in mice and isogenic human iPSC-derived astrocytes and cerebral organoids. Results showed that 4F enhanced APOE secretion and lipidation in both cellular and organoid models in the absence or presence of aggregated Aβ42. Compared to E3 astrocytes, E4 astrocytes were prone to Aβ42-induced inhibition of APOE secretion and lipidation and increased accumulation of lipid droplets. 4F treatment ameliorated the inhibitory effects of Aβ42 and reduced lipid droplet accumulation. These findings support the therapeutic potential of HDL-mimetic peptides for E4-associated dysfunction in AD. Show less

Telomere length (TL), a biomarker of biological aging, but its association with Alzheimer's disease (AD) remains unclear. We estimated TL in whole-genome sequencing data from 35,014 Alzheimer's Disease Sequencing Project participants using TelSeq, which after quality control yielded a dataset including 6,973 persons of European ancestry (EA), 4,188 African Americans (AA), 4,005 Caribbean Hispanics (CH), and 4,170 Native American Hispanics (NAH). TL was log-transformed, adjusted for age and blood cell counts, and z-scaled. Scaled TL was dichotomized into long and short groups according to the median. An AD GWAS for the interaction of TL with variants having a minor allele count >20 was performed in each ancestry group using logistic regression models including SNP and TL main effects and a SNP×TL interaction term. AD risk was associated with shorter TL (β = -0.18, We identified variants that significantly impact AD risk through their interaction with TL, suggesting that TL maintenance pathways may be central to AD pathogenesis. Show less

Short-chain fatty acids (SCFAs) produced by gut microbial fermentation influence host metabolism and neuroinflammatory processes implicated in Alzheimer's disease (AD). However, the relationship between fecal SCFAs, microbial taxa, and cerebral amyloid-β (Aβ) burden in cognitively unimpaired individuals remains unclear. Fecal SCFAs were quantified using GC-MS, and microbial species were profiled by shotgun metagenomics in 87 participants. Associations between SCFAs, demographics, APOE ε4 status, and Aβ burden were tested using nonparametric statistics and multivariable regression. Microbial-SCFA links were evaluated using Spearman correlations and multivariate ordinations, with mediation analysis exploring potential indirect pathways. Acetate was the predominant SCFA and demonstrated the most robust microbial associations. Higher acetate concentrations were positively associated with Show less

Recent trials in Alzheimer's disease (AD) demonstrate encouraging outcomes. These trials target risk mechanisms identified through genetic analysis whilst directly aiming to reduce progression rates. Evidence from other neurodegenerative diseases suggests the genetics of progression is distinct from risk of disease. To expand these initial successes and improve clinical outcomes further we need to understand genetics of progression of disease. These can be deduced through rigorous analysis of meticulously phenotyped longitudinal cohorts. In this study we first looked at known genetic drivers of risk, namely polygenic risk scores for AD and A total of 387 individuals with, genetic data, amyloid positivity and in active decline (ADNI (n=222) and AIBL(n=165)) were used to perform generalised mixed effects linear model genome wide association studies of longitudinal cognitive decline as measured by mini mental state examination. The resulting summary statistics were subjected z, and colocalization analyses. Established AD risk factors, including These findings enhance our understanding of the biological underpinnings of AD progression, opening new avenues for therapeutic intervention. Show less

Atherosclerosis is a chronic inflammatory disease driven by dysregulated lipid metabolism and macrophage dysfunction. However, the role of An adenovirus encoding These findings demonstrate that The online version contains supplementary material available at 10.1186/s12944-025-02805-1. Show less

Cholesterol plays a crucial role in regulating synaptic membrane fluidity and ion channels. Due to the blood-brain barrier, cholesterol in the brain is primarily self-synthesized by astrocytes. However, limited research has been conducted on the effects of polystyrene nanoplastic (PS-NPs) on intracranial cholesterol metabolic pathways. In this study, we exposed whole-brain organoids (WBOs) to PS-NPs and identified significant changes in endoplasmic reticulum stress and cholesterol biosynthesis pathways through whole-transcriptome sequencing. To investigate potential mechanisms of altered cholesterol pathways, we constructed a Transwell neuronal-astrocyte co-culture model. Results demonstrated that PS-NPs induced significant endoplasmic reticulum stress in astrocytes, specifically manifested by elevated levels of ATF4 and CHOP, along with increased autophagy indicated by the elevated LC3-II/I ratio. PS-NPs significantly inhibited the AKT/ACLY pathway of cholesterol biosynthesis, leading to marked reductions in acetyl-CoA and cholesterol within astrocytes (P < 0.05). In addition, PS-NPs led to a significant reduction of apolipoprotein APOE, which hindered cholesterol transport and ultimately inhibited synaptin (SYN) formation. In summary, PS-NPs induce endoplasmic reticulum stress and autophagy in astrocytes, impair cholesterol de novo synthesis and apolipoprotein-mediated transport, ultimately inhibiting neuronal synaptogenesis. Furthermore, specific inhibition of ERs restored cholesterol synthesis in astrocytes and neuronal synapses. This study demonstrates that PS-NPs produce neurotoxic effects by affecting cholesterol homeostasis in the brain. Show less

