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Alzheimer's disease (AD) is a progressive neurodegenerative disorder marked by decreased amyloid-beta (Aβ) clearance, enhanced Aβ aggregation, an increased risk of amyloid-related imaging abnormalities (ARIA), and blood-brain barrier (BBB) dysfunction. The Show less

Previous studies have shown that plasma amyloid-beta oligomers (AβOs), the toxic form of amyloid-beta (Aβ), are a critical issue in the development or worsening of Alzheimer's disease (AD) and can be regarded as a blood marker for screening in dementia. We examined plasma AβOs with their related biomarkers in a case-control study to clarify these issues. A total of 16 patients diagnosed with Alzheimer's dementia (AD) and 16 cognitively normal controls (NCs) were recruited to compare their plasma biomarkers, AβO, Aβ Show less

Apolipoprotein E (APOE) epsilon4 (ε4) is a major genetic risk factor for late-onset Alzheimer's disease (AD), with women exhibiting heightened vulnerability to APOE ε4-associated cognitive impairment. Despite recognition of this sexual dimorphism, the underlying biological mechanisms remain incompletely understood. We performed weighted gene co-expression network analysis (WGCNA) on RNA-seq data from the Mayo Clinic cohort ( Four co-expression modules ( we reveal a female-specific APOE ε4-driven molecular network linking endothelial dysfunction to tau pathology. These hub genes provide potential biomarkers, while vincamine represents a targeted prevention and therapeutic candidate for high-risk APOE ε4-positive women. Show less

Driving integrates multiple cognitive, sensory, and motor systems and may serve as a real-world indicator of functional decline in aging. Older adults with mild cognitive impairment (MCI) often experience subtle driving changes before formal dementia diagnosis, but longitudinal, real-world evidence is limited. This study examined whether naturalistic driving data can differentiate older adults with MCI from those with normal cognition (NC) over time and evaluated the discriminative ability of driving features compared with conventional risk factors. We conducted a prospective, observational cohort study of community-dwelling older drivers enrolled in the Driving Real-World In-Vehicle Evaluation System Project at Washington University. Participants underwent annual Clinical Dementia Rating assessment, neuropsychological testing, and apolipoprotein ε4 (APOE ε4) genotyping. Driving behaviors were captured daily for up to 40 months using global positioning system-enabled in-vehicle dataloggers, recording trip frequency, duration, distance, time of day, speeding, hard braking, and spatial mobility (entropy, maximum distance, radius of gyration). Longitudinal changes were analyzed using linear mixed-effect models, adjusting for age, sex, race, education, and APOE ε4. Logistic regression with reciever operator curve analysis evaluated discrimination between older adults with MCI and those with NC, compared with conventional sociodemographic and genetic markers. Among 298 participants (MCI, n = 56; NC, n = 242; mean age 75.1 years; 45.6% female), the groups were similar in age, sex, race, and APOE ε4 status at baseline, as well as in most driving behaviors. Over time, drivers with MCI showed greater reductions in monthly trip count (MCI: -0.501, standard error [SE]: 0.21, 95% CI [-0.923 to -0.083] vs NC: -0.523, SE: 0.09, 95% CI [-0.709 to -0.337]; MCI was associated with progressive declines in driving frequency, complexity, and spatial range, supporting naturalistic driving data as a potential unobtrusive digital biomarker for early cognitive decline. Limitations of the study include a predominantly White, highly educated sample and a lack of external validation, warranting cautious interpretation. Continuous monitoring could augment clinical assessments, inform driving safety decisions, and guide interventions to preserve mobility in aging. Show less

The activation of blood monocytes and the infiltration of monocyte-derived macrophages into the vessel walls are the central part of atherosclerosis. However, the mechanisms underlying the processes remain unclear. Here, we report that G-protein signaling modulator 1 (GPSM1) plays a critical role in atherogenesis. We found that GPSM1 expression in lesional macrophages was increased during atherosclerosis development both in mice and humans. Myeloid-specific GPSM1 ablation protects mice against atherosclerosis and reduces aortic inflammation in both Show less

