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Lecanemab, an antibody directed at Aβ-protofibrils and plaque, showed meaningful delay in disease progression and biological effects consistent with disease modification in the phase 3 Clarity AD trial. The objective of this paper is to present efficacy and safety results in ApoE ε4 non-carriers or heterozygotes population of Clarity AD. Clarity AD is an 18-month, randomized study (core) in participants with early AD, with an open-label extension phase (OLE) phase. Academic and clinical centers. All eligible ApoE ε4 participants were randomized 1:1 across 2 treatment groups (placebo and lecanemab 10 mg/kg biweekly); the results presented herein are for the ApoE4 heterozygote or non-carrier participants. Endpoints included change from baseline at 18 months in the global cognitive and functional scale, CDR-SB, amyloid positron emission tomography (PET), Alzheimer's Disease Assessment Scale-Cognitive Subscale 14 (ADAS-Cog14), Alzheimer's Disease Cooperative Study-Activities of Daily Living Scale for Mild Cognitive Impairment (ADCS-MCI-ADL), and health-related quality-of-life (HRQoL) assessments. Amyloid imaging related abnormalities (ARIA) occurrence was monitored throughout the study by central reading of magnetic resonance imaging. Following 18 months treatment in the Core, eligible participants transitioned to the OLE where they received open-label lecanemab. Clinical outcomes (CDR-SB, ADAS-Cog14, and ADCS-MCI-ADL) were evaluated by examining 'delayed start' (core:placebo followed by OLE:lecanemab) and 'early start' (core:lecanemab followed by OLE:lecanemab) cohorts as well as natural history cohorts. Time to progression to next stage of AD was also evaluated through 36 months. 1795 participants with early AD were enrolled in Clarity AD, of which 1521 were ApoE ε4 heterozygotes or non-carriers (85 %). Lecanemab significantly reduced clinical decline on CDR-SB at 18 months compared to placebo in the ApoEε4 heterozygotes or non-carriers subgroup. Amyloid PET, ADAS-Cog14, ADCS-MCI-ADL, and HRQoL results were consistent with the CDR-SB findings. In the analysis subgroup, the most common adverse reactions for lecanemab were infusion-related reactions (26 %), ARIA-H (13 %), fall (11 %), headache (11 %), and ARIA-E (9 %). In the OLE, lecanemab-treated participants continued to accrue benefit in CDR-SB through 36 months, with continued separation through 36 months relative to the ADNI natural history cohort. Delayed start results follow a parallel trajectory relative to early start results, but do not catch up, confirming a disease modifying effect and reflecting importance of early treatment initiation. Results were similar for ADAS-Cog14 and ADCS-MCI-ADL. Lecanemab reduced the risk of progression to next stage of AD by 28 % on lecanemab as compared to the ADNI natural history cohort. In the ApoE ε4 heterozygotes or non-carrier subgroup of Clarity AD, lecanemab slowed decline in disease progression and reduced markers of amyloid, with expanding benefit over time. Clarity AD NCT03887455. Show less

Heterogeneity in the long-term progression of Alzheimer's disease (AD) challenges the efficiency of clinical trials. Identifying long-term prognostic factors is critical for enhancing trial efficiency, although it has been limited by the lack of appropriate statistical approaches. We applied a recently developed statistical model-based AI method to identify the baseline prognostic factors for long-term cognitive decline in a clinical trial population. We analyzed pooled placebo arm data (N = 1,597) from four Phase III trials in patients with mild-to-moderate AD. Long-term trajectories for the Mini-Mental State Examination (MMSE), 11- and 14-item versions of the Alzheimer's Disease Assessment Scale-Cognitive subscale (ADAS-Cog11, ADAS-Cog14), and Clinical Dementia Rating-Sum of Boxes (CDR-SB) were predicted from their short-term data (≤80 weeks). Trajectories were compared between subgroups defined by six baseline factors (age, sex, apolipoprotein E ε4 [APOE ε4] status, years of education, years from diagnosis, and years from disease onset) using the area under the curve (AUC). Longer years of education (≥13 years) was the most robust predictor associated with faster progression across all four outcomes (e.g., for 20-year ADAS-Cog11, AUC ratio, 1.11, p < 0.001). Younger age (<74 years) was associated with a faster decline in MMSE and ADAS-Cog scores, but not in CDR-SB. APOE ε4 status, sex, years from diagnosis, and years from disease onset were not significantly associated with long-term progression. Baseline educational level and age were significant prognostic factors of long-term cognitive decline. These findings will help optimize patient stratification in future clinical trials on AD. Show less