Physical activity, grip strength, sedentary behaviors, and sleep duration were found to be associated with risk of developing stroke and dementia. However, the combined influence of these factors on stroke and dementia remains unclear. To investigate the combined influence of these multiple lifestyle and functional factors on risk of stroke and dementia and their subtypes and to investigate the potential interaction between combined factors and the apolipoprotein E gene ε4 allele ( Data were obtained from the UK Biobank, including 474,983 participants. A score ranging from 0 to 4 was assigned based on adherence to healthy factors: meeting physical activity recommendations, grip strength above the sex-specific median, sleep duration of 7–8 h/day, and sedentary time < 6 h/day. Cox proportional hazards models estimated hazard ratios (HRs) and 95% confidence intervals (CIs) for incident stroke and dementia, adjusting for potential confounders. Over a median follow-up of 10.1 years, 4,992 incident strokes and 2,120 dementias were recorded. Compared with participants with 0–1 healthy factor, adjusted HRs (95% CIs) for total stroke were 0.85 (0.79–0.92), 0.71 (0.66–0.77), and 0.65 (0.59–0.72) for those with 2, 3, and 4 healthy factors, respectively (P-trend < 0.001). Similar inverse associations were observed for ischemic stroke and intracerebral hemorrhage but not subarachnoid hemorrhage. For dementia, HRs (95% CIs) were 0.74 (0.66–0.83), 0.64 (0.56–0.71), and 0.43 (0.39–0.51) across increasing numbers of healthy factors ( The cumulative association of multiple healthy factors with reduced risk of stroke and dementia highlights the importance of adopting a lifestyle with more elements of healthy factors for the prevention of these neurological diseases. The online version contains supplementary material available at 10.1186/s12889-025-25305-4. Show less

We discovered and validated miRNA biomarkers for Alzheimer's disease (AD) in human cerebrospinal fluid (CSF). However, as more easily accessible biofluids are preferred for clinical assays, we compared the performance of the AD miRNAs in CSF to plasma to determine their potential use as AD biomarkers in this readily available biofluid. We obtained 320 donor- and date-matched normal control (NC) and AD CSF and plasma samples from the AD Neuroimaging Initiative, then analyzed 57 candidate AD miRNAs in both biofluids by RT-qPCR. For analysis, we divided the sample sets into 80% for discovery and 20% for validation. We then used predictive modeling of the 57 candidate AD miRNAs in the discovery phase to develop AD classifiers for each biofluid that showed similar performance in both CSF and plasma. However, in the validation phase AD classification performance was only maintained for the plasma models. When the plasma miRNA models were combined with clinical predictors (APOE genotype, age, sex, years of education) there was a boost in classification performance to a level comparable to the CSF proteins (Aβ Show less

Atherosclerosis (AS) is a prevalent chronic arterial disease characterized by excessive cholesterol accumulation in the arterial intima. While substantial progress has been made in elucidating its risk factors and pathogenesis, the upstream signaling molecules that drive the initiation and progression of AS remain poorly understood. Analysis of monocyte samples from the GSE23746 database revealed that Histone Deacetylase 6 (HDAC6) expression was significantly downregulated in patients with carotid atherosclerosis compared to healthy controls. In vitro experiments further demonstrated that HDAC6 deficiency markedly promotes foam cell formation in macrophages, a process dependent on its deacetylase activity. Mechanistically, HDAC6 interacts with signal transducer and activator of transcription 3 (STAT3) and regulates its acetylation at K685, a critical modification that facilitates macrophage foam cell formation. Specifically, the loss of HDAC6-mediated deacetylation leads to increased STAT3-K685 acetylation, which in turn upregulates the expression of CD36 and SRA, thereby enhancing cholesterol uptake in macrophages. Our findings establish HDAC6 as a protective regulator in atherosclerosis, which maintains lipid metabolic homeostasis by modulating the STAT3-CD36/SR-A axis. We also observed that systemic HDAC6 knockout exacerbated atherosclerotic progression in high-fat diet-fed ApoE Show less