Early diagnosis of Alzheimer's disease (AD), particularly during its preclinical and prodromal phases, remains a major challenge. Plasma biomarkers such as phosphorylated tau at threonine 217 (p-tau217), amyloid-β (Aβ) isoforms, neurofilament light chain (NfL), and glial fibrillary acidic protein (GFAP) show promise for early detection; however, their relationships with medial temporal lobe (MTL) subfield atrophy and potential inter-biomarker pathways remain unclear. This study aimed to address this gap by investigating the associations between plasma biomarkers and MTL subfield atrophy, and by assessing potential mediation pathways. We conducted a cross-sectional study using data from 330 participants in the Alzheimer's Disease Neuroimaging Initiative (ADNI), including cognitively normal (CN) and mild cognitive impairment (MCI) groups. High-resolution coronal T2-weighted MRI quantified MTL subfield volumes using the ASHS protocol. Plasma biomarkers were measured using ultrasensitive immunoassays. The cohort included 209 CN participants (mean age [SD] = 69.3 [6.9] years; 64.2% women; 24.4% APOE ε4 carriers) and 121 MCI participants (mean age [SD] = 71.3 [7.3] years; 48.8% women; 27.9% APOE ε4 carriers). MCI individuals showed significantly higher plasma concentrations of p-tau217, p-tau217/Aβ Show less

This study evaluates photon-counting CT (PCCT) for the imaging of mouse femurs and investigates how APOE genotype, sex, and humanized nitric oxide synthase (HN) expression influence bone morphology during aging. A custom-built micro-CT system with a photon-counting detector (PCD) was used to acquire dual-energy scans of mouse femur samples. PCCT projections were corrected for tile gain differences, iteratively reconstructed with 20 µm isotropic resolution, and decomposed into calcium and water maps. PCD spatial resolution was benchmarked against an energy-integrating detector (EID) using line profiles through trabecular bone. The contrast-to-noise ratio quantified the effects of iterative reconstruction and material decomposition. Femur features such as mean cortical thickness, mean trabecular spacing (TbSp_mean), and trabecular bone volume fraction (BV/TV) were extracted from calcium maps using BoneJ. The statistical analysis used 57 aged mice representing the APOE22, APOE33, and APOE44 genotypes, including 27 expressing HN. We used generalized linear models (GLMs) to evaluate the main interaction effects of age, sex, genotype, and HN status on femur features and Mann-Whitney U tests for stratified analyses. PCCT outperformed EID-CT in spatial resolution and enabled the effective separation of calcium and water. Female HN mice exhibited reduced BV/TV compared to both male HN and female non-HN mice. While genotype effects were modest, a genotype-by-sex stratified analysis found significant effects of HN status in female APOE22 and APOE44 mice only. Linear regression showed that age significantly decreased cortical thickness and increased TbSp_mean in male mice only. These results demonstrate PCCT's utility for femur analysis and reveal strong effects of sex/HN interaction on trabecular bone health in mice. Show less

