Introduction: The study aimed to compare plasma Epoxyeicosatrienoic Acid (EET) isomers (5,6-EET, 8,9-EET, 11,12-EET, and 14,15-EET) in patients with advanced-stage late-onset Alzheimer’s Disease (AS-LOAD) versus healthy controls matched by age and sex. materials and methods: 2. Materials and Methods 2.1. Study Population This study included 60 participants: 30 patients with AS-LOAD who were being followed at the Community Mental Health Center of the Nigde Training and Research Hospital, and 30 age- and sex-matched cognitively healthy volunteers recruited from the hospital’s outpatient clinics. The diagnosis of AD in the patient group was made according to the criteria of the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-V), based on clinical psychiatric evaluation. The control group consisted of individuals without any psychiatric disorders, as confirmed by DSM-V criteria and clinical examination, who volunteered to participate in the study. All procedures were conducted in accordance with the ethical standards of the Declaration of Helsinki. This study was approved by the Nigde Omer Halisdemir University Non-Interventional Clinical Research Ethics Committee (Approval No: 2025/70). 2.2. Collection of Blood Samples Participants and their guardians were informed about the study, and written informed consent was obtained before blood collection. Five mL of blood was collected from each participant into sterile EDTA tubes. The blood samples were centrifuged at 3000 rpm for 10 minutes to separate plasma. Plasma samples were stored at -80°C until EET level analyses were performed. 2.3. Determination of Plasma EET Levels Before the LC-MS/MS experiment, standards for all compounds were purchased from Cayman Chemicals (Ann Arbor, MI). The formic acid, Millipore water, dichloromethane, methanol (MeOH), and ammonium formate used were LC-grade and were obtained from Merck (Darmstadt, Germany). Quantification of plasma EET levels was performed by a validated liquid chromatography coupled with tandem mass spectrometry (LC-MS/MS) method in the research and development laboratory of Bome Trivitron Industry Products Foreign Trade Inc., as previously described by Duflot et al.[19]. LC-MS/MS analysis was conducted using a Shimadzu 8040 LC-MS/MS system (Shimadzu, Japan) equipped with an electrospray ionization (ESI) source operating in positive ion mode. This system was coupled with a Shimadzu Prominence UFLC system (Shimadzu, Kyoto, Japan), which included a DGU-20A3 degasser, a Nexera-X2 pump, a SIL-20ACHT temperature-controlled autosampler, and a CTO-20AC column oven. Chromatographic separation was performed on a Kinetex C18 column (2.6 μm particle size, 50 mm length × 3 mm inner diameter). Instrument parameters were set to maintain a column temperature of 30°C with a flow rate of 0.6 mL/min. A gradient elution method was employed using methanol/formic acid and ammonium formate/formic acid mixtures as the mobile phases. System control and data acquisition were performed using LabSolutions software, and quantification was conducted in multiple reaction monitoring (MRM) mode. Endogenous EETs were accounted for by normalizing analyte peak areas to zero via linear regression. Calibration curve slopes and linearity were determined from analyte-to-internal standard peak ratios at each spiked concentration. The results were evaluated against the standard calibration curve. 2.4. Statistical Analysis All statistical analyses were performed using IBM SPSS Statistics version 18. The Kolmogorov–Smirnov and Shapiro–Wilk tests were applied to assess the normality of data distribution. Depending on data distribution, comparisons between groups were conducted using the Kruskal–Wallis and Mann–Whitney U tests for nonparametric variables, and one-way ANOVA for demographic parameters such as age and sex. A p-value of ≤ 0.05 was considered statistically significant. Methods: In this cross-sectional case-control study, 30 patients with AS-LOAD were compared with 30 cognitively healthy (control) individuals. Plasma EET levels were analyzed by liquid chromatography coupled with Liquid Chromatography-tandem Mass Spectrometry (LC-MS/MS). results: The statistical analysis of the demographic characteristics of the AS-LOAD and healthy control groups is presented in Table 1. No statistically significant differences were observed between the control and AS-LOAD groups in terms of mean age or sex distribution (p > 0.05). In our study examining plasma EET levels in patients with AS-LOAD, we found that plasma concentrations of EET isomers (5,6-EET, 8,9-EET, 11,12-EET, and 14,15-EET) were significantly decreased in AS-LOAD patients compared with age- and sex-matched healthy controls (p < 0.05, Figure 1). Specifically, plasma levels of 14,15-EET (29.37 ± 25.65 vs. 90.80 ± 91.02 ng/dL), 11,12-EET (65.79 ± 38.65 vs. 240.1 ± 237.73 ng/dL), 8,9-EET (57.52 ± 6.46 vs. 144.58 ± 133.77 ng/dL), and 5,6-EET (7.31 ± 8.62 vs. 11.76 ± 11.32 ng/dL) were significantly lower in the patient group compared to the controls (Figure 1). Results: Plasma concentrations of all measured EET regioisomers were significantly lower in patients with AS-LOAD compared with controls. Significant reductions were observed for 14,15-EET (p = 0.007), 11,12-EET (p = 0.001), 8,9-EET (p = 0.007), and 5,6-EET (p = 0.011). Discussion: EETs are reportedly implicated in AD development, with most previous investigations using animal models and targeted enzymes involved in EET metabolism, particularly soluble epoxide hydrolase (sEH). Furthermore, no studies have specifically examined EET metabolism in patients with advanced AD. This study revealed defective EET signaling with consequent increased sEH activity in AS-LOAD, suggesting that decreased EET might contribute to tau-mediated neurodegeneration, oxidative stress, and neuroinflammation in these patients. Conclusion: This study emphasizes the crucial role of EETs in AD pathology. Targeting EET metabolism could offer a promising therapeutic strategy for preventing AD. Studies that track disease progression are therefore a prerequisite for delaying its disease onset; thus, larger-scale longitudinal studies are needed to confirm these findings.
