@article {pmid41160465,
year = {2025},
author = {Alaka, SA and Ngan, SC and MacPherson, RE and Pickett, W and Chen, CP and Sze, SK},
title = {Enhancing dementia risk prediction with heart rate and machine learning in the Canadian Longitudinal Study on Aging.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877251390562},
doi = {10.1177/13872877251390562},
pmid = {41160465},
issn = {1875-8908},
abstract = {BackgroundAccurate and accessible risk assessment tools are essential for effective dementia management. The Cardiovascular Risk Factors, Aging, and Incidence of Dementia (CAIDE) model is the widely used tool to assess mid-life dementia risk.ObjectiveTo determine whether adding resting heart rate (RHR), a simple, readily measurable, non-invasive vital sign, improves dementia risk prediction within the CAIDE model using machine learning methods.MethodsData from 27,768 participants of comprehensive cohort in the Canadian Longitudinal Study on Aging were analyzed to predict 3-year dementia risk. Predictive models were developed using random forest and support vector machine algorithms. Performance was assessed using key metrics, including area under the receiver operating characteristic curve (AUC), sensitivity, specificity, Matthew's correlation coefficient (MCC), and Brier score. Internal cross-validation was used to ensure model robustness.ResultsAmong the 18,013 participants with complete data for analysis, 516 (2.86%) exhibited dementia. Incorporating RHR into the CAIDE model led to a significant improvement in predictive accuracy. Random forest models with RHR achieved an AUC of 0.67 and an MCC of 0.32 in training data, compared to 0.65 and 0.29 in the test data. Similarly, support vector machines demonstrated a 2-3% increase in both AUC and MCC with the inclusion of RHR.ConclusionsIncorporating RHR modestly but significantly improves the predictive performance of the CAIDE model using machine learning methods. This approach may support earlier identification of at-risk individuals using non-invasive, routinely available data, representing a step toward scalable and practical dementia risk screening in clinical and community settings.},
}

@article {pmid41160464,
year = {2025},
author = {Kim, M and Kwon, H and Sohn, S and Lee, WJ and Cho, K and Kim, GW},
title = {Alzheimer's disease diagnosis and treatment: From pathophysiological insights to therapeutic advances in the era of precision neurology (2025 review).},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877251391820},
doi = {10.1177/13872877251391820},
pmid = {41160464},
issn = {1875-8908},
abstract = {Alzheimer's disease (AD) is a multifactorial neurodegenerative disorder marked by progressive cognitive decline, functional impairment, and ultimately, loss of independence. Traditional models centered on amyloid-β and tau pathology have expanded to encompass interconnected processes such as neuroinflammation, synaptic dysfunction, and gut-brain axis disruption, underscoring the multifactorial nature of the disease. In this review, we delivered that advances in diagnosis now integrate fluid biomarkers within the A/T/N/X framework, high-resolution neuroimaging, and artificial intelligence, enabling earlier and more precise disease characterization. On the therapeutic front, the approval of anti-amyloid monoclonal antibodies marks a paradigm shift toward disease-modifying approaches, yet challenges remain regarding efficacy, safety, and accessibility. Complementary strategies, including cognitive interventions and innovative drug delivery systems, highlight the need for multidimensional care that extends beyond pharmacology to improve patient quality of life. Furthermore, emerging avenues such as stem cell therapy, multitarget drug development, and precision medicine approaches illustrate a field in transition-shifting from symptomatic management toward personalized strategies aimed at altering the course of AD.},
}

@article {pmid41160462,
year = {2025},
author = {Singh, S and Kumar, U},
title = {Brain region-specific dopamine receptor changes and astrocyte activation influence tau pathology through CDK5 in Alzheimer's disease models.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877251389961},
doi = {10.1177/13872877251389961},
pmid = {41160462},
issn = {1875-8908},
abstract = {BackgroundThe abnormal extracellular accumulation of amyloid-β (Aβ) plaques and intracellular tau inclusions are hallmarks of early events in the pathogenesis of Alzheimer's disease (AD). Although growing evidence implicates neurotransmitter dysregulation in AD-associated neurodegeneration, the influence of these pathological hallmarks on dopaminergic signaling remains poorly understood. This study reports changes in dopamine receptor (DR), Aβ, and astrocyte distribution in the cortex and hippocampus of 5XFAD mice.ObjectiveTo investigate how Aβ pathology alters dopamine receptor subtype expression in the AD brain and neuronal models, and whether this contributes to tau phosphorylation and CDK5 activation.MethodsWe examined DR1-DR5 expression and localization in the cortex and hippocampus of 5XFAD mice using immunohistochemistry, qPCR, and western blot. SH-SY5Y cells were differentiated with retinoic acid and treated with Aβ1-42; MC-65 cells produced endogenous Aβ via tetracycline withdrawal. DR1, DR2, and DR3 agonists were used to assess effects on cAMP, CDK5, and tau phosphorylation.ResultsIn AD brains, Gs-coupled DR1 and DR5 were upregulated, while Gi-coupled DR2, DR3, and DR4 were downregulated at mRNA and protein levels. SH-SY5Y and MC-65 cells recapitulated these subtype-specific changes following Aβ exposure. In the cortex, receptor alterations were implicated in increased CDK5 and tau phosphorylation. DR activation modulated cAMP and kinase pathways in a receptor- and cell-specific manner. The cortex showed greater vulnerability to Aβ-associated degeneration, whereas the hippocampus was more susceptible to inflammation and tau pathology.ConclusionsThese findings reveal a role for DR subtypes in regulating tau phosphorylation and CDK5, with implications for AD-related cognitive dysfunction.},
}

@article {pmid41160460,
year = {2025},
author = {Cury, RM and da Silva, T and Cezar-Dos-Santos, F and Fakih, YRC and Narvaez, KAR and Gouvea, MC and Espínola, C and Ferreira, CF and de Castro, WAC and Pamplona, FA and Silva, EGD and Bicca, MA and Nascimento, FP},
title = {A randomized clinical trial of low-dose cannabis extract in Alzheimer's disease.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877251389608},
doi = {10.1177/13872877251389608},
pmid = {41160460},
issn = {1875-8908},
abstract = {BackgroundPreclinical and clinical evidence suggest that low-dose cannabinoids could ameliorate Alzheimer's disease (AD) signs and symptoms. We designed this trial to evaluate the safety and efficacy of low-dose THC-CBD balanced cannabinoid extract in the treatment of patients with AD-associated dementia.ObjectiveThe objective of this phase 2 trial was to evaluate the safety and efficacy of a balanced THC-CBD cannabinoid extract for symptomatic patients with AD.MethodsA Phase 2, randomized, double-blind, placebo-controlled, clinical trial including patients between 60 and 80 years-old diagnosed with AD-associated dementia. For 26 weeks, participants orally received either placebo or THC-CBD extract (0.350 mg/THC and 0.245 mg/CBD), daily.ResultsAt week 26, Mini-Mental State Exam total score was significantly higher in cannabis- when compared to placebo-treated patients, which was assessed using the mixed model analysis. No significant difference was detected between placebo and cannabis groups in terms of secondary outcomes and adverse events incidence.ConclusionsTo this date, this is the longest clinical trial evaluating cannabinoids effects on AD patients. We initially demonstrate that low-dose THC-CBD potentially can be an effective and safe therapeutic option for AD-related dementia. Nonetheless, larger and longer trials are necessary to confirm this finding and establish cannabinoid administration as therapy for AD dementia.Trial RegistrationThe Brazilian Registry of Clinical Trials (ReBEC) registration #U1111-1258-2058 - REBEC (ensaiosclinicos.gov.br).},
}

@article {pmid41160459,
year = {2025},
author = {Hellquist, E and Janelidze, S and Weidung, B and Franzon, K and Giedraitis, V and Ingelsson, M and Bali, D and Velickaite, V and Zetterberg, H and Hansson, O and Kilander, L},
title = {Plasma p-tau217 correlates strongly with cerebrospinal fluid Aβ42 and increases over a ten-year period in amyloid-positive, non-demented very old men.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877251390387},
doi = {10.1177/13872877251390387},
pmid = {41160459},
issn = {1875-8908},
abstract = {BackgroundPlasma phosphorylated tau217 (p-tau217) is a robust biomarker of Alzheimer's disease (AD) pathology. However, its full potential as a dynamic marker has still not been verified in very old persons, i.e., those with the highest incidence of AD.ObjectiveTo examine the cross-sectional and longitudinal associations between plasma p-tau217 concentration and cerebrospinal fluid (CSF) AD biomarkers. Further, to investigate the performance of p-tau217 as a predictor of amyloid status in a cohort of very old men.MethodsCSF AD biomarkers were analyzed in thirty-five 89-year-old men. Amyloid-β (Aβ) positivity was defined according to CSF Aβ42 level. Plasma p-tau217 concentration was measured at the mean age of 82, 87, and 91. Incident dementia diagnoses in survivors were identified through medical records up to the age of 102.ResultsPlasma p-tau217 strongly correlated with CSF Aβ42 concentration in Aβ-positive (n = 16, Spearman ρ: rho = -0.63, p = 0.009) but not in Aβ-negative (n = 19, rho = 0.111, p = 0.652) men and predicted Aβ status (area under the curve, AUC 0.91). Plasma p-tau217 increased over ten years in the Aβ-positive group, while it remained unchanged in the negative group (p = 0.018).ConclusionsOur findings indicate that plasma p-tau217 is a predictor of brain Aβ deposition also in very old individuals.},
}

@article {pmid41160457,
year = {2025},
author = {Jiao, Y and Ding, Y and Luo, N and Niu, M and Zhong, M and Liu, J and Zhao, A and Li, Y and , },
title = {MicroRNA biomarkers in cerebrospinal fluid and plasma predicting cognitive decline in Alzheimer's disease.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877251390836},
doi = {10.1177/13872877251390836},
pmid = {41160457},
issn = {1875-8908},
abstract = {BackgroundMicroRNAs (miRNAs) have emerged as key regulators in Alzheimer's disease (AD), yet their function as biomarkers remains uncertain due to inconsistent findings in blood and cerebrospinal fluid (CSF).ObjectiveWe aimed to identify miRNAs that track disease progression, providing valuable insights into AD pathophysiology.MethodsThis study focused on analyzing alterations in miRNA expression levels in CSF and plasma samples, and their association with cognitive decline and hippocampal volume changes in AD patients using data from the Alzheimer's Disease Neuroimaging Initiative (ADNI) database.ResultsIntegrative analyses identified a consistent set of miRNA alterations associated with AD. While a t-test showed a selective decrease of CSF miR-185-5p in AD versus healthy controls, logistic regression identified broader signatures in plasma (hsa-miR-125b-5p, hsa-miR-26a-5p, hsa-miR-376a-3p) and CSF (hsa-miR-499a-3p, alongside CSF hsa-miR-146a-5p, hsa-miR-16-5p, and hsa-miR-185-5p). LASSO regression further refined these to a reproducible decrease in plasma hsa-miR-125b-5p and CSF hsa-miR-185-5p, alongside an increase in plasma hsa-miR-26a-5p in AD. Together, these approaches reveal convergent miRNA dysregulation in plasma and CSF, suggesting their relevance to AD pathophysiology. Further analysis showed that lower plasma hsa-miR-125b-5p and hsa-miR-26a-5p, as well as lower CSF hsa-miR-185-5p, were associated with accelerated cognitive decline measured by ADAS13 scores. Reduced CSF hsa-miR-185-5p was significantly linked to hippocampal atrophy, with similar trends for the plasma miRNAs. Furthermore, CSF hsa-miR-185-5p levels correlated with amyloid pathology, suggesting a potential role in AD pathology.ConclusionsThese results highlight the role of CSF and plasma miRNA biomarkers in predicting cognitive and clinical decline in patients with AD.},
}

@article {pmid41160443,
year = {2025},
author = {Lim, MJ and Cheung, CY and Chong, JR and Chua, J and Hilal, S and Lai, MK and Maier, AB and Schmetterer, L and Tan, BY and Venketasubramanian, N and Wong, TY and Xu, X and Yeo, BT and Zhou, JH and Chen, CL},
title = {HARMONISATION - A multimodal prospective study of vascular cognitive impairment in multi-ethnic Asians: Cohort profile, progress, current contributions, and future impact.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877251389006},
doi = {10.1177/13872877251389006},
pmid = {41160443},
issn = {1875-8908},
abstract = {Vascular cognitive impairment (VCI) describes cerebrovascular disease (CeVD)-associated cognitive disorders regardless of pathogenesis, ranging from a prodrome to dementia. Heterogeneity in the etiology and severity of CeVD, and significant co-occurrence with Alzheimer's disease (AD) pathology has hampered investigations. Research into VCI is especially relevant in Asia, where cognitive impairment and dementia, often due to VCI, grows due to rapidly aging populations and high prevalence of vascular risk factors. This manuscript reviewed the rationale, unique positioning, design, methodology, and findings from the HARMONISATION study, a prospective observational study of VCI and AD in multi-ethnic Asians. HARMONISATION aimed to discover and validate novel biomarkers as effective diagnostic and prognostic tools, and translate findings into improved patient care, disease management and treatment-utilizing comprehensive multimodal clinical, neuroimaging, retinal, and blood biomarker data to address critical research gaps such as the etiology and clinical importance of mixed dementia, relationships between AD and CeVD pathology, and challenges of heterogenous CeVD pathology. HARMONIZATION recruited and deeply phenotyped 700 older multi-ethnic Asians with no cognitive impairment, mild cognitive impairment, and dementia for up to 5 years of follow-up. It has yielded developments in biomarker identification, validation, interactions and analysis methods; disease mechanisms and progression; clinical prognostics for VCI and AD; improved patient care and management; and enabled future development of novel interventions in Asians, and globally. An ongoing extension study will allow up to 10 years follow-up to further explore specific modifiable processes of VCI and the contributions of vascular events to cognitive impairment.},
}

@article {pmid41160347,
year = {2025},
author = {Brixner, DI and Zhao, C and Toyosaki, H and Frech, FH and Rosenbloom, MH},
title = {Initial Real-World Evidence for Lecanemab in the United States.},
journal = {Drugs & aging},
volume = {},
number = {},
pages = {},
pmid = {41160347},
issn = {1179-1969},
abstract = {BACKGROUND: Lecanemab is the first anti-amyloid monoclonal antibody with full approval in the US for the treatment of early Alzheimer's disease (AD). This observational study aimed to provide information about patient demographics, clinical characteristics, provider specialty, and lecanemab utilization patterns.

METHODS: This observational study used open administrative claims from the PurpleLab, a database encompassing medical and pharmacy claims derived from diverse sources, such as clearinghouses and Pharmacies. We included patients receiving one or more lecanemab doses between January 6, 2023 and October 31, 2024, and having continuous clinical activity ≥ 6 months prior to the first lecanemab infusion. The observation period ran from the first lecanemab infusion to the latest clinical activity or data availability. Treatment gaps were calculated as the number of gap days in lecanemab supply between consecutive infusions.

RESULTS: Among the study population (n = 4261), mean age was 75.2 years, 77.8% were White, 98.4% lived in urban settings, 81.7% were treated by neurologists, 77.3% had AD, and 31.7% had mild cognitive impairment. Mean follow-up period was 171.1 days. Lecanemab infusions averaged 1.9 per patient per month (SD 1.0), 16.3 days apart (SD 11.0), and 2.8% of patients experienced a treatment interruption ≥90 days.

CONCLUSIONS: Lecanemab utilization followed US FDA-approved prescribing information. Disparities for minority and rural-based populations were observed suggesting opportunities to improve access for underserved populations.},
}

@article {pmid41160337,
year = {2025},
author = {Alam, P and Sharma, P and Kirtipal, N and Akhtar, A},
title = {Targeting cathepsin B activity by natural inhibitors: a structural dynamics and network pharmacology approach for amyloid-beta dysregulation in Alzheimer's disease.},
journal = {Molecular diversity},
volume = {},
number = {},
pages = {},
pmid = {41160337},
issn = {1573-501X},
support = {ORF-2025-945//King Saud University/ ; },
abstract = {Alzheimer's disease (AD) is characterized by progressive cognitive decline and pathological accumulation of amyloid-beta (Aβ). Cathepsin B (CatB) has been implicated in both Aβ degradation and amyloidogenic APP processing; this compartment-dependent dualism makes CatB a complex but intriguing target, where selective inhibition of pathogenic activities (rather than global inhibition) is likely required for therapeutic benefit. In this research, we used an integrated computational pipeline to discover effective CatB inhibitors from a natural product-like compound library. A tiered virtual screening methodology (HTVS, SP, XP) was complemented by MMGBSA rescoring to yield F3382-3724, F6617-5583, and F6617-3074 as strong candidates. DFT B3LYP-D3/6-31G optimization confirmed F6617-5583 to possess the most stable electronic structure, followed by F3382-3724. Molecular dynamics simulations of 500 ns indicated that all complexes exhibited protein RMSD values below 2.0 Å, with F6617-5583 achieving conformational stability earlier, showing ligand RMSD values between 3.0-3.5 Å similar to the reference inhibitor. MMGBSA calculations identified F6617-5583 as the most potent binder (ΔG_bind = - 74.92 ± 3.10 kcal/mol), primarily stabilized by van der Waals and lipophilic interactions. Consistent interactions involving catalytic residues such as Trp30 and Trp221 facilitated stable ligand retention. PCA and Free Energy Landscape analyses further supported the localization of F6617-5583 in a low-energy conformational pocket indicative of strong and specific binding. A compound-gene interaction network constructed using NetworkX and Matplotlib revealed distinct connectivity patterns, providing insights into potential polypharmacological effects. Collectively, these results establish F6617-5583 as the lead CatB inhibitor, while F3382-3724 remains a promising secondary candidate for further optimization in Alzheimer's disease therapeutics.},
}

@article {pmid41160330,
year = {2025},
author = {Talaat, M and Hassan, H and Mosilhy, EA and Taha, NA and Elsaid, M and Sharafeldin, MN and Ghallab, YK and Lotfy, MA and Abdelqawy, MA and Ahmed, AA and Soliman, ME},
title = {Nano-antioxidants for neurodegenerative disorders: a scoping review.},
journal = {Discover nano},
volume = {20},
number = {1},
pages = {194},
pmid = {41160330},
issn = {2731-9229},
abstract = {BACKGROUND: Antioxidants showed usefulness in treating or preventing neurodegenerative diseases (NDDs). However, antioxidants have limited bioavailability owing to the BBB limiting drug access to the CNS. Nano drug delivery systems (NDDS) provide innovative solutions to pass the BBB and enhance antioxidant activity. Although an incredible number of preclinical trials are in the literature, it has not been translated into clinical practice.

OBJECTIVES: This scoping review aims to systematically summarize the current evidence, study the characteristics of the available literature, and identify research gaps.

METHODS: This review was conducted following the PRISMA-ScR guidelines. We searched PubMed for all primary studies investigating nano-antioxidants in the context of NDDs within the last five years. Data were extracted and analyzed on the year of publication, contributing affiliations, type of research, the investigational antioxidant agent, and the drug delivery matrix. In addition, we examined the association between NDDS and the year of publication, plus the association with the country of publication.

RESULTS: A total of 171 were included in the analysis. We found that all the articles included were pre-clinical trials. Organic and lipid-nanocarriers were the most frequently adopted (31.95% and 26.04%, respectively). Surprisingly, nanoplatforms were mentioned in only one trial. Our analysis showed that only 24 articles (14.04%) of the included trials adopted comparative studies.

We noticed a significant underrepresentation of nanoplatform applications and comparative designs. We provided new insights into nanoplatforms research. Moreover, we believe that it is crucial to establish rigorous validation systems and methodological approaches to predict the destiny of these nanocarriers in vivo and inspire the formulation of cost-effective functionalized nanoparticles with less stability or sterility drawbacks.},
}

@article {pmid41160319,
year = {2025},
author = {Sarikamis Johnson, B and Ercin, N and Kalkan Cakmak, R and Besli, N and Beker, M and Beker, MC and Celik, U},
title = {Exploring the effects of squalene in the PERK/ATF4/eIF2α/CHOP signalling pathway in an in vitro Alzheimer Disease model and in silico approach.},
journal = {Metabolic brain disease},
volume = {40},
number = {8},
pages = {300},
pmid = {41160319},
issn = {1573-7365},
support = {123Z925//Scientific and Technological Research Council of Türkiye/ ; 2021-067//University of Health Sciences, Türkiye/ ; },
mesh = {Humans ; *Alzheimer Disease/metabolism/drug therapy ; Activating Transcription Factor 4/metabolism ; eIF-2 Kinase/metabolism ; *Signal Transduction/drug effects ; Eukaryotic Initiation Factor-2/metabolism ; Endoplasmic Reticulum Stress/drug effects ; Transcription Factor CHOP/metabolism ; *Squalene/pharmacology/therapeutic use ; Unfolded Protein Response/drug effects ; Reactive Oxygen Species/metabolism ; Molecular Docking Simulation ; Amyloid beta-Peptides ; Oxidative Stress/drug effects ; Mesenchymal Stem Cells/drug effects/metabolism ; Cells, Cultured ; Peptide Fragments ; },
abstract = {Recent studies emphasize the pivotal role of endoplasmic reticulum (ER) stress in Alzheimer's disease (AD), highlighting the need for further investigation into this critical link. In response to ER stress, cells increase reactive oxygen species (ROS) production, leading to heightened oxidative stress. This interplay has sparked interest in antioxidant molecules such as squalene (SQ) as potential therapeutic agents. The primary objective of this study was to examine the impact of SQ on the unfolded protein response (UPR) pathway triggered by ER stress in an in vitro AD model. Herein, molecular docking analysis was performed to evaluate SQ interactions with target proteins, followed by in vitro assays. Human bone marrow-derived mesenchymal stem cells were differentiated into neuronal-like cells and characterized via immunostaining. The cells were then exposed to Aβ1-42 toxicity to establish an in vitro AD model. To assess the effects of SQ treatment following Aβ1-42 exposure, UPR-related proteins (BIP, p-PERK, PERK, eIF2α, p-eIF2α, ATF4, CHOP) were analysed by Western blotting; ROS levels were quantified to evaluate oxidative stress, and a TUNEL assay was performed to assess apoptosis. Our findings indicate that SQ alters protein expression within the UPR pathway in the AD experimental model. Notably, amyloid-β levels were significantly reduced in the SQ-treated group (p˂0.001). Furthermore, SQ reduced ROS levels. These results suggest that SQ holds potential as a therapeutic agent for mitigating amyloid-β toxicity.},
}

Humans
*Alzheimer Disease/metabolism/drug therapy
Activating Transcription Factor 4/metabolism
eIF-2 Kinase/metabolism
*Signal Transduction/drug effects
Eukaryotic Initiation Factor-2/metabolism
Endoplasmic Reticulum Stress/drug effects
Transcription Factor CHOP/metabolism
*Squalene/pharmacology/therapeutic use
Unfolded Protein Response/drug effects
Reactive Oxygen Species/metabolism
Molecular Docking Simulation
Amyloid beta-Peptides
Oxidative Stress/drug effects
Mesenchymal Stem Cells/drug effects/metabolism
Cells, Cultured
Peptide Fragments

@article {pmid41160288,
year = {2025},
author = {Motamedzadeh, A and Karimzad, Y and Ferdosi, F and Nabavizadeh, F and Rahmati-Dehkordi, F and Dadgostar, E and Aschner, M and Validad, A and Kazemi, B and Tamtaji, OR},
title = {Potential of Benfotiamine in the treatment of neuropsychological disorders.},
journal = {Molecular biology reports},
volume = {53},
number = {1},
pages = {26},
pmid = {41160288},
issn = {1573-4978},
mesh = {Humans ; *Thiamine/analogs & derivatives/pharmacology/therapeutic use ; Oxidative Stress/drug effects ; *Neuroprotective Agents/pharmacology/therapeutic use ; Animals ; *Mental Disorders/drug therapy/metabolism ; Signal Transduction/drug effects ; Thiamine Deficiency/drug therapy/metabolism ; },
abstract = {Neuropsychiatric disorders pose significant health challenges. Current drug therapies are often inadequate, highlighting the urgent need for new and effective treatments. Thiamine deficiency has been implicated in the pathophysiology of various neuropsychiatric disorders. In this context, benfotiamine, a synthetic thiamine derivative, has gained increasing attention for its potential therapeutic effects across a range of neuropsychiatric conditions. Emerging evidence supports the neuroprotective effects of benfotiamine, which are mediated through its modulation of diverse cellular and molecular pathways, i.e., Tau phosphorylation, amyloid β, oxidative stress, neuroinflammation, as well as synaptic plasticity via the glycogen synthase kinase-3β (GSK3β) signaling pathway. In this narrative review, we provide a comprehensive overview of the cellular and molecular pathways modulated by benfotiamine in the context of neuropsychiatric disorders. Specifically, we highlight its effects on oxidative stress, inflammatory signaling, mitochondrial function, glucose metabolism, and advanced glycation end-product (AGE) formation, all of which contribute to its neuroprotective and potentially therapeutic properties.},
}

Humans
*Thiamine/analogs & derivatives/pharmacology/therapeutic use
Oxidative Stress/drug effects
*Neuroprotective Agents/pharmacology/therapeutic use
Animals
*Mental Disorders/drug therapy/metabolism
Signal Transduction/drug effects
Thiamine Deficiency/drug therapy/metabolism