Olfactory impairment is common in older age and is a known early feature of several dementia diseases. Blood-based biomarkers of Alzheimer's disease (AD) now offer a scalable method for detecting pathophysiological mechanisms related to olfactory decline in the general population. However, few studies have examined how these biomarkers relate to long-term olfactory trajectories. Most existing work has been limited to cross-sectional settings. In this population-based study, we used biomarker data collected at baseline and followed participants for up to 15 years, enabling us to test whether early biological changes are temporally linked to subsequent olfactory decline. Data came from the ongoing Swedish National Study on Aging and Care in Kungsholmen (SNAC-K), a longitudinal population-based study with baseline assessments from March 21, 2001, through August 30, 2004. We included participants without prevalent neurodegenerative diseases who completed olfactory assessment at baseline. The 15-year follow-up was finished in December 2019. Data were analysed from December 2023 to April 2024. Serum-derived biomarkers of tau phosphorylated at threonine 217 (p-tau217) and at theorine181 (p-tau181), total tau (t-tau), amyloid-β ratio (Aβ42/Aβ40), neurofilament light chain (NfL), and glial fibrillary acidic protein (GFAP) were obtained at baseline. Linear mixed models examined associations between biomarker quartiles and Sniffin' Sticks odor identification performance over 15 years, adjusting for demographics, health conditions, and semantic knowledge. We included 1868 participants (mean [SD] age 71.3 [9.9] years; 1122 females [60.1%]). In fully adjusted models, higher quartiles of p-tau217, p-tau181, NfL, and GFAP, and lower quartiles of Aβ42/Aβ40, were associated with steeper olfactory decline, with the steepest decline among participants in the highest quartiles (β for Q4 vs Q1: -0.20 [95% CI: -0.26 to -0.15] for p-tau217; -0.19 [95% CI: -0.25 to -0.13] for p-tau181; -0.23 [95% CI: -0.29 to -0.17] for NfL; β = -0.17 [95% CI: -0.23 to -0.11] for GFAP. Participants in the lowest Aβ42/Aβ40 quartile declined more steeply than those in the highest (β = -0.09 [95% CI: -0.14 to -0.04]). Associations appeared stronger in the oldest participants, in APOE ε4 carriers for p-tau181, in non-carriers for NfL and GFAP, and among former smokers for NfL. Blood-based biomarkers of AD were consistently associated with faster olfactory decline in older adults, particularly in the highest biomarker quartiles. These results provide large-scale longitudinal evidence, across up to 15 years of follow-up, that olfactory decline in the general population is linked to AD-related blood biomarkers, supporting the hypothesis that common olfactory losses in ageing partly reflect dementia-related processes. Show less

Subjective cognitive decline (SCD) serves as an initial symptom of preclinical Alzheimer's disease (AD). The accumulation of amyloid-beta (Aβ) is acknowledged as a critical risk factor for the eventual progression to mild cognitive impairment or dementia in individuals with SCD, highlighting the necessity for early detection and intervention. Previous studies have identified the retina and choriocapillaris as potential biomarkers for AD; however, these investigations have not thoroughly examined large and medium-sized choroidal vessels. Ultra-wide swept-source optical coherence tomography angiography (SS-OCTA), an innovative noninvasive imaging modality, facilitates rapid and precise quantitative assessment of retinal and choroidal boundaries and vasculature through dynamic scanning, encompassing large and medium-sized choroidal vessels. This study aims to characterize the outer retinal and choroidal vasculature and structure in individuals with SCD, examine the correlation between altered choroidal vasculature parameters and amyloid burden, and the presence of the apolipoprotein E (APOE) ε4 allele in SCD participants, to identify potential ocular biomarkers for high-risk SCD screening. In this study, 57 individuals with SCD and 45 matched normal controls were enrolled. Ultra-wide SS-OCTA was employed to assess the thickness of the outer retina and choroid and the blood flow within the choriocapillaris and large, medium-sized choroidal vessels. Show less

Sub-optimal metabolism is linked to dementia risk, yet metabolic traits rarely occur in isolation. Using data from 308,019 UK Biobank participants, we examined associations of six diverse metabolic subgroups (I-VI) - previously derived via a self-organising map (SOM) that captures patterns of co-occurring metabolic biomarker traits in the population - and 39 individual biomarkers, with incident all-cause dementia, Alzheimer's disease (AD), and vascular dementia (VaD). Biomarker associations were assessed using both linear and nonlinear (restricted cubic spline) models. After adjusting for age, sex, socioeconomic, and lifestyle factors, subgroup analyses showed that participants in the two leanest and two most adipose subgroups had higher risk of dementia outcomes compared to others. Subgroups with high adiposity exhibited elevated VaD risk, which was linked to hypertension, hyperglycaemia, and liver stress (Subgroup II); inflammation, microalbuminuria, and low apolipoprotein A1 (III). For AD, the risk was elevated in the lean subgroups (IV, V), characterised by low body mass index (BMI), triglycerides, and urate, and high sex-hormone binding globulin; as well as for adipose Subgroup II. APOE-ε4 allele count had limited influence on dementia associations with metabolic subgroups and biomarkers. This marked metabolic heterogeneity in dementia risk suggests that metabolic profiling could inform targeted prevention strategies. Interpretation of these findings is supported by previously reported MRI profiles of the metabolic subgroups, providing biological context. Show less