Engagement in physical and cognitive activities is associated with a decreased risk of mild cognitive impairment (MCI) and dementia, but the association with Alzheimer disease (AD) neuroimaging biomarkers is less clear. We thus examined associations of physical and cognitive activities with longitudinal trajectories of AD neuroimaging biomarkers among older adults free of dementia. We conducted a longitudinal study within the population-based Mayo Clinic Study of Aging (mean follow-up durations 1.3-3.4 years). Participants were aged 50 years or older and were cognitively unimpaired or had MCI at baseline. Engagement in physical and cognitive activities during 12 months before baseline was assessed through questionnaires. Participants underwent AD neuroimaging biomarker assessments at 1 or more time points. We ran linear mixed-effect models to examine associations between physical and cognitive activity composite scores and trajectories of individual yearly change in amyloid deposition (Pittsburgh compound B [PiB]-PET centiloid), tau burden (tau-PET standardized uptake value ratio [SUVR]), and regional glucose hypometabolism (fluorodeoxyglucose [FDG]-PET SUVR), adjusted for age, sex, We included 1,176 participants (47% female; mean [SD] age, 68.7 [9.6] years) for PiB-PET trajectories, 399 participants (49% female; mean [SD] age, 71.9 [11.0] years) for tau-PET trajectories, and 983 participants (46% female; mean [SD] age, 67.9 [9.2] years) for FDG-PET trajectories. PiB-PET and tau-PET measures increased during follow-up (3.4 [SD 4.0] and 1.3 [SD 2.1] years, respectively), whereas FDG-PET values decreased over 2.9 (SD 3.5) years of follow-up. Participants with higher total physical activity (interaction estimate 0.0017; 95% CI 0.0003-0.0031; Physical activity was associated with less synaptic dysfunction and cognitive activity with less synaptic dysfunction and lower amyloid burden over time, albeit effect sizes were small. Further research is needed to validate findings and clarify causal inference between physical and cognitive activities and AD neuroimaging biomarkers. Show less

Lipids play a critical role in atherosclerosis. Low-density lipoprotein (LDL)-cholesterol and certain lipid classes like sphingomyelins are associated with inflammation and poor cardiovascular outcomes. Phosphatidylserine (PS), on the other hand, is a negatively charged anti-inflammatory phospholipid class involved in efferocytosis. In this study, we sought to investigate its anti-atherosclerotic properties through a combination of complementary human lipidomics analyses, Human lipidomics studies were performed on the 300OB cohort comprising 300 obese and overweight individuals at risk of cardiovascular disease. In humans, we identified PS as an anti-inflammatory and atheroprotective biomarker. Hence, we developed a high-density lipoprotein (HDL)-like formulation enriched in PS to exploit its properties in a targeted fashion in mice. Collectively, our results demonstrate that HDL-associated PS potently suppresses inflammation and atheroprogression, and holds promise as a viable approach to improve immunomodulatory therapies. Show less

Physical activity (PA) has been associated with reduced Alzheimer's disease (AD) risk, but whether protective effects vary across genetic risk levels remains unclear. Previous studies were limited by self-reported PA measures and simplified genetic models. In this study, we aimed to examine the association between accelerometer-measured physical activity and the risk of incident AD in a large population-based cohort, and to explore potential interactions between PA and polygenic risk scores for AD. We analyzed 93,578 UK Biobank participants aged 40-70 years with accelerometer data and genome-wide genotyping. PA was measured continuously (milligravity, mg) and dichotomized at the optimal point from maximally selected rank statistics. Genetic risk was assessed using polygenic risk scores (PRS) and APOE ε4 status. Cox models estimated hazard ratios for incident AD across genetic risk strata during median 15.5-year follow-up. Among 401 AD cases, high PA reduced risk by 48% (HR 0.517; 95% CI 0300-0.891), while high PRS increased risk nearly twofold (HR 2.423; 95% CI 1.757-3.343). PA's protective association remained consistent across all PRS and APOE ε4 strata. No significant multiplicative or additive interaction was found between PA and genetic risk (RERI = - 0.566, 95% CI - 4.574-3.441). Dose-response analysis revealed maximum benefit with optimal threshold at 21.7 mg corresponding to light-intensity activity. Objectively measured PA substantially reduces AD risk regardless of genetic predisposition. Even light-intensity activity provides meaningful protection, supporting PA as a broadly applicable preventive strategy across all genetic risk levels. Show less