INTRODUCTION:The current study was carried out to assess the pharmacological action of combine effect of Poloxamer 188, Lycopene, and Quercetin on memory and energy deficit in Huntington's disease-like signs induced by 3 Nitropropionic acid in Wistar rats. METHODS:After one week of acclimatization all animals were randomly assigned in six groups, (n = 6), as normal control, Huntington's disease control, Lycopene treated (25 mg/kg po), Quercetin treated (50 mg/kg po), combinations with and without Poloxamer 188 (80 mg/kg po) with adjunct administration of 3 nitropropionic acid (10 mg/kg i.p.) except in normal control. Memory and energy deficits were induced by i.p. administration of 3 Nitropropionic acid (10 mg/kg) for 14 days. A novel object recognition test was assessed on the 14th and 15th days of the experiment, post-treatment, and other biochemical parameters were examined at the end of the experiment. RESULT:The results showed that the 3-nitropropionic acid administration for 14 days produced memory and energy deficits in rats. Moreover, the combination of Lycopene and Quercetin, with and without Poloxamer 188, showed significant effects on memory enhancement, energy deficit, and body weight compared to single-drug therapy. However, the combination did not produce a significant increase in brain weight compared to single-drug therapy. Moreover, the combination also showed remarkable enhancement in Succinate dehydrogenase activity and reduction in Lactate dehydrogenase activity compared to monotherapy. DISCUSSION:The combined therapy of lycopene, quercetin, and poloxamer 188 significantly improved 3-nitropropionic acid-induced cognitive deficits by reducing oxidative stress and enhancing cholinergic function. This synergistic effect also normalized key mitochondrial enzymes, suggesting strong neuroprotective potential against Huntington's disease progression. CONCLUSION:Administration of 3-nitropropionic acid for 14 days produces memory and energy deficits in rats. Combining the effects of Lycopene and Quercetin, with or without Poloxamer 188, enhances memory and reduces energy deficit more effectively than mono-therapy. This study assessed the effects of combined lycopene, quercetin, and poloxamer 188 treatment on cognition and energy deficits in a 3-nitropropionic acid-induced rat model. Treating with a combination of the three compounds resulted in behavioral and biochemical improvements compared to the disease control group. There may be a tendency for the combined treatments to have additive effects on the subjects compared to individual treatments. However, the results of this study should be interpreted with caution.
Cortisol, regulated by the hypothalamic-pituitary-adrenal (HPA) axis, is critical for stress response, metabolism, and immune function. Its dysregulation is increasingly implicated in neurodegenerative disorders, including Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), amyotrophic lateral sclerosis (ALS), and multiple sclerosis (MS). This review synthesizes evidence on cortisol's role in neurodegenerative disorders, exploring its mechanisms, clinical implications, and therapeutic potential. This study analyzed preclinical models, clinical studies, and biomarker data to elucidate cortisol's impact on neurodegeneration. Key mechanisms include glucocorticoid and mineralocorticoid receptor-mediated effects on synaptic plasticity, neuroinflammation, and oxidative stress. In AD, elevated cortisol accelerates cognitive decline, hippocampal atrophy, and amyloid-β accumulation. In PD, higher cortisol levels correlate with gait dysfunction and dopaminergic neuron loss. HD shows variable cortisol profiles, with early hypocortisolism shifting to hypercortisolism in later stages, linked to depression. In ALS, elevated cortisol hastens disease progression and neuroinflammation. In MS, HPA axis hyperactivity is associated with cognitive deficits and lesion activity, though it may support remyelination. Chronic stress exacerbates these effects across disorders, promoting neuronal vulnerability. Cortisol dysregulation is a significant contributor to neurodegenerative pathology, acting as both a biomarker and therapeutic target. Emerging interventions, including glucocorticoid receptor antagonists, cortisol synthesis inhibitors, and stress reduction strategies, show promise in mitigating neuronal damage. Personalized, stage-specific therapies and longitudinal studies are needed to optimize cortisol-targeted treatments for neurodegenerative diseases.