@article {pmid41160251,
year = {2025},
author = {El-Seedi, HR and Salama, S and Shetaia, AA and Elashal, MH and El-Wahed, AA and Karav, S and Saeed, A and Alzahrani, MA and Zou, X and Hritcu, L and Cheng, G and Salem, MF and Zhong, Z and Guo, Z and Khalifa, SAM},
title = {From the hive to the brain: synergistic potential of honeybee products with alzheimer's drugs.},
journal = {Metabolic brain disease},
volume = {40},
number = {8},
pages = {299},
pmid = {41160251},
issn = {1573-7365},
mesh = {*Alzheimer Disease/drug therapy/metabolism ; Humans ; Animals ; Bees ; *Neuroprotective Agents/therapeutic use/pharmacology ; *Brain/drug effects/metabolism ; *Propolis/therapeutic use/pharmacology ; Drug Synergism ; *Bee Venoms/therapeutic use/pharmacology ; Antioxidants/therapeutic use/pharmacology ; Cholinesterase Inhibitors/therapeutic use ; },
abstract = {Alzheimer's disease (AD) is the most common cause of dementia. The disease spreads over the world and has an impact on human health and welfare. The patients suffer from cognitiv disability in addition to economic and social effects. It is urgently necessary to find effective medication for cognitive decline because it appears to be a central focus of neurological and neurodegenerative illnesses. Cognitive decline is an intriguing pathophysiological state. Such underlying causes of cognitive impairment linked to neurodegeneration include oxidative damage and diminished cholinergic neurotransmission. The approved therapies for neurodegenerative diseases like AD are known to have undesirable side effects and merely offer symptomatic alleviation. Honeybee products have long been recognized for their therapeutic and health-improving properties. The antioxidant and anti-inflammatory activities of bee products and their ingredients are promising agents for AD. The current review aimed to collect and expose the different studies conducted on the neuroprotective potential of honeybee products such as bee venom and propolis or their active components chrysin, ferulic acid, and quercetin in combination with the conventional anti-AD or anti-dementia treatments such as donepezil and rivastigmine. Additionally, the active component chitosan was found to form effective nanoparticles in treating the neurodegenerative diseases in concern. Although the studies collected on this topic were few, they highlighted the potential synergistic effect of honeybee products in treating AD. In conclusion, bee products combined with donepezil and rivastigmine can be considered a potential neuroprotective agent against AD. Further studies are needed to support the preclinical studies and promote the clinical trials.},
}

*Alzheimer Disease/drug therapy/metabolism
Humans
Animals
Bees
*Neuroprotective Agents/therapeutic use/pharmacology
*Brain/drug effects/metabolism
*Propolis/therapeutic use/pharmacology
Drug Synergism
*Bee Venoms/therapeutic use/pharmacology
Antioxidants/therapeutic use/pharmacology
Cholinesterase Inhibitors/therapeutic use

@article {pmid41160221,
year = {2025},
author = {Meyer, ZA and Rambharose, S},
title = {Gold nanoparticles incorporating rutin hydrate for targeting oxidative stress-driven neurodegeneration.},
journal = {Biometals : an international journal on the role of metal ions in biology, biochemistry, and medicine},
volume = {},
number = {},
pages = {},
pmid = {41160221},
issn = {1572-8773},
support = {RA171114287300//National Research Foundation/ ; },
abstract = {Neurodegenerative disorders (NDs), exemplified by Alzheimer's disease (AD), present a global health challenge driven by oxidative stress, with current therapies hampered by poor blood-brain barrier (BBB) permeability. In this study, green-synthesized rutin hydrate (RH)-capped metallic gold nanoparticles (RH-AuNPs) were developed and, for the first time, evaluated for stability, biocompatibility, and antioxidant potential in SH-SY5Y cells under oxidative stress, compared to conventional gold NPs (AuNPs) and free RH. Nanoparticles (NPs) were characterized using UV-Visible spectroscopy, dynamic light scattering for particle size and distribution and surface charge, Fourier transform infrared spectroscopy (FTIR) and scanning transmission electron microscopy (STEM). Their in chemico antioxidant potential was assessed via DPPH assay, while in vitro biocompatibility was evaluated using WST-1, and cellular antioxidant activity was determined using both plate-based DCF assay, fluorescence DCF microscopy, and MitoSOX microscopy to assess intracellular and mitochondrial ROS. The RH-AuNPs exhibited favourable physicochemical traits (λmax = 523 nm, size = 34.043 ± 0.041 nm, polydispersity index (PDI) = 0.391 ± 0.003, and zetapotential (ZP) = -30.23 ± 0.569 mV) and robust biocompatibility (> 80% cell viability). Their antioxidant activity matched established antioxidants and significantly surpassed conventional AuNPs. Critically, in vitro studies demonstrated RH-AuNPs' potent antioxidant radical scavenging, outperforming both AuNPs and the RH, thereby inferring their neuroprotective capabilities. RH-AuNPs represent a promising green-synthesized neurotherapeutic platform that combines antioxidant potency, biocompatibility, and ideal characteristics, which would enable downstream potential for effective BBB penetration and neuronal protection against oxidative stress.},
}

@article {pmid41159614,
year = {2025},
author = {García-Roldán, E and Almodóvar-Sierra, Á and Luque-Tirado, A and Marín Cabañas, AM and Bernal Sánchez-Arjona, M and Franco-Macías, E},
title = {Preliminary Validation of the FCD-Q8 Tool in Functional Cognitive Disorder and Early Alzheimer's Disease: A Biomarker-Verified Case-Control Study.},
journal = {European journal of neurology},
volume = {32},
number = {11},
pages = {e70383},
doi = {10.1111/ene.70383},
pmid = {41159614},
issn = {1468-1331},
support = {//Instituto de Salud Carlos III/ ; },
mesh = {Humans ; Female ; *Alzheimer Disease/diagnosis/psychology ; Male ; Aged ; Case-Control Studies ; Middle Aged ; Cross-Sectional Studies ; Biomarkers/cerebrospinal fluid ; Neuropsychological Tests ; Psychometrics ; *Cognition Disorders/diagnosis ; Surveys and Questionnaires ; Sensitivity and Specificity ; Diagnosis, Differential ; },
abstract = {BACKGROUND: Differentiating functional cognitive disorder (FCD) from early Alzheimer's disease (eAD) through clinical interview alone is challenging and may lead to unnecessary testing. We aimed to assess the diagnostic accuracy of the Functional Cognitive Disorder Questionnaire-8 (FCD-Q8) and examine its psychometric properties.

METHODS: In this cross-sectional, phase 1 case-control study at a tertiary memory clinic in Seville, Spain, 78 adults with memory complaints were recruited: 44 with biomarker-verified eAD (positive CSF or amyloid PET; GDS 3-4) and 34 with FCD (negative biomarkers and clinical internal inconsistency). A blinded neuropsychologist administered the FCD-Q8. The primary outcome was diagnostic accuracy (area under the ROC curve [AUC], sensitivity, and specificity). Secondary outcomes included internal consistency (Cronbach's α with 95% CI) and item characteristics using two-parameter logistic Item Response Theory (2PL IRT).

RESULTS: Participants had a mean age of 67.5 years (SD ± 7.1); 59% were female. The FCD-Q8 demonstrated good diagnostic accuracy with an AUC of 0.87 (95% CI 0.78-0.95). At a cut-off ≥ 5, sensitivity was 76.5% and specificity 88.6%. Internal consistency was moderate (α = 0.61; 95% CI 0.47-0.70). 2PL IRT analysis showed that items related to checking behaviours were the most discriminative (difficulty 3.70), while questions on compound statements and premorbid self-appraisal were the least discriminative. Attending the clinical interview alone was the most difficult item (1.47).

CONCLUSION: The FCD-Q8 demonstrated good diagnostic utility to distinguish FCD from eAD in biomarker-verified populations. These findings support progression to a subsequent prospective validation phase, which could further establish its clinical and research applicability.},
}

Humans
Female
*Alzheimer Disease/diagnosis/psychology
Male
Aged
Case-Control Studies
Middle Aged
Cross-Sectional Studies
Biomarkers/cerebrospinal fluid
Neuropsychological Tests
Psychometrics
*Cognition Disorders/diagnosis
Surveys and Questionnaires
Sensitivity and Specificity
Diagnosis, Differential

@article {pmid41159537,
year = {2025},
author = {Jurkova, K and Navratilova, H and Musilek, K and Benek, O},
title = {Human Cyclophilins-An Emerging Class of Drug Targets.},
journal = {Medicinal research reviews},
volume = {},
number = {},
pages = {},
doi = {10.1002/med.70021},
pmid = {41159537},
issn = {1098-1128},
support = {//This study was supported by the Ministry of Health of the Czech Republic (no. NU22J-02-00006) and the University of Hradec Kralove (Faculty of Science, the Excellence project no. 2202/2024-2025)./ ; },
abstract = {Cyclophilins are a family of enzymes with peptidyl-prolyl isomerase activity found in all cells of all organisms. To date, 17 cyclophilin isoforms have been identified in the human body, participating in diverse biological processes. Consequently, cyclophilins have emerged as promising targets for drug development to address a wide array of human diseases. This review describes the structural characteristics of individual cyclophilin isoforms and explores the roles that they play in human health and diseases, such as in viral infections, Alzheimer's disease, Parkinson's disease, cardiovascular diseases, or cancer. Additionally, the review addresses inhibition of cyclophilins, particularly focusing on the development of selective small-molecule inhibitors of individual cyclophilins, which possess a significant potential as novel therapeutics.},
}

@article {pmid41159290,
year = {2025},
author = {Tao, R and Chen, Y and Yang, T and Hu, S and Lv, W and Li, X and Wang, Z and Zhang, R and Wu, Z and Hou, T and Xu, Z and Wang, Y and Liu, X and Li, X},
title = {Precision Design of Fluorogenic Probes via Orthogonal Tuning of Binding and Photophysics for Isoform-Selective ALDH2 Imaging.},
journal = {Journal of the American Chemical Society},
volume = {},
number = {},
pages = {},
doi = {10.1021/jacs.5c13638},
pmid = {41159290},
issn = {1520-5126},
abstract = {Fluorogenic probes that report enzyme activity are essential for studying biological functions. However, designing them for targets with low catalytic turnover and narrow substrate specificity remains a significant challenge. Here, we present a precision design framework that separates the requirements for sensitivity and selectivity by integrating molecular docking, quantum chemical modeling of fluorogenic mechanisms, and targeted fine-tuning of the probe structures. As a proof of concept, we developed A5, a fluorogenic substrate for aldehyde dehydrogenase 2 (ALDH2) that exhibits high isoform selectivity and a >240-fold signal enhancement over the standard NADH assay. A5 enables quantitative imaging of ALDH2 activity across multiple biological scales─in blood samples, live cells, and intact mouse brains─and supports the identification of small-molecule activators with therapeutic potential in an Alzheimer's disease model. This work establishes a modular strategy for creating activity-based probes tailored to challenging enzymatic targets, with broad applications in precision imaging, drug discovery, and mechanistic biochemistry.},
}

@article {pmid41159032,
year = {2025},
author = {Desai, AA and Smith, MD and Zupancic, JM and Makowski, EK and Zhang, Y and Gerson, JE and Moore, SJ and Sutter, AB and Ferris, SP and Ivanova, MI and Murphy, GG and Paulson, HL and Tessier, PM},
title = {Directed evolution of drug-like Aβ conformation-specific antibodies.},
journal = {Frontiers in immunology},
volume = {16},
number = {},
pages = {1655893},
pmid = {41159032},
issn = {1664-3224},
mesh = {*Amyloid beta-Peptides/immunology/chemistry ; Humans ; *Directed Molecular Evolution/methods ; *Antibodies, Monoclonal/immunology/genetics/chemistry ; Protein Conformation ; Alzheimer Disease/immunology ; Epitopes/immunology ; Antibody Affinity ; Immunoglobulin G/immunology/genetics ; Antibodies, Monoclonal, Humanized/immunology ; Antibody Specificity ; Protein Engineering ; },
abstract = {Monoclonal antibodies that recognize conformational epitopes in protein aggregates are important for research, diagnostic, and therapeutic applications related to neurodegenerative disorders such as Alzheimer's and Parkinson's diseases. Unfortunately, it remains challenging to discover and engineer high-quality conformational antibodies that are specific for protein aggregates and possess optimal combinations of three key binding properties, namely high affinity, high conformational specificity, and low off-target binding. Here we report a directed evolution approach for generating high-quality conformational antibodies against Alzheimer's Aβ fibrils in the native IgG format. Our directed evolution approach uses targeted mutagenesis, yeast surface display, cell sorting, and deep sequencing to identify antibody candidates with optimized binding properties. Notably, we find that this approach yields robust isolation of IgGs with higher affinity, higher conformational specificity, and lower off-target binding than multiple clinical-stage Aβ antibodies, including aducanumab and crenezumab. This antibody engineering platform can be readily applied to generate conformational antibodies against diverse types of peptide and protein aggregates linked to human diseases.},
}

*Amyloid beta-Peptides/immunology/chemistry
Humans
*Directed Molecular Evolution/methods
*Antibodies, Monoclonal/immunology/genetics/chemistry
Protein Conformation
Alzheimer Disease/immunology
Epitopes/immunology
Antibody Affinity
Immunoglobulin G/immunology/genetics
Antibodies, Monoclonal, Humanized/immunology
Antibody Specificity
Protein Engineering

@article {pmid41158909,
year = {2025},
author = {Sakharkar, M and Sure, A and Tan, M and Paz-Lansberg, M and Levi, J},
title = {Impact of Hearing Loss on Memory Loss in Patients With Self-Reported Olfactory Dysfunction.},
journal = {Cureus},
volume = {17},
number = {9},
pages = {e93357},
pmid = {41158909},
issn = {2168-8184},
abstract = {Introduction The association between hearing loss and dementia, and olfactory dysfunction (OD) and dementia, respectively, is well-elucidated. Several neurodegenerative diseases, including Alzheimer's disease and Parkinson's disease, impact the olfactory system early in their progression. Despite these established correlations, the independent effect of hearing loss on memory in patients with self-reported olfactory dysfunction is poorly elucidated, which this study aims to investigate, especially in light of the prevalence of anosmia post-COVID-19. Methods A total of 591 records of adult patients with self-reported olfactory dysfunction without a history of traumatic brain injury (TBI) from 2015 to 2020 from a single academic institution were analyzed. Patients were stratified based on demographic, memory loss (including mild cognitive impairment (MCI)), and clinical factors. Univariate and multicollinearity analyses assessed for correlations, with significant covariates utilized in a logistic regression model. Results In univariate analyses, hearing impairment (p<0.001), history of stroke (p<0.001), coronary artery disease (CAD) (p<0.001), hypertension (HTN) (p<0.001), and obstructive sleep apnea (OSA) (p=0.020) were significant. Primary language spoken, smoking history, myocardial infarction (MI), and diabetes mellitus (DM) were not significant. In logistic regression, hearing impairment was significantly associated with memory loss (p<0.001). Other significant covariates included stroke (p=0.004), CAD (p=0.022), and HTN (p<0.001). Conclusions Our results show that hearing impairment is significantly associated with memory loss, specifically in patients with self-reported olfactory dysfunction. This highlights the increased risk of memory loss in this population, underscoring the need for further research into screening and pathophysiology of memory loss in hard-of-hearing patients with olfactory dysfunction post-COVID-19.},
}

@article {pmid41158696,
year = {2025},
author = {Lopez Alcaraz, JM and Oloyede, E and Taylor, D and Haverkamp, W and Strodthoff, N},
title = {Explainable and externally validated machine learning for neurocognitive diagnosis via ECGs.},
journal = {General psychiatry},
volume = {38},
number = {5},
pages = {e102107},
pmid = {41158696},
issn = {2517-729X},
abstract = {BACKGROUND: Electrocardiogram (ECG) analysis has emerged as a promising tool for detecting physiological changes linked to non-cardiac disorders. Given the close connection between cardiovascular and neurocognitive health, ECG abnormalities may be present in individuals with co-occurring neurocognitive conditions. This highlights the potential of ECG as a biomarker to improve detection, therapy monitoring and risk stratification in patients with neurocognitive disorders, an area that remains underexplored.

AIMS: We aimed to demonstrate the feasibility of predicting neurocognitive disorders from ECG features across diverse patient populations.

METHODS: ECG features and demographic data were used to predict neurocognitive disorders, as defined by the International Classification of Diseases 10th revision, focusing on dementia, delirium and Parkinson's disease. Internal and external validations were performed using the Medical Information Mart for Intensive Care IV and ECG-View datasets. Predictive performance was assessed by the area under the receiver operating characteristic curve (AUROC) scores, and Shapley values were used to interpret feature contributions.

RESULTS: Significant predictive performance was observed for several neurocognitive disorders. The highest predictive performance was observed for F03: dementia, with an internal AUROC of 0.848 (95% confidence interval (CI) 0.848 to 0.848) and an external AUROC of 0.865 (95% CI 0.864 to 0.965), followed by G30: Alzheimer's disease, with an internal AUROC of 0.809 (95% CI 0.808 to 0.810) and an external AUROC of 0.863 (95% CI 0.863 to 0.864). Feature importance analysis revealed both established and novel ECG correlates.

CONCLUSIONS: These findings suggest that ECG holds promise as a non-invasive, explainable biomarker for selected neurocognitive disorders. This study demonstrates robust performance across cohorts and lays the groundwork for future clinical applications, including early detection and personalised monitoring.},
}

@article {pmid41158661,
year = {2025},
author = {Tao, F and Lin, M and Meng, X and Huang, L and Zhuo, B and Jiang, S and Deng, S and Meng, Z and Shi, J},
title = {Copper homeostasis and cuproptosis: implications for neurodegenerative diseases.},
journal = {Frontiers in aging neuroscience},
volume = {17},
number = {},
pages = {1688554},
pmid = {41158661},
issn = {1663-4365},
abstract = {Copper (Cu) is a vital trace element required for sustaining life and is involved in numerous critical metabolic processes within the body. Cuproptosis, a newly recognized type of Cu-dependent cell death, is mechanistically distinct from apoptosis, autophagy, pyroptosis, and ferroptosis. It is characterized by abnormal Cu accumulation and aberrant interactions with key enzymes of the tricarboxylic acid (TCA) cycle, which lead to protein aggregation, loss of iron-sulfur cluster proteins, and proteotoxic stress, ultimately leading to cell death. Recent studies have revealed that Cu dyshomeostasis and cuproptosis are intricately linked to the pathological progression of several neurodegenerative diseases, including Alzheimer's disease (AD), Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), Huntington's disease (HD), Wilson's disease (WD), and Menkes disease (MD). In this review, we systematically elucidate the systemic Cu metabolism, the molecular mechanisms of cuproptosis, and its intricate interplay with different neurodegenerative disorders. We also examined the relationship between cuproptosis and other types of cell death. Finally, we discuss therapeutic strategies targeting cuproptosis and Cu dyshomeostasis to combat neurodegenerative diseases and propose potential directions for future research.},
}

@article {pmid41158654,
year = {2025},
author = {Chiba, T and Hattori, Y and Asakura, K and Sano, Y and Saito, S and Minami, M and Yamamoto, H and Ihara, M},
title = {Taxifolin for prevention of COGnitive impairment (T-COG trial): a study protocol for a randomized, double-blind, placebo-controlled trial.},
journal = {Frontiers in nutrition},
volume = {12},
number = {},
pages = {1686381},
pmid = {41158654},
issn = {2296-861X},
abstract = {BACKGROUND: In 2023 and 2024, the novel anti-β-amyloid antibodies lecanemab and donanemab have been approved for treatment of mild cognitive impairment and mild dementia in several countries, including Japan and the United States. Although they successfully eliminate accumulated β-amyloid, they merely delay cognitive deterioration and do not improve cognitive function. This suggests that β-amyloid elimination is insufficient for cognitive improvement. Therefore, novel treatments with pleiotropic neuroprotective effects are warranted. Taxifolin, a bioactive flavonoid, shows pleiotropic effects, such as inhibition of amyloid-β aggregation and oligomerization and hippocampal neuroinflammation, as well as stimulation of brain lymphatic vessel formation in our previous experimental studies. Furthermore, our preliminary observational study showed that oral administration of taxifolin was associated with cognitive improvement in patients with mild cognitive impairment or mild dementia.

METHODS: This is a randomized, double-blind, placebo-controlled, crossover trial involving 60 patients with mild cognitive impairment or mild dementia. All participants will take 100-mg taxifolin or placebo capsules orally once daily for 12 weeks. The washout period will be 6 weeks. The primary objective is to determine the effect of taxifolin on cognitive impairment using the Montreal Cognitive Assessment. The main secondary objectives are to evaluate the impact of taxifolin on (i) prevention further cognitive decline, as evaluated by changes in the scores for total Alzheimer's Disease Assessment Scale-Cognitive Subscale 14 and trail making test and (ii) changes in white matter hyperintensity volume and number of cerebral microbleeds on brain magnetic resonance imaging.

DISCUSSION: This T-COG trial may provide valuable insights into new therapeutic approaches, considering that taxifolin has multitarget neuroprotection, which could prevent further cognitive decline, along with its highly safe profile and inexpensive cost.

CLINICAL TRIAL REGISTRATION: https://jrct.mhlw.go.jp, jRCTs051250004.},
}

@article {pmid41158599,
year = {2025},
author = {Zhang, RZ and Li, L and Ma, C and Dou, TT and Wei, YT and Yan, XK},
title = {Advances in the Understanding of Mitochondrial Inflammatory Regulation in the Pathogenesis of Alzheimer's Disease.},
journal = {Journal of inflammation research},
volume = {18},
number = {},
pages = {14475-14491},
pmid = {41158599},
issn = {1178-7031},
abstract = {Mitochondria, beyond serving as the powerhouse of the cell, play a pivotal role in the regulation of inflammatory responses. Mitochondrial dysfunction-induced immune activation and chronic inflammation are deeply implicated in the pathogenesis of Alzheimer's disease (AD), influencing its onset and progression through multiple inflammatory pathways. This review summarizes the involvement of several mitochondrial-related mechanisms in AD, including the release of mitochondrial DNA (mtDNA), signal transduction via mitochondrial antiviral-signaling protein (MAVS), the accumulation of mitochondrial damage-associated molecular patterns (DAMPs), the regulation of mitophagy, and the activation of the cyclic GMP-AMP synthase-stimulator of interferon genes (cGAS-STING) pathway. These insights aim to shed new light on mitochondrial inflammation as a regulatory mechanism in AD and to explore its potential as a therapeutic target.},
}

@article {pmid41158522,
year = {2025},
author = {Liu, T and Zhao, X and Cai, T and Li, W and Zhang, M},
title = {Metabolic reprogramming in Helicobacter pylori infection: from mechanisms to therapeutics.},
journal = {Frontiers in cellular and infection microbiology},
volume = {15},
number = {},
pages = {1678044},
pmid = {41158522},
issn = {2235-2988},
mesh = {Humans ; *Helicobacter pylori/metabolism/pathogenicity/genetics ; *Helicobacter Infections/metabolism/microbiology/drug therapy ; Animals ; *Host-Pathogen Interactions ; Gastric Mucosa/microbiology/metabolism/pathology ; Lipid Metabolism ; Glucose/metabolism ; Stomach Neoplasms/microbiology ; Bacterial Proteins/metabolism ; Metabolic Reprogramming ; },
abstract = {Helicobacter pylori (H. pylori), a key gastric mucosal pathogen, causes chronic gastritis, peptic ulcers, and gastric cancer. H. pylori remodel the gastric microenvironment through metabolic reprogramming to drive pathogenesis. CagA[+] strains disrupt lipid metabolism, increasing non-alcoholic fatty liver disease, cardiovascular, and Alzheimer's risks via PPAR interference, GBA1 demethylation, and altered FABP1/APOA1 expression, reversible by eradication. In glucose metabolism, H. pylori promote carcinogenesis via Lonp1-induced glycolysis, PDK1/Akt dysregulation, and HKDC1/TGF-β1/MDFI-mediated epithelial-mesenchymal transition, while exacerbating high-fat diet-induced dysbiosis. Infection manipulates macrophage immunometabolism. Bacterial utilization of host L-lactate through H. pylori gene clusters enables proliferation, gland colonization, and immune evasion by suppressing complement activation and TNF/IL-6 secretion. Lactate-targeting strategies show therapeutic promise. Amino acid dysregulation involves H. pylori biotin protein ligase (HpBPL)-mediated catabolism and γ-glutamyl transpeptidase-induced glutathione hydrolysis, depleting antioxidants while inducing dendritic cell tolerance. branched-chain amino acids accumulation activates mTORC1, and cystine-glutamate transporter inhibition with miR-30b upregulation exacerbates mucosal damage, forming a self-sustaining "metabolic reprogramming-immune evasion-tissue destruction" cycle. These mechanisms collectively enable H. pylori to propel gastric carcinogenesis, highlighting metabolism-targeted interventions as future solutions. This review summarizes how H. pylori remodel the gastric microenvironment and drives pathogenesis by manipulating host lipid, glucose, lactate, and amino acid metabolism.},
}

Humans
*Helicobacter pylori/metabolism/pathogenicity/genetics
*Helicobacter Infections/metabolism/microbiology/drug therapy
Animals
*Host-Pathogen Interactions
Gastric Mucosa/microbiology/metabolism/pathology
Lipid Metabolism
Glucose/metabolism
Stomach Neoplasms/microbiology
Bacterial Proteins/metabolism
Metabolic Reprogramming

