Journal of Alzheimer's Disease最新文献

BackgroundAlzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by cognitive decline, memory loss and neuronal dysfunction. While amyloid-β plaques and tau tangles remain central to AD pathology, emerging evidence implicates ferroptosis, an iron-dependent, regulated form of cell death marked by lipid peroxidation and oxidative stress, as a critical contributor to disease progression.ObjectiveThis study investigates the interplay between major AD risk factors including chronic alcoholism, alcohol-nicotine co-abuse, aging, genetic predisposition, comorbidities and lifestyle habits and ferroptosis-related molecular pathways.MethodsGEO datasets and 115 ferroptosis-related genes were analyzed using z-score/FDR and Limma, followed by GO/KEGG/GSEA enrichment, machine-learning-based gene selection with ROC-AUC validation, immune-cell profiling using CIBERSORT, and hub gene-miRNA network construction via NetworkAnalyst.ResultsOur findings demonstrate that these risk factors converge on shared mechanisms involving iron dysregulation, oxidative stress and lipid imbalance which are hallmarks of ferroptosis. We identified seven ferroptosis-associated biomarker genes CYBB, FERMT1, BAX, SOD1, ACSL4, TP53, and FTH1 as being significantly dysregulated in AD. Integrative gene-miRNA interaction analysis revealed several hub miRNAs including hsa-miR-34a (TP53, SOD1, BAX), hsa-miR-34b and hsa-miR-34c (TP53, FERMT1), hsa-miR-125a-5p (FERMT1, TP53) and hsa-miR-20a-5p (ACSL4, BAX) suggesting a network of coordinated post-transcriptional regulation. Additionally, we observed strong neuroinflammatory signatures in AD with increased infiltration of pro-inflammatory macrophages (M1), CD8⁺ T cells, monocytes and neutrophils. This heightened immune activity may be exacerbated by ferroptotic cell death and associated oxidative stress forming a vicious cycle of neurodegeneration. Finally, we propose glutathione and alpha-tocopheral (vitamin E) as potential therapeutic compounds due to their antioxidative role in preventing ferroptosis.ConclusionsOverall, our study provides novel insights into the mechanistic connections between ferroptosis, miRNA regulation, immune responses and AD pathology highlighting potential biomarkers and therapeutic targets.

Single-cell RNA-sequencing has identified that Alzheimer's disease (AD) pathology in humans is associated with activation of disease-associated microglia (DAM). Microglial signatures of human AD have not been consistently identified in AD mouse models. Since the inflammatory response of rats is more like humans, we profiled microglial transcriptomes in aging TgF344-AD rats, which overexpress two human AD risk genes. Classic DAM gene activation (ApoE, Trem2, Gpnmb), and upregulation (MHC class-II) and downregulation (Ifngr1 and Fkbp5) of human AD microglial genes were identified in aging TgF344-AD rats. Thus, the TgF344-AD rat better recapitulates the microglial gene signature observed in human AD.

Alzheimer's disease (AD) is an age-related neurodegenerative disorder that is characterized by neurocognitive dysfunction, deposition of amyloid-β (Aβ) plaques, and formation of hyperphosphorylated tau protein. Oxidative stress and neuroinflammation are the main pathological events in AD development. AD is a gender-dependent brain disorder that is predominant in females. Cessation of production of female hormones, such as 17β-estradiol (either due to menopausal or surgical menopause causes), exhibited pro-AD and neurotoxic activities that deteriorate cognitive functions and promote AD development. We investigated the key regulatory role of gender-dependent factors that control the process of AD neuropathogenesis, on the activities of Nucleotide-binding domain, leucine-rich-containing family, pyrin domain-containing-3 (NLRP3) inflammasome, Nuclear factor erythroid 2-related factor 2 (Nrf2), and Apolipoprotein E (APOE). This review aimed to examine the impact of gender-based differences on incidence rates of AD dementia and to reveal the mechanisms regulating the gender differences in AD. In addition, we highlighted the anti-AD activities of sex hormones and the current application of hormonal replacement therapy and estrogen receptor beta-based therapeutic interventions. Furthermore, we presented the impact of gender differences on metabolism in the brain, insulin resistance, and astrocytic activity.