Branched-chain amino acids (BCAAs) have been associated with cognitive function, with conflicting evidence suggesting both potential benefits and risks in neurodegenerative diseases such as Alzheimer’s disease (AD) and mild cognitive impairment (MCI), highlighting the need for further investigation. This study aimed to explore the relationship between total BCAAs, cognitive function, and brain structure, specifically examining hippocampal volumes and their potential mediating effects in individuals with AD, MCI, and cognitively normal (CN) individuals. Cognitive function was assessed using the CDR-SB scale, total BCAAs were measured in serum through NMR metabolomics, and hippocampal volumes were evaluated using voxel-based morphometry (VBM). This study found that elevated total BCAAs were initially associated with increased hippocampal volumes in MCI, though this relationship became non-significant after adjusting for confounding factors such as age, gender, education, and ApoE ɛ4 status. Increased hippocampal volumes, however, remained consistently linked to better cognitive function in both MCI and AD, regardless of adjustments. Importantly, mediation analysis revealed indirect effects of elevated total BCAAs on improved cognitive function via increased hippocampal volumes, with being significant only in MCI before controlling for confounders; however, this mediation relationship disappeared after adjusting for age, gender, education, and ApoE ɛ4 status. These findings suggested that BCAAs may be associated indirectly with improved cognitive function, with increased hippocampal volume acting as a key mediator, particularly in MCI. However, the effects of BCAAs were sensitive to confounding factors such as age, gender, education, and APOE-ɛ4 status, which we accounted for in our analyses; however, other unmeasured factors such as dietary intake may also affect the observed associations, underscoring the importance of considering these variables in future studies. Show less

Atherosclerosis (AS) is a cardiovascular disorder accompanied by endothelial dysfunction and vascular inflammation. We aim to investigate the effects of Ras guanine nucleotide-releasing protein 3 (RasGRP3), a guanine nucleotide exchange factor in AS. Decreased RasGRP3 protein expression was observed in the endothelium of high-fat diet-fed ApoE The online version contains supplementary material available at 10.1007/s10753-026-02473-y. Show less

Atherosclerosis (AS) is a chronic disease characterized by lipid deposition in the vascular intima. As the pathological basis of cardiovascular diseases, AS represents a major contributor to global morbidity and mortality. While Gualou Huoxue Jiedu Decoction (GHJD) has been widely used in clinical practice for the treatment of AS, the molecular mechanisms remain unclear. To investigate the anti-atherosclerotic effects and underlying mechanisms of GHJD. Apoe GHJD alleviated plaque formation, improved lipid metabolism, and suppressed inflammation in vivo. Multi-omics analysis revealed that DNA methylation of Mfap4 could be a pivotal target of GHJD efficacy. In vitro assays confirmed that GHJD suppressed Mfap4 transcription and translation, leading to downregulation of integrin receptor family expression and inhibition of VSMC phenotypic switching. GHJD exerts anti-atherosclerotic effects through epigenetic modulation of Mfap4 and downstream integrin/FAK signaling pathway, thereby inhibiting VSMC phenotypic switching. These findings provide pharmacological evidence supporting GHJD as a potential therapy for AS and, for the first time, validate MFAP4 as a pharmacological target, offering new insights into AS prevention and treatment. Show less

Atherosclerotic plaques are the leading cause of cardiovascular events. Single-cell approaches have identified diverse human plaque cell phenotypes but their spatial distribution and interactions remain unclear. Here, intercellular communication patterns in human plaque microenvironments were mapped to reveal novel targets to prevent atherosclerotic events. Spatial transcriptomics (Visium, 10x) from 13 carotid plaques, and single-cell transcriptomics (cells = 51 981) were used to analyse cell phenotypes, cell trajectories, and intercellular communications. Cells contributing to plaque stability were explored using deconvolution of plaque bulk RNA-seq data (n = 78), histology, and survival analyses. Key cells and pathways were validated in apolipoprotein E (Apoe)-/- mice and in vitro. Genome-wide association study enrichment analyses were conducted using summary statistics of atherosclerotic diseases. LINCS L1000 data were used to explore drug repurposing. A fibroblast-like vascular smooth muscle cell (VSMC) phenotype associated with extracellular matrix formation pathways (validated in Apoe-/- mice) emerged as a key regulator of intra-plaque ligand-receptor signalling, in particular in the cap region. A higher proportion of fibroblast-like VSMCs was found in asymptomatics, associated with stable plaque features and predicted a lower risk of future events. Genes specific to this VSMC phenotype were enriched in coronary artery disease and myocardial infarction. Finally, compounds, which could induce key marker genes were identified and validated in vitro. This study provides the first comprehensive spatial transcriptomics map of cell communication in human plaque microenvironments. A pivotal role of a fibroblast-like VSMC, orchestrating intraplaque cell signalling and contributing to plaque stability, was identified. Targeting these cells might present promising novel avenues for therapies. Show less