@article {pmid41158286,
year = {2025},
author = {Zhou, J and Park, S and Dong, S and Tang, X and Wei, X},
title = {Artificial intelligence-driven transformative applications in disease diagnosis technology.},
journal = {Medical review (2021)},
volume = {5},
number = {5},
pages = {353-377},
pmid = {41158286},
issn = {2749-9642},
abstract = {The integration of artificial intelligence (AI) in medical diagnostics represents a transformative advancement in healthcare, with projected market growth reaching $188 billion by 2030. This comprehensive review examines the latest developments in AI-driven diagnostic technologies across multiple disease domains, particularly focusing on cancer, Alzheimer's disease (AD), and diabetes. Through systematic bibliometric analysis using GraphRAG methodology, we analyzed research publications from 2022 to 2024, revealing the distribution and impact of AI applications across various medical fields. In cancer diagnostics, AI systems have achieved breakthrough performances in analyzing medical imaging and molecular data, with notable advances in early detection capabilities across 19 different cancer types. For AD diagnosis, AI-powered tools have demonstrated up to 90 % accuracy in risk detection through non-invasive methods, including speech pattern analysis and blood-based biomarkers. In diabetes care, AI-integrated systems incorporating deep neural networks and electronic nose technology have shown remarkable accuracy in predicting disease onset before clinical manifestation. These developments collectively indicate a paradigm shift toward more precise, efficient, and accessible diagnostic approaches. However, challenges remain in standardization, data quality, and clinical implementation. This review synthesizes current progress while highlighting the potential for AI to revolutionize medical diagnostics through enhanced accuracy, early detection, and personalized patient care.},
}

@article {pmid41158073,
year = {2025},
author = {Liu, T and Fan, J and Shi, J and Mao, T and Zhou, X and Du, K and Wang, L and Wang, X},
title = {TET3 downregulation induces circadian disruption of BMAL1 through its DNA methylation-mediated repression in Alzheimer's disease.},
journal = {Acta biochimica et biophysica Sinica},
volume = {},
number = {},
pages = {},
doi = {10.3724/abbs.2025189},
pmid = {41158073},
issn = {1745-7270},
abstract = {Circadian disruptions appear at the presymptomatic stage of Alzheimer's disease (AD) and may exacerbate mental dysfunction in AD. The downregulation of brain and muscle ARNT-like protein 1 (BMAL1), a key clock element for the maintenance of circadian rhythms, has been linked to epigenetic mechanisms. Our previous study revealed that the mRNA level of DNA demethylase ten-eleven translocation (Tet) 3 was reduced in the hippocampi of APPswe/PS1dE9 (APP/PS1) mice. However, the effects of TET3 on BMAL1 downregulation and circadian dysregulation in AD are still unclear. Our investigation first confirms that Tet3 mRNA and protein levels are decreased in both APP/PS1 mice and APPswe cells. In addition, decreased levels of 5hmC are observed in HT22 cells after TET3 knockdown, whereas TET3 overexpression reverses the reduction in 5hmC. Critically, we report that TET3 knockdown remethylates the Bmal1 promoter, thus downregulating BMAL1 expression in HT22 cells. In contrast, TET3 overexpression could upregulate BMAL1 by decreasing its methylation level. These results indicate that reduced TET3 is responsible for BMAL1 downregulation through decreased TET3 demethylation. Additionally, TET3 knockdown could lead to circadian disruption of BMAL1 in U2OS cells, whereas overexpression of TET3 alleviates the dysregulated biological rhythm in Aβ-treated U2OS cells. Our data suggest that TET3 plays a vital role in modulating the circadian rhythm at the epigenetic level through DNA demethylation.},
}

@article {pmid41157967,
year = {2025},
author = {Mastenbroek, SE and Collij, LE and Anijärv, TE and Rittmo, J and Young, AL and Strandberg, O and Smith, R and Spotorno, N and Palmqvist, S and Mattsson-Carlgren, N and Janelidze, S and Parchi, P and Vogel, JW and Barkhof, F and Ossenkoppele, R and Hansson, O},
title = {Biological classification of memory clinic patients.},
journal = {Brain : a journal of neurology},
volume = {},
number = {},
pages = {},
doi = {10.1093/brain/awaf411},
pmid = {41157967},
issn = {1460-2156},
abstract = {Neurodegenerative diseases have traditionally been defined in vivo based on clinical symptoms. However, the development of biomarkers has enabled a shift toward in vivo biological definitions. There is now a need to characterize memory clinic populations using multi-dimensional biomarker information. Here, we employed a data-driven approach to develop a biological framework for categorizing individuals in a heterogenous memory clinic cohort based on the presence, extent, and sequence of several common pathologies. We studied 1,677 individuals, including subjective cognitive decline (SCD, n=255), mild cognitive impairment (MCI, n=400), all cause dementia (n=393), and cognitively normal controls (n=625) from the BioFINDER-2 cohort (median age [IQR]=72.0 [16.2] years; 50.3% female). The Subtype and Stage Inference (SuStaIn) model was applied to biomarkers of amyloid-β (Aβ) (cerebrospinal fluid [CSF] Aβ42/Aβ40), tau (temporal meta-ROI positron emission tomography [PET]), neuronal α-synuclein (CSF seed amplification assay [SAA]), vascular pathology (MRI-based white matter hyperintensities [WMHs]), and regional atrophy (MRI-based cortical thickness) to identify biomarker-based clusters across the entire dataset. We then applied this framework to cognitively symptomatic individuals (n=788) to compare clinical symptoms, disease progression rate, and brain changes (atrophy and functional connectivity) across profiles. We identified five biomarker clusters reflecting established clinico-pathological entities, closely corresponding to (i) Alzheimer's disease (AD, n=317 [40.2%]); (ii) α-Synuclein disease (αSyn, n=123 [15.6%]), (iii) Vascular disease (n=67 [8.5%]); (iv) Mixed AD and Vascular diseases (Mixed, n=207 [26.3%]); and (v) a heterogenous group of individuals characterized by atrophy without any of the major brain pathologies, here termed Non-Vascular-Alzheimer-Synuclein (NOVAS, n=74 [9.4%]). The AD profile was characterized by global cognitive impairment and cortical atrophy in AD-associated regions. The αSyn profile was associated with visuospatial and executive dysfunction, motor impairment, hallucinations, and functional connectivity disruptions throughout the brain, despite less overall atrophy compared to all others. The Vascular profile showed language and motor impairments and both the Vascular and Mixed profiles demonstrated atrophy in cingulate and subcortical regions, alongside reduced periventricular white matter integrity. The NOVAS profile was older, demonstrated pronounced hippocampal and amygdala atrophy, and baseline memory deficits, possibly reflecting neurodegenerative diseases for which currently no robust biomarkers are available, such as primary tauopathies and TDP-43 proteinopathies (e.g. LATE). In longitudinal analyses, the AD profile showed the fastest global cognitive decline, while αSyn demonstrated an accelerated decline in language, executive, and visuospatial functioning. To conclude, classifying individuals using a multimodal biomarker approach can provide valuable diagnostic and prognostic insights, with potential implications for clinical trials.},
}

@article {pmid41157961,
year = {2025},
author = {Cruz-Aguilar, MA and Hernández-Arteaga, E and Ramírez-Salado, I and Hernández-González, M and Guevara, MA},
title = {Melatonin reorganizes the sleep EEG spectral power in Alzheimer's disease: a preliminary principal component analysis-based comparison of placebo and treatment effects.},
journal = {Neurological research},
volume = {},
number = {},
pages = {1-16},
doi = {10.1080/01616412.2025.2578344},
pmid = {41157961},
issn = {1743-1328},
abstract = {OBJECTIVES: Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by amyloid-β plaque accumulation, tau pathology, and cortical atrophy, leading to widespread synaptic dysfunction and cognitive decline. Sleep disturbances are highly prevalent in AD and are thought to both reflect and exacerbate underlying neurodegenerative processes. Melatonin, an indoleamine synthesized by the pineal gland, is central to the regulation of circadian rhythms and sleep - wake cycles. In healthy individuals, melatonin enhances non-rapid eye movement (NREM) sleep and attenuates beta activity during wakefulness. In AD populations, it has been associated with improved sleep quality and potential neuroprotective effects against amyloid-related pathology. Electroencephalography (EEG) offers a non-invasive method to monitor neurophysiological changes associated with AD. Principal component analysis (PCA), a dimensionality reduction technique, enables the identification of latent neural patterns within complex EEG data.

METHODS: In this preliminary study, PCA was applied to EEG recordings from eight individuals with mild-to-moderate AD during both wakefulness and sleep under placebo and melatonin conditions. EEG derivations included bipolar (F7-T3, F8-T4, F3-F4, O1-O2) and referential (C3-A1, C4-A2) configurations.

RESULTS: Preliminary PCA suggests that melatonin administration may induce a stage-dependent reorganization of EEG spectral activity, characterized by a relative enhancement of slow-frequency activity and an apparent increase in spectral segregation during NREM sleep.

DISCUSSION: These preliminary findings suggest that melatonin could optimize stage-specific neural dynamics, supporting its therapeutic potential in AD-related sleep disruption.},
}

@article {pmid41157948,
year = {2025},
author = {Carver, S and Taraszka, K and Groha, S and Gusev, A},
title = {Discovery of disease-associated cellular states using ResidPCA in single-cell RNA and ATAC sequencing data.},
journal = {HGG advances},
volume = {},
number = {},
pages = {100538},
doi = {10.1016/j.xhgg.2025.100538},
pmid = {41157948},
issn = {2666-2477},
abstract = {To advance understanding of cellular heterogeneity in disease from single-cell sequencing data, we introduce Residual Principal Component Analysis (ResidPCA), a robust method for identifying cell states that explicitly models cell type heterogeneity. In simulations, ResidPCA achieved more than fourfold higher accuracy than conventional Principal Component Analysis (PCA) and over threefold higher accuracy than Non-negative Matrix Factorization (NMF)-based methods in detecting states expressed across multiple cell types. Applied to single-cell RNA sequencing (scRNA-seq) of light-stimulated mouse visual cortex cells, ResidPCA captured stimulus-driven variability with an accuracy more than fivefold higher than NMF-based approaches. In single-nucleus datasets from an Alzheimer's disease cohort, ResidPCA identified 44 chromatin accessibility-based states from single-nucleus ATAC-seq (snATAC-seq) and 42 transcriptional states from single-nucleus RNA-seq (snRNA-seq). Thirty snATAC-seq states were significantly enriched for Alzheimer's disease heritability, often more so than established cell types such as microglia. The snATAC-seq state most significantly enriched for heritability further elucidates a recently implicated neuron-oligodendrocyte-microglial mechanistic axis, linking early amyloid production in neurons and oligodendrocytes with later microglial activation and immune response. Together, these results highlight ResidPCA's ability to uncover previously hidden biological variation in single-cell data and reveal disease-relevant cell states.},
}

@article {pmid41157910,
year = {2025},
author = {Liu, S and Huang, YN and Park, T and Lee, EH and Chaudhuri, S and Adzibolosu, N and Bice, PJ and Dage, JL and Brosch, JR and Gao, S and Apostolova, LG and Wilcock, DM and Risacher, SL and Saykin, AJ and Nho, K},
title = {Plasma proteomic Alzheimer's risk score: Biological age clock and pseudotime trajectory.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21},
number = {10},
pages = {e70851},
doi = {10.1002/alz.70851},
pmid = {41157910},
issn = {1552-5279},
support = {P30 AG010133/GF/NIH HHS/United States ; P30 AG072976/GF/NIH HHS/United States ; R01 AG075959/GF/NIH HHS/United States ; R01 AG082348/GF/NIH HHS/United States ; R01 AG081951/GF/NIH HHS/United States ; R01 AG057739/GF/NIH HHS/United States ; R01 AG070883/GF/NIH HHS/United States ; U01 AG024904/GF/NIH HHS/United States ; R01 LM013463/GF/NIH HHS/United States ; T32 AG071444/GF/NIH HHS/United States ; U24 AG074855/GF/NIH HHS/United States ; U01 AG068057/GF/NIH HHS/United States ; U01 AG072177/GF/NIH HHS/United States ; U01 AG24904/GF/NIH HHS/United States ; U19 AG074879/GF/NIH HHS/United States ; R01 AG019771/GF/NIH HHS/United States ; U19 AG024904/GF/NIH HHS/United States ; R01 AG068193/GF/NIH HHS/United States ; R01 AG081951/GF/NIH HHS/United States ; R01 LM012535/GF/NIH HHS/United States ; //ADNI Health Enhancement Scientific Program/ ; },
mesh = {Humans ; *Alzheimer Disease/blood/diagnosis ; *Proteomics ; Biomarkers/blood ; Male ; Female ; Aged ; *Aging ; Aged, 80 and over ; Brain ; },
abstract = {INTRODUCTION: Alzheimer's disease (AD) involves progressive cognitive decline. Plasma proteomics data may provide insights into disease risk and mechanisms.

METHODS: Plasma proteomics data (N = 498) by the SomaScan 7k platform from the Indiana AD Research Center was used to calculate proteomics-based Alzheimer's risk scores: organ-specific aging clocks and pseudotime trajectory. The Alzheimer's risk scores were investigated for associations with plasma- and imaging-based biomarkers for AD and diagnosis and evaluated for classification performance for diagnosis and biomarker positivity status.

RESULTS: Cognition-optimized brain and liver age acceleration showed significant associations with AD diagnosis and biomarkers. Pseudotime showed a molecular trajectory from cognitively normal to AD individuals, in association with plasma and imaging biomarkers. Previously known plasma biomarkers yielded better classification performance with inclusion of proteomics-based Alzheimer's risk scores.

DISCUSSION: The findings highlight proteomics-derived biological aging clocks and pseudotime trajectory as potential biomarkers to complement current biomarker frameworks and identify disease mechanisms.

HIGHLIGHTS: Plasma proteomic aging clocks and pseudotime provide potential markers for Alzheimer's disease (AD) risk. Cognition-optimized brain aging and pseudotime link to diagnosis and AD biomarkers. Brain aging clock and pseudotime improve the diagnosis classification performance. Pseudotime outperformed established plasma biomarkers for diagnosis classification.},
}

Humans
*Alzheimer Disease/blood/diagnosis
*Proteomics
Biomarkers/blood
Male
Female
Aged
*Aging
Aged, 80 and over
Brain

@article {pmid41157904,
year = {2025},
author = {Uzun, C and Li, Y and Liu, S},
title = {APOE ε4 disrupts neuronal and network-level function in the anterior olfactory nucleus: Influence of age and sex.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21},
number = {10},
pages = {e70865},
doi = {10.1002/alz.70865},
pmid = {41157904},
issn = {1552-5279},
support = {R01AG069196/NH/NIH HHS/United States ; R01AG074216/NH/NIH HHS/United States ; R01AG077541/NH/NIH HHS/United States ; },
mesh = {Animals ; *Apolipoprotein E4/genetics ; Male ; Female ; Mice, Transgenic ; Mice ; *Neurons/physiology ; Sex Factors ; Age Factors ; Humans ; Alzheimer Disease/genetics ; *Olfactory Pathways ; *Aging/physiology ; },
abstract = {INTRODUCTION: Apolipoprotein E (APOE) ε4 is the strongest genetic risk factor for sporadic Alzheimer's disease (AD), which features early olfactory dysfunction and pathology. However, how APOE ε4 interacts with age and sex to affect cellular and network function in vulnerable regions such as the anterior olfactory nucleus (AON) remains unclear.

METHODS: In vivo recordings in awake transgenic mice were used to assess how APOE ε4, age, and sex interact to influence single-cell excitability and network activity.

RESULTS: APOE ε4 reduces excitability in the AON; adult females show higher excitability than males, a difference that is lost with age. Excitability and network activity vary by genotype and sex, while aging consistently increases network power, underscoring their complex interplay in an AD-vulnerable circuit.

DISCUSSION: APOE ε4, age, and sex interact to shape excitability and network dynamics in the anterior olfactory nucleus, a region affected early in AD. These actions may underlie early olfactory dysfunction and offer electrophysiological markers for early detection and genotype-, age-, and sex-specific interventions.

HIGHLIGHTS: This is the first study on the interactive impact of three Alzheimer's disease risk factors on anterior olfactory nucleus neural functions. Apolipoprotein E ε4 reduces neuronal excitability regardless of age and sex. Females show higher excitability than males in the adult group but not in aged group. Age increases excitability in a genotype-dependent manner. Network oscillations vary by genotype and sex but are consistently enhanced by age.},
}

Animals
*Apolipoprotein E4/genetics
Male
Female
Mice, Transgenic
Mice
*Neurons/physiology
Sex Factors
Age Factors
Humans
Alzheimer Disease/genetics
*Olfactory Pathways
*Aging/physiology

@article {pmid41157902,
year = {2025},
author = {Turan, E and Çeltik, B and Dağlar, G and Kaya, I and Tu Fekçi, M and YANDıM, C},
title = {Comparisons between young, aged, and Alzheimer's brains reveal specific expression patterns for a subset of transposons and satellite repeats.},
journal = {Journal of biosciences},
volume = {50},
number = {},
pages = {},
pmid = {41157902},
issn = {0973-7138},
mesh = {Humans ; *Alzheimer Disease/genetics/pathology/metabolism ; *Brain/metabolism/pathology ; *DNA, Satellite/genetics ; *DNA Transposable Elements/genetics ; Aged ; Male ; Female ; Transcriptome/genetics ; *Aging/genetics ; Aged, 80 and over ; Adult ; Gene Expression Profiling ; Middle Aged ; Gene Expression Regulation ; Histones/metabolism/genetics ; },
abstract = {Recent studies have highlighted the involvement of repeat-derived transcripts in the pathological transcriptome of Alzheimer's disease (AD). However, it remains unclear whether these transcripts arise as a consequence of aging or are directly associated with AD pathology. Particularly, the specific contribution of satellite repeats to this phenomenon has not been systematically investigated. In this study, we profiled the non-coding expression patterns of all repetitive DNA elements - including satellites - across healthy young, healthy aged, and aged AD brain samples. Comparative transcriptome analysis revealed only a single differentially expressed repeat between aged and young brains. In contrast, AD brains exhibited significant expression changes in eight specific repeat elements relative to their healthy aged counterparts. Among these AD-specific repeats, the satellite repeat HSATII showed the highest fold change and a modest increase in histone acetylation levels, suggesting potential regulatory or feedback mechanisms in AD pathology. Weighted Gene Co-Expression Network Analysis (WGCNA) identified modules of co-expressed genes and repeats, revealing a network moderately correlated with the AD phenotype and indicating complex interactions between repeats and genes during disease onset. Collectively, our comprehensive analysis of repeat expression in post-mortem human AD brains demonstrates alterations in transposon and satellite repeat expression patterns that are distinct from agerelated changes.},
}

Humans
*Alzheimer Disease/genetics/pathology/metabolism
*Brain/metabolism/pathology
*DNA, Satellite/genetics
*DNA Transposable Elements/genetics
Aged
Male
Female
Transcriptome/genetics
*Aging/genetics
Aged, 80 and over
Adult
Gene Expression Profiling
Middle Aged
Gene Expression Regulation
Histones/metabolism/genetics

@article {pmid41157172,
year = {2025},
author = {Carata, E and Destino, M and Tenuzzo, BA and Panzarini, E},
title = {Inter-Organ Crosstalk in Neurodegenerative Disease.},
journal = {Life (Basel, Switzerland)},
volume = {15},
number = {10},
pages = {},
doi = {10.3390/life15101499},
pmid = {41157172},
issn = {2075-1729},
abstract = {Inter-organ communication plays a vital role in the pathogenesis of neurodegenerative diseases (ND), including Alzheimer's disease (AD), Parkinson's disease (PD), and Amyotrophic Lateral Sclerosis (ALS). Emerging research highlights the involvement of the gut-brain axis, immune system, and peripheral metabolic systems in modulating neuroinflammation, protein misfolding, and neuronal dysfunction by releasing cytokines, adipokines, growth factors, and other soluble factors, which in turn affect neuronal health and systemic inflammation. This review explores the complex bidirectional interactions between the brain and peripheral organs, including the gut, adipose tissue, liver, muscle, bone and immune system. Notably, the gut microbiome's role in neurodegenerative diseases through the gut-brain axis, the impact of adipose tissue in inflammation and metabolic regulation, and the muscle-brain axis with its neuroprotective myokines are also discussed. Additionally, we examine the neuro-immune axis, which mediates inflammatory responses and exacerbates neurodegeneration, and liver-brain axis that is implicated in regulating neuroinflammation and promoting disease progression. Dysregulation of inter-organ pathways contributes to the systemic manifestations of neurodegenerative diseases, offering insights into both potential biomarkers and therapeutic targets, and, in turn, promising strategies for preventing, diagnosing, and treating neurodegenerative diseases.},
}

@article {pmid41157133,
year = {2025},
author = {Slater, O and Kontoyianni, M},
title = {Factors Driving Amyloid Beta Fibril Recognition by Cell Surface Receptors: A Computational Study.},
journal = {Molecules (Basel, Switzerland)},
volume = {30},
number = {20},
pages = {},
doi = {10.3390/molecules30204116},
pmid = {41157133},
issn = {1420-3049},
mesh = {*Amyloid beta-Peptides/metabolism/chemistry/genetics ; Humans ; Toll-Like Receptor 4/metabolism/chemistry ; Protein Binding ; Receptor for Advanced Glycation End Products/metabolism/chemistry/genetics ; *Alzheimer Disease/metabolism/genetics/pathology ; Lipopolysaccharide Receptors/metabolism/chemistry ; Toll-Like Receptor 2/metabolism/chemistry ; Mutation ; *Receptors, Cell Surface/metabolism/chemistry ; Hydrogen-Ion Concentration ; },
abstract = {Alzheimer's disease (AD) has been studied extensively and is characterized by plaques deposited throughout the brain. Plaques are made of beta-amyloid (Aβ) peptides which have undergone fibrillogenesis to form insoluble Aβ fibrils (fAβ) that are neurotoxic. Receptor for Advanced Glycation End end products (RAGE), toll-like receptors (TLRs) 2 and 4, and co-receptor CD14 recognize negatively charged binding regions on fAβ to activate microglia and release proinflammatory cytokines. In this study, we used two experimentally resolved fAβ structures (type I and II) isolated from AD brain tissue to elucidate binding patterns of fAβ with RAGE, TLR2, TLR4, and CD14 and investigated whether binding was affected by fibril structure or system pH. Receptors TLR2 and RAGE formed tight complexes with both type I and II fibrils, while TLR4 showed selectivity for type I. CD14 binding was less tight and selective for type II. Binding was pH dependent for CD14, TLR4, and RAGE but not TLR2. We explored the effects of familial mutations on fibril structure to determine whether mutants of type I or II structures are feasible. Finally, we investigated whether mutations affected binding interactions of fAβ with proteins. The Arctic (Glu22Gly), Dutch (Glu22Gln), and Iowa (Asp23Asn) mutations showed similar effects on binding affinity. Italian (Glu22Lys) mutations abrogated binding, whereas type I and II fibrils with Flemish (Ala21Gly) mutations were not shown to be feasible. Results highlight the adaptability of immune receptors in recognizing damaging molecules, with fibril structure and pH being the main recognition determinants predicated on disease progression. In silico mutations showed that aggregates similar to type I and II structures were plausible for some familial mutations.},
}

*Amyloid beta-Peptides/metabolism/chemistry/genetics
Humans
Toll-Like Receptor 4/metabolism/chemistry
Protein Binding
Receptor for Advanced Glycation End Products/metabolism/chemistry/genetics
*Alzheimer Disease/metabolism/genetics/pathology
Lipopolysaccharide Receptors/metabolism/chemistry
Toll-Like Receptor 2/metabolism/chemistry
Mutation
*Receptors, Cell Surface/metabolism/chemistry
Hydrogen-Ion Concentration

@article {pmid41156809,
year = {2025},
author = {Wadop, YN and Vasquez, EL and Mathews, JJ and Muhammad, JAS and Pirela Mavarez, R and Satizabal, CL and Gonzales, MM and Tanner, J and Maestre, G and Fonteh, AN and Seshadri, S and Kautz, TF and Fongang, B},
title = {Differential Patterns of Gut and Oral Microbiomes in Hispanic Individuals with Cognitive Impairment.},
journal = {Microorganisms},
volume = {13},
number = {10},
pages = {},
doi = {10.3390/microorganisms13102350},
pmid = {41156809},
issn = {2076-2607},
support = {P30 AG066546/AG/NIA NIH HHS/United States ; 5P30AG059305-03/AG/NIA NIH HHS/United States ; RF1AG061729A1/AG/NIA NIH HHS/United States ; 5U01AG052409-04/AG/NIA NIH HHS/United States ; NS017950, UF1NS125513, K01NS126489/NS/NINDS NIH HHS/United States ; },
abstract = {Alterations in both oral and gut microbiomes have been associated with Alzheimer's disease and related dementia (ADRD). While extensive research has focused on the role of gut dysbiosis in ADRD, the contribution of the oral microbiome remains relatively understudied. This study aims to evaluate distinct patterns and potential synergistic effects of oral and gut microbiomes in a cohort of predominantly Hispanic individuals with cognitive impairment (CI) and without cognitive impairment (NC). We conducted 16S rRNA gene sequencing on stool and saliva samples from 32 participants (17 CI, 15 NC; 62.5% female, mean age = 70.4 ± 6.2 years) recruited in San Antonio, Texas, USA. Differential abundance analysis evaluated taxa with significant differences between both groups. While diversity metrics showed no significant differences between CI and NC groups, differential abundance analysis revealed an increased presence of oral genera such as Dialister, Fretibacterium, and Mycoplasma in CI participants. Conversely, CI individuals exhibited a decreased abundance of gut genera, including Shuttleworthia, Holdemania, and Subdoligranulum, which are known for their anti-inflammatory properties. No evidence was found for synergistic contributions between oral and gut microbiomes in the context of CI. Our findings suggest that like the gut microbiome, the oral microbiome of CI participants undergoes significant modifications. Notably, the identified oral microbes have been previously associated with periodontal diseases and gingivitis. These results underscore the necessity for further investigations with larger sample sizes to validate our findings and elucidate the complex interplay between oral and gut microbiomes in ADRD pathogenesis.},
}