Neuroinflammation is central to Alzheimer's disease (AD) pathogenesis, yet its contribution to region-specific brain atrophy remains unclear. We examined whether cerebrospinal fluid (CSF) biomarkers predict longitudinal atrophy in the hippocampus and basal forebrain and mediate the impact of AD pathology. Data from 227 DELCODE participants with baseline CSF measures and longitudinal structural MRI were analyzed. Four latent factors (synaptic, microglia, chemokine/cytokine, complement) were derived to capture shared variance across biomarkers. Latent factors represent unobserved biological domains inferred from related CSF markers. In addition, four single biomarkers (neurogranin, sTREM2, YKL-40, ferritin) were tested separately. Regional atrophy rates were estimated using linear mixed-effects models including biomarker × time, A/T classification, diagnosis, and covariates (age, sex, education, ApoE-ε4). Individual slopes were then entered into mediation models. Higher synaptic latent factor (β = - 0.019, pFDR = 0.021) and YKL-40 (β = - 0.020, pFDR = 0.025) significantly predicted hippocampal atrophy. Only these two markers remained significant after correction for multiple comparisons. Mediation analyses revealed significant indirect effects of the synaptic latent factor and YKL-40 on hippocampal atrophy across all A/T groups. No biomarker was associated with basal forebrain atrophy (pFDR > 0.05). Latent factors captured shared biological variance across related biomarkers and provided a more robust representation of underlying biological domains than single biomarkers. This approach identified synaptic dysfunction and astroglial activation as key links between AD pathology and hippocampal neurodegeneration. These findings highlight synaptic and glial pathways as promising targets for disease-modifying interventions. Show less

This study aimed to perform a Meta-Analysis based on GWAS data and utilized them for multi-step analyses. Final data included 1,198,682 subjects (255,810 cases and 942,872 controls) in 26 studies among 11 ethnicities. R package utilized for GWAS Meta-Analysis, a Primary Gene List (PGL), and then a Secondary Gene List (SGL) were generated. All of the in-depth silico, systems biology, and Pharmacogenomics (PGx) analyses were performed by STRING-MODEL, miRTargetLink2, NetworkAnalyst, Enrichr, and PharmGKB. The cumulative effect size in a random effects model for the risk of AD was 1.55 [95% CI: 1.41-1.71]. APOE, APP, SPI1, hsa-miR-17-5p, hsa-miR-155-5p, hsa-miR-340, hsa-miR-125b, hsa-miR-199a-3p, hsa-miR-199a-5p, and hsa-miR-1908-5p, SP1, MYC, MAX, E2F1, Valproic acid, and Tretinoin were the most significant findings. According to the Enrichment Analysis, Immune System R-HSA-168,256 (q-value = 5.85E-07) and Amyloid Fiber Formation R-HSA-977,225 (q-value = 1.57E-05) were the most significant pathways. Amyloid-Beta Binding (GO:0001540) (q-value = 3.64E-04) in molecular function were among the most significant GOs. DDAs found Alzheimer Disease (q-value = 8.72E-45) with the highest incidence. PGx approaches, uncovered 40 potential annotations, among them, two annotations of rs429358 (APOE) were both directly associated with AD. Briefly, almost all of the findings presented in this study are supported by prior reports along with new findings. Show less