Neuroscience is making tremendous progress toward precision medicine, with nanotechnology playing a critical role in overcoming hurdles to successful brain medication delivery. Nano magnetism, namely biohybrid magnetoelectric nanocarriers (MENs), has emerged as a potential method for targeted and non-invasive medication delivery in neurological illnesses. These nanocarriers possess magnetoelectric properties, enabling stimulus-responsive drug release that is externally controlled. This allows for precise targeting across the blood-brain barrier (BBB), with exceptional spatial and temporal resolution. MENs can deliver neurotherapeutics deep into brain regions by combining magnetic guidance with electrical stimulation, thereby improving treatment outcomes for conditions such as Alzheimer's, Parkinson's, epilepsy, and glioblastoma. Furthermore, their biohybrid nature, which is accomplished by functionalizing nanocarriers with biocompatible coatings, peptides, or membranes produced from neural cells, increases biostability, decreases immune response, and improves neuron targeting. This review investigates the underlying concepts of magnetoelectric nanocarriers, production processes, and interactions with brain tissue. It dives deeper into recent advances in precision neural drug delivery, including the effect of external magnetic and electric fields on regulated drug release, neurostimulation, and neuromodulation. While MENs have tremendous promise, long-term biocompatibility, precise control systems, and regulatory restrictions continue to impede clinical translation. Future research should concentrate on enhancing nanocarrier design, increasing targeting efficiency, and undertaking large-scale preclinical and clinical trials. Magnetoelectric nanocarriers have the potential to transform non-invasive neurotherapeutics by bridging the gap between nano magnetism and neuroscience, resulting in safer and more successful treatment paradigms for complex brain illnesses.
Frontotemporal Dementia is an umbrella term for several neurodegenerative disorders that have a similar presentation pattern, which is accompanied by neural damage and brain tissue loss in the frontal and temporal regions. Recent studies have observed that the heterogeneity of Frontotemporal Dementia (FTD) is reflected in clinical features, genetics, and molecular perspectives. Specifically, the major forms of pathology in FTD are linked to abnormal protein accumulation, which includes tau, TAR DNA-binding protein 43 (TDP-43), and fused in sarcoma (FUS). Moreover, genetic research on FTD has identified vital mutations in MAPT (Microtubule-associated protein Tau), GRN (Progranulin Gene), and C9ORF72 genes (Chromosome 9 open reading frame genes). Recent developments in neuroimaging, biomarker levels in body fluids, and molecular profiling have increased diagnostic precision, enabling earlier detection of disease subtypes. Neurofilament light chain (NfL), progranulin, and several other biomarkers, together with novel neuroimaging approaches, are currently being applied for disease classification, prognosis, and disease treatment monitoring. These developments have accelerated the application of precision medicine for FTD, including antisense oligonucleotides, progranulin-restorative drugs, tau-specific therapies, and gene therapy. Despite advances in elucidating the biology of FTD, no disease-modifying therapies have yet been developed, and treatments remain symptomatic until now. Undoubtedly, there are many challenges when taking into account variable presentation, overlapping pathologies, and the lack of robust biomarkers. The aim of this paper is to provide an in-depth analysis of the epidemiology, clinical features, molecular pathologies, biomarkers, and potential therapeutic approaches concerning FTD, with a particular emphasis on the growing role of precision medicine. Omics technologies, biomarker- based patient stratification, and hypothesis-driven clinical trials are undoubtedly essential steps towards personalized therapy for FTD.
Neuropsychiatric symptoms (NPS) are highly prevalent in Alzheimer’s disease (AD). Consequently, potentially inappropriate medication (PIM) use is particularly common among older adults with AD. Psychotropic polypharmacy may increase the risk of various adverse outcomes beyond cognitive decline. Although geriatric prescribing criteria and dementia-care guidelines offer important safety recommendations, a clinically integrated framework for potentially inappropriate psychotropic medication use in older adults with AD remains insufficiently developed. This article is a narrative review rather than a systematic review or meta-analysis. The authors searched the literature in PubMed, Embase, and the Cochrane Library, focusing on studies, guidelines, consensus statements, regulatory safety warnings, and medication-safety criteria published between January 2015 and June 2026. This review specifically examines anticholinergic drugs, antipsychotics, benzodiazepines and Z-drugs, tricyclic antidepressants, and select newer antidepressants-including selective serotonin reuptake inhibitors (SSRIs), serotonin-norepinephrine reuptake inhibitors (SNRIs), mirtazapine, trazodone, and paroxetine-guided by the 2023 American Geriatrics Society (AGS) Beers Criteria®. Current evidence indicates that these medications may contribute to cognitive decline through anticholinergic burden, sedation, and pharmacodynamic interactions with cholinesterase inhibitors, such as donepezil and memantine. However, the strength of evidence varies considerably across drug classes and study designs, ranging from randomized controlled trials to observational studies and expert consensus. This study also summarizes current nonpharmacological strategies and proposes a structured clinical medication review framework. Overall, this review highlights the importance of minimizing inappropriate psychotropic use in AD, prioritizing non-pharmacological interventions, and conducting individualized risk-benefit assessments in clinical practice.