Atherosclerotic vascular diseases remain the leading cause of death despite the use of lipid-lowering drugs. The development of more efficacious therapies targeting endothelial inflammation and endothelial-to-mesenchymal transition (EndMT) is an essential endeavor, aiming for better treatment outcomes. The increased mutation frequency of the The results of liquid chromatography-mass spectrometry, immunostaining, RNA sequencing, and Western blot in mouse and human arteries with atherosclerotic plaques identified TBK1 as one of the key mediators of EndMT and atherogenesis. Its role was then investigated in endothelium-specific TBK1 knockdown An increased expression of TBK1 was observed by liquid chromatography-mass spectrometry analysis in the aortas of The interaction between activated TBK1 and PAK1IP1 inhibits the binding of PAK1IP1 to PAK1, which, in turn, increases the phosphorylation of PAK1 and ERK1/2 in endothelial cells. This process drives EndMT. Endothelium-specific TBK1 knockdown or GSK8612 treatment inhibits EndMT and plaque formation. Safe TBK1 inhibitors could be developed into effective agents for the treatment of atherosclerotic vascular disease. Show less

Cereal vinegar sediment (CVS), a byproduct of traditional vinegar fermentation, has been regarded as a health-promoting product. However, its role in genetically induced hyperlipidemia remains unclear. This study systematically evaluated the effects of Dade-CVS (DD-CVS) and Hengshun-CVS (HS-CVS) on apolipoprotein-E-deficient ( Show less

This review overviewed the recent paradigm shifts in the diagnosis and management of Alzheimer's disease (AD), emphasizing the 2024 Alzheimer's Association (AA) revised criteria, advances in cerebrospinal fluid (CSF) and blood-based biomarkers (BBMs), and practical considerations for anti-amyloid monoclonal antibody therapy. We conducted a narrative appraisal of consensus frameworks (2018 National Institute on Aging-Alzheimer's Association [NIA-AA] amyloid, tau, and neurodegeneration [AT(N)] and the 2024 AA criteria), clinical practice guidance from AA released in 2025, regulatory status of CSF and BBMs. Intended-use settings (triage vs. confirmatory) of BBMs and implementation of anti-amyloid anti-body treatments (lecanemab or donanemab) in real-world practice in Korea were also reviewed. The 2024 AA criteria define AD biologically and designate A and T as core biomarkers; Core 1 biomarkers can establish AD irrespective of symptoms, whereas Core 2 biomarkers refine staging. A two-cutoff BBM strategy (positive/intermediate/negative) reduces misclassification and guides confirmatory CSF/positron emission tomography (PET) or retesting. BBMs now approach CSF/PET accuracy for amyloid detection, enable triage and, in selected settings, confirmation, and show utility for monitoring treatment response. Integration of clinical stages (1-6) with biological stages (A-D) clarifies syndrome-pathology discordance. Special scenarios-maintenance after induction, APOE ε4 homozygotes, Down syndrome, and serious mental illness-require individualized risk-benefit assessment. In South Korea, constrained access to tau PET and some BBMs necessitates Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition, Text Revision-anchored evaluation with selective biomarker testing. Biomarker-oriented diagnosis and anti-amyloid therapies are reshaping AD care. Priorities include rigorous validation of BBMs across populations, equitable access to core biomarkers, safety strategies, and real-world evidence to implement maintenance and special-population care pathways. Show less