@article {pmid41156633,
year = {2025},
author = {Li, DY and Choi, ES and Bao, X},
title = {HSV-1 as a Potential Driver of Alzheimer's Disease.},
journal = {Pathogens (Basel, Switzerland)},
volume = {14},
number = {10},
pages = {},
doi = {10.3390/pathogens14101022},
pmid = {41156633},
issn = {2076-0817},
support = {AI166543, AG069226, AG075725/GF/NIH HHS/United States ; ERP-1252718//American Lung Association/ ; Investigator-Initiated Research Award//TARCC/ ; },
mesh = {*Alzheimer Disease/virology/pathology/etiology/metabolism ; Humans ; *Herpesvirus 1, Human/pathogenicity/physiology ; *Herpes Simplex/complications/virology/drug therapy ; Animals ; Antiviral Agents/therapeutic use ; Amyloid beta-Peptides/metabolism ; tau Proteins/metabolism ; },
abstract = {Herpes simplex virus type 1 (HSV-1) is a continuous health challenge, and current antiviral treatments cannot cure the virus. As life expectancy continues to increase worldwide, HSV-1 should remain a focus to minimize its associated health complications within the aging population. While often asymptomatic, HSV-1 causes oral and cutaneous lesions and establishes latency with periodic reactivation. Antivirals reduce symptoms but do not eradicate the virus. Emerging evidence links HSV-1 to Alzheimer's disease (AD) via chronic neuroinflammation, amyloid-beta and tau accumulation, oxidative stress, and synaptic dysfunction, with viral proteins detected in AD-affected brain regions. This review assesses the current evidence for HSV-1 in dementia pathogenesis, examines antiviral strategies as potential neuroprotective interventions, and outlines the experimental models required to establish causality.},
}

*Alzheimer Disease/virology/pathology/etiology/metabolism
Humans
*Herpesvirus 1, Human/pathogenicity/physiology
*Herpes Simplex/complications/virology/drug therapy
Animals
Antiviral Agents/therapeutic use
Amyloid beta-Peptides/metabolism
tau Proteins/metabolism

@article {pmid41156564,
year = {2025},
author = {Baek, HI and Kwon, SY and Noh, HJ and Son, SY and Joo, JC and Park, SJ},
title = {Efficacy and Safety of Lactobacillus delbrueckii subsp. lactis CKDB001 Supplementation on Cognitive Function in Mild Cognitive Impairment: A Randomized, Double-Blind, Placebo-Controlled Clinical Trial.},
journal = {Nutrients},
volume = {17},
number = {20},
pages = {},
doi = {10.3390/nu17203313},
pmid = {41156564},
issn = {2072-6643},
support = {2025-RISE-13-WSU//Ministry of Education/ ; 2025-RISE-13-WSU//This clinical study was funded by Chong Kun Dang Bio Corporation and Genome & Company. The authors acknowledge the support of the Regional Innovation System & Education (RISE) program through the Jeonbuk RISE Center, funded by the Ministry of Education (M/ ; },
mesh = {Humans ; *Cognitive Dysfunction/therapy/microbiology/psychology ; Double-Blind Method ; Aged ; Male ; Female ; *Probiotics/administration & dosage/adverse effects ; Middle Aged ; *Cognition/drug effects ; Aged, 80 and over ; Gastrointestinal Microbiome ; *Lactobacillus delbrueckii ; *Dietary Supplements ; Treatment Outcome ; Feces/microbiology ; },
abstract = {BACKGROUND: Modulation of the gut-brain axis using probiotics present a promising approach for enhancing cognitive function in mild cognitive impairment (MCI). In prior non-clinical research, Lactobacillus delbrueckii subsp. lactis CKDB001 (LL) exhibited potential to enhance cognitive function. We therefore conducted a clinical trial to assess the efficacy and safety of LL supplementation in MCI.

METHODS: A 12-week, randomized, double-blind, placebo-controlled, multi-center trial was performed in 100 participants aged 55-80 years. Subjects were randomly assigned to receive LL (n = 50, 5.0 × 10[9] CFU/day) or placebo (n = 50). Efficacy and safety were evaluated at baseline and after 12 weeks.

RESULTS: LL supplementation resulted in significantly greater improvements than placebo in the Alzheimer's Disease Assessment Scale-Cognition 13 total score, the memory sub-score, reaction time for Part A of the Trail Making Test, and word/color reaction times on the Stroop test. Taxonomic and metabolomic profiling of fecal samples showed significantly greater changes in the relative abundance of beneficial microorganisms in the LL group, with the most pronounced shifts at the family (Lactobacillaceae, Bifidobacteriaceae) and genus (Lactobacillus) levels. In addition, the LL group exhibited significantly higher fecal levels of indole-derived metabolites, including 5-hydroxyindole-3-acetic acid, indole-3-lactic acid, and indole-3-glycol. Safety assessments indicated LL was safe and well-tolerated, with no clinically relevant changes in laboratory findings or adverse events.

CONCLUSIONS: These findings suggest that LL supplementation may enhance cognitive function in MCI by modulating the gut-brain axis through effects on gut microbiota and related metabolites, and could serve as a safe functional food to support cognitive health.},
}

Humans
*Cognitive Dysfunction/therapy/microbiology/psychology
Double-Blind Method
Aged
Male
Female
*Probiotics/administration & dosage/adverse effects
Middle Aged
*Cognition/drug effects
Aged, 80 and over
Gastrointestinal Microbiome
*Lactobacillus delbrueckii
*Dietary Supplements
Treatment Outcome
Feces/microbiology

@article {pmid41156471,
year = {2025},
author = {Zhang, J and Zhang, J},
title = {Natural Small-Molecule Bergapten Ameliorates Amyloid-β Pathology and Neuroinflammation in Alzheimer's Disease.},
journal = {Nutrients},
volume = {17},
number = {20},
pages = {},
doi = {10.3390/nu17203218},
pmid = {41156471},
issn = {2072-6643},
support = {2022QH2300//Fujian Medical University/ ; },
mesh = {Animals ; *Alzheimer Disease/drug therapy/metabolism/pathology ; Mice ; *Amyloid beta-Peptides/metabolism ; Microglia/drug effects/metabolism ; Molecular Docking Simulation ; *Neuroinflammatory Diseases/drug therapy ; Disease Models, Animal ; Male ; Maze Learning/drug effects ; MAP Kinase Signaling System/drug effects ; Memory/drug effects ; *Anti-Inflammatory Agents/pharmacology ; },
abstract = {BACKGROUND: The pathogenesis of Alzheimer's disease (AD) is complex, and effective treatments remain elusive. Growing evidence suggests that dietary factors may play a significant role in preventing or alleviating AD. Bergapten (BG), a natural compound with anti-inflammatory properties, has been studied; however, its specific role in neuroinflammation and AD pathogenesis remains unclear.

METHODS: Through public databases and bioinformatics tools, the possible molecular mechanisms of BG's effects on AD were analyzed. Six-month-old 5×FAD mice underwent intragastric administration of BG for 30 consecutive days. Learning and memory abilities were assessed using the novel object recognition (NOR) test and the Morris water maze (MWM) test. Immunofluorescence staining, Western blot and q-PCR was conducted to assess the underlying mechanisms. In vitro experiments used Aβ-stimulated BV2 microglial cells for BG intervention.

RESULTS: Bioinformatics analysis revealed the MAPK signaling pathway as the top-ranked pathway. Molecular docking studies further demonstrated strong binding interactions between BG and key proteins within the MAPK pathway. In behavioral studies, NOR test and MWM test demonstrated that BG treatment improved learning and memory abilities in 5×FAD mice. Additionally, BG treatment significantly reduced Aβ deposition, pro-inflammatory cytokine levels, and inhibited excessive microglial activation in these mice. Consistent with in vivo findings, BG effectively decreased pro-inflammatory cytokines in Aβ-stimulated BV2 microglial cells. Mechanistic studies revealed that BG attenuates neuroinflammatory responses by inhibiting the MAPK signaling pathway both in vivo and in vitro.

CONCLUSIONS: Our findings suggest that BG mitigates AD pathological features by suppressing MAPK-mediated neuroinflammation and represents a promising natural small molecule for the prevention and treatment of AD.},
}

Animals
*Alzheimer Disease/drug therapy/metabolism/pathology
Mice
*Amyloid beta-Peptides/metabolism
Microglia/drug effects/metabolism
Molecular Docking Simulation
*Neuroinflammatory Diseases/drug therapy
Disease Models, Animal
Male
Maze Learning/drug effects
MAP Kinase Signaling System/drug effects
Memory/drug effects
*Anti-Inflammatory Agents/pharmacology

@article {pmid41156455,
year = {2025},
author = {Pietruszkiewicz, J and Mrozek, K and Zwierz, M and Wińska, A and Suprunowicz, M and Oracz, AJ and Waszkiewicz, N},
title = {The Neuroprotective Potential of Vitamin D3.},
journal = {Nutrients},
volume = {17},
number = {20},
pages = {},
doi = {10.3390/nu17203202},
pmid = {41156455},
issn = {2072-6643},
support = {B.SUB.25.437//Medical University of Białystok/ ; },
mesh = {Humans ; *Cholecalciferol/pharmacology/therapeutic use ; *Neuroprotective Agents/pharmacology/therapeutic use ; *Neurodegenerative Diseases/drug therapy/prevention & control ; Vitamin D Deficiency/drug therapy/complications ; Oxidative Stress/drug effects ; Animals ; *Neuroprotection/drug effects ; },
abstract = {Vitamin D3 plays a pivotal role not only in bone health but also in the functioning of the nervous system, particularly in the context of age-related neurodegenerative diseases such as Alzheimer's disease, multiple sclerosis, and Parkinson's disease. Vitamin D3 deficiency has been associated with cognitive decline, heightened inflammation, and shortened leukocyte telomere length, which may contribute to accelerated cellular aging. Therapeutic interventions involving vitamin D3 have been reported in selected clinical studies and meta-analyses to potentially enhance cognitive function, decrease amyloid β biomarkers, and prolong telomere length, although heterogeneity remains across study designs and populations. Furthermore, vitamin D3 has been shown to influence the expression of genes implicated in DNA repair and oxidative stress response, including NRF2, OGG1, MYH, and MTH1. This narrative review synthesizes current knowledge on the molecular mechanisms of vitamin D3 action in the context of neuroprotection and discusses potential directions for future research, including its possible therapeutic applications in neurodegenerative diseases.},
}

Humans
*Cholecalciferol/pharmacology/therapeutic use
*Neuroprotective Agents/pharmacology/therapeutic use
*Neurodegenerative Diseases/drug therapy/prevention & control
Vitamin D Deficiency/drug therapy/complications
Oxidative Stress/drug effects
Animals
*Neuroprotection/drug effects

@article {pmid41156316,
year = {2025},
author = {Antonioni, A and Della Valle, A and Leitner, C and Raho, EM and Cesnik, E and Capone, JG and Flacco, ME and Casoni, F and Proserpio, P and Ferini-Strambi, L and Galbiati, A},
title = {Sleep Disturbances Across Dementias and Cognitive Decline: Study Protocol for a Systematic Review and Network Meta-Analysis of Polysomnographic Findings.},
journal = {Journal of clinical medicine},
volume = {14},
number = {20},
pages = {},
doi = {10.3390/jcm14207437},
pmid = {41156316},
issn = {2077-0383},
abstract = {Sleep disturbances are increasingly recognized as early and clinically meaningful features in the pathophysiology of neurodegenerative diseases. Polysomnography (PSG), i.e., the gold standard for objectively characterizing sleep architecture, may provide non-invasive and scalable biomarkers for both early detection and differential diagnosis of dementia. This systematic review and network meta-analysis aims to synthesize existing evidence on PSG-derived sleep alterations across the neurodegenerative continuum, including subjective cognitive impairment, mild cognitive impairment, Alzheimer's disease, frontotemporal dementia, Lewy body dementia, and Parkinson's disease dementia, compared to healthy controls. It will adhere to the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) guidelines for reporting systematic reviews that include network meta-analyses, and it has been registered with the International Prospective Register of Systematic Reviews (PROSPERO) under registration number CRD420251114418. We will include peer-reviewed studies with nocturnal PSG data from adult participants, categorized using validated diagnostic criteria, and scored according to the most recent American Academy of Sleep Medicine guidelines. Both pairwise and network meta-analyses will be conducted using standardized mean differences to quantify group-level effects. Additional analyses will explore the correlations between PSG parameters, severity of cognitive impairment, behavioral symptoms, treatments, and relevant comorbidities. Longitudinal data, where available, will be analyzed separately to evaluate prognostic value. This study will provide a comprehensive synthesis of PSG alterations across neurodegenerative disorders, offering insights into their diagnostic utility and potential as early markers for stratification in clinical trials of disease-modifying therapies.},
}

@article {pmid41156228,
year = {2025},
author = {Christodoulou, RC and Vamvouras, G and Sarquis, MD and Petrou, V and Papageorgiou, PS and Rivera, L and Morales Gonzalez, C and Rivera, G and Papageorgiou, SG and Vassiliou, E},
title = {From Microbleeds to Iron: AI Prediction of Cerebrospinal Fluid Erythrocyte Load in Alzheimer's Disease.},
journal = {Journal of clinical medicine},
volume = {14},
number = {20},
pages = {},
doi = {10.3390/jcm14207360},
pmid = {41156228},
issn = {2077-0383},
abstract = {Background/Objectives: Cerebrospinal fluid erythrocyte load (CTRED) reflects occult red-blood-cell ingress into brain/CSF and consequent heme-iron exposure, a toxic pathway relevant to Alzheimer's disease (AD). We aimed to develop explainable machine learning (ML) models that classify high vs. low CTRED from routine, largely non-invasive inputs, and to position a blood-first workflow leveraging contemporary plasma amyloid-tau biomarkers. Methods: Twenty-six ADNI participants were analyzed. Inputs were age, sex, mean arterial pressure (MAPres), amyloid (Aβ42), total tau, phosphorylated tau, and hippocampal atrophy rate (APC) derived from longitudinal MRI. APC was computed from normalized hippocampal volumes. CTRED was binarized at the median (0 vs. >0). Data were split into train (n = 20) and held-out test (n = 6). Five classifiers (linear SVM, ridge, logistic regression, random forests, and MLP) were trained in leakage-safe pipelines with stratified five-fold cross-validation. To provide a comprehensive assessment, we presented the contribution AUC, thresholded performance metrics, summarized model performance, and the permutation feature importance (PFI). Results: On the test set, SVM, ridge, logistic regression, and random forests achieved AUC = 1.00, while the MLP achieved AUC = 0.833. Across models, PFI consistently prioritized p-tau/tau, Aβ42, and MAPres; age, sex, and APC contributed secondarily. The attribution profile aligns with mechanisms linking BBB dysfunction and amyloid-related microvascular fragility with tissue vulnerability to heme-iron. Conclusions: In this proof-of-concept study, explainable ML predicted CTRED from routine variables with biologically coherent drivers. Although ADNI measurements were CSF-based and the sample was small, the framework is non-invasive by adding plasma p-tau217/Aβ1-42 for amyloid, tau inputs, and integrating demographics, hemodynamic context, and MRI. External, plasma-based validation in larger cohorts is warranted, alongside extension to MCI and multimodal correlation (QSM, DCE-MRI) to establish clinically actionable CTRED thresholds.},
}

@article {pmid41155880,
year = {2025},
author = {Naki, T and Peter, S and Alven, S},
title = {Polymeric Nanocarrier-Based Drug Formulations for Enhancing Nose-to-Brain Delivery.},
journal = {Pharmaceutics},
volume = {17},
number = {10},
pages = {},
doi = {10.3390/pharmaceutics17101242},
pmid = {41155880},
issn = {1999-4923},
abstract = {Neurological-related diseases are among the most debilitating and difficult to manage. Many possible pharmacological treatments for neurological diseases struggle to cross the blood-brain barrier (BBB) to achieve concentrations that can produce a therapeutic benefit. This is primarily because of the existence of the BBB, which poses significant hurdles for both therapeutic and diagnostic efforts by restricting the entry of most medications. Nasal-to-brain drug transportation has surfaced as an encouraging approach to tackle the difficulties linked with conventional drug administration techniques for neurological disorders. In response, innovative methods for improving drug delivery focus on breaking down the BBB via physical techniques, including optical and photothermal therapy, electrical stimulation, and acoustic or mechanical stimulation. Nanocarriers represent a promising approach for facilitating nasal systemic and brain delivery of active compounds. Hence, the achievement of therapeutically relevant concentrations of exogenous molecules within the body is significantly contingent upon the nanocarriers' capability to surpass biological barriers. Polymers in nanocarrier formulations can result in significantly enhanced nose-to-brain drug delivery by protecting drugs from premature biodegradation, increasing permeability, improving mucoadhesion, and targeting specific cells in the brain. Polymeric nanocarriers are frequently functionalized with cell-penetrating peptides to further improve the specificity of the loaded therapeutic molecules. This review focuses on the use of nanocarrier-based therapeutic agents to enhance the efficacy of nose-to-brain delivery systems.},
}

@article {pmid41155704,
year = {2025},
author = {Pirvu, AS and Varut, RM and Trasca, DM and Stoica, GA and Radivojevic, K and Carmen, S and Arsenie, CC and Popescu, C},
title = {Cyclodextrins as Active Therapeutic Agents: Beyond Their Role as Excipients.},
journal = {Pharmaceuticals (Basel, Switzerland)},
volume = {18},
number = {10},
pages = {},
doi = {10.3390/ph18101592},
pmid = {41155704},
issn = {1424-8247},
abstract = {Cyclodextrins (CDs) have traditionally been recognized as excipients that enhance solubility and stability of drugs. However, growing evidence shows that CDs themselves can act as active therapeutic agents. Their unique supramolecular properties enable them to interact with biological membranes, mobilize cholesterol, and modulate immune responses. This review highlights four therapeutic areas where CDs demonstrate particular promise. First, in gene and mRNA therapy, cationic CD derivatives form nanoparticles that protect nucleic acids, promote endosomal escape, and achieve targeted delivery. Second, in neurodegenerative disorders such as Niemann-Pick type C and Alzheimer's disease, hydroxypropyl-β-CD facilitates cholesterol clearance and reduces pathological lipid accumulation. Third, in detoxification, the γ-CD derivative sugammadex exemplifies a clinically approved agent that encapsulates neuromuscular blockers to reverse anesthesia. Finally, CDs have emerged as safe vaccine adjuvants, inducing robust systemic and mucosal immunity with reduced IgE responses compared to alum. Together, these examples illustrate a paradigm shift: CDs are not only versatile excipients but also active molecules with direct therapeutic effects. Future translation will require careful optimization of safety, scalability, and regulatory compliance, but CDs are poised to contribute meaningfully to next-generation medicines.},
}

@article {pmid41155671,
year = {2025},
author = {Kim, GW and Kim, YS and Afroze Bondhon, T and Balakrishnan, R and Han, JH and Kwon, JW and Kim, WJ and Choi, DK},
title = {Rubus occidentalis Ethanol Extract Attenuates Neuroinflammation and Cognitive Impairment in Lipopolysaccharide-Stimulated Microglia and Scopolamine-Induced Amnesic Mice.},
journal = {Pharmaceuticals (Basel, Switzerland)},
volume = {18},
number = {10},
pages = {},
doi = {10.3390/ph18101557},
pmid = {41155671},
issn = {1424-8247},
support = {2025.//Konkuk University/ ; },
abstract = {Background/Objectives: Neuroinflammatory mechanisms, primarily mediated by activated microglia, play a key role in the progression of conditions such as mild cognitive impairment associated with Alzheimer's disease. Rubus occidentalis (R. occidentalis), a black-fruited raspberry native to North America, is reported to possess antimicrobial, antidiabetic, and anticancer properties. This study investigated the neuroprotective and anti-neuroinflammatory effects of a 100% ethanol extract from premature R. occidentalis fruits (ROE) in lipopolysaccharide (LPS)-stimulated BV-2 microglial cells and a scopolamine-induced amnesic mouse model. Methods: C57BL/6N mice were orally administered ROE (100 or 200 mg/kg/b.w.) and donepezil (DNZ, 5 mg/kg) for 9 days and intraperitoneally injected with scopolamine (2 mg/kg/b.w.) for two days. Spatial learning and cognitive function were assessed using the Y-maze and Morris water maze tests. Protein and mRNA levels were examined both in vitro and in vivo through Western blotting and RT-PCR analysis. Results: In vitro, ROE improved cell viability and reduced nitric oxide overproduction in LPS-stimulated BV-2 cells, attenuated LPS-induced phosphorylation and degradation of IκB-α (thereby limiting NF-κB p65 nuclear translocation), and suppressed phosphorylation of MAPK signaling components. In vivo, ROE administration enhanced spatial learning and memory in scopolamine-treated C57BL/6N mice, increased hippocampal levels of brain-derived neurotrophic factor (BDNF) and phosphorylated CREB, and reduced the expression of iNOS and COX-2. Conclusions: Collectively, these results suggest that ROE possesses neuroprotective properties mediated by inhibition of NF-κB and MAPK signaling, promotion of CREB/BDNF pathways, and amelioration of neuroinflammation and cognitive deficits. Thus, ROE may represent a promising therapeutic candidate for neuroinflammatory disorders.},
}

@article {pmid41155642,
year = {2025},
author = {Ormazabal, P and Bastías-Pérez, M and Inestrosa, NC and Cisternas, P},
title = {Adipokines at the Metabolic-Brain Interface: Therapeutic Modulation by Antidiabetic Agents and Natural Compounds in Alzheimer's Disease.},
journal = {Pharmaceuticals (Basel, Switzerland)},
volume = {18},
number = {10},
pages = {},
doi = {10.3390/ph18101527},
pmid = {41155642},
issn = {1424-8247},
abstract = {The parallel global increase in obesity and Alzheimer's disease (AD) underscores an urgent public health challenge, with converging evidence indicating that metabolic dysfunction strongly contributes to neurodegeneration. Obesity is now recognized not only as a systemic metabolic condition but also as a modifiable risk factor for AD, acting through mechanisms such as chronic low-grade inflammation, insulin resistance, and adipose tissue dysfunction. Among the molecular mediators at this interface, adipokines have emerged as pivotal regulators linking metabolic imbalance to cognitive decline. Adipokines are hormone-like proteins secreted by adipose tissue, including adiponectin, leptin, and resistin, that regulate metabolism, inflammation and can influence brain function. Resistin, frequently elevated in obesity, promotes neuroinflammation, disrupts insulin signaling, and accelerates β-amyloid (Aβ) deposition and tau pathology. Conversely, adiponectin enhances insulin sensitivity, suppresses oxidative stress, and supports mitochondrial and endothelial function, thereby exerting neuroprotective actions. The imbalance between resistin and adiponectin may shift the central nervous system toward a pro-inflammatory and metabolically compromised state that predisposes to neurodegeneration. Beyond their mechanistic relevance, adipokines hold translational promise as biomarkers for early risk stratification and therapeutic monitoring. Importantly, natural compounds, including polyphenols, alkaloids, and terpenoids, have shown the capacity to modulate adipokine signaling, restore metabolic homeostasis, and attenuate AD-related pathology in preclinical models. This positions adipokines not only as pathogenic mediators but also as therapeutic targets at the intersection of diabetes, obesity, and dementia. By integrating mechanistic, clinical, and pharmacological evidence, this review emphasizes adipokine signaling as a novel axis for intervention and highlights natural compound-based strategies as emerging therapeutic approaches in obesity-associated AD. Beyond nutraceuticals, antidiabetic agents also modulate adipokines and AD-relevant pathways. GLP-1 receptor agonists, metformin, and thiazolidinediones tend to increase adiponectin and reduce inflammatory tone, while SGLT2 and DPP-4 inhibitors exert systemic anti-inflammatory and hemodynamic benefits with emerging but still limited cognitive evidence. Together, these drug classes offer mechanistically grounded strategies to target the adipokine-inflammation-metabolism axis in obesity-associated AD.},
}