We test the hypothesis that high levels of neuroplasticity in the context of Alzheimer's disease (AD) risk factors are involved in AD pathogenesis by investigating interactions between cerebrospinal fluid (CSF) levels of growth-associated protein-43 (GAP-43) and AD risk factors (female sex, cerebrovascular risk, mild cognitive impairment, apolipoprotein E [APOE] ε4 genotype, amyloid positivity) on CSF biomarkers of AD pathology (amyloid beta 42/40[Aβ42/40], phosphorylated tau (p-tau)) and neurodegeneration (tau). Baseline GAP-43 levels in 161 non-demented older adults were related to cross-sectional and longitudinal (mean follow-up = 4 years) CSF biomarkers of AD, adjusting for covariates, with GAP-43 x AD risk factor interaction terms. Higher GAP-43 was cross-sectionally related to all AD biomarkers (p-values < 0.0001) and predicted longitudinal reductions in Aβ42 (p < 0.0001). Associations were stronger in AD risk groups. We found strong support linking increased levels of neuroplasticity in the context of AD risk factors to the pathological cascade of AD over a 4-year mean follow-up period. Cerebrospinal fluid growth-associated protein-43 (GAP-43) is associated with Alzheimer's disease (AD) biomarkers cross-sectionally and longitudinally. GAP-43 interacts with AD risk factors to predict AD biomarkers. Increased neuroplastic activity may play a role in AD pathogenesis. Show less

The repertoire of adhesion receptors and ligands is supported by molecules, which are primarily recognized for their roles in immunity. We have recently shown that the co-stimulatory molecule CD40 ligand (CD154/CD40L) is pro-atherogenic and serves as an adhesive ligand for cells expressing the integrin Mac-1 (CD11b/CD18). Here, we studied the role of endothelial CD40L in several models of cardiovascular inflammation. We generated mice with an endothelial cell-specific deficiency of CD40L, Bmx-Cre In this functional validation study, we demonstrate that endothelial cell-expressed CD40L serves as an adhesion molecule in different models of acute inflammation in the aortic, peritoneal, mesenteric, and coronary vasculature. CD40L may therefore represent a promising therapeutic target at the interface of adaptive immunity and myeloid inflammation. Show less

Perform a large-scale Meta-analysis of Genetic data available from high-density single-nucleotide polymorphism (SNP) microarrays and whole-genome sequencing (WGS). Single-nucleus (sn) RNA-seq data from dorsolateral prefrontal cortex. 567,521 eligible participants for AD genetic association studies were selected from referred and volunteer samples, of which 119,852 were excluded for analysis exclusion criteria. 67 and 17 significant cell-type-gene pairs were identified in We identified a set of Show less