Alzheimer's Disease (AD) involves progressive brain changes at both the structural and ultrastructural levels, which begin long before patients present with clinical symptoms. These changes relate to the complex processes of amyloid-β deposition, tau accumulation, synaptic damage, glial activation, impaired vascular function, and disruption of large-scale brain networks. Understanding these neurobiological changes is essential for improving diagnosis, biomarker development, and targeted therapy. We conducted a search across PubMed, Scopus, and Web of Science using the terms "Alzheimer's disease," "brain structure," "ultrastructure," "cryo-electron microscopy," and "neuroimaging." We limited our review to peer-reviewed papers published in English. Recent developments in cryo-electron microscopy, super-resolution imaging, in situ cryo-electron tomography, and correlative microscopy have revealed the molecular and subcellular features of amyloid plaques and tau filaments, as well as the associated cellular pathology of AD. These investigations refine current pathophysiological models and improve understanding of molecular-level changes in the brain. Improvements in structural and molecular imaging provide potential new biomarkers and therapeutic targets in AD. Advances in imaging and structural neuroscience could support earlier disease detection and improve clinical outcomes. These advances are helping to connect molecular pathology with structural brain remodelling and may support more precise biomarker interpretation and therapeutic development.
INTRODUCTION:Alzheimer's Disease (AD) is a neurological condition that increases in severity from a gradual start. Previous studies have found an association between long sleep (LS) and AD. To slow its progression, it is important to recognize biomarkers associated with the early stages of both AD and LS. METHODS:This study aimed to use two-sample Mendelian Randomization (MR) to identify blood and urine biomarkers associated with AD and LS. Thirty-five biomarkers from blood and urine were included as exposures in the MR analysis, while AD and LS were considered the outcomes. The AD dataset included 39,106 patients and 46,828 controls from Europe. Data on sleep duration were obtained from a GWAS in 34,184 cases and 305,742 controls of European ancestry. This study included 35 blood and urine biomarkers across 355,891 participants, including 318,953 white British, 23,582 non-white British, 6,019 African, and 7,338 South Asian participants from the UK Biobank. RESULTS:Cystatin C, CRP, and Non-Albumin protein showed genetic association with AD and LS. The genetic association results after Bonferroni's correction are significant for Non-Albumin Protein in AD and LS. DISCUSSION:This study provides further insight into the genetic associations and relationships among AD, LS, and other biomarkers; it also presents several potential candidates for AD and LS diagnosis and treatment. The opposing roles of C-reactive Protein, Cystatin C, and Non-Albumin protein in AD and LS warrant a greater exploration of their differential functions at various ages and in specific brain microenvironments in future studies. CONCLUSION:This study provides a theoretical basis for the diagnosis and treatment of AD and LS. More experiments are needed in the future to verify this prediction.
Alzheimer's Disease (AD) is considered a devastating and often underrecognized global health burden. Despite extensive ongoing research, effective treatments remain limited by an incomplete understanding of its multifarious pathogenesis, more than a century since the first report of AD in 1906. This review proposes a novel conceptual framework that draws parallels between entropy- driven systemic collapse in physical systems and neurodegeneration in AD. Specifically, it highlights how entropy may lead to systemic collapse, whether in a dead star that forms a black hole or in an AD-afflicted brain region. Though differing in biological and physical scales, AD and black holes share analogous features, including rising entropy, irreversible degeneration, and system decay, that are fundamental to understanding their underlying physics. Both AD and black holes represent systems characterized by irreversible loss of structure, energy, and information. In AD, progressive neural death leads to cognitive impairment, synapse loss, and brain atrophy, reflecting impaired energy utilization and increasing entropy within neural networks. Similarly, a black hole forms from stellar collapse, where energy becomes gravitationally confined and entropy increases as information is lost beyond the event horizon. Diagnostic exploration of both phenomena relies on interpreting waves and signals, neuroimaging in the brain, and the detection of electromagnetic or gravitational waves in space, revealing how the breakdown of structure and the dissipation of accessible energy signify a fundamental loss of order in complex systems. This conceptual framework may help inspire innovative energy-based therapeutic approaches for AD before the disease reaches an irreversible stage of pathogenesis.