@article {pmid41155586,
year = {2025},
author = {Pinheiro, PSM and Diniz, LP and Franco, LS and Siqueira, M and Gomes, FCA},
title = {Histone Deacetylases in Neurodegenerative Diseases and Their Potential Role as Therapeutic Targets: Shedding Light on Astrocytes.},
journal = {Pharmaceuticals (Basel, Switzerland)},
volume = {18},
number = {10},
pages = {},
doi = {10.3390/ph18101471},
pmid = {41155586},
issn = {1424-8247},
support = {//Ministério da Saúde, Departamento de Ciência e Tecnologia (MS-DECIT)/ ; //Fundação Carlos Chagas Filho de Amparo à Pesquisa do Estado do Rio de Janeiro/ ; //National Council for Scientific and Technological Development/ ; },
abstract = {Histone deacetylases (HDACs) are crucial enzymes involved in the regulation of gene expression through chromatin remodeling, impacting numerous cellular processes, including cell proliferation, differentiation, and survival. In recent years, HDACs have emerged as therapeutic targets for neurodegenerative diseases (NDDs), such as Alzheimer's disease, Parkinson's disease, and Huntington's disease, given their role in modulating neuronal plasticity, neuroinflammation, and neuronal survival. HDAC inhibitors (HDACi) are small molecules that prevent the deacetylation of histones, thereby promoting a more relaxed chromatin structure and enhancing gene expression associated with neuroprotective pathways. Preclinical and clinical studies have demonstrated that HDACi can mitigate neurodegeneration, reduce neuroinflammatory markers, and improve cognitive and motor functions, positioning them as promising therapeutic agents for NDDs. Given the complexity and multifactorial nature of NDDs, therapeutic success will likely depend on multi-target drugs as well as new cellular and molecular therapeutic targets. Emerging evidence suggests that HDACi can modulate the function of astrocytes, a glial cell type critically involved in neuroinflammation, synaptic regulation, and the progression of neurodegenerative diseases. Consequently, HDACi targeting astrocytic pathways represent a novel approach in NDDs therapy. By modulating HDAC activity specifically in astrocytes, these inhibitors may attenuate pathological inflammation and promote a neuroprotective environment, offering a complementary strategy to neuron-focused treatments. This review aims to provide an overview of HDACs and HDACi in the context of neurodegeneration, emphasizing their molecular mechanisms, therapeutic potential, and limitations. Additionally, it explores the emerging role of astrocytes as targets for HDACi, proposing that this glial cell type could enhance the efficacy of HDACs-targeted therapies in NDD management.},
}

@article {pmid41155570,
year = {2025},
author = {Atanasova, M},
title = {Small-Molecule Inhibitors of Amyloid Beta: Insights from Molecular Dynamics-Part B: Natural Compounds.},
journal = {Pharmaceuticals (Basel, Switzerland)},
volume = {18},
number = {10},
pages = {},
doi = {10.3390/ph18101457},
pmid = {41155570},
issn = {1424-8247},
support = {Grant No BG16RFPR002-1.014-0018//the Centre of Excellence in Informatics and ICT funded by the Research, Innovation and Digitalization for Smart Transformation Programme 2021-2027 and co-financed by the European Union/ ; agreement D01-98/26.06.2025//the National Road Map/ ; },
abstract = {Alzheimer's disease (AD) is the most common form of dementia, characterized by progressive memory loss and cognitive decline. Its key pathological hallmarks include extracellular amyloid plaques composed of amyloid beta (Aβ) peptides and intracellular neurofibrillary tangles formed by hyperphosphorylated tau protein. Although numerous studies have investigated the complex pathology of AD, its underlying mechanisms remain incompletely understood. The amyloid cascade hypothesis continues to be the leading model of AD pathogenesis. It suggests that Aβ aggregation is the initial trigger of neurotoxicity, setting off a cascade of pathological events including inflammation, oxidative stress, tau hyperphosphorylation, synaptic dysfunction, and, ultimately, dementia. Molecular dynamics (MD) is a powerful tool in structure-based drug design (SBDD). By simulating biomolecular motions at the atomic level, MD provides unique insights into molecular properties, functions, and inhibition mechanisms-insights often inaccessible through other experimental or computational techniques. When integrated with experimental data, MD further deepens our understanding of molecular interactions and biological processes. Natural compounds, known for their pleiotropic pharmacological activities, favorable safety profiles, and general tolerability (despite occasional side effects), are increasingly explored for their potential in both the treatment and prevention of various diseases, including AD. In this review, we summarize current findings from MD simulations of natural compounds with anti-amyloidogenic potential. This work builds upon our previous publication, which focused on endogenous compounds and repurposed drugs. The review is structured as follows: an overview of the amyloid cascade hypothesis; a discussion of Aβ oligomeric structures and their stabilizing interactions; a section on molecular dynamics, including its challenges and future directions; and a comprehensive analysis of the inhibitory mechanisms of natural compounds, categorized by their shared structural features.},
}

@article {pmid41155565,
year = {2025},
author = {Sikiric, P and Seiwerth, S and Skrtic, A and Staresinic, M and Strbe, S and Vuksic, A and Sikiric, S and Bekic, D and Soldo, D and Grizelj, B and Novosel, L and Beketic Oreskovic, L and Oreskovic, I and Stupnisek, M and Boban Blagaic, A and Dobric, I},
title = {BPC 157 Therapy: Targeting Angiogenesis and Nitric Oxide's Cytotoxic and Damaging Actions, but Maintaining, Promoting, or Recovering Their Essential Protective Functions. Comment on Józwiak et al. Multifunctionality and Possible Medical Application of the BPC 157 Peptide-Literature and Patent Review. Pharmaceuticals 2025, 18, 185.},
journal = {Pharmaceuticals (Basel, Switzerland)},
volume = {18},
number = {10},
pages = {},
doi = {10.3390/ph18101450},
pmid = {41155565},
issn = {1424-8247},
abstract = {The healing issue is a central, not completely understood, problem in pharmacology, approached by many concepts. One of the most well-known is Robert's and Szabo's concept of cytoprotection, which holds innate cell (epithelial (Robert), endothelial (Szabo)) integrity, protection/maintenance/reestablishing in the stomach to be translated to other organ therapy (cytoprotection→organoprotection) via cytoprotection agent's effect. Thereby, we defend stable gastric pentadecapeptide BPC 157 therapy, efficacy, pleiotropic beneficial effects along with high safety (LD1 not achieved) against Józwiak and collaborators' review speculating its negative impact, speculation of angiogenesis toward tumorogenesis, increased NO and eNOS, toward damaging free radicals formation, and neurodegenerative diseases (Parkinson's disease and Alzheimer's disease). Contrarily, in wound healing and general healing capabilities as reviewed, as a cytoprotective agent, and native cytoprotection mediator, BPC 157 controls angiogenesis and the NO-system healing functions, and counteracts the pathological presentation of neurodegenerative diseases in acknowledged animal models (i.e., Parkinson's disease and Alzheimer's disease), and presents prominent anti-tumor potential, in vivo and in vitro. BPC 157 resolved cornea transparency maintenance, cornea healing "angiogenic privilege" (vs. angiogenesis/neovascularization/tumorogenesis), does not produce corneal neovascularization, but rather opposes it, and per Folkman's concept, it demonstrates anti-tumor effect in vivo and in vitro. BPC 157 exhibits a distinctive effect on NO-level (increase vs. decrease), always combined with counteraction of free radicals formation, and in mice and rats, BPC 157 therapy counteracts Parkinson's disease-like and Alzheimer's disease-like disturbances. Thus, BPC 157 therapy means targeting angiogenesis and NO's cytotoxic and damaging actions, but maintaining, promoting, or recovering their essential protective functions.},
}

@article {pmid41155541,
year = {2025},
author = {Perez, DM},
title = {α1A-Adrenergic Receptor as a Target for Neurocognition: Cautionary Tale from Nicergoline and Quinazoline Non-Selective Blockers.},
journal = {Pharmaceuticals (Basel, Switzerland)},
volume = {18},
number = {10},
pages = {},
doi = {10.3390/ph18101425},
pmid = {41155541},
issn = {1424-8247},
support = {RO1AG066627/GF/NIH HHS/United States ; },
abstract = {Decades ago, previous studies that used non-selective ergot derivatives suggested that blockage of the α1A-adrenergic receptor mildly increased cognition through increased blood flow to the brain due to vasodilation and, thus, could be used as a treatment for dementia. However, further studies indicated that nicergoline was non-specific and hit many different targets. Today, a similar scenario is developing with the use of non-selective α1-AR antagonists of the quinazoline class, referred to as "osins", as potential treatments for COVID-19/SARS, post-traumatic stress disorder, cancer, and neurodegenerative disorders, such as Parkinson's, Alzheimer's, and amyotrophic lateral sclerosis. While there is extensive evidence of neuroprotection from many clinical trials, the mechanism of action of quinazolines is often not α1-AR-mediated but keyed to its glycolysis-enhancing effects through activation of the enzyme phosphoglycerate kinase 1 (PGK1). These studies have incorrectly labeled the α1A-adrenergic receptor as an "old target" to treat Alzheimer's and other neurocognitive diseases, hampering drug development. This review will summarize these and other studies to indicate that activation, not blockage, of norepinephrine's actions, through α1A-AR, mediates cognitive, memory, and neuroprotective functions that may reverse the progression of neurocognitive diseases.},
}

@article {pmid41155528,
year = {2025},
author = {Tanaka, M},
title = {Special Issue "Translating Molecular Psychiatry: From Biomarkers to Personalized Therapies".},
journal = {International journal of molecular sciences},
volume = {26},
number = {20},
pages = {},
doi = {10.3390/ijms262010238},
pmid = {41155528},
issn = {1422-0067},
mesh = {Humans ; *Precision Medicine/methods ; *Biomarkers/metabolism ; *Mental Disorders/therapy/diagnosis/genetics/metabolism ; *Psychiatry/methods ; Schizophrenia ; },
abstract = {Psychiatry stands at a turning point, where molecular insights promise to revolutionize how we diagnose, monitor, and treat neuropsychiatric conditions, including Alzheimer's, Parkinson's, depression, dementia, and schizophrenia (SCZ), among others [...].},
}

Humans
*Precision Medicine/methods
*Biomarkers/metabolism
*Mental Disorders/therapy/diagnosis/genetics/metabolism
*Psychiatry/methods
Schizophrenia

@article {pmid41155525,
year = {2025},
author = {Lin, GB and Liu, HH and Kuo, YY and Chen, YM and Hsu, FT and Wang, YW and Kung, Y and Ching, C and Chao, CY},
title = {Thermal Cycling Stimulation via Nasal Inhalation Attenuates Aβ25-35-Induced Cognitive Deficits in C57BL/6 Mice.},
journal = {International journal of molecular sciences},
volume = {26},
number = {20},
pages = {},
doi = {10.3390/ijms262010236},
pmid = {41155525},
issn = {1422-0067},
support = {NSTC 113-2112-M-002-024//National Science and Technology Council/ ; NSTC 112-2112-M-002-033//National Science and Technology Council/ ; MOST 110-2112-M-002-004//Ministry of Science and Technology/ ; },
mesh = {Animals ; *Amyloid beta-Peptides/metabolism/toxicity ; Mice ; Mice, Inbred C57BL ; *Cognitive Dysfunction/therapy/metabolism/chemically induced ; Male ; *Peptide Fragments/toxicity ; Hippocampus/metabolism ; Disease Models, Animal ; Alzheimer Disease/therapy/metabolism ; *Hyperthermia, Induced/methods ; Administration, Inhalation ; Maze Learning ; },
abstract = {Alzheimer's disease (AD) remains a significant public health challenge, with current treatments limited partly due to the difficulty of delivering therapeutics across the blood-brain barrier (BBB). The nose-to-brain (N-2-B) pathway offers a promising alternative to circumvent the BBB, but no drugs have yet been clinically applied via this route for AD. Mild stress is thought to activate intrinsic protective mechanisms against neurodegeneration, but traditional methods lack specificity and practicality. To address this, we propose the inhalation of mildly heated air as thermal stimulation, which utilizes the N-2-B pathway to induce mild stress and stimulate cerebral activity. This study employs thermal cycling-hyperthermia (TC-HT) in developing thermal cycling-stimulation via nasal inhalation (TCSNI), providing cyclic stimulation to maintain pathway activity while minimizing thermal injury. In C57BL/6 mice, TCSNI showed no adverse olfactory effects. In β-amyloid (Aβ)-treated mice, TCSNI significantly enhanced cognitive performance in Y-maze and novel object recognition (NOR) assessments, suggesting cognitive improvement. Mice hippocampal protein analyses indicated a reduction in Aβ accumulation, alongside increased expression of heat shock protein 70 (HSP70), insulin-degrading enzyme (IDE), and phosphorylated Akt (p-Akt). These results suggest that N-2-B-delivered TCSNI effectively modulates protein expression and enhances cognitive function, highlighting its potential for further exploration in AD treatment.},
}

Animals
*Amyloid beta-Peptides/metabolism/toxicity
Mice
Mice, Inbred C57BL
*Cognitive Dysfunction/therapy/metabolism/chemically induced
Male
*Peptide Fragments/toxicity
Hippocampus/metabolism
Disease Models, Animal
Alzheimer Disease/therapy/metabolism
*Hyperthermia, Induced/methods
Administration, Inhalation
Maze Learning

@article {pmid41155487,
year = {2025},
author = {Petrou, A and Deruvo, C and Purgatorio, R and Lichitsky, B and Komogortsev, AN and Kartsev, VG and de Candia, M and Catto, M and Altomare, CD and Geronikaki, A},
title = {Investigating Amphoteric 3,4'-Biscoumarin-Based ortho-[(Dialkylamino)methyl]phenols as Dual MAO and ChE Inhibitors.},
journal = {International journal of molecular sciences},
volume = {26},
number = {20},
pages = {},
doi = {10.3390/ijms262010197},
pmid = {41155487},
issn = {1422-0067},
mesh = {*Monoamine Oxidase Inhibitors/chemistry/pharmacology ; Humans ; *Monoamine Oxidase/metabolism/chemistry ; *Cholinesterase Inhibitors/chemistry/pharmacology ; Molecular Docking Simulation ; *Coumarins/chemistry/pharmacology ; Acetylcholinesterase/metabolism/chemistry ; Butyrylcholinesterase/metabolism/chemistry ; *Phenols/chemistry/pharmacology ; Structure-Activity Relationship ; },
abstract = {Nineteen previously and newly synthesized amphoteric 8-[(dialkylamino)methyl]-7-hydroxy-4-(2-oxo-2H-chromen-3-yl)-2H-chromen-2-ones were assayed as inhibitors of monoamine oxidases (MAO-A and B) and cholinesterases (AChE and BChE). Five of the tested compounds (2b, 2c, 3c, 5b, and 5c), namely those bearing the less bulky alkyls in the Mannich base 8-CH2NR2 (R = Me, Et) and the halogens (Cl, Br) at C6 of the 4-coumarin-3-yl moiety, showed moderate inhibitory potencies toward human MAO-A in the single-digit micromolar range (IC50s from 1.49 to 3.04 µM). In particular, the 6'-Cl derivatives 2b and 5b proved to be reversible competitive inhibitors of human MAO-A with Ki values of 0.272 and 0.326 µM. Among the tested compounds, 3c proved to also be a moderate inhibitor of human AChE (IC50 4.27 µM). Molecular docking calculations suggested binding modes of the most active compounds to MAO-A and AChE binding sites consistent enough with the experimental data. Chemoinformatic tools suggest for the most active compounds, including the dual MAO-A/AChE inhibitor 3c, full compliance with Lipinski's rule of five, high probability of gastrointestinal absorption, but low blood-brain barrier (BBB) permeability. While further efforts are required to improve their CNS distribution, herein new phenolic Mannich bases have been identified that may have potential for treating neurodegenerative syndromes.},
}

*Monoamine Oxidase Inhibitors/chemistry/pharmacology
Humans
*Monoamine Oxidase/metabolism/chemistry
*Cholinesterase Inhibitors/chemistry/pharmacology
Molecular Docking Simulation
*Coumarins/chemistry/pharmacology
Acetylcholinesterase/metabolism/chemistry
Butyrylcholinesterase/metabolism/chemistry
*Phenols/chemistry/pharmacology
Structure-Activity Relationship

@article {pmid41155414,
year = {2025},
author = {Ishibashi, E and Araya, K and Nakamura, K and Shimamori, K and Uwai, K and Kuragano, M and Tokuraku, K},
title = {Aggregation Characteristics of Tau Phosphorylated by Various Kinases as Observed by Quantum Dot Fluorescence Imaging.},
journal = {International journal of molecular sciences},
volume = {26},
number = {20},
pages = {},
doi = {10.3390/ijms262010122},
pmid = {41155414},
issn = {1422-0067},
support = {JPMJPF2213//Japan Science and Technology Agency/ ; JP24K08627//JSPS KAKENHI/ ; },
mesh = {*tau Proteins/metabolism/chemistry ; *Quantum Dots ; Phosphorylation ; Humans ; Glycogen Synthase Kinase 3 beta/metabolism ; *Protein Aggregates ; Cyclin-Dependent Kinase 5/metabolism ; Optical Imaging/methods ; Alzheimer Disease/metabolism ; },
abstract = {This study focused on the abnormal phosphorylation of tau and its aggregation process, characteristic of Alzheimer's disease, and aimed to compare the morphology and formation process of phosphorylated tau aggregates produced by four kinases: Cdk5/p25, GSK3β, MARK4, and p38α. Using quantum dots for 2D and 3D structural analysis, tau aggregates were confirmed in non-phosphorylated tau (non p-tau), as well as tau phosphorylated by GSK3β and MARK4. Aggregation initiation times were observed around 72 h for non-p-tau, and around 96 h for GSK3β and MARK4 phosphorylated tau. The thickness of non-p-tau aggregates was approximately 11 μm, while GSK3β aggregates were significantly thicker (13 μm) and exhibited increased density. TEM analysis suggested that tau forming wavy filaments was less prone to forming large aggregates. ThT assays and CD spectra showed an increased β-sheet structure for all kinases. Non-p-tau and GSK3β exhibited an increased right-twisted β-sheet structure, while Cdk5/p25, MARK4, and p38α showed an increased left-twisted β-sheet structure. The direct correlation between kinase activity and tau aggregate morphology revealed in this study provides a potential mechanistic basis for understanding disease heterogeneity and establishing novel therapeutic targets for AD specifically or for other neurodegenerative diseases as well.},
}

*tau Proteins/metabolism/chemistry
*Quantum Dots
Phosphorylation
Humans
Glycogen Synthase Kinase 3 beta/metabolism
*Protein Aggregates
Cyclin-Dependent Kinase 5/metabolism
Optical Imaging/methods
Alzheimer Disease/metabolism

@article {pmid41155374,
year = {2025},
author = {Honjo, A and Yako, H and Miyamoto, Y and Yagi, M and Yamamoto, M and Nishi, A and Sakagami, H and Yamauchi, J},
title = {Knocking Down FRMD4A, a Factor Associated with the Brain Development Disorder and a Risk Factor for Alzheimer's Disease, Using RNA-Targeting CRISPR/Cas13 Reveals Its Role in Cell Morphogenesis.},
journal = {International journal of molecular sciences},
volume = {26},
number = {20},
pages = {},
doi = {10.3390/ijms262010083},
pmid = {41155374},
issn = {1422-0067},
mesh = {*Alzheimer Disease/genetics/metabolism/pathology ; Animals ; *CRISPR-Cas Systems ; Neurons/metabolism/cytology ; Mice ; *Morphogenesis/genetics ; *Cytoskeletal Proteins/genetics/metabolism ; *Membrane Proteins/genetics/metabolism ; Gene Knockdown Techniques ; Humans ; *Brain/metabolism ; Cell Line ; },
abstract = {Genetic truncation or mutation of the gene encoding band 4.1, ezrin, radixin, and moesin (FERM) domain protein containing 4A (FRMD4A) is associated with brain developmental diseases, including microcephaly with global developmental delay. It has also been identified as a risk factor for Alzheimer's disease. By analogy with other FERM domain-containing proteins, FRMD4A is believed to regulate cell morphogenesis and/or cell polarization in central nervous system (CNS) cells; however, it remains unclear whether and how dysfunction of FRMD4A and/or its closely homologous protein FRMD4B causes abnormal morphogenesis in neuronal cells. Here, we describe for the first time the roles of FRMD4A and FRMD4B in process elongation in neuronal cells. Knockdown of Frmd4a or Frmd4b using specific RNA-targeting clustered regularly interspaced short palindromic repeat (CRISPR) and Cas13-fitted gRNAs led to decreased process elongation in primary cortical neurons. Similar decreases in neuronal marker expression were observed in the N1E-115 cell line, a model of neuronal differentiation. Furthermore, hesperetin, an aglycone of the citrus flavonoid hesperidin known to promote neuroprotective signaling, recovered the decreased process elongation induced by the knockdown of Frmd4a or Frm4b. Hesperetin also stimulated phosphorylation of mitogen-activated protein kinases/extracellular signal-regulated kinases (MAPKs/ERKs), which could help promote neuronal processes. These results suggest that FRMD4A and FRMD4B regulate process elongation through a possible signaling pathway linked to the sustained phosphorylation of MAPKs/ERKs. Crucially, this study reveals that, at the molecular and cellular levels, hesperetin can restore normal phenotypes when FRMD4A protein or FRMD4B protein is impaired.},
}

*Alzheimer Disease/genetics/metabolism/pathology
Animals
*CRISPR-Cas Systems
Neurons/metabolism/cytology
Mice
*Morphogenesis/genetics
*Cytoskeletal Proteins/genetics/metabolism
*Membrane Proteins/genetics/metabolism
Gene Knockdown Techniques
Humans
*Brain/metabolism
Cell Line

@article {pmid41155356,
year = {2025},
author = {Trifonova, EA and Pashchenko, AA and Ivanov, RA and Kochetov, AV and Lashin, SA},
title = {Genetic and Pathogenic Overlaps Between Autism Spectrum Disorder and Alzheimer's Disease: Evolutionary Features and Opportunities for Drug Repurposing.},
journal = {International journal of molecular sciences},
volume = {26},
number = {20},
pages = {},
doi = {10.3390/ijms262010066},
pmid = {41155356},
issn = {1422-0067},
mesh = {*Autism Spectrum Disorder/genetics/drug therapy ; Humans ; *Alzheimer Disease/genetics/drug therapy/metabolism ; *Drug Repositioning ; Gene Regulatory Networks ; TOR Serine-Threonine Kinases/metabolism/genetics ; Genetic Predisposition to Disease ; Evolution, Molecular ; Signal Transduction ; },
abstract = {Autism spectrum disorder (ASD) and Alzheimer's disease (AD) are neurodevelopmental and neurodegenerative disorders, respectively. While exome sequencing is routinely employed during the early stages of ASD diagnosis, it rarely influences therapeutic strategies. To address this gap, we have reconstructed and analyzed the gene networks linking autism spectrum disorders, Alzheimer's disease, and mTOR signaling. In addition, we have performed a phylostratigraphic analysis that reveals similarities and differences in the evolution of both ASD and Alzheimer's disease predisposition genes. We have shown that almost half of the genes predisposing to autism and two-fifths of the genes predisposing to Alzheimer's disease are directly related to the mTOR signaling pathway. Analysis of Phylostratigraphic Age Index (PAI) value distributions revealed a significant enrichment of evolutionarily ancient genes in both ASD- and AD-related gene sets. When studying the distribution of ASD predisposition genes by Divergence Index (DI) values, a significant enrichment with genes having extremely low DI = 0 has been found. Such low DI values indicate that most likely these genes are under stabilizing selection. Using the ANDVisio tool, both pharmacological and natural mTOR regulators with potential for ASD treatment were selected, such as propofol, dexamethasone, celecoxib, statins, berberine, resveratrol, quercetin, myricetin, mio-inositol, and several amino acids.},
}

*Autism Spectrum Disorder/genetics/drug therapy
Humans
*Alzheimer Disease/genetics/drug therapy/metabolism
*Drug Repositioning
Gene Regulatory Networks
TOR Serine-Threonine Kinases/metabolism/genetics
Genetic Predisposition to Disease
Evolution, Molecular
Signal Transduction

@article {pmid41155299,
year = {2025},
author = {Zegarra-Valdivia, J and Khan, MZ and Putzolu, A and Cipriani, R and Pignatelli, J and Torres Aleman, I},
title = {Influence of Lifestyle on Brain Sensitivity to Circulating Insulin-like Growth Factor 1.},
journal = {International journal of molecular sciences},
volume = {26},
number = {20},
pages = {},
doi = {10.3390/ijms262010008},
pmid = {41155299},
issn = {1422-0067},
support = {PIBA21//Basque Government/ ; },
mesh = {Animals ; *Insulin-Like Growth Factor I/metabolism ; Male ; Mice ; Diet, High-Fat/adverse effects ; Female ; Mice, Inbred C57BL ; Social Isolation ; *Life Style ; *Brain/metabolism ; Depression/metabolism/blood ; Anxiety/metabolism ; Prefrontal Cortex/metabolism ; Behavior, Animal ; },
abstract = {Lifestyle factors, including social relationships and diet, influence mood homeostasis, a mechanism often dysregulated in high-incidence mental illnesses like depression and Alzheimer's dementia (AD). Given that insulin-like growth factor 1 (IGF-1) modulates mood and its blood levels are altered in both AD and affective disorders, we investigated whether IGF-1 activity in the brain was affected in mice subjected to social isolation or a high-fat diet (HFD). We found that both lifestyle conditions increased anxiety and depression-like behavior in C57BL/6 mice of both sexes, as determined by the elevated zero maze/open field tests and the forced swim test, respectively. These lifestyle conditions were associated with loss of neuronal responses to systemic IGF-1. Enhanced neuronal activity in the prefrontal cortex-measured via Ca[++] fiber photometry following intraperitoneal IGF-1 administration-was absent in both socially isolated and HFD-fed mice. However, only the HFD-fed group exhibited elevated serum IGF-1 levels. These findings suggest that loss of brain IGF-1 input may contribute to the observed mood disturbances, providing potential new targets to explore the heightened risk of depression and AD associated with loneliness and unhealthy diets in humans. Importantly, because reduced IGF-1 activity in the brain is not consistently reflected in serum levels, serum measurements are an unreliable indicator of brain IGF-1 activity.},
}

