Alexander disease (AxD) is a rare progressive astrogliopathy and leukodystrophy caused by heterozygous pathogenic variants in the gene encoding glial fibrillary acidic protein (GFAP). Cognitive problems in AxD have long been recognized, but domain-specific neuropsychological descriptions of adult-onset Alexander disease (AO-AxD) remain sparse. We report a genetically confirmed 53-year-old man with AO-AxD who underwent comprehensive neuropsychological assessment because of progressive cognitive and behavioral complaints. The profile was characterized by deficient verbal episodic memory retrieval and reduced set-shifting efficiency, with relatively preserved recognition memory, language, visuospatial abilities, and most attentional measures. Structural MRI showed characteristic medullary and upper cervical cord involvement but only limited supratentorial white matter abnormalities. To contextualize the case, we reviewed published AO-AxD reports with domain-specific neuropsychological testing. The available literature remains limited and heterogeneous, but suggests that cognitive manifestations in AO-AxD may include retrieval-based memory deficits, executive inefficiency, and visuospatial difficulties. We discuss these findings in relation to white matter dementia, fronto-subcortical and fronto-hippocampal network dysfunction, and potential astrocyte-mediated mechanisms.

Tiling across the central nervous system, astrocytes contact synapses, blood vessels and other glial cells through highly specialised processes, allowing them to regulate local brain environments across multiple spatial and temporal scales. These anatomical and signalling features make astrocytes attractive substrates for modulating brain function and repair. Here, we frame "astrocyte engineering" as the intentional design of molecular access, sensing and effector modules in astrocytes to interrogate or modify local brain states. This Review focuses on how astrocyte interface biology can be converted into engineering logic, from genetic access and signalling perturbation to emerging sensor-effector designs. We first outline how astrocyte morphology, diversity and intercellular interactions shape the logic of cell-specific targeting. We then summarise tools for astrocyte-specific gene delivery and signalling control, including adeno-associated virus (AAV)-based strategies and G-protein coupled receptor (GPCR) signalling modulation approaches that can alter disease-relevant phenotypes. Further, we discuss recent proof-of-concept studies that equip astrocytes with new recognition or effector functions, including chimeric antigen receptor (CAR) astrocytes, synNotch-based systems, and trophic-factor delivery. We propose that future astrocyte engineering should be guided by omics-based design principles that link cell state, molecular access, input recognition, and effector selection.

The tumor suppressor protein p53 is a known modulator of neurodegenerative disease (ND) processes. Although p53 expression is increased in the brains of patients with Alzheimer's disease, Parkinson's disease, and ischemic stroke, its role in mood disorders such as anxiety and depression remains unclear. To investigate the role of p53 in behavioral responses to chronic stress, we examined behavioral and molecular alterations in p53 knockout (p53) mice and wild type mice. In p53 mice, increased vulnerability to chronic unpredictable mild stress (CUMS)-induced anxiety- and depression-like behaviors was observed following CUMS exposure. In parallel with these behavioral changes, BDNF expression was reduced, whereas glutamate levels were elevated in the prefrontal cortex of p53 mice. Increased calcium-associated staining and NMDAR2B expression were observed together with increased neuronal injury- and cell death-related markers. In primary cortical neurons derived from p53 mice, corticosterone treatment resulted in greater increases in glutamate levels, NMDAR2B expression compared to wild-type controls. Cell death markers (cleaved caspase-3, p-p38, p-JNK) were upregulated, while neuroprotective signals (BDNF, p-Akt, p-ERK, p-CREB) were suppressed in p53 mice, and corticosterone-treated primary neuronal cells from p53 mice. These findings indicate that p53 deficiency is associated with enhanced vulnerability to CUMS-induced anxiety- and depression-like behaviors and is accompanied by alterations in calcium handling, glutamate homeostasis, neuronal injury-related markers, and BDNF-associated neuroprotective signaling.