Glioblastoma (GBM) remains one of the most intractable malignancies owing to the dual challenges of the blood brain barrier (BBB) and profound immunosuppression. Here, we present a nanobomb (OMV-ApoE@ALF) that integrates heterologous production of the aromatic polyketide albofungin (ALF) with programmable outer membrane vesicles (OMVs) displaying ApoE peptides for GBM immunotherapy. OMV-ApoE@ALF efficiently crossed the BBB, accumulated in tumors, and functioned as a lysosomal nanobomb to boost pyroptosis and activate cGAS-STING pathway, thereby promoting dendritic cell maturation, T-cell infiltration, and durable antitumor immunity. Mechanistically, OMV-ApoE@ALF delivered ALF into lysosomes, inducing lysosomal disruption, reactive oxygen species (ROS) production, and subsequent mitochondrial damage. Crucially, this lysosomal rupture also suppressed protective autophagy of tumor cells themselves, thereby reinforcing the cascade activation between caspase-3/GSDME-dependent pyroptosis and cGAS-STING signaling pathway. This lysosomal disruption-nanobomb represents a new strategy for advancing GBM immunotherapy. Show less

The association and mechanisms between biotin and dementia remain unclear. We investigated the association through a population and animal study. UK Biobank data were used to evaluate the association of biotin with incident dementia and brain structural alteration. To validate our findings, we established a biotin-deficient mouse model, and performed behavioural tests, immunofluorescence, RT-qPCR, Western blotting, and molecular docking. In humans, higher biotin intake was significantly associated with reduced risks of all-cause dementia (moderate: 0.83 [0.74-0.94]; high: 0.78 [0.68-0.89]), Alzheimer's disease (AD, moderate: 0.74 [0.61-0.89]; high: 0.79 [0.64-0.98]), and delayed-onset dementia (DOD, moderate: 0.810 [0.715-0.918]; high: 0.776 [0.672-0.896]), but not vascular dementia (VD) and early-onset dementia (EOD). Neuroimaging results revealed a "pseudo-atrophy" pattern-reduced cortical volume with increased tissue intensity-resembling structural remodelling rather than neurodegeneration. In mice, biotin deficiency triggered region-specific alteration of APP, PSEN1, and APOE in the hippocampus and prefrontal cortex. It was accompanied by elevated Aβ42 levels and an increased Aβ42/40 ratio. Molecular docking suggested that biotin physically interacts with the catalytic pocket of PSEN1 and the receptor-binding domain of APOE. Dietary biotin is associated with a lower risk of dementia, especially AD, potentially by inhibiting amyloidogenic processing and modulating APOE-mediated clearance. The observed neuroimaging and molecular patterns suggest that maintaining adequate biotin intake is a viable strategy for dementia prevention. This work was supported by the National Natural Science Foundation of China (No. 82273619). Show less

Protocatechuic acid (PCA), a natural compound found in a variety of Chinese herbal medicines and plant foods, has been documented to inhibit atherosclerosis partially by reducing inflammation burden in arterial endothelial cells. Interestingly, in vitro studies showed that PCA at physiologically reachable concentrations does not affect inflammation burden in TNF-α-stimulated aortic endothelial cells, whereas it increases the content of exosomal miR-10b secreted by macrophages that have engulfed apoptotic cells (efferocytic macrophages). This study was aimed at investigating whether the in vivo anti-inflammatory effect of PCA in arterial endothelial cells was due to the uptake of efferocytic macrophage exosomal miR-10b. A transwell co-culture system of aortic endothelial cells with efferocytic macrophages was used to evaluate the effect of PCA on NF-κB-mediated inflammation in aortic endothelial cells. An inhibitor of exosome secretion, GW4869, was applied to confirm the role of exosomes played in the anti-inflammatory effect of PCA. The aortic endothelial cells were administrated with exosomes isolated from PCA-treated efferocytic macrophages or miR-10b mimic or antagomir to ascertain the role of miR-10b in downregulating inflammation effect of PCA. Bioinformatics analyses, loss-of- and gain-of-function assays and luciferase reporter gene assays were performed to identify targeting relationship between miR-10b and mitogen-activated protein kinase kinase kinase 7 (MAP3K7)/β-transducin repeat-containing protein (β-TrCP). Besides, Apoe PCA at physiologically reachable concentrations inhibited NF-κB-mediated inflammation in TNF-α-stimulated aortic endothelial cells co-cultured with efferocytic macrophages, in which treatment of GW4869 reversed this effect. Exosomes isolated from PCA-treated efferocytic macrophages inhibited inflammation and increased miR-10b levels in aortic endothelial cells. Mechanistically, exosomal miR-10b post-transcriptionally repressed MAP3K7 and β-TrCP, both of which promote NF-κB activation. Knockdown of Map3k7 and Btrc with siRNA in aortic endothelial cells abolished the inhibitory effects of exosomes isolated from PCA-treated efferocytic macrophages on NF-κB-mediated inflammation. Consistently, oral administration of PCA increased miR-10b level and inhibited Map3k7 and Btrc mRNA expression as well as inflammation in aortic endothelial cells in Apoe Our current findings suggest that PCA could transfer exosomal miR-10b from efferocytic macrophages to endothelial cells and thus inhibit NF-κB-mediated inflammation in arterial endothelial cells through repressing MAP3K7 and β-TrCP, two new targets of miR-10b. Show less