Animals
*Insulin-Like Growth Factor I/metabolism
Male
Mice
Diet, High-Fat/adverse effects
Female
Mice, Inbred C57BL
Social Isolation
*Life Style
*Brain/metabolism
Depression/metabolism/blood
Anxiety/metabolism
Prefrontal Cortex/metabolism
Behavior, Animal

@article {pmid41155297,
year = {2025},
author = {Akgüller, Ö and Balcı, MA and Cioca, G},
title = {Network-Medicine-Guided Drug Repurposing for Alzheimer's Disease: A Multi-Dimensional Systems Pharmacology Approach.},
journal = {International journal of molecular sciences},
volume = {26},
number = {20},
pages = {},
doi = {10.3390/ijms262010003},
pmid = {41155297},
issn = {1422-0067},
mesh = {*Drug Repositioning/methods ; *Alzheimer Disease/drug therapy/metabolism ; Humans ; Blood-Brain Barrier/metabolism/drug effects ; *Network Pharmacology/methods ; Machine Learning ; },
abstract = {Alzheimer's disease (AD) drug development faces persistent challenges from blood-brain barrier limitations and inadequate integration of medicinal chemistry considerations with computational predictions. We developed a comprehensive Central Nervous System (CNS)-focused network medicine framework integrating machine-learning-validated BBB penetration prediction (95.7% accuracy, 0.992 AUC-ROC), modality-specific tractability assessment, and transparent evidence classification to identify viable drug repurposing candidates. CNS-specific pre-filtering refined 24,474 DGIdb compounds to 8247 CNS-relevant drugs, analyzed through multi-dimensional network scoring and systematic pharmaceutical property assessment. Modality stratification generated separate rankings for small molecules (3667 candidates), peptides (73 candidates), and biologics (3 candidates), acknowledging distinct BBB penetration mechanisms. Analysis revealed 64.8% of small molecules achieving Class I (Highly Tractable) status, with 83.6% demonstrating favorable BBB penetration. Plerixafor emerged as the top-ranked small molecule (score: 1.170), while trofinetide achieved the highest peptide ranking (score: 1.387), though classified as speculative, pending AD-specific validation. Successful identification of the FDA-approved AD therapeutics memantine and donepezil among the top candidates validated the computational performance, while the predominance of mechanistic evidence classifications (86.7%) highlighted that network predictions represent hypothesis-generating tools requiring systematic experimental validation rather than definitive therapeutic recommendations. The framework bridges computational predictions with pharmaceutical development requirements, providing actionable prioritization for systematic preclinical investigation addressing AD intervention.},
}

*Drug Repositioning/methods
*Alzheimer Disease/drug therapy/metabolism
Humans
Blood-Brain Barrier/metabolism/drug effects
*Network Pharmacology/methods
Machine Learning

@article {pmid41155255,
year = {2025},
author = {Bagyinszky, E and An, SSA},
title = {Targeting Granulin Haploinsufficiency in Frontotemporal Dementia: From Genetic Mechanisms to Therapeutics.},
journal = {International journal of molecular sciences},
volume = {26},
number = {20},
pages = {},
doi = {10.3390/ijms26209960},
pmid = {41155255},
issn = {1422-0067},
support = {RS-2021-NR060117//National Research Foundation Korea/ ; RS-2023-0025139//National Research Foundation Korea/ ; },
mesh = {*Frontotemporal Dementia/genetics/therapy/metabolism/pathology ; *Haploinsufficiency ; Humans ; Animals ; *Progranulins/genetics/metabolism ; Genetic Therapy/methods ; Mutation ; },
abstract = {Frontotemporal dementia (FTD) is the second most common early-onset dementia after Alzheimer's disease, characterized by progressive neurodegeneration primarily in the frontal and temporal lobes. Granulin (GRN) gene for encoding the progranulin (PGRN) protein was a key genetic contributor to FTD. PGRN was a multifunctional protein involved in lysosomal function, neuroinflammation, and neuronal survival. This review discusses the contributions of GRN haploinsufficiency to FTD pathogenesis with an emphasis on genetic mutations, downstream cellular consequences, relevant animal and cellular models, and emerging therapeutic strategies. Loss-of-function mutations in GRN were responsible up to ~50% reduction in PGRN levels, resulting in lysosomal dysfunction, TDP-43 aggregation, impaired microglial homeostasis, and enhanced neuroinflammation. Multiple in vitro and in vivo models recapitulated these pathological features. Novel therapeutic approaches, such as AAV-mediated gene therapy, stop codon readthrough compounds, SORT1 inhibitors, and antisense oligonucleotides, were investigated to restore PGRN levels and to mitigate disease progressions. However, challenges included the oncogenic risks of overexpression and the limited translational success in clinical trials to date. Targeting GRN haploinsufficiency became a promising avenue for FTD therapy. Improved models and refined delivery systems would be essential to develop safe and effective treatments. Future work should also focus on biomarker-guided interventions in presymptomatic mutation carriers.},
}

*Frontotemporal Dementia/genetics/therapy/metabolism/pathology
*Haploinsufficiency
Humans
Animals
*Progranulins/genetics/metabolism
Genetic Therapy/methods
Mutation

@article {pmid41155218,
year = {2025},
author = {Lee, J and Lee, E and Kwon, H and Moon, S and Bae, HJ and Hwang, JH and Cho, GH and Kong, H and Park, MH and Kim, SK and Kim, DH and Jung, JW},
title = {Synaptic Plasticity-Enhancing and Cognitive-Improving Effects of Standardized Ethanol Extract of Perilla frutescens var. acuta in a Scopolamine-Induced Mouse Model.},
journal = {International journal of molecular sciences},
volume = {26},
number = {20},
pages = {},
doi = {10.3390/ijms26209925},
pmid = {41155218},
issn = {1422-0067},
support = {S3400191//Ministry of SMEs and Startups/ ; },
mesh = {Animals ; Scopolamine/toxicity ; Mice ; Male ; *Plant Extracts/pharmacology/chemistry ; *Perilla frutescens/chemistry ; *Neuronal Plasticity/drug effects ; Disease Models, Animal ; Mice, Inbred ICR ; Hippocampus/drug effects/metabolism ; Long-Term Potentiation/drug effects ; Ethanol/chemistry ; *Cognition/drug effects ; Receptors, N-Methyl-D-Aspartate/metabolism ; *Cognitive Dysfunction/drug therapy/chemically induced ; Maze Learning/drug effects ; },
abstract = {In our previous study, we demonstrated that a standardized ethanol extract of Perilla frutescens var. acuta (PE) alleviates memory deficits in an Alzheimer's disease mouse model by inhibiting amyloid β (Aβ) aggregation and promoting its disaggregation. However, the extent to which PE exerts additional cognitive benefits independent of Aβ pathology remained unclear. Here, we aimed to evaluate the effects of PE on synaptic plasticity and learning and memory functions. Male ICR mice were used, and cognitive impairment was induced by scopolamine administration. PE was orally administered at doses determined from previous studies, and cognitive performance was assessed using the passive avoidance, Y-maze, and Morris water maze tests. In parallel, hippocampal slices were employed to examine the effects of PE on synaptic plasticity. PE (100 and 300 μg/mL) significantly enhanced long-term potentiation (LTP) in a concentration-dependent manner without altering basal synaptic transmission. This facilitation of LTP was blocked by scopolamine (1 μM), a muscarinic acetylcholine receptor (mAChR) antagonist, and IEM-1460 (50 μM), a calcium-permeable α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (CP-AMPAR) inhibitor, indicating the involvement of mAChR and CP-AMPAR pathways. In vivo, PE (100, 250, and 500 mg/kg) treatment improved memory performance across all behavioral tasks and upregulated hippocampal synaptic proteins including GluN2B, PSD-95, and CaMKII. Collectively, these results demonstrate that PE ameliorates scopolamine (1 mg/kg)-induced cognitive impairment by enhancing synaptic plasticity, likely through modulation of mAChR, CP-AMPAR, and NMDA receptor signaling. These findings highlight the therapeutic potential of PE for memory deficits associated with cholinergic dysfunction.},
}

Animals
Scopolamine/toxicity
Mice
Male
*Plant Extracts/pharmacology/chemistry
*Perilla frutescens/chemistry
*Neuronal Plasticity/drug effects
Disease Models, Animal
Mice, Inbred ICR
Hippocampus/drug effects/metabolism
Long-Term Potentiation/drug effects
Ethanol/chemistry
*Cognition/drug effects
Receptors, N-Methyl-D-Aspartate/metabolism
*Cognitive Dysfunction/drug therapy/chemically induced
Maze Learning/drug effects

@article {pmid41155192,
year = {2025},
author = {Kowalczyk, T and Muskała, M and Piekarski, J and Kowalski, M and Staszewski, M and Konuklugil, B and Rijo, P and Sitarek, P},
title = {Therapeutic Promise and Biotechnological Prospects of Dendroaspis polylepis Venom Proteins: Mambalgins, Fasciculins, and Dendrotoxins.},
journal = {International journal of molecular sciences},
volume = {26},
number = {20},
pages = {},
doi = {10.3390/ijms26209895},
pmid = {41155192},
issn = {1422-0067},
mesh = {Humans ; Animals ; *Snake Venoms/chemistry/therapeutic use/pharmacology ; *Neurotoxins/therapeutic use/pharmacology/chemistry ; Neoplasms/drug therapy ; Biotechnology/methods ; },
abstract = {Animal toxins contain various bioactive peptides and proteins which have evolved to interact in specific ways. As such, they are a good starting point for developing new drugs and vaccines. This paper examines three natural neurotoxins derived from the black mamba (Dendroaspis polylepis), which show significant pharmacological potential: mambalgins, fasciculins and dendrotoxins. All three may be of value in the treatment of pain, cancer and neurodegenerative disease. Mambalgins provide similar pain relief to opioids but without the risk of addiction; they act by selectively blocking acid-sensitive ion channels (ASICs), especially ASIC1a. Thanks to this inhibitory activity they also demonstrate selective activity against glioblastoma, melanoma and leukemia cells as innovative anticancer drugs. Fasciculins are very strong inhibitors of acetylcholinesterase (AChE) and hence offer promise in multi-target drugs and as treatments for treating Alzheimer's disease. Dendrotoxins such as DTX-K and DTX-I are able to modulate neuronal excitability and synaptic transmission by blocking voltage-gated potassium channels (Kv1.1, Kv1.2, Kv1.6); both have been shown to be effective against cancer cells, and to influence the cardiovascular, immune, and digestive systems. Recent advances in recombinant biotechnology and protein engineering have allowed their safe production with increased therapeutic value. The review examines the translational potential of D. polylepis venom proteins and highlights the need for additional preclinical research on bioactive molecules of toxin origin.},
}

Humans
Animals
*Snake Venoms/chemistry/therapeutic use/pharmacology
*Neurotoxins/therapeutic use/pharmacology/chemistry
Neoplasms/drug therapy
Biotechnology/methods

@article {pmid41155152,
year = {2025},
author = {Girolimetti, G and Calcagnile, M and Bucci, C},
title = {Potential Role of Membrane Contact Sites in the Dysregulation of the Crosstalk Between Mitochondria and Lysosomes in Alzheimer's Disease.},
journal = {International journal of molecular sciences},
volume = {26},
number = {20},
pages = {},
doi = {10.3390/ijms26209858},
pmid = {41155152},
issn = {1422-0067},
support = {PNRR-MAD-2022-12375822//Next Generation EU-NRRP M6C2-Investment 2.1/ ; },
mesh = {*Alzheimer Disease/metabolism/pathology ; *Lysosomes/metabolism/pathology ; Humans ; *Mitochondria/metabolism/pathology ; Animals ; Neurons/metabolism/pathology ; },
abstract = {Alzheimer's disease (AD) is a neurodegenerative disorder characterized by a gradual decline in cognitive abilities and a progressive loss of the neuronal system resulting from neuronal damage and death. The maintenance of neuronal homeostasis is intricately connected to the crosstalk and balance among organelles. Indeed, intracellular organelles are not just isolated compartments in the cell; instead, they are interdependent structures that can communicate through membrane contact sites (MCSs), forming physical connection points represented by proteinaceous tethers. Mitochondria and lysosomes have fundamental physiological functions within neurons, and accumulating evidence highlights their dysfunctions as AD features, strongly associated with the neurodegenerative process underlying the development and progression of AD. This review explores mitochondria-lysosome communication through MCSs, the tethering proteins and their functions in the cell, discussing the methodological challenges in measuring the structure and dynamics of contacts, and the potential role of altered mitochondria-lysosome communication in the context of organelle dysfunction related to neuron impairment in AD pathogenesis. The different abundance of the tethering proteins was considered in healthy physiological and in AD-related conditions to assess the possible organelle communication dysregulation and the subsequent cellular function alterations, and to evaluate the role of mitochondria-lysosome MCSs in the pathogenesis of this disorder.},
}

*Alzheimer Disease/metabolism/pathology
*Lysosomes/metabolism/pathology
Humans
*Mitochondria/metabolism/pathology
Animals
Neurons/metabolism/pathology

@article {pmid41155149,
year = {2025},
author = {Frei, M and Wirawan, R and Wein, T and Bracher, F},
title = {Lead Structure-Based Hybridization Strategy Reveals Major Potency Enhancement of SirReal-Type Sirt2 Inhibitors.},
journal = {International journal of molecular sciences},
volume = {26},
number = {20},
pages = {},
doi = {10.3390/ijms26209855},
pmid = {41155149},
issn = {1422-0067},
support = {project ID: 325871075-SFB1309//Deutsche Forschungsgemeinschaft (DFG, German Research Foundation) with funds from SFB1309 (Chemical Biology of Epigenetic Modifications)/ ; },
mesh = {*Sirtuin 2/antagonists & inhibitors/chemistry/metabolism ; Molecular Docking Simulation ; Humans ; Structure-Activity Relationship ; *Histone Deacetylase Inhibitors/chemistry/pharmacology ; },
abstract = {Selective and potent inhibitors of the NAD[+]-dependent deacetylase Sirt2 represent a valuable epigenetic strategy for the treatment of currently incurable diseases such as Parkinson's disease, Huntington's disease, Alzheimer's disease, and multiple sclerosis. Guided by molecular docking and MM/GBSA validation studies, a lead structure-based hybridization strategy was developed, resulting in a series of very effective Sirt2 inhibitors. With RW-93, we present a highly potent and subtype selective Sirt2 inhibitor (IC50 = 16 nM), which as a next generation SirReal-type inhibitor significantly surpasses established Sirt2 inhibitors and contributes to the extension of the current SAR profile. The structural modification strategy employed in this study proved to be highly promising, resulting in the identification of the most potent low-molecular-weight Sirt2 inhibitor reported to date, providing a promising target for further medicinal chemistry-driven SAR studies.},
}

*Sirtuin 2/antagonists & inhibitors/chemistry/metabolism
Molecular Docking Simulation
Humans
Structure-Activity Relationship
*Histone Deacetylase Inhibitors/chemistry/pharmacology

@article {pmid41155106,
year = {2025},
author = {Rahman, S and Rahman, MM and Bhatt, S and Sundararajan, R and Faezipour, M},
title = {NeuroNet-AD: A Multimodal Deep Learning Framework for Multiclass Alzheimer's Disease Diagnosis.},
journal = {Bioengineering (Basel, Switzerland)},
volume = {12},
number = {10},
pages = {},
doi = {10.3390/bioengineering12101107},
pmid = {41155106},
issn = {2306-5354},
abstract = {Alzheimer's disease (AD) is the most prevalent form of dementia. This disease significantly impacts cognitive functions and daily activities. Early and accurate diagnosis of AD, including the preliminary stage of mild cognitive impairment (MCI), is critical for effective patient care and treatment development. Although advancements in deep learning (DL) and machine learning (ML) models improve diagnostic precision, the lack of large datasets limits further enhancements, necessitating the use of complementary data. Existing convolutional neural networks (CNNs) effectively process visual features but struggle to fuse multimodal data effectively for AD diagnosis. To address these challenges, we propose NeuroNet-AD, a novel multimodal CNN framework designed to enhance AD classifcation accuracy. NeuroNet-AD integrates Magnetic Resonance Imaging (MRI) images with clinical text-based metadata, including psychological test scores, demographic information, and genetic biomarkers. In NeuroNet-AD, we incorporate Convolutional Block Attention Modules (CBAMs) within the ResNet-18 backbone, enabling the model to focus on the most informative spatial and channel-wise features. We introduce an attention computation and multimodal fusion module, named Meta Guided Cross Attention (MGCA), which facilitates effective cross-modal alignment between images and meta-features through a multi-head attention mechanism. Additionally, we employ an ensemble-based feature selection strategy to identify the most discriminative features from the textual data, improving model generalization and performance. We evaluate NeuroNet-AD on the Alzheimer's Disease Neuroimaging Initiative (ADNI1) dataset using subject-level 5-fold cross-validation and a held-out test set to ensure robustness. NeuroNet-AD achieved 98.68% accuracy in multiclass classification of normal control (NC), MCI, and AD and 99.13% accuracy in the binary setting (NC vs. AD) on the ADNI dataset, outperforming state-of-the-art models. External validation on the OASIS-3 dataset further confirmed the model's generalization ability, achieving 94.10% accuracy in the multiclass setting and 98.67% accuracy in the binary setting, despite variations in demographics and acquisition protocols. Further extensive evaluation studies demonstrate the effectiveness of each component of NeuroNet-AD in improving the performance.},
}

@article {pmid41155081,
year = {2025},
author = {Bergamasco, L and Coletta, A and Olmo, G and Cermelli, A and Rubino, E and Rainero, I},
title = {AI-Based Facial Emotion Analysis for Early and Differential Diagnosis of Dementia.},
journal = {Bioengineering (Basel, Switzerland)},
volume = {12},
number = {10},
pages = {},
doi = {10.3390/bioengineering12101082},
pmid = {41155081},
issn = {2306-5354},
support = {105128 / 2023.0366//Fondazione CRT/ ; },
abstract = {Early and differential diagnosis of dementia is essential for timely and targeted care. This study investigated the feasibility of using an artificial intelligence (AI)-based system to discriminate between different stages and etiologies of dementia by analyzing facial emotions. We collected video recordings of 64 participants exposed to standardized audio-visual stimuli. Facial emotion features in terms of valence and arousal were extracted and used to train machine learning models on multiple classification tasks, including distinguishing individuals with mild cognitive impairment (MCI) and overt dementia from healthy controls (HCs) and differentiating Alzheimer's disease (AD) from other types of cognitive impairment. Nested cross-validation was adopted to evaluate the performance of different tested models (K-Nearest Neighbors, Logistic Regression, and Support Vector Machine models) and optimize their hyperparameters. The system achieved a cross-validation accuracy of 76.0% for MCI vs. HCs, 73.6% for dementia vs. HCs, and 64.1% in the three-class classification (MCI vs. dementia vs. HCs). Among cognitively impaired individuals, a 75.4% accuracy was reached in distinguishing AD from other etiologies. These results demonstrated the potential of AI-driven facial emotion analysis as a non-invasive tool for early detection of cognitive impairment and for supporting differential diagnosis of AD in clinical settings.},
}

@article {pmid41154720,
year = {2025},
author = {Srokowska, M and Żwierełło, W and Wszołek, A and Gutowska, I},
title = {Neurobiochemical Effects of a High-Fat Diet: Implications for the Pathogenesis of Neurodegenerative Diseases.},
journal = {Biology},
volume = {14},
number = {10},
pages = {},
doi = {10.3390/biology14101317},
pmid = {41154720},
issn = {2079-7737},
abstract = {The global rise in high-fat diet (HFD) consumption and obesity has raised concerns about their long-term effects on brain health. This review addresses how HFDs, including ketogenic diets (KDs), influence the central nervous system (CNS) and may contribute to neurodegenerative processes. The findings show that prolonged HFD exposure is associated with altered brain metabolism, increased oxidative stress, neuroinflammation, and impaired synaptic plasticity, particularly in regions like the hippocampus and hypothalamus. These changes may affect cognitive function and accelerate neurodegenerative mechanisms linked to disorders such as Alzheimer's and Parkinson's disease. While certain types of KD appear to exert neuroprotective effects-such as improved motor outcomes in experimental Parkinson's disease models-evidence remains inconsistent, and concerns about their long-term safety persist. This review emphasizes that the impact of high-fat nutrition on the CNS depends on fat type, exposure duration, and individual factors such as age and sex. Overall, further research is needed to distinguish between harmful and potentially therapeutic dietary fat patterns and to better understand their influence on brain health across the lifespan.},
}

@article {pmid41154661,
year = {2025},
author = {Flores, CC and Lee, Y and Davis, CJ and Solverson, P and Gerstner, JR},
title = {A Neural-Glial Model of the ApoE-SORT1-FABP7 Axis Tied to Sleep Disruption and Alzheimer's Disease Pathophysiology.},
journal = {Biomolecules},
volume = {15},
number = {10},
pages = {},
doi = {10.3390/biom15101432},
pmid = {41154661},
issn = {2218-273X},
support = {1R35GM133440-05/NH/NIH HHS/United States ; 1R21AG096297-01/NH/NIH HHS/United States ; },
mesh = {*Alzheimer Disease/metabolism/physiopathology/genetics/pathology ; Humans ; *Apolipoproteins E/metabolism/genetics ; *Neuroglia/metabolism/pathology ; *Fatty Acid-Binding Protein 7/metabolism/genetics ; *Adaptor Proteins, Vesicular Transport/metabolism/genetics ; Animals ; Neurons/metabolism/pathology ; *Sleep Wake Disorders/metabolism/genetics ; Signal Transduction ; Tumor Suppressor Proteins ; },
abstract = {Alzheimer's disease (AD) is a complex neurodegenerative disorder where age, genetic factors and sleep disturbance significantly influence disease risk. Recent genome-wide association studies identified a C/T missense variant (rs141749679) in the sortilin (SORT1) gene linked to heightened AD risk, revealing SORT1's role as a key player in the disease's pathophysiology. This type I membrane glycoprotein is implicated in amyloid β (Aβ) accumulation and associated lipid dysregulation, particularly through its interaction with apolipoprotein E (ApoE). SORT1 facilitates the uptake of ApoE-bound polyunsaturated fatty acids (PUFAs), conversion to endocannabinoids (eCBs), and the regulation of anti-inflammatory pathways via peroxisome proliferator-activated receptors (PPARs). Notably, this neuroprotective signaling is contingent on the APOE allele, exhibiting functionality in presence of ApoE3 but disrupted with ApoE4. Additionally, the brain-type fatty acid binding protein, FABP7, mediates this signaling cascade, emphasizing its role in neuron-glia communication. FABP7 is known to regulate sleep across species and binds PUFAs and eCBs. Therefore, dysfunction of the ApoE-SORT1-FABP7 axis may underlie the neuroprotective loss observed in AD, linking sleep disruption and lipid homeostasis to disease progression. This perspective aims to elucidate the intricate neural-glial mechanisms governing the ApoE-SORT1-FABP7 interaction and their implications for targeting therapeutic interventions in Alzheimer's disease.},
}

*Alzheimer Disease/metabolism/physiopathology/genetics/pathology
Humans
*Apolipoproteins E/metabolism/genetics
*Neuroglia/metabolism/pathology
*Fatty Acid-Binding Protein 7/metabolism/genetics
*Adaptor Proteins, Vesicular Transport/metabolism/genetics
Animals
Neurons/metabolism/pathology
*Sleep Wake Disorders/metabolism/genetics
Signal Transduction
Tumor Suppressor Proteins

@article {pmid41154610,
year = {2025},
author = {Shulepko, MA and Che, Y and Paramonov, AS and Kocharovskaya, MV and Kulbatskii, DS and Ivanova, AA and Chugunov, AO and Bychkov, ML and Kirichenko, AV and Shenkarev, ZO and Kirpichnikov, MP and Lyukmanova, EN},
title = {Pro-Inflammatory Protein PSCA Is Upregulated in Neurological Diseases and Targets β2-Subunit-Containing nAChRs.},
journal = {Biomolecules},
volume = {15},
number = {10},
pages = {},
doi = {10.3390/biom15101381},
pmid = {41154610},
issn = {2218-273X},
support = {//Shenzhen High-level University Construction Funding (M.A.S. and Y.C.)/ ; 24-14-00419//Russian Science Foundation (E.N.L., D.S.K., M.L.B.)./ ; },
mesh = {Humans ; Animals ; *Receptors, Nicotinic/metabolism/chemistry ; Up-Regulation ; *Nervous System Diseases/metabolism/genetics ; Neurons/metabolism ; Molecular Docking Simulation ; Rats ; Astrocytes/metabolism ; Hippocampus/metabolism ; },
abstract = {Prostate stem cell antigen (PSCA) is a Ly6/uPAR protein that targets neuronal nicotinic acetylcholine receptors (nAChRs). It exists in membrane-tethered and soluble forms, with the latter upregulated in Alzheimer's disease. We hypothesize that PSCA may be linked to a wider spectrum of neurological diseases and could induce neuroinflammation. Indeed, PSCA expression is significantly upregulated in the brain of patients with multiple sclerosis, Huntington's disease, Down syndrome, bipolar disorder, and HIV-associated dementia. To investigate PSCA's structure, pharmacology, and inflammatory function, we produced a correctly folded water-soluble recombinant analog (ws-PSCA). In primary hippocampal neurons and astrocytes, ws-PSCA differently regulates secretion of inflammatory factors and adhesion molecules and induces pro-inflammatory responses by increasing TNFβ secretion. Heteronuclear NMR and [15]N relaxation measurements reveal a classical β-structural three-finger fold with conformationally disordered loops II and III. Positive charge clustering on the molecular surface suggests the functional importance of ionic interactions by these loops. Electrophysiological studies in Xenopus oocytes point on ws-PSCA inhibition of α3β2-, high-, and low-sensitive variants of α4β2- (IC50 ~50, 27, and 15 μM, respectively) but not α4β4-nAChRs, suggesting targeting of the β2 subunit. Ensemble docking and molecular dynamics simulations predict PSCA binding to high-sensitive α4β2-nAChR at α4/β2 and β2/β2 interfaces. Complexes are stabilized by ionic and hydrogen bonds between PSCA's loops II and III and the primary and complementary receptor subunits, including glycosyl groups. This study gives new structural and functional insights into PSCA's interaction with molecular targets and provides clues to understand its role in the brain function and mental disorders.},
}