Vascular dementia (VaD), the second most common cause of dementia, is closely associated with chronic cerebral hypoperfusion and progressive cognitive decline; however, its molecular and cellular basis remains incompletely understood. Dysregulated intercellular communication within the neurovascular unit may contribute to the cellular and pathological alterations observed in VaD. To identify candidate signaling pathways associated with VaD, we integrated single-cell transcriptomic analysis, microarray data analysis, pseudotemporal trajectory analysis, and experimental validation. Pleiotrophin (PTN) and LAMININ signaling emerged as consistently altered intercellular communication pathways and were associated with microglial state transitions along pseudotime. In a right unilateral common carotid artery occlusion (rUCCAO) mouse model, VaD mice exhibited cognitive impairment, microglial activation, myelin loss, white matter injury, enhanced inflammatory responses, and oxidative stress. Expression analyses further confirmed alterations in PTN- and laminin-related molecules, whereas untargeted metabolomics revealed concurrent disturbances in glutamate-related metabolism. These molecular and metabolic alterations were associated with behavioral deficits and VaD-related pathological changes. Collectively, our findings identify altered PTN/laminin signaling and glutamate metabolic dysregulation as candidate molecular features of VaD and provide a basis for investigating their functional relevance. Pathway-specific functional studies are still required to establish their causal contributions to VaD progression.

Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by neuronal loss and cognitive decline. A key pathological feature of AD is the reduction of acetylcholine (ACh) levels resulting from the enzymatic activity of acetylcholinesterase (AChE) and butyrylcholinesterase (BChE). Therefore, inhibition of these enzymes remains a well-established therapeutic strategy for AD management. In this study, a novel series of phenothiazine-tetrazole hybrids was designed and synthesized as potential cholinesterase inhibitors. Their inhibitory activities against AChE and BChE were evaluated in vitro, and IC₅₀ values were determined in the micromolar range. Among the tested derivatives, Compound E3a (IC₅₀ = 10.664 μM) and Compound E5b (IC₅₀ = 10.315 μM) exhibited the strongest AChE inhibition, whereas Compound D5b showed the highest activity toward BChE (IC₅₀ = 18.734 μM). Enzyme kinetic analysis revealed that E5b and E3a act as competitive AChE inhibitors, with Ki values of 1.313 ± 0.032 μM and 1.520 ± 0.033 μM, respectively. To elucidate the molecular basis of inhibition, molecular docking studies were performed, followed by 500 ns molecular dynamics simulations, MM-PBSA binding free energy calculations, and free energy landscape analyses. The computational results revealed that Compound E3a forms a more dynamically and thermodynamically stabilized complex with AChE, primarily driven by favorable van der Waals interactions. ADMETlab 3.0 predictions further indicated acceptable preliminary drug-like features, although lipophilicity, solubility, CYP liability, and toxicity-related endpoints require further optimization and experimental validation. Collectively, these findings highlight phenothiazine-tetrazole hybrids as promising scaffolds for the rational development of next-generation cholinesterase inhibitors for Alzheimer's therapy.

INTRODUCTION: Kaempferol (KAE), a natural flavonoid with substantial anti-inflammatory activity, has demonstrated efficacy against Alzheimer's disease (AD). However, the fundamental mechanisms are not yet fully understood. OBJECTIVES: The objective of this study was to elucidate the role of KAE in alleviating microglia-mediated neuroinflammation in AD and its underlying mechanisms. METHODS: The 3 × Tg-AD mice and LPS-stimulated BV2 microglial cells were employed as in vivo and in vitro model respectively. The HK-TAT peptide was utilized to induce mitochondrial dissociation of HK2, and 3-BP was applied as a HK2 inhibitor. Transcriptomic and metabolomic analyses were performed to discover the inhibitory effect of KAE on HK2. Immunofluorescence and Western blotting were employed to explore the suppressive role of KAE in cytosolic HK2-mediated NF-κB signaling. Additionally, the interaction between KAE and HK2 was investigated through molecular docking, validated by SPR, and confirmed via CETSA. RESULTS: Our findings demonstrated that KAE significantly attenuated LPS-induced microglial activation, along with the release of pro-inflammatory factors and enhanced glycolytic activity. In vivo, KAE partially rescued cognitive impairment and neuronal damage in 3 × Tg-AD mice. Microglial activation was also markedly suppressed. Mechanistically, we revealed that dissociation of HK2 from mitochondria to the cytosol was sufficient to induce microglial activation, and this process was consequently constrained by the suppression of HK2 level and activity using 3-BP. By reducing HK2 levels, KAE suppressed cytosolic HK2-mediated IκBα phosphorylation and subsequent nuclear translocation of NF-κB. Furthermore, KAE not only downregulated HK2 transcription but also bound to HK2, promoting its ubiquitination-mediated degradation. CONCLUSION: Our data indicate that KAE alleviates microglia-mediated neuroinflammation in AD, which correlates with the suppression of HK2 and the modulation of cytosolic HK2-dependent NF-κB activation.