Mitochondria play an essential role in regulating various physiological functions including bioenergetics, calcium homeostasis, redox signaling, and lipid metabolism and also are involved in the pathogenesis of cardiovascular diseases. However, the relationship between mitochondrial calcium homeostasis in vascular smooth muscle cells (VSMCs) and atherosclerosis remains poorly understood. Here, we demonstrate that cholesterol induces mitochondrial calcium overload and lipid accumulation in VSMCs, which is resulted from dysregulation of mitochondrial calcium uniporter (MCU), as evidenced by genetic and pharmacologic inhibition of MCU. Furthermore, MCU inhibitors alleviate Western diet-induced atherosclerosis in ApoE-/- mice. Mechanistically, high-fat and high-cholesterol diets induce the contact between mitochondria and the endoplasmic reticulum (ER) in VSMCs as indicated by transmission electron microscopy, proximity ligation assay and immunofluorescence staining, which increases the formation of mitochondria-associated membranes (MAMs), leading to Ca2 + release from the ER into the mitochondria and thus elevating Ca2 + in the mitochondria. Using mitochondrial calcium uptake 1 (MICU1) mutant and Ca2 + detection assay, we confirmed that this increased Ca2 + binds to MICU1, a blocker of MCU, to impair its ability to block MCU, thus enabling the MCU to remain open and resulting in mitochondrial calcium overload. Further, mitochondrial calcium overload dysregulates fatty acid β-oxidation by modulating medium-chain acyl-CoA dehydrogenase (ACADM), thereby leading to lipid deposition. The inhibition of MCU alleviates the pathological changes elecited by cholesterol. Our findings unveil the previously unrecognized role of MAM-MICU1-MCU axis in cholesterol-induced mitochondrial calcium overload and atherosclerosis, indicating that MCU represents a promising therapeutic target for the treatment of atherosclerosis. Show less

Mild cognitive impairment (MCI) is a cognitive decline syndrome in the elderly, often a precursor to dementia. It is a heterogeneous condition that can signal degenerative disorders like Alzheimer's or non-degenerative conditions such as vascular issues, depression, or poorly managed diabetes. Early detection of MCI is crucial for timely intervention, and differentiating its phenotypes helps in understanding its causes, progression, and treatment. EEG, which records brain electrical activity, consists of rhythmic and arrhythmic components. Examining these inherently overlapping EEG components calls for quantification, ensuring that an appropriate physiological mechanism is attributed to a given neural response. This study explores the interaction between APOE ε4 (APOE4) and cognitive impairment on non-oscillatory EEG activity. We examined aperiodic EEG activity using a parameterized spectral estimation approach in a sample comprising 751, 142, and 279 cognitively normal (CN), non-amnestic (naMCI), and amnestic (aMCI) MCI patients, respectively. The 5-min EEG was recorded using a prefrontal two-channel EEG device in a resting state, eyes closed. Cognitive decline was assessed using the Seoul Neuropsychological Screening Battery (SNSB) and the Mini-Mental State Examination (MMSE). The analyses were performed using various statistical methods, including independent We found interactions between APOE4 and cognitive states in the aperiodic EEG exponent and the spectral power ratio (SPR). Distinct patterns were observed in the exponent, offset, and SPR between APOE4 non-carriers and carriers across the CN, naMCI, and aMCI. Among the APOE4 carriers, the aMCI individuals exhibited heightened aperiodic activity and a reduced SPR than the naMCI. Furthermore, the CN had a lower SPR compared to the naMCI. However, no differences in the aperiodic component and SPR were observed in the APOE4 non-carriers across the cognitive states. The higher aperiodic component and a reduced SPR observed in aMCI relative to naMCI in APOE4 carriers may indicate an interplay between genetic predisposition, neuropathological changes, and cognitive decline. These aperiodic components, combined with APOE4 status, represent promising neurophysiological markers that may help identify individuals at elevated risk for cognitive decline or progression toward AD. Show less

To explore neurodynamic bases underlying subjective cognitive decline (SCD) based on edge-centric functional network. 211 SCD patients and 210 healthy controls (HC) were recruited from the Alzheimer's Disease Neuroimaging Initiative. Edge time series (ETS) were obtained based on resting-state functional magnetic resonance data. The top 10% co-fluctuation signals of all time points in ETS were extracted to construct the high-amplitude frame networks, and the co-fluctuation signals from the remaining time points were used to construct the low-amplitude frame networks. In both network states, the graph theory and network-based statistics (NBS) analyses were used to compare SCD and HC. The correlation of the imaging indicators with cognitive scores and apolipoprotein E (APOE) ε4 genes was performed by Spearman correlation analysis. SCD exhibited lower peak amplitude and longer trough-to-trough duration (TTD) compared to HC. In both network states, the normalized clustering coefficient, normalized characteristic path length, small-worldness, and global efficiency of SCD were significantly reduced, and the altered nodal centralities of SCD predominantly exhibited a decreasing trend. However, the high-amplitude frame network identified more altered brain regions compared to the low-amplitude frame network. Furthermore, a SCD-related subnetwork was found in the high-amplitude frame network, which was composed of 11 brain regions and 13 edges. TTD was positively related to the number of APOE ε4 genes; the normalized characteristic path length, the betweenness centrality of right postcentral gyrus, and the connection between bilateral angular gyrus were correlated with cognitive scores. Our findings demonstrate that the edge-centric network framework reveals details of brain network alterations in SCD through different perspectives, and these alterations hold potential as novel biomarkers for SCD. Show less