Humans
Animals
*Receptors, Nicotinic/metabolism/chemistry
Up-Regulation
*Nervous System Diseases/metabolism/genetics
Neurons/metabolism
Molecular Docking Simulation
Rats
Astrocytes/metabolism
Hippocampus/metabolism

@article {pmid41154596,
year = {2025},
author = {Igarashi, K and Tsukie, T and Washiyama, K and Onda, K and Miyagi, Y and Inagawa, S and Shimizu, S and Miyashita, A and Onodera, O and Ikeuchi, T and Kasuga, K},
title = {Association of Plasma Placental Growth Factor with White Matter Hyperintensities in Alzheimer's Disease.},
journal = {Biomolecules},
volume = {15},
number = {10},
pages = {},
doi = {10.3390/biom15101367},
pmid = {41154596},
issn = {2218-273X},
support = {JPMH24GB1001//MHLW Research on Dementia Program/ ; 20K20497 and 23K18262//Japan Society for the Promotion of Science (JSPS) KAKENHI/ ; },
mesh = {Humans ; *Placenta Growth Factor/blood ; *Alzheimer Disease/blood/pathology/diagnostic imaging/cerebrospinal fluid ; Female ; Male ; *White Matter/pathology/diagnostic imaging/metabolism ; Aged ; Biomarkers/blood/cerebrospinal fluid ; Magnetic Resonance Imaging ; Aged, 80 and over ; Amyloid beta-Peptides/cerebrospinal fluid ; Middle Aged ; },
abstract = {Autopsy studies have shown that Alzheimer's disease (AD) often coexists with cerebrovascular injury, affecting cognitive outcomes and the effectiveness of anti-amyloid-beta (Aβ) drugs. No fluid biomarkers of cerebrovascular injury have been identified yet. We investigated the association between white matter hyperintensities (WMH) severity and fluid biomarkers, including cerebrospinal fluid (CSF) neurofilament light chain and plasma placental growth factor (PlGF) levels. This study included 242 patients from memory clinics. Magnetic resonance imaging (MRI), CSF, and plasma samples were collected. Patients were classified as AD+ or non-AD based on the CSF Aβ42/Aβ40 ratio. In the discovery cohort (79 AD+ and 20 non-AD patients with 3D-T1 images), we analyzed the association between WMH volume and plasma PlGF. In the validation cohort (54 AD+ patients without 3D-T1 images), we analyzed the association between WMH grading and plasma PlGF. Among AD+ patients in the discovery cohort, plasma PlGF levels remained significantly associated with WMH volume and grading after adjusting for age, sex, and global cognition. Among the AD+ patients in the validation cohort, the high-PlGF (above median) group had significantly greater WMH volumes and a higher number of patients with a high WMH grading than the low-PlGF (below median) group. Plasma PlGF is a promising marker of cerebrovascular injury in AD.},
}

Humans
*Placenta Growth Factor/blood
*Alzheimer Disease/blood/pathology/diagnostic imaging/cerebrospinal fluid
Female
Male
*White Matter/pathology/diagnostic imaging/metabolism
Aged
Biomarkers/blood/cerebrospinal fluid
Magnetic Resonance Imaging
Aged, 80 and over
Amyloid beta-Peptides/cerebrospinal fluid
Middle Aged

@article {pmid41154594,
year = {2025},
author = {Kumari, S and Singh, AK and Kumar, M and Pradhan, R and Rao, AR and Yadav, Y and Kumar, P and Haldar, P and Kaur, P and Dey, S},
title = {Targeting a Tau Kinase Cdk5, Cyclin-Dependent Kinase: A Blood-Based Diagnostic Marker and Therapeutic Earmark for Alzheimer's Disease.},
journal = {Biomolecules},
volume = {15},
number = {10},
pages = {},
doi = {10.3390/biom15101365},
pmid = {41154594},
issn = {2218-273X},
support = {54/1/GER/2020- NCD-II//Indian Council of Medical Research/ ; },
mesh = {Humans ; *Alzheimer Disease/blood/diagnosis/drug therapy ; *Cyclin-Dependent Kinase 5/blood/antagonists & inhibitors/metabolism/chemistry ; Female ; Male ; Aged ; Biomarkers/blood ; Aged, 80 and over ; Cognitive Dysfunction/blood/diagnosis ; Middle Aged ; tau Proteins ; Protein Kinase Inhibitors/pharmacology ; },
abstract = {Protein kinases are important molecules of Alzheimer's Disease (AD), driving neuronal demise and the emergence of the disease's destructive hallmarks. Cdk5 has recently been highlighted as a key therapeutic target for AD. This study evaluated the expression levels of Cdk5 and Mcl1 (Cdk5's substrate) in blood samples of 61 AD, 55 Mild Cognitive Impairment (MCI), and 57 Geriatric Controls (GC), and explored the in vitro inhibition of Cdk5. The serum levels of Cdk5 and Mcl1 were measured by Surface Plasmon Resonance (SPR) and verified by Western blot and RT-PCR. Molecular modeling and simulation studies were used to identify a potent hit targeting Cdk5 and validated by binding studies using SPR. The peptide rescue effect was analyzed by MTT assay in the AD cellular model. SPR analysis revealed a significant change in Cdk5 and Mcl1 levels in the serum samples of AD and MCI compared to GC. Results were validated by Western blot and RT-PCR. Binary logistic regression analysis revealed that the concentration of both Cdk5 and Mcl1 was independently associated with disease after adjusting for certain parameters. ROC analysis established an optimum diagnostic cutoff value for Cdk5 [24.97 ng/µL (AUC-0.90)] and Mcl1 [23.08 ng/µL (AUC-0.94)] with high sensitivity and specificity. The peptide YCWS strongly binds to Cdk5's ATP binding site, confirmed by molecular modeling and SPR. In the AD cellular model, peptide YCWS rescued neurotoxicity, increased Mcl1 levels, and reduced destructive hallmarks by inhibiting Cdk5. It can be concluded that Cdk5 is a promising molecule as a circulatory biomarker for the diagnosis of the early stages of AD, and its peptide inhibitor YCWS is a potential therapeutic agent.},
}

Humans
*Alzheimer Disease/blood/diagnosis/drug therapy
*Cyclin-Dependent Kinase 5/blood/antagonists & inhibitors/metabolism/chemistry
Female
Male
Aged
Biomarkers/blood
Aged, 80 and over
Cognitive Dysfunction/blood/diagnosis
Middle Aged
tau Proteins
Protein Kinase Inhibitors/pharmacology

@article {pmid41154564,
year = {2025},
author = {Wei, C and Chen, X and Sun, M and Cao, J and Liao, D and Cheng, Z and Wang, H},
title = {α-Asarone Maintains Protein Homeostasis Through SKN-1-Mediated Proteasome and Autophagy Pathways to Mitigate Aβ-Associated Toxicity in Caenorhabditis elegans.},
journal = {Antioxidants (Basel, Switzerland)},
volume = {14},
number = {10},
pages = {},
doi = {10.3390/antiox14101255},
pmid = {41154564},
issn = {2076-3921},
support = {32370420//National Natural Science Foundation of China/ ; 31670347//National Natural Science Foundation of China/ ; 23ZR1467200//Natural Science Foundation of Shanghai/ ; },
abstract = {Acorus tatarinowii Schott (A. tatarinowii), a traditional Chinese medicine, has been widely used in the treatment of dementia, particularly AD. α-Asarone is the main active component of A. tatarinowii oil, and its neuroprotective effects and underlying molecular mechanism in AD remain unclear. In this study, we utilized different transgenic Caenorhabditis elegans (C. elegans) AD models to investigate the neuroprotective mechanism of α-asarone in vivo. Our findings revealed that α-asarone significantly ameliorated Aβ- and tau-induced phenotypic abnormalities, including deficits in chemotaxis-related learning, hyposensitivity to exogenous serotonin, and impaired neuronal integrity. Furthermore, the α-asarone treatment effectively reduced Aβ-induced oxidative stress. Mechanistically, α-asarone reduced Aβ accumulation and maintained protein homeostasis by stimulating proteasome degradation and autophagy in an SKN-1/Nrf2-dependent manner. Our study highlights the potential of α-asarone as an SKN-1/Nrf2 activator and its capability to facilitate proteostasis, supporting its therapeutic potential for AD treatment.},
}

@article {pmid41154559,
year = {2025},
author = {Yoon, JH and Maeng, J and Kim, Y and Koo, G and Shim, JS and Im, S and Jung, S and Shin, J and Kim, SS and Maeng, S},
title = {Roasted Astragalus membranaceus Inhibits Cognitive Decline in 5xFAD Mice by Activating the BDNF/CREB Pathway.},
journal = {Antioxidants (Basel, Switzerland)},
volume = {14},
number = {10},
pages = {},
doi = {10.3390/antiox14101250},
pmid = {41154559},
issn = {2076-3921},
support = {RS-2022-RD010294//Rural Development Administration/ ; 5120200313836//Ministry of Education of Korea/ ; },
abstract = {Alzheimer's disease (AD) is a complex pathological process that incurs significant societal costs, yet effective treatments have not yet been developed. Novel compounds targeting β-amyloid, based on the amyloid cascade hypothesis, have failed to demonstrate clinical efficacy. Among natural products with diverse mechanisms, components contained in Astragali radix have shown anti-dementia effects in various preclinical studies, including improved cognitive function, reduced β-amyloid levels, and decreased insulin resistance. This study administered a water-extracted roasted Astragali radix (RA) to 3-month-old female 5xFAD mice for 3 months, observing changes in cognitive behavior, blood glucose, and neural signaling. RA lowered glucose levels, improved working memory, fear avoidance memory, and spatial memory, and reduced anxiety behavior in 5xFAD mice. In the hippocampus, the protein expression of BDNF and p-CREB/CREB was increased, while p-JNK/JNK was decreased. The effects of RA were similar to unroasted Astragali radix in 5xFAD mice, with some components being more abundant. Therefore, RA enhances its taste and aroma, making it suitable for long-term consumption in the form of tea, which could be effective in preventing neurodegenerative diseases such as dementia.},
}

@article {pmid41154546,
year = {2025},
author = {Mancuso, C},
title = {The Heme Oxygenase/Biliverdin Reductase System as a Therapeutic Target to Counteract Cellular Senescence in Alzheimer's Disease.},
journal = {Antioxidants (Basel, Switzerland)},
volume = {14},
number = {10},
pages = {},
doi = {10.3390/antiox14101237},
pmid = {41154546},
issn = {2076-3921},
abstract = {Alzheimer's disease (AD) is a neurodegenerative disorder involving free radical overload, neuroinflammation, and a deranged cell stress response. In particular, the modulation of the heme oxygenase/biliverdin reductase (HO/BVR) system, a key component of the brain stress response, is currently regarded as a promising therapeutic approach for AD. Cellular senescence, defined as a process of cell cycle arrest due to oxidative stress, DNA damage, mitochondrial dysfunction, and oncogene activation, has been identified as a pivotal factor in the development of AD. A mounting body of research has demonstrated that the accumulation of senescent cells in the brain can lead to a variety of neurotoxic effects, including synaptic dysfunction, the destruction of the blood-brain barrier, and impaired remyelination. Finally, the release of proinflammatory molecules by senescent cells further exacerbates neurodegeneration. A considerable number of xenobiotics, with well-documented neuroprotective effects through the activation of the HO/BVR system, have been shown to modulate pathways involved in cellular senescence outside the brain. Unfortunately, a direct link between HO/BVR and cellular senescence in AD is yet to be established. This compelling evidence should motivate basic and clinical researchers to address such a significant gap in knowledge and conduct novel studies in this field.},
}

@article {pmid41154499,
year = {2025},
author = {Íñigo-Catalina, L and Ortiz-Cabello, M and Navarro, E and Esteras, N and Rancan, L and Paredes, SD},
title = {Melatonin-Mediated Nrf2 Activation as a Potential Therapeutic Strategy in Mutation-Driven Neurodegenerative Diseases.},
journal = {Antioxidants (Basel, Switzerland)},
volume = {14},
number = {10},
pages = {},
doi = {10.3390/antiox14101190},
pmid = {41154499},
issn = {2076-3921},
support = {PID2022-139936OA-I00//Spanish Ministry of Science and Innovation/ ; PID2022-137011OA-I00/ AEI/10.13039/501100011033/ FEDER, EU//Spanish Ministry of Science and Innovation/ ; RYC2021-034267-I//Spanish Ministry of Science and Innovation - Ramón y Cajal fellowship/ ; CT25/24//Complutense University of Madrid-Banco Santander - Contratos predoctorales de personal investigador en formación/ ; },
abstract = {Neurodegeneration is intrinsically linked to aging through processes such as oxidative stress, mitochondrial dysfunction, and chronic inflammation. Nuclear factor erythroid 2-related factor 2 (Nrf2) emerges as a central transcription factor regulating these molecular events and promoting cytoprotective responses. In neurodegenerative diseases, notably, frontotemporal dementia (FTD) and Parkinson's disease (PD), genetic mutations-including MAPT, LRRK2, PINK1, PRKN, and SNCA-have been reported to alter Nrf2 signaling, both in vitro and in vivo. Melatonin, a neurohormone widely known for its strong antioxidant and mitochondria-stabilizing properties, has been shown to activate Nrf2 and restore redox balance in several experimental models of neurodegeneration. Its effects include a reduction in tau hyperphosphorylation, α-synuclein aggregation, and neuroinflammation. While most data are derived from sporadic models of Alzheimer's disease and PD, emerging evidence supports a role for melatonin in familial forms of FTD and PD as well. Thus, targeting Nrf2 through melatonin may offer a promising approach to mitigating neurodegeneration, especially in the context of mutation-driven pathologies. Further investigation is warranted to explore mutation-specific responses and optimize the therapeutic strategies.},
}

@article {pmid41154306,
year = {2025},
author = {Harb, AA and Brock-Spano, KA and Silverman, JR and Thomas, JR and Pothen, AS},
title = {The Relationship Between Diet and the Neuropathological Hallmarks of Alzheimer's Disease in Cognitively Normal Adults: A Systematic Narrative Review.},
journal = {Healthcare (Basel, Switzerland)},
volume = {13},
number = {20},
pages = {},
doi = {10.3390/healthcare13202628},
pmid = {41154306},
issn = {2227-9032},
abstract = {Background/Objectives: Alzheimer's disease (AD) remains a leading cause of mortality with millions suffering worldwide. The number of annual cases is sharply increasing primarily due to growing older adult populations. To date, there is neither an effective prevention nor cure for AD. Recently, AD was specified using biomarkers, facilitating research into primary and secondary prevention strategies, including dietary interventions. This systematic narrative review maps the literature on dietary prevention of AD by synthesizing the evidence on diet and AD biomarkers in cognitively normal adults. Additionally, it explores limitations in the current evidence base and identifies areas for future research. Methods: Search terms and inclusion/exclusion criteria were set, and PubMed and EBSCOhost were searched for articles up through September 2025. Out of 331 results, 14 articles passed the inclusion/exclusion criteria and were included in this review. Results: Most studies were cross-sectional (n = 8), followed by cohort (n = 4), with one study including both cross-sectional and longitudinal analyses (n = 1). Only one intervention study was published. Various dietary exposures were tested, with most studies (n = 5) supporting a protective relationship between the Mediterranean diet and prevention of the neuropathological hallmarks of AD. However, the evidence base varies in methodology. Future research would benefit from greater consensus in methodology and should prioritize prospective cohort and randomized trial designs. Conclusions: Evidence from this review suggests existence of a potential role for dietary interventions, especially the Mediterranean diet, in AD prevention. However, further research is needed to address existing gaps. (248 words).},
}

@article {pmid41154214,
year = {2025},
author = {Kooshki, M and Rezeai-Farimani, R and Moradpour, A and Baradaran Rahimi, V and Askari, VR},
title = {How Swimming Modulates Inflammatory Pathways in Pain, Neurodegenerative, and Metabolic Disorders.},
journal = {Brain sciences},
volume = {15},
number = {10},
pages = {},
doi = {10.3390/brainsci15101121},
pmid = {41154214},
issn = {2076-3425},
abstract = {Background: As a non-weight-bearing full-body exercise, swimming may reduce inflammation and boost anti-inflammatory agents to decrease the risk of cardiovascular, neurological, and rheumatological disorders. This systematic review examines the current evidence on the role of swimming exercise in modulating immune responses through inflammatory pathways. Methods: First, the PubMed and Scopus databases were searched through December 2024 for studies on swimming and inflammation. The initial search using keywords yielded 509 articles; 102 met the inclusion criteria after screening for relevance, language, and full-text availability. Results: This study suggests that regular swimming reduces neuroinflammation by enhancing BDNF, CREB, and PI3K/Akt signaling while suppressing both mRNA and protein levels of NF-κB, TNF-α, and IL-6 in the brain. In metabolic tissues, it activates SIRT1 and PGC-1α, improving mitochondrial biogenesis and antioxidant defense. Swimming also upregulates PPAR-α and eNOS while downregulating iNOS, leading to reduced vascular inflammation, oxidative stress, and fibrosis in renal and cardiac tissues. Moreover, the enhanced production of IL-10 and the decreasing levels of IL-1β and CRP contribute to systemic anti-inflammatory effects. Conclusions: Consequently, the available evidence suggests that swimming can be a low-impact, full-body exercise with potential therapeutic options in managing inflammation-related conditions such as cardiovascular disease, diabetes, and obesity. Future studies should focus on human clinical trials, investigate mechanisms, and assess longer time frames.},
}

@article {pmid41154211,
year = {2025},
author = {Labuza, A and Pidikiti, H and Alldred, MJ and Ibrahim, KW and Peng, KY and Pasato, J and Heguy, A and Mathews, PM and Ginsberg, SD},
title = {Aging, Rather than Genotype, Is the Principal Contributor to Differential Gene Expression Within Targeted Replacement APOE2, APOE3, and APOE4 Mouse Brain.},
journal = {Brain sciences},
volume = {15},
number = {10},
pages = {},
doi = {10.3390/brainsci15101117},
pmid = {41154211},
issn = {2076-3425},
support = {AG014449//National Institute of Aging/ ; AG017617//National Institute of Aging/ ; AG072599//National Institute of Aging/ ; AG074004//National Institute of Aging/ ; AG077103//National Institute of Aging/ ; AG085572//National Institute of Aging/ ; },
abstract = {Background: Apolipoprotein E (APOE) is the strongest genetic risk determinant for late-onset Alzheimer's disease (AD). The APOE3 allele is risk-neutral, the APOE4 allele increases the risk of developing AD, and the APOE2 allele is neuroprotective. Methods: We utilized RNA sequencing of hemi-brains from a mouse model homozygous for each of these humanized APOE alleles to study gene expression profiles between mice aged 12 months of age (MO) and 18 MO, independent of β-amyloid and tau pathology. Results: More than half of the differentially expressed genes (DEGs) within each genotype were shared with at least one other APOE allele, including 1610 DEGs that were shared across the three genotypes. These DEGs represent changes driven by aging rather than APOE genotype. Aging induced DEGs and biological pathways involving metabolism, synaptic function, and protein synthesis, among others. Alterations in these pathways were also identified by DEGs unique to APOE4, suggesting that the APOE4 allele drives the aging phenotype. In contrast, fewer pathways were identified from DEGs unique to APOE2 or APOE3. Conclusions: Transcriptomic results suggest that the most significant impact on brain-level expression changes in humanized APOE mice is aging and that APOE4 exacerbates this process. These in vivo findings within an established model system are consistent with brain aging being the greatest risk factor for AD and suggest that APOE4 expression promotes an aging phenotype in the brain that interacts with, and contributes to, aging-driven AD risk. Results reinforce the impact age and APOE allele contribute to AD and age-related neurodegeneration, and foster greater mechanistic understanding as well as inform therapeutic intervention.},
}

@article {pmid41154195,
year = {2025},
author = {Zhang, B and Li, Y and Li, H and Shen, X and Zhu, Z},
title = {Therapeutic Advances in Targeting the Amyloid-β Pathway for Alzheimer's Disease.},
journal = {Brain sciences},
volume = {15},
number = {10},
pages = {},
doi = {10.3390/brainsci15101101},
pmid = {41154195},
issn = {2076-3425},
abstract = {Alzheimer's disease (AD) is the most common cause of dementia, characterized by progressive cognitive decline and neuropathological hallmarks, including amyloid-β (Aβ) plaques, neurofibrillary tangles (NFTs), and neurodegeneration. Since the amyloid cascade hypothesis was proposed, Aβ has remained a central therapeutic target, with interventions aiming to reduce Aβ production, aggregation, or downstream toxicity. This review first outlines the historical development of the Aβ hypothesis and the two major APP processing pathways (α-cleavage and β-cleavage), highlighting the role of biomarkers in early diagnosis, patient stratification, and regulatory approval. We then summarize the development and clinical outcomes of anti-Aβ small-molecule drugs, including β-secretase inhibitors, γ-secretase modulators, Aβ aggregation inhibitors, receptor/synapse modulators, and metabolic or antioxidant modalities. We further review the progression of biologic therapies, with a particular focus on monoclonal antibodies, vaccines, and emerging gene-silencing strategies, such as small interfering RNA (siRNA) and antisense oligonucleotides. Finally, we discuss future perspectives, including next-generation biologics, multi-target approaches, optimized delivery platforms, and early-prevention strategies. Collectively, these efforts underscore both the challenges and opportunities in translating anti-Aβ therapies into meaningful clinical benefits for patients with AD.},
}

@article {pmid41154191,
year = {2025},
author = {Shim, JH and Baek, HM and Hoon, J},
title = {Regional Brain Volume Changes Across Adulthood: A Multi-Cohort Study Using MRI Data.},
journal = {Brain sciences},
volume = {15},
number = {10},
pages = {},
doi = {10.3390/brainsci15101096},
pmid = {41154191},
issn = {2076-3425},
support = {2021R1A6C101A432//Republic of Korea Basic Science Institute (National Research Facilities and Equipment Center)/ ; },
abstract = {Background/Objectives: Age-related structural changes in the human brain provide essential insights into cognitive aging and the onset of neurodegenerative diseases. This study aimed to comprehensively characterize age-related volumetric changes across multiple brain regions in a large, diverse, cognitively healthy cohort spanning adulthood (ages 21-90), integrating Korean, Information eXtraction from Images (IXI), and Alzheimer's Disease Neuroimaging Initiative (ADNI) MRI datasets of cognitively healthy participants to characterize normative volumetric changes across adulthood using demographically diverse datasets. Methods: High resolution 3T T1-weighted MRI images from three distinct cohorts (totaling 1833 subjects) were processed through an optimized neuroimaging pipeline, combining advanced preprocessing with neural network-based segmentation. Volumetric data for 95 brain structures were segmented and analyzed across seven age bins (21-30 through 81-90). Pipeline reliability was validated against FreeSurfer using intraclass correlation coefficients (ICC) and coefficients of variation (CoV). Regression-based correction was used to correct for sex and cohort effects on brain region volume. Then, percentage change in each mean bilateral volumes of regions across the lifespan were computed to describe volumetric changes across life spans. Results: The segmentation pipeline demonstrated excellent agreement with FreeSurfer (mean ICC: 0.9965). Drastic volumetric expansions were observed in white matter hypointensities (122.6%), lateral ventricles (115.9%), and inferior lateral ventricles (116.8%). Moderate-to-notable shrinkage was found predominantly in the frontal lobe (pars triangularis: 21.5%), parietal lobe (inferior parietal: 20.4%), temporal lobe (transverse temporal: 21.6%), and cingulate cortex (caudal anterior cingulate: 16.1%). Minimal volume changes occurred in regions such as the insula (3.7%) and pallidum (2.6%). Conclusions: This study presents a comprehensive reference of normative regional brain volume changes across adulthood, highlighting substantial inter-regional variability. The findings can provide an essential foundation for differentiating normal aging patterns from early pathological alterations.},
}