Alzheimer's Disease (AD) is a neurodegenerative disorder that characterizes depletion of memory, cognition, and a change in behavioural patterns. There is no standard treatment that completely cures this prevalent disease. This review delves into the existing pathologies of AD, which include the Aβ plaques accumulation, neurofibrillary tangles and Lewy bodies formation, and the influence of the P2X7 receptor on cellular mechanisms of neuronal cells like microglial cells, astrocytes and oligodendrocytes and also its influence on pathways such as JAK2/STAT3, NGF signalling, (Transactive response DNA binding protein) TDP-43 Proteinopathy, Wnt/β-Catenin signalling, and FGF7/FGFR2/PI3K/Akt causing AD. It discusses the unifying role of the P2X7 receptor mediating these pathways that link to the occurrence and progression of AD. The role of the Purinergic receptor (P2X7 receptor), a ligand-gated ion channel activated by extracellular ATP, was examined across existing cellular mechanisms and possible pathways involved in AD, as well as the co-pathologies encompassed and their hypothetical relationship with the P2X7 receptor. Additionally, the current P2X7 receptor antagonists treating neurotoxicity are discussed along with existing pre-clinical and clinical data. This may further advance drug development by targeting the P2X7 receptor to mitigate AD across multiple mechanisms.
The WNT signaling pathway plays a significant role in various biological processes during embryonic development, childhood, and adulthood. It is involved in neurogenesis, synapse formation, and such cognitive processes as learning and memory in the CNS. Dysregulated WNT signaling is associated with cognitive decline, synaptic dysfunction, neuronal loss, and has been associated with diseases like leukemia and colorectal cancer. The studies show that WNT/β-catenin signaling affects the cellular, molecular, and metabolic mechanisms that promote disease progression. The WNT pathway is a potential therapeutic target because it helps maintain neuronal survival, supports the growth of new nerve cells, and enhances synaptic plasticity. WNT signaling is important for stem cell selfrenewal and differentiation. Research is being conducted on therapeutic methods targeting WNT signaling to treat neurological diseases and cancer. This review explores the connection between WNT signaling and the pathology of Alzheimer's disease. This review explores the role of WNT signaling in AD pathogenesis, with a focus on the Wnt/β-catenin pathway as a therapeutic target. It summarizes existing findings to demonstrate that WNT signaling is a context-dependent regulatory network in which a shift from protective canonical activity to dysregulated non-canonical and inflammatory pathways contributes to disease progression.
INTRODUCTION/OBJECTIVE:Alzheimer's Disease (AD) is characterized by progressive cognitive decline and disrupted neural oscillations. Recently, 40 Hz gamma stimulation has emerged as a potential non-invasive therapy. This review evaluates the safety, tolerability, and clinical outcomes of this intervention based on evidence from the past decade. METHODS:A literature search was conducted across PubMed, Web of Science, Google Scholar, and ClinicalTrials.gov for studies published during the last ten years. Registered and ongoing studies were also identified through ClinicalTrials.gov. Extracted data included stimulation modality, stimulation parameters, safety and tolerability outcomes, and reported effects on functional connectivity, brain atrophy, cognitive performance, and sleep-related measures. RESULTS:Thirty studies were identified, comprising eight sensory-based 40-Hz gamma stimulation approaches, 12 40-Hz transcranial Alternating Current Stimulation (tACS) protocols, and 10 ongoing clinical trials. Among the 20 completed studies, 40-Hz gamma stimulation was reported to be safe and well-tolerated. The synthesized evidence from these completed trials suggests potential beneficial effects on functional connectivity, brain atrophy progression, cognitive outcomes, and sleep-related measures. DISCUSSION:Gamma stimulation may represent a promising approach for modulating neural network activity and cognitive function in AD. Nevertheless, current evidence remains limited by small sample sizes, methodological heterogeneity, differences in stimulation protocols, and short follow-up periods. These factors limit the ability to draw definitive conclusions regarding therapeutic efficacy. CONCLUSION:40-Hz gamma stimulation is a feasible and generally well-tolerated non-invasive intervention with potential relevance for AD treatment. Further large-scale, randomized, and controlled studies are required to establish standardized stimulation protocols, determine long-term efficacy, and clarify its clinical utility.
Alzheimer’s Disease (AD) is a progressive neurodegenerative disorder characterized by a decline in cognitive abilities and memory impairment, representing the most common form of dementia worldwide. First described by Alois Alzheimer in 1906, AD continues to pose significant global health and socioeconomic challenges, with incidence anticipated to exceed 14 million cases by 2060. Despite decades of investigation, the specific pathophysiology -comprising multifactorial mechanisms such as genetic predisposition, environmental influences, lifestyle factors, amyloid-β (Aβ) plaques, neurofibrillary tangles, tau pathology, as well as vascular disease - remains incompletely understood. This review provides a comprehensive summary of the current knowledge regarding these mechanisms, and it explores the field's new therapeutic modalities, such as monoclonal antibodies, ultrasound-based treatments, and novel diagnostic tools based on biomarkers. It also discusses the socioeconomic burden of AD and regional challenges in the Middle East, as well as the impact of the COVID-19 pandemic on dementia care. While many of AD's underlying causes are aggressive and difficult to treat, new research in genetics, natural compounds, and groundbreaking therapies offers hope for better diagnosis and treatment. Above all, this study emphasizes the importance of having more effective chemotherapeutic or radiological approaches for ADs, as well as a robust medical system capable of providing these treatments to the patients.