Apolipoprotein E (apoE), encoded by the polymorphic APOE gene, plays a key role in lipid transport and metabolism. The three major APOE alleles are ε2, ε3, and ε4, with ε4 being the strongest genetic risk factor for late-onset Alzheimer's disease. We generated human induced pluripotent stem cells from peripheral blood mononuclear cells of a 67-year-old male patient with Alzheimer's disease carrying the APOE ε4/ε4 genotype. The generated cell line displayed typical iPSC morphology, a normal karyotype, trilineage differentiation potential, and pluripotency-marker expression, providing a resource for investigating APOE ε4-associated disease mechanisms and preclinical therapeutic screening.

Although mounting evidence supports that neighborhood greenspaces (e.g., trees and parks) may benefit cognitive health in older age, fewer studies have investigated benefits to brain health measured via magnetic resonance imaging (MRI). We used data on 892 older adults without dementia from three Alzheimer's Disease Research Centers, examining whether neighborhood greenspace (i.e., greenness and percentage park space) is associated with white matter hyperintensity (WMH) and hippocampal volumes from MRI. We also examined whether associations varied by sex, racial group, urbanicity, or apolipoprotein E genotype (genetic risk factor for Alzheimer's disease). Linear regression models that accounted for neighborhood clustering controlled for demographics, research center, cognitive function, neighborhood deprivation, and comorbidities (e.g., hypertension, diabetes, obesity). Interaction terms (e.g., greenness×sex) were added to the models to evaluate potential effect modification. Living in greener neighborhoods was associated with fewer WMH and greater hippocampal volume in the overall sample. In stratified analyses, the beneficial greenness-WMH association was restricted to Black (not White) participants (i.e., significant interaction). In contrast, an adverse association between park space and lower hippocampal volumes was detected among Black (not White) participants (i.e., significant interaction). Overall, this study suggests associations between living in neighborhoods with more greenspace and MRI biomarkers of lower cerebrovascular and dementia risk, although results were mixed for Black individuals. Our findings need replication in other cohorts that are ethnoracially diverse and that represent different geographic regions, and future studies are needed explain the counterintuitive associations between park space and hippocampal volume among Black older adults.

The synovial lining maintains joint integrity, produces lubricating fluid, and forms a sterile barrier disrupted in inflammatory joint disease. It consists of specialized fibroblasts and macrophages, but its developmental timing and mechanisms are not well understood. We used genetic mouse models, imaging, and single-cell transcriptomic profiling to delineate this process. We found that the lining is immature in fetal human and newborn mouse joints. In mice, fibroblasts provide full coverage at birth, whereas macrophages are scarce. The macrophage lining layer gradually forms during the first weeks of life in a colony-stimulating factor 1 (CSF1)-dependent process, largely monocyte-independent, involving fetal-derived Cx3cr1 macrophages and Aqp1 intermediates. Both lining macrophages and fibroblasts undergo substantial transcriptional changes postnatally, acquiring their specific identity, upregulating key genes such as Prg4 (fibroblasts) and Vsig4 (macrophages), and establishing active signaling units. Early postnatal life is therefore a critical window for synovial lining maturation with implications for joint health and disease.

Historically the development of amyloid-β plaques and tau neurofibrillary tangles have been used as the hallmarks of Alzheimer's disease (AD). However, there is increasing evidence suggests that these pathological hallmarks are secondary to deeper metabolic defect in the brain. AD is progressively being recognized as a metabolic synaptic disorder characterized by insulin resistance, impaired cellular energy homeostasis, mitochondrial dysfunction, and synaptic degeneration. Synaptic plasticity is closely linked to the insulin-sensitive system of glucose utilization, mitochondrial activity, and local protein synthesis that render the synapses highly sensitive to the malfunction of the metabolic system. Recent discoveries highlight the important role of exosomes in mediating communication between neural cells by transferring regulatory miRNAs across neuronal networks. Exosomal miRNAs regulate insulin signaling, synaptic gene expression, mitochondrial function, and neuroinflammation. In AD, exosomal miRNA profiles are significantly altered, with enrichment of miR-29, miR-34a, miR-146a, and miR-21, alongside depletion of synapse-supporting miR-132. These changes contribute to insulin resistance, impaired glucose transporter trafficking, dendritic spine destabilization, and reduced expression of synaptic proteins such as PSD-95 and synaptophysin, ultimately leading to cognitive decline. Importantly, neuron-derived exosomes can cross the blood-brain barrier, making their miRNA cargo promising biomarkers and therapeutic targets for early AD diagnosis and precision treatment.