BackgroundThe association between varicella-zoster virus (VZV) infection and Alzheimer's disease (AD) risk has shown inconsistent results. Given difficulties in early diagnosis and limited therapeutic options for AD, identifying modifiable risk factors is significant for prevention.ObjectiveTo systematically evaluate the impact of VZV infection on AD risk and explore protective effects of antiviral treatment and vaccination.MethodsWe searched PubMed and Web of Science databases up to April 2025. The Newcastle-Ottawa Scale assessed study quality. Random-effects models were used for meta-analysis using risk ratios (RR) as the primary effect measure, with sensitivity and subgroup analyses conducted.ResultsTwenty-one studies were included. Meta-analysis showed: (1) herpes zoster patients had significantly higher AD risk (RR = 1.12, 95% CI: 1.01-1.24, p = 0.04); (2) patients receiving antiviral treatment had lower AD risk (RR = 0.55, 95% CI: 0.37-0.82, p = 0.003); (3) vaccinated individuals had lower AD risk (RR = 0.72, 95% CI: 0.68-0.78, p < 0.0001). The strongest association occurred in the >70 years age group, demonstrating age as an important effect modifier.ConclusionsThis meta-analysis provides systematic evidence supporting that VZV infection increases AD risk while confirming protective effects of antiviral treatment and vaccination. These findings support including herpes zoster vaccination in preventive healthcare for elderly populations.

BackgroundAlzheimer's disease (AD) diagnosis has shifted from a purely clinical framework to a clinical-biological paradigm, driven by biomarker integration. This evolution is motivated by the wider availability of reliable biomarkers and the advent of disease-modifying treatments.ObjectiveTo assess changes over time in clinical characteristics, diagnostic pathways, and healthcare resource utilization in a real-world cohort of individuals with cognitive impairment attending a Memory Clinic.MethodsThis secondary data retrospective observational study analyzed two patient cohorts with newly diagnosed cognitive impairment: one from 2017-2019 and another from 2021-2023. Anonymized medical records and structured hospital data were examined using natural language processing to extract demographic and clinical information, diagnostic pathways, treatment patterns and comorbidities.ResultsThe 2021-2023 cohort was significantly younger, exhibited higher baseline Mini-Mental State Examination scores, and underwent more instrumental assessments than the 2017-2019 cohort. These findings likely reflect a shift in public awareness and attitudes toward cognitive health. AD diagnoses increased in both cohorts over time, while mild cognitive impairment diagnoses declined. The use of diagnostic combinations was more frequent in the recent cohort, in which clinical-biological diagnoses were significantly more prevalent.ConclusionsThis study provides real-world insights into the evolving landscape of cognitive impairment diagnostics and care, underscoring a shift toward earlier, biologically grounded diagnosis, supporting precision medicine in AD care. The expanded use of biomarkers reflects evolving practice standards and prepares the ground for disease-modifying therapies in AD.

BackgroundAlzheimer's disease (AD) is a severe neurological disorder for which a complete cure is not currently available. Therefore, predicting the risk of AD in elderly individuals with normal cognitive function is crucial for early prevention, treatment, and family-provided daily care preparation.ObjectiveThis study aimed to establish a risk prediction model for the progression from normal cognitive function to AD in elderly via deep learning (DL) methods to provide a reference for clinical decision-making and the development of screening tools for the early diagnosis of AD.MethodsDeepSurv, DeepHit, and Cox models were constructed, and the consistency index (C-index), integrated Brier score (IBS), and area under the ROC curve (AUC) were used to evaluate the accuracy, calibration and discriminative power of the three prediction models.ResultsThe overall predictive ability of the model was relatively stable, with concordance indices of 0.82 (DeepSurv), 0.83 (DeepHit), and 0.81 (Cox) and IBSs of 0.08, 0.07, and 0.05, respectively. From the perspective of the C-index indicator, the consistency of the deep learning model was better than that of the Cox model.ConclusionsRisk prediction models for the progression from normal cognitive function to AD can be established using easily obtainable early-stage predictors, which are expected to be used for rapid screening of the risk of developing AD in elderly after clinical validation.

BackgroundSoda consumption is associated with vascular risk, but little is known about soda in relation to dementia.ObjectiveWe hypothesized that both regular and diet soda consumption were associated with increased dementia risk.MethodsWe utilized data from longitudinal population-based Northern Manhattan Study. Regular and diet soda consumption were assessed by food frequency questionnaire. Dementia was adjudicated during follow-up after a series of comprehensive neuropsychological and functional assessments. Cox proportional hazards models examined the associations between regular and diet soda consumption and dementia risk, adjusting for demographics and vascular risk factors.ResultsOf 947 dementia-free participants (mean baseline age=64 ± 8 years, 41% men, 64% Hispanic, 16% non-Hispanic White, 18% non-Hispanic Black), 20% developed dementia during follow-up, 4.8% drank regular soda >1/day and 2.3% drank diet soda >1/day. Diet soda was associated with increased dementia risk (per diet soda/day aIRR=1.39, 95% CI = 1.09-1.75), specifically among non-Hispanic White and Black participants but not among Hispanics. Those who consumed >1 diet soda per day had a 4.15- fold increased risk versus ≤1/day (95% CI = 1.81-9.49), adjusting for sociodemographics and behavioral risk factors. The association was not apparent after excluding those with obesity or diabetes, highlighting a potential for reverse causation. Although no significant association was observed between regular soda consumption and dementia, a nonstatistically significant trend was observed (unadjusted p = 0.07).ConclusionsThe results support a potential increased dementia risk associated with frequent consumption of diet soda. Further study is needed into the impacts of obesity and diabetes.