INTRODUCTION:The pathogenesis of Alzheimer's disease (AD) is complex, with immune system dysregulation playing a critical role. However, the specific molecular mechanisms linking peripheral immune responses to central pathologies in AD remain unclear. This study aims to systematically screen for reliable plasma biomarkers of AD by integrating transcriptomics, Mendelian randomization (MR) of plasma proteomics, and bioinformatics analyses, and to explore their potential pathogenic mechanisms and therapeutic drugs. MATERIALS AND METHODS:Transcriptomic sequencing of plasma samples from three AD patients and three healthy controls was first performed to identify differentially expressed genes (DEGs) and perform functional enrichment analyses. The aim of this study is to provide a preliminary indication of gene expression changes based on real patient samples for subsequent MR and bioinformatics analyses, rather than serving as confirmatory evidence. Following this, two-sample MR was performed to explore the potential causal relationship between plasma proteins and AD in genetic prediction, and MR-positive results were intersected with transcriptome DEGs to identify highconfidence targets. After that, protein-protein interaction (PPI) analysis, functional enrichment (GO/KEGG), and transcription factor (TF) target network analysis were conducted. Based on the KEGG pathway analysis, the causal association between antibodies related to Epstein-Barr virus and AD in genetic prediction was further evaluated. In the end, the diagnostic power of core biomarkers was validated in the GEO dataset. Potential therapeutic drugs were screened in the CTD database, followed by verification through molecular docking and molecular dynamics simulation. RESULT:Our transcriptomic enrichment analysis of DEGs indicates that AD is significantly correlated with viral infection and immune and inflammatory pathways. According to the results of MR analyses, 36 plasma proteins have a causal effect on AD in genetic prediction. Among these 36 targets, two pathways are identified as enriched: "EBV Infection" and "Efferocytosis". Seven core targets are CR2, ICAM1, TAPBP, TNFAIP3, THBS1, SCARF1, and SIRPG. Also, the concentration of antibodies against EBV EBNA-1 and VCA p18 was confirmed by MR analyses to be risk factors for AD. According to drug predictions, molecular docking, and molecular dynamics simulations, resveratrol can stabilize CR2. DISCUSSION:This study systematically identifies major plasma immune biomarkers associated with AD and proposes a mechanism by which EBV infection regulates plasma proteins CR2, TNFAIP3, and THBS1, which may affect AD risk. Resveratrol is thought to have preventive and protective effects, as predicted computationally. CONCLUSION:This study systematically identified key plasma markers associated with AD. Resveratrol is likely to become a potentially effective preventive and protective drug in the prevention and treatment of AD, providing new ideas and targets for immune intervention of AD.
Introduction: Early-Onset (EOAD) and Late-Onset Alzheimer’s Disease (LOAD) are often described as presenting distinct cognitive phenotypes. However, reported differences are inconsistent and may reflect demographic and severity-related confounding rather than stable etiological distinctions. Materials and Methods: A retrospective analysis was conducted in 776 patients with clinically diagnosed Alzheimer’s disease (EOAD, n = 175; LOAD, n = 601). Cognitive performance was assessed using the Addenbrooke’s Cognitive Examination III (ACE-III) and the Mini-Mental State Examination (MMSE). Dementia severity was staged using the Functional Assessment Staging Tool (FAST). Cognitive outcomes were analysed using age- and severity-adjusted ANCOVA models including a diagnosis × age interaction. Severity-stratified and domain-level analyses were also performed. results: Unadjusted analyses revealed limited EOAD–LOAD differences in the Attention and Visuospatial domains, with small effect sizes. After adjustment for demographic factors and dementia severity, no cognitive measure reliably differentiated EOAD from LOAD. Cognitive decline followed parallel trajectories in both groups and was primarily driven by disease severity. Results: Unadjusted analyses revealed limited EOAD-LOAD differences in the Attention and Visuospatial domains, with small effect sizes. After adjustment for demographic variables and dementia severity, no cognitive measure reliably differentiated EOAD from LOAD. Cognitive performance showed similar cross-sectional patterns across groups and was primarily determined by dementia severity. Discussion: Small, stage-dependent differences observed at mild and moderate stages did not persist in more advanced dementia and did not indicate stable cognitive dissociation between EOAD and LOAD. Conclusions: After adjustment for demographic factors and dementia severity, EOAD and LOAD do not exhibit distinct cognitive profiles on ACE-III. Cognitive performance reflects disease stage rather than age at onset, supporting the use of ACE-III for staging cognitive impairment rather than for differentiating EOAD from LOAD in typical amnestic presentations.