Extensive research has demonstrated that gut microbiota and its metabolites-including short-chain fatty acids, trimethylamine N-oxide (TMAO), and bile acids-play a crucial role in the pathophysiology of coronary artery disease (CAD).The bidirectional interaction between the gut microbiota and the cardiovascular system significantly influences host metabolic and inflammatory homeostasis. As a result, targeted modulation of the gut microbiota emerges as a promising adjunctive therapeutic strategy for CAD, offering potential benefits with minimal side effects. This study aims to elucidate the therapeutic mechanisms of the clinically validated Chinese medicine formula HJ11 in mitigating coronary heart disease (CHD), with a particular focus on its regulation of the heart-gut axis and associated atherosclerotic processes. This study established an ApoE-/- mouse model of atherosclerosis and treated with HJ11 via gavage.We investigated the effects of HJ11 on the gut microenvironment in these atherosclerotic mice. Gut microbial composition and faecal metabolite profiles were analyzed using 16S rDNA sequencing and metabolomics. Additionally, an in vitro model of atherosclerosis was used to examine whether HJ11 exerts anti-inflammatory effects by modulating the TLR4/MYD88/IκB-α signaling pathway. HJ11 exerted protective effects on coronary atherosclerosis by reducing systemic serum lipid levels and inhibiting plaque formation, vascular inflammation, and collagen deposition, while also alleviating aortic injury. It suppressed endothelial inflammation and inhibited the proliferation of vascular smooth muscle cells. In the gut, HJ11 alleviated intestinal structural damage and enhanced barrier integrity. Notably, it promoted the function of Akkermansia, a beneficial bacterium known to influence TLR4 expression. Finally, in an in vitro atherosclerosis model, HJ11 decoction inhibited cell proliferation and migration by inactivating the TLR4/MYD88/IκB-α signaling pathway-an effect that was abolished by TLR4 overexpression. Show less

The ocular surface microbiome (OSM) in patients with meibomian gland dysfunction (MGD) differs from that of healthy individuals. However, the precise role of OSM in MGD remains unknown. Therefore, we aimed to investigate the mechanism of OSM in the inflammation of MGD and the effects of topical sodium butyrate (SB) treatment in ApoE ApoE Five-month-old ApoE ApoE Show less

Progression in Alzheimer's disease (AD) involves three main interrelated biological axes-tau deposition, neurodegeneration, and neuroinflammation-that jointly drive cognitive decline. Although several cerebrospinal fluid (CSF) and plasma biomarkers along these axes are well validated for diagnosis, their value for prognosis remains uncertain. We assessed how baseline markers of each axis predict cognitive trajectories in biomarker-confirmed AD. We included 136 A + T + N + individuals (median follow-up = 24 months [IQR 12-24]; mean = 17.6 months [SD = 12.4]). Tau-deposition markers (CSF p-Tau181; plasma p-Tau181 and p-Tau217), neurodegeneration markers (CSF t-Tau; CSF and plasma neurofilament light chain, NfL) and a neuroinflammation marker (plasma glial fibrillary acidic protein, GFAP) were quantified using CLEIA, ELISA or Simoa, and stratified into tertiles. Participants were classified by age at onset, clinical phenotype, and APOE ε4 status. Cognition was assessed annually with a comprehensive neuropsychological battery. Linear mixed-effects models (MMRM) were used to test biomarker-cognition associations and interactions with clinical variables. Elevated CSF p-Tau181 and NfL levels were associated with greater decline in memory and executive function. Among plasma biomarkers, p-Tau217 and GFAP showed the strongest associations with widespread cognitive decline, particularly in language, visuospatial, and executive domains. These associations were independent of age at onset, clinical phenotype, and APOE ε4 status. Our findings highlight the potential prognostic value of fluid biomarkers in AD, especially CSF p-Tau181 and NfL, and plasma p-Tau217 and GFAP. These results suggest promise for improving disease monitoring, although prognostic utility at the individual level remains uncertain. Show less

Efficacy outcomes in clinical trials are based on well-powered analyes of the entire participating population. Trial populations will comprise many types of demographic and biological subgroups, including individuals of different sexes, groups of older and younger individuals, participants with or without the apolipoprotein E ε4 ( Clinical trials are sized to allow well-powered conclusions based on analysis of the entire participating population.Trial populations geared to be representative of the subgroups of the older population with AD are underpowered to allow drawing confident conclusions about efficacy or safety in subgroups.Strategies such as non-inferiority analysis combined with transparent reporting of the analytic framework may facilitate understanding treatment efficacy and safety in subgroups. Show less