Respiratory tract infections (RTIs) remain a major global cause of morbidity, yet the causal role of circulating plasma proteins in RTI susceptibility is unclear. We aimed to systematically identify plasma proteins that causally influence the risk of upper and lower respiratory tract infections (URTIs, LRTIs) using a proteome-wide Mendelian randomization (MR) framework. We performed two-sample MR analyses using genetic instruments for 2923 plasma proteins from 54,219 UK Biobank participants and outcome data from the FinnGen consortium (97,696 URTI and 28,542 LRTI cases). Colocalization analyses were conducted to confirm shared genetic architecture. Functional enrichment and protein-protein interaction (PPI) analyses were used to elucidate potential biological pathways. We identified 11 plasma proteins with significant causal associations with RTI risk. Four proteins (FKBP1B, GFRA1, UBE2L6, and CSF3) showed consistent effects for both URTI and LRTI, with moderate-to-strong colocalization evidence for UBE2L6 and GFRA1. The remaining seven proteins demonstrated infection-specific associations: YAP1 and MST1 (URTIs), and APOE, IL1RL1, and FKBPL (LRTIs). PPI and Gene Ontology (GO) enrichment analyses highlighted tumor necrosis factor (TNF) as a central hub, with cytokine-cytokine receptor interaction and leukocyte-mediated immunity as dominant pathways. This proteome-wide MR and colocalization study identifies novel plasma proteins and immune pathways implicated in RTI susceptibility, providing insights into potential biomarkers and therapeutic targets for infection prevention and management. Further validation in diverse populations and tissue-specific proteomic studies is warranted. Show less

Abdominal aortic aneurysm (AAA) is a serious disease with no effective pharmacological therapy. Although inflammation is recognized as a key regulator of AAA, targeting inflammatory pathways once the disease is established does not improve outcomes. Understanding the earliest molecular indicators could clarify precise biological targets and prognostic markers for AAA. Using ApoE-deficient mice, we performed RNA-Seq on suprarenal abdominal aortas (SRAs) from Ang II- and saline-treated mice 24 h after infusion. We further developed a unique model of hyperlipidemic mice in which the expression of the inhibitor of nuclear factor kappa B kinase subunit beta (IKKβ) can be conditionally suppressed in vascular smooth muscle cells (VSMCs). RNA-Seq data revealed early IKKβ-dependent cellular anabolic processes in SRAs, including activation of the mammalian target of rapamycin complex 1 (mTORC1) pathway. Furthermore, deletion of the Show less

Alzheimer's disease (AD) is characterized by amyloid plaques that form complex microenvironments in the brain. However, the molecular composition of these plaques and their temporal regulation are not well defined. Here, we developed a sensitive workflow for quantitative proteomic profiling of single plaques using refined laser capture microdissection and data-independent acquisition mass spectrometry (LCM-DIA-MS). From >200 plaques and control regions in AD mouse models (5xFAD and APP-KI) and human brains, we quantified >7,000 proteins, revealing stage-dependent, cell-type-related remodeling of the amyloid proteome (amyloidome). Temporal profiling uncovered early immune and lysosomal activation followed by engagement of RNA processing and synaptic pathways. Cross-model and cross-species analyses determined a conserved amyloidome including APOE, MDK, PTN, and HTRA1, validated by co-localization in imaging analysis. Network analysis highlighted modules in lipid transport, vesicle organization, and autophagy. These findings establish amyloid plaques as conserved, dynamic multicellular hubs that link amyloid accumulation to downstream cellular events. Show less