Many patients are suffering from atherosclerosis without typical risk factors, which can cause severe cardiovascular complications. Trimethylamine N-oxide (TMAO), derived from gut microbes, is a key unconventional contributor to the development of atherosclerosis. Here we present a strategy performed by orally administered nano-functionalized probiotics (PDMF@LGG) to inhibit TMAO through the gut microbiota-trimethylamine (TMA)-TMAO axis. PDMF@LGG, composed of polydopamine-coated Lacticaseibacillus rhamnosus GG and nanoparticles based on a reactive oxygen species (ROS)-responsive polymeric prodrug of fluoromethylcholine (FMC), can promote the retention of probiotics and nanoparticles in the intestine to persistently scavenge elevated ROS and release drugs. This process suppresses TMA production and absorption, lowering plasma TMAO levels. The therapeutic effects on male ApoE Show less

Neuroprotective properties of estrogen have poorly translated to reduced neurodegeneration in clinical trials of systemic estrogen replacement therapy. To more directly assess biological processes associated with brain estrogen (estrone, estradiol) levels, we recruited 81 women (42 non-white) and 28 men (13 non-white) for cerebrospinal fluid (CSF) hormone, targeted proteomic, and volumetric brain analysis. In the mostly post-menopausal women, we found CSF estrogen levels to only modestly correlate with their corresponding plasma levels, and were additionally influenced by body mass index or age. CSF estrone was also correlated with a marker of Alzheimer’s disease (AD) neuropathologic change (CSF Aβ42/Aβ40), but this was not the case for the more biologically active CSF estradiol. Aptamer-based proteomic analysis of 1,075 CSF markers for inflammation, proteolysis, signaling, and DNA/RNA regulation revealed CSF estrogen levels to associate with alternative complement pathway proteins, and shifts observed in AD (apoE, RAGE). Parallel MRI analysis correlated higher CSF estrogen with smaller volumes of the brain somatosensory and posterior-medial networks without influence from cognition or neurodegeneration. Analysis using plasma estrogens only partially reproduced CSF estrogens’ biochemical correlates but provided inconclusive relationships with brain volume correlates. These findings highlight the association between CSF levels of the more biologically active estradiol and CSF inflammatory pathways involving AD risk genes as potential mechanisms linking hormone status to AD risks, and suggest caution in using CSF estrone or plasma estrogens when interpreting treatment or preventive studies. The online version contains supplementary material available at 10.1186/s12974-025-03657-3. Show less

The APOE4 variant was the strongest genetic risk factor for sporadic Alzheimer's disease (AD). Individuals with APOE4 have an increased risk of developing the disease at an early age of onset. Similarly, APOE4 carriers are predisposed to high cholesterol levels and tend to have an increased risk of cardiovascular disease (CVD). The global allele frequency of APOE4 was 13.7%, underlining its widespread impact on global human health. Conversely, the relatively rare APOE2 allele was a genetic protective factor against AD and CVD. However, the mechanisms underlying this association remain to be elucidated. The apolipoprotein E (APOE) protein coats lipoprotein particles and mediates lipid transport and metabolism in the peripheral circulation and central nervous system (CNS). Although initial studies causally linked APOE lipoprotein particles (APOE particles) with lipid homeostasis, our understanding of the physiological and pathological effects of APOE particles has extended to amyloid-β (Aβ) accumulation, tau hyperphosphorylation and spread, as well as neuroinflammation in AD initiation and progression. Moreover, the most examined functions of APOE particles are reverse cholesterol transport, anti-inflammatory, anti-oxidation, and improvement of endothelial dysfunction in atherosclerotic CVD. This review outlines what is known about the structure and functions of APOE particles, emphasizing their involvement in AD and CVD pathogenesis, while also considering the crosstalk between the peripheral circulation and CNS. In addition, we discuss how these APOE particles act as therapeutic targets. Show less