BACKGROUND: The number of older adults living with dementia is increasing in China and worldwide. Three-level prevention is vital to delay the occurrence and development of dementia. However, the current state of these services remains suboptimal. This study aimed to explore the programs and challenges in providing dementia prevention services. METHODS: A one-year ethnographic study, including semi-participatory observations and in-depth interviews, was conducted in nine settings in China from July 2022 to June 2023. Twenty-four service providers and 26 residents or family members were observed, and seventeen of these 50 participants were interviewed. Data collection was guided by the Rainbow Model. A combination of deductive and inductive content analysis was applied to identify the challenges. RESULTS: Dementia-friendly communities, Dementia Screening Program, Medical Consortia, and Long-term care services were the main programs in dementia three-level prevention services. This study identified 32 challenges, including four at system level, ten at organizational level, seven each at professional and clinical levels, and four additional challenges. CONCLUSIONS: Enriching the diversity of programs and strengthening primary prevention services will be beneficial for improving the dementia three-level services. The challenges identified in this study can provide valuable insights to guide targeted interventions, inform policy, and optimize service delivery for relevant stakeholders.

INTRODUCTION: Differentiating the nonfluent/agrammatic and logopenic variants of primary progressive aphasia (PPA; nfvPPA and lvPPA, respectively) remains clinically challenging due to overlapping subtle speech and language impairments. We investigated whether automated connected speech analysis can support differential diagnosis. METHODS: We analyzed connected speech from 84 Italian speakers with PPA (23 nfvPPA, 23 semantic variant [svPPA], and 38 lvPPA) using a picture-description task. Prosodic, phonological, and morphosyntactic features were extracted. Machine-learning classifiers were trained for binary (lvPPA vs. nfvPPA) and multiclass (lvPPA, nfvPPA, svPPA) classification. Explainability analyses identified key features. RESULTS: The combination of speech and language features effectively discriminated among PPA variants. Binary classification reached 81.67% accuracy, while multiclass classification reached 63.86% accuracy. Noun rate, local jitter, articulation rate, and total pauses were among the most informative features. DISCUSSION: Automated analysis of connected speech provides objective linguistic biomarkers that enhance diagnostic accuracy and support reliable differentiation of PPA variants in clinical practice.

BACKGROUND: Phase 3 trials of the anti-amyloid monoclonal antibodies lecanemab and donanemab in Alzheimer's disease demonstrated modest slowing of cognitive decline over 18 months. Subsequent open-label extensions (OLE) suggested greater long-term benefit based on comparisons with historical untreated cohorts, which are vulnerable to selection and attrition bias. METHODS: We simulated longitudinal Clinical Dementia Rating-Sum of Boxes trajectories using mixed-effects models calibrated to reproduce published means, variances and attrition patterns from the Clarity-AD and TRAILBLAZER-ALZ 2 trials, separately for early- and delayed-start cohorts and in combined analyses. Observed annualised slopes were also directly compared between double-blind (DB) and OLE phases. Placebo effects were estimated by comparing DB placebo arms with matched untreated historical cohorts derived from published natural history data. RESULTS: Simulations closely reproduced reported trajectories. In both trials, the early-start cohorts showed significantly faster annualised decline during OLE than during DB treatment (lecanemab ∆=0.53; 95% CI 0.40 to 0.66; donanemab ∆=0.66; 95% CI 0.41 to 0.91), whereas delayed-start cohorts showed no meaningful phase-related differences. OLE decline rates approximated those observed in DB placebo groups. In the lecanemab trial, DB placebo participants declined more slowly than matched untreated controls; decline in the donanemab trial varied by baseline severity. CONCLUSIONS: Despite selective retention favouring slower progressors, both lecanemab and donanemab accelerated cognitive decline during OLE phases and paralleled placebo-level declines.