Amyloid-β (Aβ) PET imaging is a core biomarker and is considered sufficient for the biological diagnosis of Alzheimer's disease (AD). However, it is typically reduced to a binary Aβ™/Aβ+ classification. In this study, we aimed to identify subgroups along the continuum of Aβ accumulation including subgroups within Aβ- and Aβ+. We used a total of 3,110 of Aβ PET scans from Alzheimer's Disease Neuroimaging Initiative (ADNI) and Anti-Amyloid Treatment in Asymptomatic Alzheimer's Disease (A4) datasets to develop Show less

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

Alzheimer's disease (AD) heterogeneity complicates early detection and trial design. Scalable predictors may aid risk stratification. We assessed whether scalable baseline plasma biomarkers and neuropsychological measures predict 5‑year cognitive and functional decline in cognitively unimpaired older adults. We analyzed 866 amyloid-positive participants from the Anti-Amyloid Treatment in Asymptomatic Alzheimer's Disease (A4) trial and 343 amyloid-negative individuals from the Longitudinal Evaluation of Amyloid Risk and Neurodegeneration (LEARN) study. Decline was defined as a ≥0.5 increase in Clinical Dementia Rating-Global Score over 240 weeks. The separate and joint value of demographics, apolipoprotein E ( The p-tau217 and PACC significantly improved prediction. Full models achieved areas under the curve (AUCs) of 0.78-0.80 across cohorts. Additional plasma biomarkers offered modest AUC gains (1%-3%). The p-tau217 and PACC enhanced prediction of preclinical decline, supporting their utility in early identification and trial enrichment in AD. Show less

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

Apolipoprotein E (APOE) and proprotein convertase subtilisin/kexin type 9 (PCSK9) are both lipid proteins and related to immunity/inflammation. We hypothesized that PCSK9 impacts on Alzheimer's disease (AD) risk in an We used the Framingham Heart Study (FHS) Offspring cohort (Gen 2), with data on plasma PCSK9 protein concentration, as the baseline exposure for 1,704 study subjects. Using Cox regression models, the outcomes were incidents of AD or all-cause dementia. Using another FHS dataset with 3,048 individuals with genetic data, we examined the association between PCSK9 genotypes and the incidence of AD/dementia, stratifying the analysis based on Higher plasma PCSK9 protein levels were associated with a lower risk of AD (HR [95%CI]: 0.74 [0.58, 0.94]; Our study suggests that high blood PCSK9 levels are protective against AD risk in Show less

Cerebrospinal fluid (CSF) proteomics offers insights into molecular changes in aging and Alzheimer's disease (AD). Key AD biomarkers, in particular amyloid-β (Aβ) and tau, in CSF are strongly associated with Show less

Socioeconomic disadvantage (SED) has been associated with poorer brain health, yet its underlying pathology remains incompletely understood. We examined whether neighborhood-level SED, measured using the Area Deprivation Index (ADI), relates to amyloid deposition assessed with amyloid positron emission tomography (PET). Participants (n = 1,110) underwent cognitive assessment using the mini mental state examination (MMSE) and PET scanning with amyloid-specific tracers. Associations between national and state ADI and MMSE and global amyloid burden were evaluated using linear models adjusting for age, sex, and APOE-ε4 carrier status. In 1,110 participants, higher neighborhood socioeconomic deprivation was associated with lower MMSE scores, with both national and state ADI measures showing significant inverse associations independent of age and sex (all p < 0.001). Higher ADI was significantly associated with greater amyloid burden among cognitively unimpaired participants (β = 0.18, Neighborhood socioeconomic disadvantage is associated with worse cognitive performance and for the first time were shown to be associated with amyloid accumulation during the preclinical phase of AD. These findings underscore the need to consider socioeconomic context in early-stage risk assessment and may help inform targeted prevention strategies aimed at reducing disparities in dementia outcomes. Show less

Triggering receptor expressed on myeloid cells-2 (TREM2) is a key immune receptor in the central nervous system that regulates microglial phagocytosis, survival, and neuroinflammatory responses. TRME2 variants have been established as genetic risk factors for Alzheimer's disease (AD). However, the therapeutic development of TREM2 modulators has been limited to antibody-based approaches that face limitations in blood-brain barrier penetration and manufacturing scalability. Furthermore, there are no FDA approved TREM2 therapeutics available to date marking an unmet therapeutic gap. Herein, we report the identification of the first TREM2 small molecule submicromolar binders as a result of optimizing compound Show less