Introduction/Background: Recent studies show that depression often occurs years before Alzheimer's disease onset in many older adults. However, it is unclear whether this link reflects a causal relationship. Materials and Methods: Summary statistics from Genome-Wide Association Studies (GWAS) of depression and Alzheimer's disease were utilized. Data associated with broad depression included up to 407,746 Europeans, and data associated with major depression disorder included up to 480,359 Europeans; the corresponding Alzheimer's disease associations from consortia included up to 488,285 European participants in the UK Biobank. Two-sample Mendelian randomization analyses served as our primary approach, with additional three-sample analyses performed to validate the findings. Results: In the sample of 407,746 participants, genetically predicted levels of broad depression showed no significant association with Alzheimer's disease risk (odds ratio, 1.00007; p = 0.908). As for the sample of 480,359 participants associated with major depressive disorder, the result was consistent (odds ratio, 0.99918, p = 0.138) with findings from broad depression. Secondary analyses present consistent results with primary findings. Statistically significant bias from pleiotropy or genetic confounding was not detected in sensitivity analyses. Discussion: The study’s findings do not support a causal role of depression in AD and are more consistent with depression reflecting early disease processes or shared mechanisms. Conclusion: This study's Mendelian randomization approach revealed no causal relationship between depression and Alzheimer's disease, consistent with depression reflecting early disease manifestations rather than a direct causal factor, and hinting at possible shared pathological processes in both conditions.
Introduction: The number of patients with Alzheimer’s Disease (AD) worldwide is expected to reach 152 million by 2050, but developing an effective AD treatment remains challenging. This study purified two polysaccharides (GSP1 and GSP2) from Ganoderma sinense, a traditional Chinese medicine, and investigated their potential therapeutic effects against AD. Materials and Methods: GSP1 and GSP2 were purified and characterized for key physicochemical properties, including monosaccharide composition and molecular weight. In vitro neuroprotective efficacy was evaluated using glutamate-challenged SH-SY5Y cells. For in vivo assessment, an AlCl₃/D-galactose induced AD mouse model was established to quantify cognitive/memory enhancement. Multiomic analysis of the gut microbiota, Short-Chain Fatty Acid (SCFAs) metabolomics, and behavioural tests were conducted to elucidate the therapeutic mechanisms of GSP1. Results: Both GSP1 and GSP2 conferred neuroprotection against toxin-induced damage. Notably, GSP1 demonstrated superior efficacy compared with GSP2, significantly enhancing cognitive/ memory performance and reducing amyloid-β plaque deposition. Furthermore, GSP1 changed gut microbial diversity and SCFA metabolic profiles. Critical genus-level correlations emerged: Turicibacter, Jeotgalicoccus, and Staphylococcus were positively associated with therapeutic outcomes, whereas Odoribacter was negatively associated. Discussion: Natural polysaccharides, particularly GSP1, demonstrate therapeutic potential against AD by modulating gut microbiota. Mechanistically, this effect is linked to reshaping microbial communities and affecting the production of neuroprotective SCFAs. Although these findings position GSP1 as a promising AD therapeutic candidate, deeper exploration of gut-brain axis mechanisms remains essential for clinical translation. Conclusion: GSP1 emerges as a promising therapeutic candidate for AD, offering a new approach to developing AD-targeted pharmaceuticals and nutraceuticals.
INTRODUCTION/BACKGROUND:Alzheimer's Disease (AD) core pathology involves amyloidβ and ptau, leading to neurodegeneration (ATN model), yet individuals with comparable core pathology show considerable biological and clinical heterogeneity, motivating new models that consider non-specific processes and co-pathology. MRI and peripheral proteomics offer complementary, non-invasive approaches for capturing biological variation beyond core pathology, and many researchers have begun integrating them. However, no systematic overview of this literature exists. This scoping review evaluated studies combining MRI and peripheral plasma proteomics in AD within revised diagnostic frameworks, summarizing strengths and gaps. MATERIALS AND METHODS:Following PRISMA 2020 guidelines, PubMed, Embase, and Scopus were searched through June 14, 2023, yielding 3,185 records; 63 studies met the inclusion criteria. For each study, study design, participant characteristics, proteomic platforms, imaging modalities, statistical approaches, and significant associations between non-core-pathological proteins and MRIderived measures were extracted. RESULTS:Across studies, methodological variability was high. Grey matter volume was the most commonly examined imaging metric, followed by cerebrovascular dysfunction, cortical thickness, white-matter and whole-brain volume, and connectivity measures. Overall, 127 non-core-pathology proteins, mostly related to inflammation/immune function, were associated with MRI metrics, though only three appeared in five or more studies. Roughly half of the studies incorporated core AD biomarkers. DISCUSSION:This scoping review of 63 studies demonstrates that integrating peripheral proteomics with MRI is an increasingly common approach in AD research, with GFAP, CRP, and IL-6 as the most frequently reported proteins, and grey matter volume and vascular dysfunction as the most commonly examined imaging phenotypes. However, effect sizes are generally modest, findings are heterogeneous, and many studies lack core AD biomarkers, highlighting the need for greater methodological consensus and more mechanistic, multimodal, and longitudinal research. CONCLUSION:Integrating MRI and peripheral proteomics is increasingly common in AD research, but consensus on analytic and imaging approaches is limited. Heterogeneity in proteomic platforms and statistical methods constrains comparability; most associations are modest, and observational designs limit causal inference. Future work should emphasize methodological harmonization, reproducibility, multivariate and machine-learning approaches, and randomized trials to test mechanistic pathways.