Alzheimer's disease (AD) is a progressive neurodegenerative disease characterized by memory loss and irreversible cognitive decline. Glycogen synthase kinase 3β (GSK-3β) is significant in tau hyperphosphorylation and neurodegeneration. The cholinergic hypothesis of AD links cognitive impairment to reduced synaptic acetylcholine (ACh). Increased acetylcholinesterase (AChE) activity exacerbates this issue. To search for a potential dual GSK-3β/AChE inhibitor, we focused on N-methylcytisine. This natural cytisine-derived alkaloid has not been studied for its various biological effects on the prevention of AD. The results indicated that N-methylcytisine displayed promising activity against GSK-3β and AChE with IC values of 11 and 22.7 µM, respectively. GSK-3β kinetic study according to the varying substrate or ATP concentrations at different N-methylcytisine levels revealed mixed-type inhibition. The results of the integrated in silico workflow indicate that N-methylcytisine exhibited favorable binding to AChE (docking score -9.6 kcal/mol; MM-GBSA -70.2 kcal/mol), comparable to the reference inhibitor galantamine (-10.8 kcal/mol; -70.6 kcal/mol). In contrast, its interaction with GSK-3β was more moderate (-5.3 kcal/mol; -50.3 kcal/mol) relative to staurosporine (-8.5 kcal/mol; -82.6 kcal/mol), consistent with its smaller scaffold. Overall, the results support a flexible, mixed-type interaction profile and highlight N-methylcytisine as a promising dual-acting candidate for Alzheimer's disease.

BACKGROUND: Artificial intelligence (AI), extended reality (XR), and socially assistive robotics (SAR) are each advancing Alzheimer's disease (AD) research and care at a rapid pace. Yet despite substantial progress within each domain, clinical implementation remains weakly integrated across diagnostic, therapeutic, and care functions, producing islands of innovation rather than coordinated care systems. METHODS: We conducted a machine-assisted semantic-bibliometric synthesis of 2,636 publications on AI-, immersive technology/VR-, and SAR-enabled approaches to AD diagnosis, intervention, and care published between 2021 and 2025. Available title-abstract metadata were encoded using SBERT embeddings, projected via UMAP, and clustered using K-Means to characterize the functional topology of the field. From this mapped corpus, we selected a semantically central subset of 50 studies for high-fidelity full-text synthesis, preserving cross-domain representativeness while maintaining interpretive tractability. RESULTS: The mapped landscape suggests a three-part pattern of architectural separation. Precision neuroimaging (Cluster C4, 22%) functions primarily as a state-oriented diagnostic domain. Immersive therapeutics (Cluster C2, 48%), the largest cluster, increasingly incorporate adaptive personalization but remain weakly connected to biomarker-based stratification. Embodied robotic care (Cluster C5, 10%) addresses behavioral stabilization with little longitudinal coupling to upstream sensing. Across all three domains, high component-level sophistication coexists with limited evidence of cross-layer coordination. CONCLUSION: Contemporary digital solutions for AD remain predominantly siloed and state-oriented rather than longitudinally integrated. We synthesize these observations into a conceptual Closed-Loop Architecture, proposed as a roadmap for future integrated digital dementia care. Advancing this agenda will depend on interoperable infrastructure, longitudinal modeling, and prospective cross-layer evaluation-not solely on further isolated gains in classification accuracy.