Opioid use is disproportionately high among People with HIV (PWH). Although combined anti-retroviral therapy (ART) can dampen HIV-associated dementia, a large fraction of PWH continue to experience neurocognitive deficits which are further exacerbated by opioid use. In the present study, we performed single cell transcriptomic profiling of cerebrospinal fluid (CSF) immune cells to explore their functional characteristics in opioid mediated neurological disorders among PWH using the SIV/rhesus macque model. In this study, we utilized CSF cells from morphine- and saline-administered, SIV-infected, ART-treated rhesus macaques (RMs). The CSF scRNA-Seq was performed longitudinally at baseline, post ramp-up with morphine (pre-infection), during acute infection, and after suppression of viremia to profile cell-specific transcriptomic signatures that mirror the CNS pathogenesis observed in opioid-dependent PWH. We observed the presence of all major immune cells in CSF, including CD4 + T Chronic opioid exposure reprograms CSF monocytes toward a DAM state that persists despite ART-mediated viral suppression, driving maladaptive immune-glial crosstalk and progressive neurocognitive dysfunction in morphine-dependent macaques with possible implications for neuroinflammation and neurodegenerative disorders that are observed in PWH. Show less

Women face greater vulnerability to dementia and Alzheimer's disease (AD), potentially due to estrogen fluctuations across the lifespan. However, its role in vascular brain health is unclear. We investigated associations between lifelong estrogen exposure-endogenous (reproductive span) and exogenous (oral contraceptives [OC], menopausal hormone therapy [MHT])-and late-life vascular brain injury, AD-related atrophy, and We included 352 cognitively unimpaired 70-years-old women from the Gothenburg H70-1944 Birth Cohort with brain MRI and 5-year follow-up. Reproductive lifespan was calculated as age at menopause or oophorectomy minus age at menarche. OC and MHT use were self-reported. Outcomes included cerebral small vessel disease (SVD), AD-related cortical thickness, and white-matter integrity (fractional anisotropy). Linear and multinomial regression and mixed-effects models were adjusted for confounders and stratified by Extended estrogen exposure throughout life-both endogenous and exogenous-appear to support late-life cerebrovascular health in women, with potential genotype-specific neuroprotective effects. Given the current absence of sex-specific prevention guidelines for cognitive disorders, future research should clarify estrogen's longterm impact on brain health and cognition to inform personalized medicine. Show less

Epidemiological evidence suggests that atherosclerosis (AS) may precede or coexist with type 2 diabetes mellitus (T2DM); however, whether anti-atherosclerotic interventions can reduce T2DM risk remains unclear. Chensinin-1b (C-1b), an antimicrobial peptide derived from the skin secretions of Rana chensinensis, has previously demonstrated anti-atherosclerotic activity, suggesting a potential therapeutic effect against T2DM in the context of AS. In an apolipoprotein E-knockout (ApoE In the early and middle stages of AS (6-10 weeks), mice fasting blood glucose (FBG) did not change, but atherosclerotic symptoms were significantly exhibited, such as the increased pro-inflammatory factors levels, aortic plaque and blood lipid levels. During the late stage of AS (14 weeks), it was found that the FBG of ApoE In ApoE Show less

Apolipoprotein E4 (APOE4) is the strongest risk allele associated with the development of late onset Alzheimer’s disease (AD). Across the CNS, astrocytes are the predominant expressor of The online version contains supplementary material available at 10.1186/s12974-026-03698-2. Show less

