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.

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.

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.

Alzheimer's disease (AD) is characterized by progressive cognitive decline, amyloid-β (Aβ) accumulation, oxidative stress, and neuroinflammation. Increasing evidence links metabolic dysfunction to AD, suggesting that antidiabetic drugs such as metformin may exert neuroprotective effects. This study investigated the effects of long-term metformin pretreatment on cognitive function, hippocampal pathology, and neuroprotective gene expression in an intracerebroventricular streptozotocin (ICV-STZ) rat model of AD. Adult male Sprague-Dawley rats were assigned to Sham, STZ, Metformin, and STZ+Metformin groups. Metformin (2 g/L in drinking water) was administered for 12 weeks before ICV-STZ injection. Spatial learning and memory were assessed using the Morris water maze. Hippocampal pathology was evaluated by H&E, Nissl, and Congo red staining, and gene expression was analyzed by quantitative PCR. ICV-STZ induced cognitive impairment, hippocampal Aβ deposition, neuronal loss, and increased expression of pro-inflammatory and oxidative stress markers. Metformin pretreatment significantly improved spatial learning and memory, reduced amyloid burden, and preserved neuronal integrity in the CA1 and CA3 regions. Metformin increased hippocampal Klotho mRNA expression, enhanced antioxidant defenses (Nrf2 and HO-1), suppressed TNF-α, IL-1β, and iNOS expression, and increased IL-10 levels. Although BDNF mRNA expression showed an upward trend, the change was not statistically significant. No significant changes in blood glucose levels were observed. In conclusion, long-term metformin pretreatment attenuated STZ-induced AD-like pathology and cognitive deficits. Its neuroprotective effects were associated with increased hippocampal Klotho expression and reduced oxidative stress and neuroinflammation, supporting further investigation of metformin and the Klotho pathway as potential preventive strategies for AD.

Alzheimer's disease (AD) is a neurodegenerative disorder pathologically characterized by amyloid-β (Aβ) deposition, tau protein hyperphosphorylation, neuronal loss, and sustained neuroinflammation. In recent years, pyroptosis, a gasdermin-mediated form of inflammatory programmed cell death, has been recognized as a potential mechanism linking innate immune activation to neurodegenerative injury. This review summarizes the major molecular pathways of pyroptosis, including the canonical inflammasome-caspase-1-GSDMD pathway, the noncanonical caspase-4/5/11-GSDMD pathway, and alternative pathways involving caspase-3/GSDME and caspase-8, with a focus on their roles in the initiation, amplification, and propagation of neuroinflammation in AD. Current evidence suggests that AD-related stimuli, including Aβ aggregation, tau pathology, mitochondrial dysfunction, oxidative stress, and lysosomal damage, can induce inflammasome activation, gasdermin cleavage, and inflammatory mediator release, thereby sustaining chronic neuroinflammation. Concurrently, microglia, neurons, astrocytes, and oligodendrocytes may exhibit varying degrees of pyroptosis-related responses, contributing to impaired Aβ clearance, neuronal injury, glial dysfunction, and myelin pathology, respectively. This review further summarizes potential therapeutic strategies targeting the NLRP3 inflammasome, caspases, gasdermins, natural bioactive compounds, and the gut-brain axis. Overall, pyroptosis provides a novel framework for understanding the interplay between neuroinflammation and neurodegeneration in AD; however, its cell-type-specific roles, stage-dependent effects, and translational potential remain to be fully elucidated.

Alzheimer's disease (AD) is the leading cause of dementia and still lacks an effective treatment that can slow or stop disease progression. In addition to amyloid-β and tau pathology, AD involves major disturbances in calcium balance, neurotransmission, and synaptic plasticity. Conventional orthosteric drugs provide limited symptomatic benefit and often interfere with physiological receptor function, underscoring the need for more selective therapeutic strategies. This review explores allosteric modulation of neurotransmitter receptors as a potential neuroprotective strategy in AD, with an emphasis on mechanisms that restore synaptic integrity, regulate calcium homeostasis, and engage disease-relevant intracellular signaling pathways. The review synthesizes preclinical and clinical evidence on allosteric modulators targeting key ionotropic receptors, including NMDA, AMPA, GABA-A, nicotinic acetylcholine, and P2X7 receptors, and G protein-coupled receptors (GPCRs) such as M1 muscarinic receptors, metabotropic glutamate receptors, and the calcium-sensing receptor. Particular attention is given to receptor selectivity, signaling bias, and translational relevance. Allosteric modulation of ionotropic receptors can influence excitability and synaptic plasticity and may preserve endogenous neurotransmission, with circuit-stabilizing effects reported mainly in preclinical studies. GPCR-directed allosteric modulators can affect AD-related processes, including amyloid- and tau-associated toxicity, excitotoxicity, and neuroinflammation, although evidence for these effects is largely preclinical and clinical translation remains challenging. Convergent pathways, such as Ca2+-dependent signaling, ERK/CREB, PI3K/Akt, and cAMP/PKA, may represent shared mediators of disease-relevant effects. Allosteric modulation may offer a more refined, receptor-specific framework for therapeutic investigation in AD. Ionotropic and GPCR-targeted agents may each produce symptomatic or preclinical disease-relevant effects, but their capacity to slow disease progression in patients remains unproven and will require current pharmacological and translational challenges to be addressed.

Alzheimer's disease (AD) is a progressive neurodegenerative disorder for which effective therapeutic interventions remain scarce, highlighting the urgent need for new molecular approaches. Small nucleolar RNAs (snoRNAs), classically known for directing ribosomal modifications, have recently emerged as multifunctional regulators of gene expression, stress responses and neuronal homeostasis. Emerging evidence shows snoRNA dysregulation in the biofluids and brain tissue of patients with AD, positioning them as promising diagnostic biomarkers and therapeutic targets. This review outlines the structural, functional and translational potential of snoRNAs, with a particular focus on their ability to modulate AD pathology while also addressing key challenges in their clinical translation, including delivery barriers, biological stability and target specificity.