PURPOSE: To synthesize current evidence on the pathophysiology, clinical relevance, and implications for age-related choroidal thinning. METHODS: A systematic literature search of relevant publications was conducted across MEDLINE, Embase, and Cochrane Library, up to and including May 2024. Identified studies reported choroidal thickness changes with aging. Data on subfoveal choroidal thickness, choroidal vascularity index, and associated factors (ethnicity, systemic disease, axial length) were analyzed (PROSPERO ID: CRD420251041101). RESULTS: Choroidal thickness declines with age, with ethnicity-specific rates ranging from -0.93 µm/year in Spanish cohorts to -4.00 µm/year in Chinese populations. Age-related choroidal thinning correlates with retinal and neurodegenerative pathologies, including glaucoma (nasal choroidal thinning >250 µm in older adult patients), myopic maculopathy (subfoveal choroidal thickness <100 µm in high myopia), and Alzheimer disease (subfoveal choroidal thickness 169 µm vs 253 µm in control patients). Enhanced depth imaging optical coherence tomography (OCT) and swept-source OCT reveal preferential vascular loss (choroidal vascularity index <30%) and stromal atrophy. Systemic risks, such as hypertension or smoking, accelerate choroidal thinning. CONCLUSIONS: Age-related choroidal thinning exists on a continuum between physiologic aging and pathology, with implications for retinal and systemic health. Future prospective studies will help determine diagnostic thresholds (subfoveal choroidal thickness <200 µm in nonmyopic adults >60 years or rapid thinning beyond ethnic normative values), management recommendations for high-risk cohorts (glaucoma, age-related macular degeneration, high myopia), and therapeutic considerations for monitoring of choroidal thickness changes from moderate- to low-certainty evidence.

Patients with chronic kidney disease (CKD) face elevated dementia risk, and vitamin D deficiency (VDD) has emerged as a potential contributor to cognitive decline. This study investigated the association between VDD and dementia development in patients with CKD using real-world data. We conducted a retrospective cohort study using the TriNetX database, analyzing patients with CKD aged ≥50 years from January 2010 to December 2022. Patients were stratified by serum 25-hydroxyvitamin D levels as follows: VDD group (<20 ng/mL) vs control group (≥30 ng/mL). The primary outcome was new-onset dementia occurring 1 to 10 years post-index, with the risk of Alzheimer's disease (AD) as a secondary outcome. During the 10-year follow-up, patients with VDD were associated with a significantly higher dementia risk (hazard ratios [HR] 1.45, 95% confidence intervals [CIs]: 1.37-1.54, P < .001). The association emerged early, with a 5-year HR of 1.52 (1.41-1.64, P < .001). The risk of AD was similarly elevated (10-year HR 1.37, 95% CI: 1.21-1.56, P < .001). Dose-response analysis revealed an increased risk even with mild insufficiency (20-30 ng/mL), while severe deficiency (<10 ng/mL) showed the highest risk. Subgroup analysis identified hypertension as a significant effect modifier, with VDD conferring an elevated risk in hypertensive patients (HR 1.43, 95% CI: 1.35-1.52) but not normotensive individuals. VDD was significantly associated with increased risks of dementia and AD in patients with CKD, following a clear dose-response pattern. The association is particularly pronounced among hypertensive patients, suggesting that VDD represents a potentially modifiable risk factor warranting clinical attention in CKD management.

Previous studies have suggested a link between gut microbiota, constipation and Alzheimer's disease (AD) as well as mild cognitive impairment (MCI). In this study, we aimed to investigate the changes in the gut microbiota and their relationship with constipation in patients with AD and MCI. A total of 90 participants (30 with AD, 30 with MCI, and 30 normal controls) were recruited from the community-based Nanning Community Elderly Population cohort. We collected fresh fecal samples for analysis and compared the differences in the gut microbiota among the groups. We also categorized these 90 participants into a constipation group and a non-constipation (normal) group using the Rome IV diagnostic criteria, allowing for a comparison of gut microbiota between these 2 groups. There were significant differences in alpha and beta diversity of the gut microbiota among the AD, MCI, and control groups, as well as between the constipation and non-constipation groups. At the genus level, the relative abundance of Lachnospira was decreased in both the AD group and the constipation group, while the relative abundance of Paeniclostridium was increased in both the MCI group and the constipation group. Our findings suggest that changes in the gut microbiota in patients with AD or MCI are partially consistent with those observed in older adults with constipation and may be involved in the pathogenesis of AD.