We tested whether inflammation indexed by soluble tumor necrosis factor receptor-1 (sTNFR1) is related to cognitive decline. We examined serum sTNFR1 with cognition in the Health and Retirement Study (HRS) and cerebrospinal fluid (CSF) sTNFR1 with tau pathology and magnetic resonance imaging (MRI)-based atrophy in the Alzheimer's Disease Neuroimaging Initiative (ADNI). Finally, we used Mendelian randomization (MR) to assess associations between genetically proxied sTNFR1 and regional brain volumes. Data were from HRS (2016-2020; N = 6028) and ADNI (N = 287). In HRS, serum sTNFR1 was log-transformed (quartiles); in ADNI, CSF sTNFR1 was analyzed. Global cognition included word recall, serial 7 s, and counting backwards. In ADNI, cognition was measured by the Clinical Dementia Rating-Sum of Boxes (CDR-SB); CSF total tau/phosphorylated tau and longitudinal MRI regional volumes were analyzed. Associations were estimated with linear and linear mixed-effects models adjusted for demographic, clinical, and genetic covariates including apolipoprotein E ε4 (APOE ε4). Incident mild cognitive impairment (MCI)/dementia was modeled with cause-specific Cox and Fine-Gray models. Incremental prediction used optimism-corrected change in area under the curve (AUC; ΔAUC), net reclassification improvement (NRI)/integrated discrimination improvement (IDI), calibration, and decision curve analysis. MR used genome-wide association study (GWAS) statistics to test effects of genetically proxied sTNFR1 on MRI-derived regional volumes. In HRS (follow-up 4 years), higher serum sTNFR1 was associated with lower baseline cognition and faster decline in global cognition (β = - 0.16/year). Higher sTNFR1 predicted MCI/dementia (Cox HR ≈ 1.17; Fine-Gray sHR ≈ 1.14); among cognitively normal individuals, risk was elevated (OR = 1.30; 95% CI, 1.03-1.63). Adding sTNFR1 to 2- and 4-year prediction models conferred small discrimination gains after internal validation (ΔAUC ≤ 0.003) and minimal or inconsistent net clinical benefit. In ADNI, higher CSF sTNFR1 was associated with greater CSF total tau and phosphorylated tau, and predicted accelerated caudate atrophy. Exploratory MR suggested a nominal association with reduced right inferior temporal volume, limited by instruments. sTNFR1 is associated with cognitive decline and tau-related selective neurodegeneration, but provides limited incremental predictive value beyond established risk factors; external validation and replication are warranted. Show less

Alzheimer's disease (AD) is the most prevalent cause of dementia and has been closely linked to βSupplemental data for this article can be accessed online at ht tps://doi.org/-amyloid accumulation. However, the efficacy and safety of anti-β-amyloid monoclonal antibodies remain debated. We systematically searched PubMed, Embase, and Cochrane databases for RCTs comparing anti-β-amyloid monoclonal antibodies with placebo in early-stage AD. Eligible trials enrolled participants with biomarker-supported AD and reported global, cognitive, or safety outcomes, including the CDR-SB, ADAS-Cog 13/14, ARIA, and brain volumetric measures. Six RCTs including 7837 participants were analyzed. Mean age ranged from 69.8 to 75.4 years, and 57.4% were APOE ε4 carriers. Anti-β-amyloid therapy was associated with small differences in global and cognitive outcomes, best described as a modest slowing of decline on the CDR-SB and ADAS-Cog scales. Treatment was associated with increased risks of ARIA-E (RR, 9.40; 95% CI, 6.98-12.66) and ARIA-H (RR, 2.40; 95% CI, 2.08-2.78), as well as greater ventricular enlargement and hippocampal atrophy. In early AD, anti-β-amyloid monoclonal antibodies are associated with modest slowing of decline accompanied by increased ARIA risk and unfavorable structural brain changes, limiting clinical applicability. www.crd.york.ac.uk/prospero identifier is CRD420251071393. Show less

Structural MRI analysis for Alzheimer's disease (AD) is limited by balancing group-level comparability in standard space with anatomical fidelity in native space. We therefore propose a multi-space, hybrid-feature framework, integrating radiomics and network metrics from both spaces to classify AD and predict mild cognitive impairment (MCI) progression. An integrated dual-space analytical framework was applied to T1-weighted MRI data. Models were developed on 1,477 participants from Alzheimer's Disease Neuroimaging Initiative (ADNI) and externally tested on an independent cohort of 1,349 participants from National Alzheimer's Coordinating Center (NACC). The framework extracts parallel radiomic and graph-based network features from both Montreal Neurological Institute (MNI) standard space and native space. These features were used to build machine learning models for three-class diagnosis (NC vs. MCI vs. AD) and 6-year prognostic prediction of MCI-to-AD conversion. For each task, the models using standard-space, native-space, and combined-space features were systematically compared. Model interpretation was performed using Shapley Additive Explanations (SHAP), and the features were validated against established AD biomarkers. The combined-space model demonstrated superior performance in both diagnostic classification (Macro-Averaged AUC: 0.96 in ADNI cohort, 0.94 in NACC cohort) and prognostic prediction of MCI-to-AD conversion (C-index: 0.83; HRs: 7.60, 95%CIs: 4.57-12.64). The extracted features in the ADNI cohort demonstrated significant correlations with APOE ε4 genotype, cognitive scores, and CSF biomarkers. Integrating multi-scale features from both standard and native spaces enhances AD diagnosis and prognosis accuracy more effectively than conventional single-space analysis. Show less