Protein truncating variants (PTVs) in To identify high-priority missense variants (HPVs), we applied ‘domain mapping of disease mutations’ for the 637 unique coding In this sample, PTVs and HPVs associated with respectively a 35- and 10-fold increased risk of early onset AD and 17- and 6-fold increased risk of overall AD. The median age at onset (AAO) of PTV- and HPV-carriers was 62 and 64 years, and Our results justify a debate on whether HPV carriers should be considered for clinical counseling. The online version contains supplementary material available at 10.1186/s13024-025-00907-z. Show less

Argyrophilic grain (AG) is a common neurodegenerative accumulation of 4 repeat tau in dendritic spine. Dementia with grain (DG) is defined as AGs with a sole pathological basis for cognitive decline. As with other multifactorial diseases, DG could result from interactions of environmental and genetic factors. However, the genetic basis of DG is largely unknown. To clarify the genetic architecture of DG pathogenesis, we conducted a genome-wide association study (GWAS) with 214 DG cases versus 12,405 controls. We have identified a candidate locus associated with the risk of DG, the SVIL locus on chromosome 10, with genome-wide significance (rs11595141, P = 4.86 Show less

Apolipoprotein E (ApoE) and monocyte chemoattractant protein-1 (MCP-1) are inflammatory markers associated with premature atherosclerosis, which leads to increased cardiovascular disease risk among people with HIV (PWH). We aimed to evaluate the association between the plasma levels of these inflammatory markers and ischemic stroke in young PWH. We conducted a prospective case-control study at the University Teaching Hospital in Lusaka, Zambia, between March 2022 and October 2024, comparing young PWH with non-cardioembolic ischemic stroke (cases) to age- and sex-matched PWH without a history of stroke (controls). Standardized data collection instruments were used to collect information on other known risk factors for stroke, including demographic, clinical, laboratory, and imaging parameters. ELISA was done to measure ApoE and MCP-1 levels in the plasma of individuals in both the case and control groups. We analyzed results for 50 cases and 50 controls. Compared to controls, cases were more likely to have (1) traditional stroke risk factors such as hypertension (42 vs. 2%, The results suggest that lower plasma ApoE levels are independently associated with non-cardioembolic ischemic stroke in young PWH. Additional studies with larger sample sizes are needed to further explore the contribution of these inflammatory markers in young-onset HIV-associated stroke. Show less

Neurodegenerative diseases, marked by complex molecular mechanisms and diverse clinical features, challenge conventional research approaches. This chapter emphasizes the value of multi-omics integration in understanding the biology of Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis (ALS). Genomic studies reveal risk variants such as APOE ε4 in Alzheimer's and rare mutations in familial forms. Transcriptomics highlights gene expression changes, including synaptic dysfunction in early Parkinson's and alternative splicing errors in TARDBP-related ALS. Proteomics identifies key protein aggregates like amyloid beta and alpha-synuclein, along with modifications such as hyperphosphorylated tau that correlate with cognitive decline. Metabolomics uncovers metabolic alterations, including mitochondrial dysfunction in Parkinson's and lipid peroxidation in ALS, which contribute to disease progression. By combining these layers with high-throughput tools like single-cell sequencing, spatial transcriptomics, and mass spectrometry, researchers can reconstruct molecular networks linking genetic risk, gene regulation, protein dysfunction, and metabolic imbalance. This approach enables patient stratification into molecular subtypes, such as neuroinflammatory clusters defined by microglial gene signatures and cytokine expression. Biomarkers from blood and cerebrospinal fluid allow for minimally invasive disease monitoring. Despite challenges such as data heterogeneity and limited standardization, multi-omics approaches support biomarker discovery and therapeutic development. Integrating these datasets with neuroimaging and digital tools enhances diagnostic precision and guides targeted interventions, such as antisense therapies for SOD1-linked ALS. Multi-omics integration is thus a critical foundation for advancing personalized strategies in neurodegenerative disease research. Show less