Given the potential importance of sleep disturbances in the pathophysiology of Alzheimer's disease (AD), as well as the fact that habitual sleep duration - an observable and modifiable lifestyle factor - has become a significant potential target for early risk warning of neurodegenerative diseases, this study utilizes data from the National Health and Nutrition Examination Survey to thoroughly examine the association between AD and habitual sleep patterns among adults in the United States. It aims to determine the correlations among sleep duration, Alzheimer's disease, and all-cause mortality, thereby providing population-based evidence for the early prevention and public health intervention of AD. Using a cross-sectional design, 29,692 participants were selected. A multiple logistic regression model was used to assess the association between sleep duration and Alzheimer's disease. Additionally, all-cause mortality status was derived from matched records obtained from the United States National Death Index. The Cox regression model was used to calculate the hazard ratios and 95% confidence intervals of all-cause mortality associated with the relationship between sleep duration and AD. Our analysis revealed a significant positive correlation between increased sleep time and AD prevalence, a relationship that persisted in the adjusted model. Subgroup analysis showed that this association remained consistent across different populations. This study clarifies the effectiveness of sleep time as a predictive tool for AD and underscores its importance in AD assessment. Based on the predictive value of sleep time, our study advocates incorporating body composition factors into AD risk assessment, thus expanding the scope of Alzheimer's disease prevention strategies.

OBJECTIVE: Recent studies suggest that combining plasma phosphorylated tau (p-tau) with β-amyloid (Aβ) may improve diagnosis accuracy for Alzheimer's disease (AD). However, the cross-sectional and longitudinal concordance of these markers with Aβ positron emission tomography (PET) positivity remains incompletely understood. This study aimed to evaluate the diagnostic performance of plasma p-tau, alone and in combination with plasma Aβ, in AD. METHODS: We included 326 participants from the Alzheimer's Disease Neuroimaging Initiative and 357 Chinese older adults from the Greater-Bay-Area Healthy Aging Brain Study who underwent Aβ-PET imaging. Longitudinal data were available for 285 Alzheimer's Disease Neuroimaging Initiative participants. Plasma p-tau181, p-tau217, Aβ42, and Aβ40 were measured on different analytical platforms. Diagnostic performance for Aβ-PET positivity was assessed using a two-cutoff approach. RESULTS: Combining plasma p-tau with Aβ42 or the Aβ42/40 ratio reduced the intermediate zone. Notably, p-tau217/Aβ42 showed stronger agreement with Aβ-PET positivity than p-tau217 alone. Among individuals classified as p-tau217/Aβ42 positive but p-tau217 intermediate, 57.1 to 83.3% were Aβ-PET positive. Longitudinally, most Stable Positive (88.0-96.1%) and Stable Negative (89.4-90.9%) cases defined by p-tau217 or p-tau217/Aβ42 were Aβ-PET positive and Aβ-PET negative, respectively. Critically, 69.7 to 75.8% of Non-positive to Positive cases defined by p-tau217/Aβ42 were Aβ-PET positive. INTERPRETATION: These findings provide novel insights into the cross-sectional and longitudinal diagnostic performance of plasma p-tau217/Aβ42 in AD. To be specific, plasma p-tau217/Aβ42 can reduce the intermediate zone and improve agreement with Aβ-PET positivity, and longitudinal p-tau217/Aβ42 monitoring is particularly informative for identifying Aβ-PET-positive patients who were p-tau217/Aβ42 negative or intermediate at baseline and were misclassified as low risk of AD. ANN NEUROL 2026.

Tau assemblies, associated with tauopathies, are believed to self-propagate through prion-like mechanisms in the central nervous system, driving neurodegeneration. Recently, protein seed amplification assays have emerged as highly sensitive methods for detecting trace amounts of misfolded protein assemblies across various neurodegenerative diseases. In this study, we utilized protein misfolding cyclic amplification (PMCA) to demonstrate that tau assemblies from the brains of transgenic mice or human patients with tauopathies can be efficiently amplified. Amplification was achieved using complex matrix substrates, such as brain homogenates or cell lysates expressing aggregation-prone mutant tau proteins, with heparin as a cofactor. This assay enabled the highly sensitive detection of tau assemblies, even at 1-million-fold dilutions of brain homogenate from aged and symptomatic THY-Tau30 transgenic mice (a model of tauopathy) and human cases of frontotemporal lobar degeneration (FTLD-P301L). Tau assemblies from Alzheimer's disease (AD) patients were also successfully amplified, albeit with lower sensitivity compared to other tauopathies. Critically, the PMCA-generated tau assemblies retained seeding competence, inducing further tau aggregation in reporter tau "biosensor" cells and in young THY-Tau30 mice following intracerebral injection. Together, our findings establish PMCA as an in vitro model for studying the seeded aggregation of tau assemblies, providing a powerful tool to advance research into tau aggregation mechanisms and the development of therapeutic interventions.