BackgroundThe cerebrospinal fluid (CSF) and plasma amyloid-β (Aβ)_40/42 ratio, p-217tau and p-181tau, and neurofilament light chain are biomarkers of Aβ proteinopathy, tau proteinopathy, and neuronal injury, respectively, in Alzheimer's disease (AD). However, direct biomarkers of cognitive function have yet to be identified.ObjectiveTherefore, the present study investigated the potential of CSF and plasma levels of drebrin, a postsynaptic protein, as biomarkers of synaptic activity and cognitive function in the human brain in clinical settings.MethodsWe developed a novel ELISA to measure CSF and plasma levels of drebrin and analyzed 68 CSF and 128 plasma samples from patients with AD and other neurological diseases.ResultsCSF drebrin levels were significantly reduced in samples of mild cognitive impairment due to AD, the dementia stages of AD, and idiopathic normal pressure hydrocephalus. Plasma drebrin levels were also significantly reduced in samples of MCI due to AD.ConclusionsCSF and plasma drebrin levels are specific biomarkers of cognitive decline in the MCI stage of AD.

BackgroundDichlorodiphenyltrichloroethane (DDT) and its metabolites (DDTs), such as dichlorodiphenyldichloroethylene (DDE) and dichlorodiphenyldichloroethane (DDD), are synthetic organochlorine pesticides with long environmental persistence. Although DDT has been phased out in many countries, DDE and DDD remain prevalent worldwide. Growing evidence links DDTs exposure to Alzheimer's disease (AD), though underlying molecular targets and mechanisms remain unclear.ObjectiveIn this study, we investigated molecular targets and pathways through which DDTs potentially induce AD using network toxicology combined with molecular docking techniques.MethodsAD-related targets associated with DDTs were identified through bioinformatics searches. Key targets were selected via STRING protein-protein interaction analysis and Cytoscape, followed by signaling pathway enrichment analysis. Diagnostic efficacy was evaluated using ROC curve analysis and nomogram modeling based on GEO datasets. Molecular docking validated binding affinity between DDTs and core target proteins predicted by AlphaFold 3.ResultsWe identified 1732 potential molecular targets linking DDTs exposure to AD. Pathway analysis revealed DDTs predominantly affect AD pathogenesis by modulating apoptosis, p53 signaling, TNF signaling, and IL-17 signaling pathways. STRING and Cytoscape analyses identified seven core targets. GEO dataset validation indicated RPL23, RPS6, and RPS8 as pivotal targets, with RPL23 having strongest predictive capacity. Molecular docking confirmed binding interactions between DDTs and RPL23, with binding energies of -7.2 kcal mol^-1 for DDT, -6.5 kcal mol^-1 for DDE, and -7.1 kcal mol^-1 for DDD.ConclusionsThis research provides novel insights into neurotoxic mechanisms of DDT and its persistent metabolites DDE and DDD, and supports enhanced public health strategies for AD prevention.

BackgroundPathogenic variants in PSEN1, PSEN2, or AβPP cause early-onset Alzheimer's disease (EOAD). Several novel variants remain of uncertain significance (VUS) due to limited evidence. The PSEN1 p.R358P variant has not been previously characterized or reported in EOAD cases.ObjectiveTo determine the pathogenicity of the PSEN1 p.R358P variant in a patient with EOAD and assess its effect on amyloid-β (Aβ) processing using a human cellular model.MethodsWe present the case of a 62-year-old female of Western European descent with memory impairment starting at 59 and a positive family history of Alzheimer's disease (AD). To evaluate the variant, a PSEN1 knockout HEK293T line was generated using CRISPR/Cas9. Cells were co-transfected with AβPP and either wild-type or mutant PSEN1, and Aβ₄₂/Aβ₄₀ levels were measured by ELISA in culture supernatants.ResultsThe proband exhibited multidomain cognitive impairment and imaging biomarkers (PiB-PET and FDG-PET) consistent with AD. Whole-exome sequencing revealed a PSEN1 (NM_000021.4:c.1073G > C:p.Arg358Pro) variant, classified as VUS by ACMG guidelines, together with a SORL1 p.G1536D variant and APOE ε4/ε4 genotype. Cells expressing PSEN1 p.R358P showed an increased Aβ₄₂/Aβ₄₀ ratio compared to wild-type, mainly due to reduced Aβ₄₀ levels. This profile partially mimicked the pathogenic PSEN1 p.A246E variant. In silico analyses predicted deleterious effects for PSEN1 p.R358P.ConclusionsOur results support a likely pathogenic role for the PSEN1 p.R358P variant in EOAD. Nonetheless, in the absence of segregation data, the variant should be considered a hot VUS.