The active ingredients of Traditional Chinese Medicine with diverse structures exhibited anti-inflammatory and lipid lowering functions, demonstrating significant therapeutic effects in inflammatory diseases of atherosclerosis. We incorporate Astaxanthin (AST) and Dihydroartemisinin (DHA) into PLGA NPs to synthesized HA@PLGA@AST/DHA NPs (HPAD NPs) for alleviating atherosclerosis. In vitro assay indicated that the designed HPAD NPs promoted cholesterol efflux of macrophages by enhancing selective lipophagy, which is benefit to lipid antigen degradation. Meanwhile, HPAD NPs regulated T-cell differentiation and crucially induced macrophages from pro-inflammatory M1 type to anti-inflammatory M2 type. In vivo study demonstrated that HPAD NPs decreased the necrotic core dimension and improved plaque stability in ApoE Show less

Alzheimer's disease (AD) is the leading cause of dementia and is often prefaced by mild cognitive impairment (MCI). Detection of AD-related changes via blood-based biomarkers would enable critical therapeutic interventions early in disease progression. Neuronal enriched extracellular vesicle (NEEV) miRNAs regulate peripheral genes as a response to early AD brain changes and hence may have biomarker potential. Plasma NEEVs were captured from plasma samples of Mexican Americans (MAs) and Non-Hispanic Whites (NHWs) using an antibody against the neuronal surface marker CD171. miRNAs isolated from NEEVs were sequenced and analyzed using miRDeep2/DEseq2 and QIAGEN RNA-seq portal for differential expression between cognitively impaired (CI) and cognitively unimpaired controls. hsa-miR-122-5p was significantly underrepresented in the CI group in both MAs and NHWs compared to the healthy control. Other population-specific miRNAs (MAs: hsa-miR-26a-5p, hsa-let-7f-5p, and hsa-miR-139-5p, NHWs: hsa-miR-133a-3p, hsa-miR-125b-5p, and hsa-miR-100-5p) identified may have biomarker potential in AD precision medicine. Some of these differentially expressed miRNAs were associated with key AD-related comorbidities such as APOE genotype, age, and metabolic burden and were predicted to target genes within NF-κB -regulated inflammatory pathways. Together, these findings suggest that dysregulated miRNA networks may serve as a mechanistic link between comorbidity burden and AD-related neuroinflammation and neurodegeneration. Show less

White matter hyperintensity (WMH), indicative of cerebral small vessel disease, has emerged as a potential biomarker for cognitive decline in Alzheimer's disease (AD). However, their predictive role across specific cognitive domains within the AD spectrum remains unclear. This study investigates the relationship between WMH volume and cognitive performance in memory, executive function, and language across the AD continuum. A cross-sectional analysis was conducted using data from the Alzheimer's Disease Neuroimaging Initiative (ADNI), comprising 557 participants categorized into cognitively normal (CN; n = 158), mild cognitive impairment (MCI; n = 334), and Alzheimer's dementia (AD; n = 65) groups. Cognitive function was assessed using composite scores for memory (ADNI-MEM), executive function (ADNI-EF), and language (ADNI-LAN). WMH volume was quantified through validated Bayesian segmentation of MRI data. Associations between cognitive scores and WMH volume, adjusted for age, gender, APOE ε4 status, and vascular risk factors, were evaluated via multiple linear regression analyses. WMH volume showed numerically progressive increases from CN to MCI and AD groups; however, between-group differences did not reach statistical significance. Within the MCI group, significant negative associations emerged between WMH volume and memory (β=-0.13, adjusted p = 0.045) and language scores (β=-0.12, adjusted p = 0.045). Conversely, these relationships were absent in both the CN and AD groups. WMH volume relates specifically to declines in memory and language abilities, particularly in individuals with MCI. These results support using WMH measurements as early markers to identify cognitive decline in AD, potentially helping to guide earlier diagnosis and treatment decisions. Show less