Low-dose aspirin is no longer routinely recommended for the primary prevention of cardiovascular disease in older adults due to a lack of net benefit over bleeding risk. We hypothesized that genetic subgroups may experience differential harm or benefit from aspirin therapy. To investigate this, we screened 572 polygenic scores (PGSs) for modification of aspirin's effect on major bleeding and major adverse cardiovascular events (MACE) in the Aspirin in Reducing Events in the Elderly (ASPREE) randomized, placebo-controlled trial of daily 100 mg aspirin. Participants were aged ≥70 years (≥65 years for US minorities) and free of cardiovascular disease, dementia, or physical disability at enrolment. Among participants with high-quality genotyping data (n = 13,571), PGS-aspirin interactions were tested using Cox proportional hazards models with Bonferroni correction for multiple testing. During a median follow-up of 4.6 years, 414 major bleeding events and 464 MACE occurred. A triglyceride-related PGS (PGS003144) significantly modified aspirin-associated bleeding (interaction P = 5.9 × 10; Bonferroni-adjusted P = 0.034). In the lowest quintile of the PGS distribution, aspirin increased major bleeding risk (HR 2.28; 95% CI: 1.45-3.58; P = 0.00036), including separate bleeding subgroups gastrointestinal (HR 3.17; 95% CI: 1.48-6.80; P = 0.0029), and intracranial bleeding (HR 4.10; 95% CI: 1.54-11.0; P = 0.0049). In contrast, in the highest quintile, aspirin was associated with lower risk of bleeding (HR 0.62; 95% CI 0.38-0.97) and reduced MACE (HR 0.66; 95% CI 0.44-0.99). Baseline serum triglycerides showed similar effect modification. These hypothesis-generating findings suggest triglyceride-related genetic variation may identify individuals with differential responses to aspirin.

Aging is the primary risk factor for chronic disease and is characterized by profound structural and architectural remodeling of human tissues. Here, we present a comprehensive assessment of these changes using 25,712 whole-slide histopathological images from 40 tissue types across 983 individuals in the Genotype-Tissue Expression cohort. By leveraging deep learning, we quantified nuanced morphological alterations to develop 'tissue clocks', predictors of biological age that reflect tissue structural integrity and physiological fitness. These clocks correlate with established aging markers, such as telomere attrition, subclinical pathologies and comorbidities. Through a systematic evaluation of biological aging rates across organs, we identified associations of tissue-specific age acceleration with demographic, lifestyle and medical factors, highlighting potentially modifiable risk factors that affect tissue aging. Furthermore, by integrating paired histology and transcriptomic data, we developed a strategy to predict tissue-specific age gaps directly from blood samples. We validated this approach by identifying disease-relevant organ aging across independent cohorts for eight prevalent diseases, including Alzheimer's disease, stroke and Crohn's disease. This work positions tissue architecture as a critical integrator of molecular and cellular changes over the course of aging, demonstrates that histopathological imaging provides a robust framework for monitoring tissue-specific aging and offers a scalable foundation for understanding organ-level physiological decline in health and disease.

We developed a high-content screening to investigate how Alzheimer's disease (AD) genetic risk factors may affect synaptic mechanisms in rat primary neuronal cultures. Of the target genes identified, we found that Plcg2 downregulation in mouse dentate gyrus neurons consistently disrupted dendritic morphology and synaptic function. In human neuronal cultures (hNCs), PLCG2 downregulation also impaired synaptic function and increased amyloid-β (Aβ) levels and Tau phosphorylation. Very rare PLCG2 loss-of-function (LoF) variants were associated with a tenfold increased AD risk. PLCG2 LoF carriers show low mRNA/protein PLCG2/PLCγ2 levels and the R953* LoF mutation compromised synaptic function and increased AD hallmarks in hNCs. Single-nucleus RNA sequencing analyses confirmed that the downregulation of PLCG2 impacted pathways related to synaptic and neuronal functions, potentially through neurexins in neurons. In conclusion, PLCγ2 downregulation could increase AD risk by impairing synaptic functions and by increasing Aβ levels and Tau phosphorylation in neurons.