INTRODUCTION:Alzheimer's disease stands as the most prevalent form of dementia, characterized by a progressive decline in cognitive function and memory. Numerous risk factors have been linked to its development, creating a complex interplay of influences. In this study, we aim to delve into the relationship between cardiovascular disease and Alzheimer's disease, exploring how conditions affecting heart health may impact the onset and progression of this debilitating neurological disorder. Through this research, we could find potential connections that inform prevention strategies and therapeutic approaches. MATERIALS AND METHODS:We adopted the PRISMA guidelines and defined the PECOS framework as follows: Population (P) = individuals; exposure (E) = cardiovascular disease; comparison (C) = without cardiovascular disease; outcome (O) = Alzheimer's disease; and study design(S) = all kinds of studies with an association between cardiovascular disease and Alzheimer's disease without time limits. A meta-analysis was conducted using case-control, cohort, and genetic studies to estimate Odds Ratios (ORs) or Hazard Ratios (HRs). RESULTS:The pooling of data in meta-analysis demonstrated that a person with any Cardiovascular Disease (CVD), Heart Failure (HF), Coronary Artery Disease (CAD), Atrial Fibrillation (AF), Hypertension (HTN), and Myocardial Infarction (MI) had more risk of developing Alzheimer's disease [CVD: HR = 1.30 (CI: 1.27-1.33) / HF: HR = 1.63 (CI: 1.37-1.94) / CAD: HR = 1.43 (CI: 1.40-1.46) / AF: HR = 1.38 (CI: 1.34-1.42) / HTN: HR = 1.22 (CI: 1,10-1.35) / MI: HR = 1.07 (CI: 1,01-1.13)]. Cross-sectional studies demonstrated an association between cardiovascular diseases and Alzheimer's disease [OR = 1.29 (CI: 1.23-1.35)]. Mendelian randomization meta-analysis did not demonstrate a causal relation between cardiovascular disease and Alzheimer's disease [AF: OR = 1.03 (CI: 1.00-1.01) / HF: OR = 1.00 (CI: 0,79-1.36)]. A Mendelian randomization meta-analysis demonstrated that a person with AD had a higher risk of developing myocardial infarction [OR = 1.07 (CI: 1.03-1.10)]. DISCUSSION:This review examines the connection between AD and CVD, noting that HF increases the risk of developing AD with a hazard ratio of 1.63. It suggests that altered brain perfusion and hypoxia appear to be one important neurodegenerative factor. Some genetic changes in individuals with CVD made them more vulnerable to AD. Effective prevention and treatment of CVD can help reduce the risk of AD. CONCLUSION:HF, AF, and CAD were the CVDs with the highest risk of developing AD. The results suggest that changes in cerebral blood perfusion are a principal neuropathological event that leads to genetic alterations that end in AD.
INTRODUCTION:Zolpidem is a widely used non-benzodiazepine hypnotic that is used as a treatment for insomnia due to its rapid onset and perceived safety. Nevertheless, rising clinical reports and post-marketing surveillance have identified serious neuropsychiatric adverse effects, such as hallucinations, perceptual disturbances, and complex sleep-related behaviors, such as sleep-driving and sleep-eating, as being frequent and often unnoticed by the patient. The consequences of such events can be severe personal injury and litigation. Regardless of these issues, there are few comparative data between zolpidem and newer hypnotics. METHODS:A narrative literature review was conducted using PubMed/MEDLINE, Scopus, and Web of Science for studies published between 2020 and 2025. RESULTS:Zolpidem was commonly linked to complex sleep acts, amnesia, and hallucinations, especially when in high dosage and when the patients had psychiatric comorbidities. On the contrary, some more recent ones, like orexin receptor antagonists, were less subject to such adverse effects, whereas the melatonin-based therapies were associated with positive safety profiles but lesser hypnotic efficacy. A number of case reports reported criminal charges in relation to zolpidem-induced altered states of consciousness. CONCLUSION:Zolpidem, despite its usefulness in the management of insomnia, has a relatively high likelihood of neuropsychiatric adverse effects, particularly among women, the elderly, psychiatric patients, and those who have undergone polypharmacy. Environmental risk-benefit evaluation must be performed cautiously and individually, prescribing zolpidem while taking into account patientspecific clinical and pharmacokinetic parameters.