Macrophage-like phenotype switching of vascular smooth muscle cells (VSMCs) is a crucial mechanism driving atherogenesis. Inhibition of a phenotype switch to macrophage-like cells is a promising strategy to prevent atherosclerosis (AS), and targeted nanotherapeutics represent one approach for implementing this strategy. To this end, we designed immunosuppressive oligodeoxynucleotide A151 functionalized selenium nanoparticles with a spearhead LacNAc (LN-A151-SeNPs) that target macrophage-like VSMCs. Nano characterization showed that the uniformity and stability of nanoparticles were optimized by modification with LacNAc and A151, resulting in an average diameter of 88.90 ± 1.45 nm, Zeta potentials of -21.1 ± 1.5 mV, a A151:Se molar ratio of 1:60 and mass ratio of 1.68:1. The effects of LN-A151-SeNPs on inhibiting VSMCs phenotype switching and attenuation of AS were investigated using [Image: see text] The online version contains supplementary material available at 10.1186/s12951-025-03925-7. Show less

Early identification of markers of cognitive decline in cognitively normal older adults is essential for dementia prevention strategies. Sensorimotor measures, such as gait speed, grip strength, and reaction time, may provide sensitive indicators of current and future impairment. This study examined associations between baseline sensorimotor function and cognitive decline in cognitively normal older adults. In this prospective cohort, 246 cognitively normal older adults from the DRIVES Project completed baseline assessments of grip strength, gait speed, simple reaction time, and the Preclinical Alzheimer Cognitive Composite (PACC). Participants were followed for a mean of 4 years. Linear mixed-effects models adjusted for demographics, APOE ε4 status, and neighborhood deprivation. Cross-sectional analyses evaluated the associations between sensorimotor measures and cerebrospinal fluid (CSF) biomarkers of amyloid, tau, and plasma neurofilament light chain (NfL). Participants (mean age: 74.9 ± 5.17 years; 48.8% female) had a mean baseline PACC score of 1.06 ± 0.50. Cross-sectionally, slower gait speed was associated with higher CSF tau/Aβ Show less

Hyaluronan and proteoglycan link protein 2 (HAPLN2) / Brain link protein-1 (Bral1) is important for the binding of chondroitin sulfate proteoglycans (CSPGs) to hyaluronan and thus for the formation of specific types of brain extracellular matrix (ECM). It is also significantly increased with aging. Moreover, machine learning has identified it as a brain-derived protein most predictive of Alzheimer's disease (AD). HAPLN2 binds to CSPGs that may sequester aggregation-prone proteins and also restrict neuronal plasticity. Because the apolipoprotein 4 (APOE4) allele increases AD risk, in the present study we have examined hippocampal lysates from APOE3 and APOE4 targeted replacement (TR) mice using unbiased proteomics, Western blot and hippocampal immunostaining. With proteomics, we observe that HAPLN2 is among the most significantly upregulated proteins in APOE4 mice. Prior work suggests HAPLN2 is particularly important to the assembly of perinodal matrix, and herein we show that it also colocalizes with Wisteria floribunda agglutinin (WFA) positive perineuronal nets (PNNs). PNNs represent a dense form of ECM that can increase GABAergic neurotransmission to alter overall excitatory/inhibitory (E/I) balance and neuronal oscillations important to mood and memory. Proteomics also detected elevated levels of high temperature requirement peptidase-1 (HTRA1), which accumulates in cerebral blood vessels harboring amyloid, in APOE4 mice. In Western blot studies, lysates from APOE4 mice also showed significantly reduced levels chondroitin-6 sulfated proteoglycans, which makes PNNs more susceptible to proteolysis and less inhibitory. In addition, immunostaining studies showed that levels of the PNN component aggrecan were increased in the hippocampus of APOE4 animals. Overall, these findings contribute to an emerging body of literature suggesting that brain extracellular matrix may be altered with aging and other risk factors for AD, and suggest that future studies should assess PNNs, peri-nodal structure and axonal conduction in the background of APOE4. Show less