@article {pmid41154171,
year = {2025},
author = {Zou, J and Liao, R and Zhang, W and Kuang, Z},
title = {Acupuncture Modulation of the Lung-Brain Axis in Alzheimer's Disease: Mechanisms and Therapeutic Perspectives.},
journal = {Brain sciences},
volume = {15},
number = {10},
pages = {},
doi = {10.3390/brainsci15101076},
pmid = {41154171},
issn = {2076-3425},
support = {2025A1515012049//Natural Science Foundation of Guangdong Province/ ; 20251096//the Research Project of the Traditional Chinese Medicine Bureau of Guangdong Province/ ; 2023A1515110788//Basic and Applied Basic Research Foundation of Guangdong Province/ ; },
abstract = {Alzheimer's disease (AD) is a prevalent neurodegenerative disorder characterized by progressive cognitive decline and an impaired quality of life, for which no curative treatment is currently available. Recent research indicates that chronic pulmonary conditions-including chronic obstructive pulmonary disease (COPD) and obstructive sleep apnea (OSA)-exhibit significant epidemiological associations with AD pathogenesis, suggesting that the lung-brain axis may contribute to AD development. Acupuncture, a core TCM intervention, shows promise for modulating multisystem functions and enhancing cognitive performance. This review synthesizes the current evidence regarding pulmonary diseases influencing AD through the lung-brain axis, elucidates potential mechanisms by which acupuncture may modulate pulmonary function and mitigate AD pathology, and explores future directions for lung-brain axis-targeted acupuncture interventions. Our overarching aim is to propose integrative, evidence-based strategies that combine Chinese and Western medicine for the prevention and management of AD.},
}

@article {pmid41154134,
year = {2025},
author = {Marongiu, A and Spanu, A and Palumbo, B and Bianconi, F and Filippi, L and Madeddu, G and Nuvoli, S},
title = {Artificial Intelligence in PET Imaging for Alzheimer's Disease: A Narrative Review.},
journal = {Brain sciences},
volume = {15},
number = {10},
pages = {},
doi = {10.3390/brainsci15101038},
pmid = {41154134},
issn = {2076-3425},
abstract = {The rapid advancements in computer processing, algorithmic development, and the availability of large-scale datasets have positioned Artificial Intelligence (AI) as a valuable tool across multiple domains, including Medicine. In the field of Nuclear Medicine neuroimaging, with Positron Emission Tomography (PET), AI has demonstrated significant potential in improving diagnostic accuracy for neurodegenerative cognitive disorders. This is especially relevant for the early diagnosis, preclinical detection, and prediction of disease progression in Alzheimer's disease (AD), the most prevalent form of cognitive impairment in individuals over 65 years of age. This narrative review aims to synthesize current advances, explore future directions, and highlight outstanding challenges in the application of Artificial Intelligence to PET imaging for the clinical management of Alzheimer's disease, with particular focus on three key modalities: [18]F-FDG PET, Amyloid PET, and Tau PET.},
}

@article {pmid41153779,
year = {2025},
author = {Zhang, P and Chaudhary, D},
title = {Leveraging Clinical Record Geolocation for Improved Alzheimer's Disease Diagnosis Using DMV Framework.},
journal = {Biomedicines},
volume = {13},
number = {10},
pages = {},
doi = {10.3390/biomedicines13102496},
pmid = {41153779},
issn = {2227-9059},
abstract = {Background: Early detection of Alzheimer's disease (AD) is critical for timely intervention, but clinical assessments and neuroimaging are often costly and resource intensive. Natural language processing (NLP) of clinical records offers a scalable alternative, and integrating geolocation may capture complementary environmental risk signals. Methods: We propose the DMV (Data processing, Model training, Validation) framework that frames early AD detection as a regression task predicting a continuous risk score ("data_value") from clinical text and structured features. We evaluated embeddings from Llama3-70B, GPT-4o (via text-embedding-ada-002), and GPT-5 (text-embedding-3-large) combined with a Random Forest regressor on a CDC-derived dataset (≈284 k records). Models were trained and assessed using 10-fold cross-validation. Performance metrics included Mean Squared Error (MSE), Mean Absolute Error (MAE), and R[2]; paired t-tests and Wilcoxon signed-rank tests assessed statistical significance. Results: Including geolocation (latitude and longitude) consistently improved performance across models. For the Random Forest baseline, MSE decreased by 48.6% when geolocation was added. Embedding-based models showed larger gains; GPT-5 with geolocation achieved the best results (MSE = 14.0339, MAE = 2.3715, R[2] = 0.9783), and the reduction in error from adding geolocation was statistically significant (p < 0.001, paired tests). Conclusions: Combining high-quality text embeddings with patient geolocation yields substantial and statistically significant improvements in AD risk estimation. Incorporating spatial context alongside clinical text may help clinicians account for environmental and regional risk factors and improve early detection in scalable, data-driven workflows.},
}

@article {pmid41153730,
year = {2025},
author = {Danesin, L and D'Este, G and Barresi, R and Piazzalunga, E and Di Garbo, A and Giustiniani, A and Semenza, C and Bottini, G and Oliveri, M and Burgio, F},
title = {Preliminary Evidence of Biological and Cognitive Efficacy of Prismatic Adaptation Combined with Cognitive Training on Patients with Mild Cognitive Impairment.},
journal = {Biomedicines},
volume = {13},
number = {10},
pages = {},
doi = {10.3390/biomedicines13102447},
pmid = {41153730},
issn = {2227-9059},
support = {Ricerca Corrente//Ministero della Salute/ ; },
abstract = {Background/Objectives: This study evaluated a novel rehabilitation tool that combines prismatic adaptation (PA) and cognitive training through serious games (SGs) in patients with mild cognitive impairment (MCI) due to prodromal Alzheimer's dementia or consequent to Parkinson's disease. While non-pharmacological interventions have been shown to improve cognition or delay dementia onset, their underlying neurobiological mechanisms, such as brain plasticity, remain unclear. Leveraging studies suggesting neuromodulatory effects of PA, we investigated whether the combined PA+SGs treatment could influence plasticity-related mechanisms, assessed through brain-derived neurotrophic factor (BDNF) serum levels, compared to cognitive training with only SGs and standard cognitive rehabilitation (SCR). Methods: Twenty three MCI patients were randomized into three intervention groups: PA+SGs (experimental group), SG-only (control group), and SCR (control group), completing ten treatment sessions. Patients underwent neuropsychological assessments and blood sampling pre- and post-treatment. Results: At baseline, demographic, clinical, and biological characteristics were comparable across groups. Post-treatment, though differences from control groups were not statistically significant, the PA+SGs group showed significant within-group improvements in memory, with trend-level changes also in executive function and visuospatial abilities, which, however, did not reach the significance threshold. Notably, only the PA+SGs group exhibited increased BDNF levels, which positively correlated with memory and language performance. Conclusions: Our findings suggest that combining PA with cognitive training may enhance cognitive functioning in MCI patients, yielding results comparable to SCR. Furthermore, PA appears to enhance neuroplasticity mechanisms that may support the behavioral improvements observed in cognitive training. Future research should validate these findings and further explore the relationship between cognitive impairment and its rehabilitation, while also considering the underlying neurobiological mechanisms.},
}

@article {pmid41153443,
year = {2025},
author = {Zhang, Y and Niu, Z and Yan, J and Chen, Y and Xue, Z and Xu, J and Ma, Y and Shi, H},
title = {Analysis of Semen Proteomic Differences Among Three Genotypes of FecB Rams in Duolang Sheep.},
journal = {Genes},
volume = {16},
number = {10},
pages = {},
doi = {10.3390/genes16101226},
pmid = {41153443},
issn = {2073-4425},
support = {2023A02004//shihongcai/ ; },
mesh = {Animals ; Sheep/genetics/metabolism ; Male ; *Semen/metabolism ; Genotype ; Proteomics/methods ; *Proteome/genetics ; },
abstract = {BACKGROUDS: To explore the differences in semen proteins among rams of three FecB genotypes (++, B+, and BB) in Duolang sheep.

METHODS: This study employed DIA quantitative proteomics technology to identify semen proteins from four wild-type (Group A), two heterozygous (Group B), and three homozygous (Group C) rams.

RESULTS: Compared with the ++ genotype, the differentially expressed proteins (DEPs) in the semen of B+ genotype rams are significantly involved in the biological process of innate immune response and are significantly enriched in the oxidative phosphorylation pathway in KEGG analysis. From a biological perspective, the innate immune response may affect the immune health of Duolang sheep, while oxidative phosphorylation influences energy metabolism, which in turn impacts reproductive performance. Compared with the BB genotype, the DEPs in the semen of B+ genotype rams participate in biological processes such as protein phosphorylation and protein hydrolysis during cellular protein catabolism. These DEPs are also significantly enriched in pathways related to Parkinson's disease and non-alcoholic fatty liver disease in KEGG analysis. These differences may affect the cellular metabolism and physiological functions of Duolang sheep, thereby being associated with their reproductive performance. Compared with the ++ genotype, the DEPs in the semen of BB genotype rams exhibit differences in molecular function, cellular component, KEGG pathway, domain function, and subcellular localization. For instance, they are involved in threonine-type endopeptidase activity and associated with pathways like Alzheimer's disease and retrograde endocannabinoid signaling.

CONCLUSIONS: These differences may have potential impacts on the physiology and reproductive performance of Duolang sheep.},
}

Animals
Sheep/genetics/metabolism
Male
*Semen/metabolism
Genotype
Proteomics/methods
*Proteome/genetics

@article {pmid41153431,
year = {2025},
author = {Carrera, I and Naidoo, V and Corzo, L and Martínez-Iglesias, O and Cacabelos, R},
title = {Epigenetic Modulation and Neuroprotective Effects of Neurofabine-C in a Transgenic Model of Alzheimer's Disease.},
journal = {Genes},
volume = {16},
number = {10},
pages = {},
doi = {10.3390/genes16101214},
pmid = {41153431},
issn = {2073-4425},
mesh = {Animals ; *Neuroprotective Agents/pharmacology ; *Alzheimer Disease/drug therapy/genetics/pathology/metabolism ; Mice ; *Epigenesis, Genetic/drug effects ; Mice, Transgenic ; Disease Models, Animal ; Humans ; },
abstract = {Background: Currently, there are limited therapeutic or preventative strategies for neurodegenerative disorders due to the challenges in alleviating the progressive neuronal loss and neuroinflammation which are the primary characteristics of these diseases, ultimately leading to cell death and functional impairment. Cocoa-derived flavanols (Theobroma cacao) have been studied as potential bioactive compounds to modify and reverse various inflammation-associated diseases because of their remarkable antioxidant properties and capacity to modulate metabolic imbalance and reactive inflammatory responses. The faba bean (Vicia faba) extract obtained through nondenaturing biotechnological processes is a potent dopamine (DA) enhancer that has shown promising results as a neuroprotective agent against degeneration. Objective: This study will examine the synergistic effects of Neurofabine-C, a hybrid compound derived from cocoa and faba bean extracts, on various brain biomarkers in mice related to inflammatory, metabolic, and neurodegenerative processes. Methods: A triple-transgenic mouse model of neurodegeneration was treated with Neurofabine-C, and biomolecular data were obtained by performing biochemical and immunohistochemical analysis. Results: Neurofabine-C prevented neuronal degeneration (NeuN), mitigated the neuro-inflammatory processes triggered (decreased expression of reactive astrocytes (GFAP)), and induced an increase in neurogenesis in the treated cortical mice brain (PAX6). Epigenetic analysis revealed significant chromatin remodeling in the hippocampus. Neuroprotective genes, including FOXO3, ATM, and TRP73, were upregulated, whereas the expression of HIF1α and APOE decreased. In parallel, DNMT3A expression increased 20-fold, HDAC3 decreased by 60%, and global 5-methylcytosine levels increased four-fold. These coordinated changes suggest that Neurofabine-C promotes neuroprotective programs through enhanced DNA methylation and reduced histone deacetylation. Conclusions: The findings indicate that Neurofabine-C exhibits multiple neuroprotective mechanisms, making it a potent bioproduct for mitigating neuroinflammatory processes associated with neurodegenerative disorders.},
}

Animals
*Neuroprotective Agents/pharmacology
*Alzheimer Disease/drug therapy/genetics/pathology/metabolism
Mice
*Epigenesis, Genetic/drug effects
Mice, Transgenic
Disease Models, Animal
Humans

@article {pmid41153395,
year = {2025},
author = {De La Cerna, JLO and Talubo, NDD and Villanueva, BHA and Tsai, PW and Tayo, LL},
title = {Conserved Blood Transcriptome Patterns Highlight microRNA and Hub Gene Drivers of Neurodegeneration.},
journal = {Genes},
volume = {16},
number = {10},
pages = {},
doi = {10.3390/genes16101178},
pmid = {41153395},
issn = {2073-4425},
mesh = {*MicroRNAs/genetics/blood ; Humans ; *Neurodegenerative Diseases/genetics/blood ; *Transcriptome/genetics ; Gene Regulatory Networks ; Gene Expression Profiling ; RNA, Messenger/genetics ; Gene Expression Regulation ; },
abstract = {Background/Objectives: Neurodegenerative diseases (NDs) such as Alzheimer's (AD), Parkinson's (PD), Huntington's (HD), and Amyotrophic Lateral Sclerosis (ALS) are clinically distinct but share overlapping molecular mechanisms. Methods: To identify conserved systemic signatures, we analyzed blood RNA-Seq datasets using Weighted Gene Co-Expression Network Analysis (WGCNA), differential expression, pathway enrichment, and miRNA-mRNA network mapping. Results: Two modules, the red and turquoise, showed strong preservation across diseases. The red module was enriched for cytoskeletal and metabolic regulation, while the turquoise module involved immune, stress-response, and proteostatic pathways. Discussion: Key hub genes, such as HMGCR, ACTR2, MYD88, PTEN, EP300, and regulatory miRNAs like miR-29, miR-132, and miR-146a, formed interconnected networks reflecting shared molecular vulnerabilities. The absence of classical heat shock proteins in preserved blood modules highlights tissue-specific expression differences between blood and neural systems. Several hub genes overlap with known pharmacological targets, suggesting potential in translational relevance. Conclusions: Together, these findings reveal conserved blood-based transcriptional modules that suggest parallel central neurodegenerative processes and may support future biomarker development and possible therapeutic exploration.},
}

*MicroRNAs/genetics/blood
Humans
*Neurodegenerative Diseases/genetics/blood
*Transcriptome/genetics
Gene Regulatory Networks
Gene Expression Profiling
RNA, Messenger/genetics
Gene Expression Regulation

@article {pmid41153388,
year = {2025},
author = {Nishio, H and Negishi, H and Awano, H and Oba, J},
title = {Genetic and Molecular Insights into the Links Between Heat Stroke, Alzheimer's Disease, and Down Syndrome: A Mini-Review.},
journal = {Genes},
volume = {16},
number = {10},
pages = {},
doi = {10.3390/genes16101171},
pmid = {41153388},
issn = {2073-4425},
mesh = {*Down Syndrome/genetics/pathology/metabolism ; *Alzheimer Disease/genetics/pathology/metabolism ; Humans ; Animals ; *Heat Stroke/genetics/pathology/complications/metabolism ; Amyloid beta-Protein Precursor/genetics/metabolism ; Risk Factors ; Amyloid beta-Peptides/genetics/metabolism ; },
abstract = {Both epidemiological and animal model studies have revealed that heat stroke is closely related to the development or exacerbation of dementia disorders. The most common form of dementia is Alzheimer's disease, which is characterized by the accumulation of amyloid-β protein in the central nervous system. Notably, a whole-genome transcriptome analysis of heat stroke patients has identified the increased expression of amyloid-β precursor protein gene and the activation of amyloid processing pathways. This finding provides a molecular basis for the theory that heat stroke is a risk factor for dementia disorders. Down syndrome-a common chromosomal abnormality-is also a dementia disorder that is characterized by the overexpression of amyloid-β precursor protein gene and the accumulation of amyloid-β protein. Thus, heat stroke may also develop or exacerbate Alzheimer's disease-like dementia in Down syndrome. For individuals with Down syndrome, heat stroke is therefore not only a life-threatening risk factor but may also be a risk factor for accelerating intellectual decline.},
}

*Down Syndrome/genetics/pathology/metabolism
*Alzheimer Disease/genetics/pathology/metabolism
Humans
Animals
*Heat Stroke/genetics/pathology/complications/metabolism
Amyloid beta-Protein Precursor/genetics/metabolism
Risk Factors
Amyloid beta-Peptides/genetics/metabolism

@article {pmid41153344,
year = {2025},
author = {Nocella, V and Manca, R and Venneri, A},
title = {Associations Between Polygenic Risk for Alzheimer's Disease and Grey Matter Volume Are Dependent on APOE, Pathological and Diagnostic Status.},
journal = {Genes},
volume = {16},
number = {10},
pages = {},
doi = {10.3390/genes16101128},
pmid = {41153344},
issn = {2073-4425},
support = {PE0000006//European Union-NextGenerationEU/ ; },
mesh = {Humans ; *Alzheimer Disease/genetics/pathology/diagnosis ; *Gray Matter/pathology/metabolism/diagnostic imaging ; Male ; Female ; Aged ; *Apolipoproteins E/genetics ; *Multifactorial Inheritance/genetics ; Aged, 80 and over ; Genetic Predisposition to Disease ; Magnetic Resonance Imaging ; Hippocampus/pathology ; Risk Factors ; },
abstract = {BACKGROUND/OBJECTIVES: Studies have shown that higher polygenic risk scores (PRSs) for Alzheimer's disease (AD) are associated with smaller volumes in temporal brain regions typically affected by this disease. These effects have also been found in cognitively unimpaired (CU) older adults. This study aimed to investigate the relationship between PRSs and brain volumes in specific areas associated with early AD.

METHODS: 342 participants were selected from the Alzheimer's Disease Neuroimaging Initiative and stratified into three groups: 114 amyloid-positive atrophic (A+N+), 114 amyloid-negative non-atrophic (A-N-), and 114 amyloid-positive non-atrophic (A+N-) people. Linear regressions were performed within each group to investigate associations between PRSs and regional grey matter volumes. Analyses were also repeated after stratifying groups by APOE status and clinical diagnosis. Two sensitivity analyses were run to investigate the impact of APOE and amyloid status and concordance across biomarkers. Multiplicity was controlled for using the Benjamini-Hochberg false discovery rate (FDR) approach.

RESULTS: Negative associations were observed between PRSs and volumes of the left amygdala and hippocampus in A+N+, right hippocampus in A+N-, and right posterior cingulate cortex in A-N- participants. Associations were found especially in A-N- participants, both ε4 allele carriers and non-carriers, and mostly confirmed in sensitivity analyses. Associations emerged only in CU and AD participants, but not in people with MCI. None of these findings survived correction for FDR.

CONCLUSIONS: These findings highlight the potential of PRSs as novel biological indicators for a deeper characterisation of AD-related neural alterations.},
}

Humans
*Alzheimer Disease/genetics/pathology/diagnosis
*Gray Matter/pathology/metabolism/diagnostic imaging
Male
Female
Aged
*Apolipoproteins E/genetics
*Multifactorial Inheritance/genetics
Aged, 80 and over
Genetic Predisposition to Disease
Magnetic Resonance Imaging
Hippocampus/pathology
Risk Factors

@article {pmid41153256,
year = {2025},
author = {Jin, C and Beran, RG and Bhaskar, SMM},
title = {Neuroimaging and Genetic Markers of Cerebral Small Vessel Disease and Cognitive Outcomes: A Systematic Review and Meta-Analysis (NEUROGEN-SVD Study).},
journal = {Diagnostics (Basel, Switzerland)},
volume = {15},
number = {20},
pages = {},
doi = {10.3390/diagnostics15202585},
pmid = {41153256},
issn = {2075-4418},
abstract = {Background/Objectives: Cerebral small vessel disease (CSVD) is a leading cause of cognitive decline and dementia. The comparative prognostic value of MRI-based neuroimaging markers and genetic risk factors such as the APOE ε4 allele for cognitive outcomes remains uncertain. The objectives of this study were to estimate the pooled prevalence of cognitive impairment in CSVD, evaluate the associations of key neuroimaging markers (white matter hyperintensities [WMHs], cerebral microbleeds [CMBs], lacunes) and APOE ε4 with cognitive outcomes, and assess their diagnostic performance. Methods: This study included a systematic review and meta-analysis in accordance with PRISMA and MOOSE guidelines, searching five databases (2005-2025). Eligible studies included adults with CSVD and MRI-visible markers reporting cognitive outcomes (mild cognitive impairment [MCI], global cognitive impairment [GCI], all-cause dementia [ACD], vascular dementia [VaD], and Alzheimer's disease [AD]). Thirty-nine studies comprising 18,425 participants were included. Pooled prevalence and associations were estimated using random-effects models, and diagnostic accuracy was evaluated. Certainty of evidence was assessed using the GRADE framework. Results: The pooled prevalence of GCI in CSVD was 57% (95% CI: 51-62%), while MCI prevalence was 46% (95% CI: 42-51%). WMHs were strongly associated with VaD (OR 10.35, 95% CI: 7.32-14.64), lacunes with ACD (OR 3.18, 95% CI: 1.24-8.20), and CMBs with AD (OR 1.52, 95% CI: 1.04-2.24). APOE ε4 carriage increased the risk of GCI (OR 1.80, 95% CI: 1.41-2.29). Across markers, diagnostic sensitivity was low, specificity was moderate-to-high, and AUROC values were modest. GRADE certainty ranged from low to moderate, with the highest confidence for WMHs and VaD. Conclusions: CSVD-related MRI markers and APOE ε4 are significantly associated with both early and late cognitive outcomes, supporting the integrated vascular-neurodegenerative continuum. The limited diagnostic sensitivity and variable certainty of evidence highlight the need for harmonized definitions, lesion quantification, and multimodal imaging-genetic approaches to improve early detection and risk stratification of CSVD-related cognitive impairment.},
}

@article {pmid41153232,
year = {2025},
author = {Aksoy, S and Daou, A},
title = {An Explainable Web-Based Diagnostic System for Alzheimer's Disease Using XRAI and Deep Learning on Brain MRI.},
journal = {Diagnostics (Basel, Switzerland)},
volume = {15},
number = {20},
pages = {},
doi = {10.3390/diagnostics15202559},
pmid = {41153232},
issn = {2075-4418},
abstract = {Background: Alzheimer's disease (AD) is a progressive neurodegenerative condition marked by cognitive decline and memory loss. Despite advancements in AI-driven neuroimaging analysis for AD detection, clinical deployment remains limited due to challenges in model interpretability and usability. Explainable AI (XAI) frameworks such as XRAI offer potential to bridge this gap by providing clinically meaningful visualizations of model decision-making. Methods: This study developed a comprehensive, clinically deployable AI system for AD severity classification using 2D brain MRI data. Three deep learning architectures MobileNet-V3 Large, EfficientNet-B4, and ResNet-50 were trained on an augmented Kaggle dataset (33,984 images across four AD severity classes). The models were evaluated on both augmented and original datasets, with integrated XRAI explainability providing region-based attribution maps. A web-based clinical interface was built using Gradio to deliver real-time predictions and visual explanations. Results: MobileNet-V3 achieved the highest accuracy (99.18% on the augmented test set; 99.47% on the original dataset), while using the fewest parameters (4.2 M), confirming its efficiency and suitability for clinical use. XRAI visualizations aligned with known neuroanatomical patterns of AD progression, enhancing clinical interpretability. The web interface delivered sub-20 s inference with high classification confidence across all AD severity levels, successfully supporting real-world diagnostic workflows. Conclusions: This research presents the first systematic integration of XRAI into AD severity classification using MRI and deep learning. The MobileNet-V3-based system offers high accuracy, computational efficiency, and interpretability through a user-friendly clinical interface. These contributions demonstrate a practical pathway toward real-world adoption of explainable AI for early and accurate Alzheimer's disease detection.},
}

@article {pmid41153125,
year = {2025},
author = {Lian, Z and Wang, Z},
title = {Dependency Grammar Approach to the Syntactic Complexity in the Discourse of Alzheimer Patients.},
journal = {Behavioral sciences (Basel, Switzerland)},
volume = {15},
number = {10},
pages = {},
doi = {10.3390/bs15101334},
pmid = {41153125},
issn = {2076-328X},
support = {23BYY144//China National Social Science Fund/ ; 2024HZ1080//Research Project of Philosophy and Social Sciences of Shaanxi Province/ ; },
abstract = {This study aims to investigate the syntactic complexity in individuals with Alzheimer's disease (AD) by conducting a comprehensive analysis that incorporates mean dependency distance (MDD), fine-grained grammatical metrics, and dependency network structures. A total of 150 adults with AD and 150 healthy controls (HC) responded in English to interview prompts based on the Cookie Theft picture description task, and the results were compared. The key findings are as follows: (1) The primary syntactic change is a strategic shift from hierarchical, clause-based constructions to linear, phrase-based ones, a direct consequence of working memory deficits designed to minimize cognitive load. (2) This shift is executed via a resource reallocation, where costly, long-distance clausal dependencies are systematically avoided in favor of a compensatory reliance on local dependencies, such as intra-phrasal modification and simple predicate structures. (3) This strategic reallocation leads to a systemic reorganization of the syntactic network, transforming it from a flexible, distributed system into a rigid, centralized one that becomes critically dependent on the over-leveraged structural role of function words to maintain basic connectivity. (4) The overall syntactic profile is the result of a functional balance governed by the principle of cognitive economy, where expressive richness and grammatical depth are sacrificed to preserve core communicative functions. These findings suggest that the syntactic signature of AD is not a random degradation of linguistic competence but a profound and systematic grammatical adaptation, where the entire linguistic system restructures itself to function under the severe constraints of diminished cognitive resources.},
}

@article {pmid41153055,
year = {2025},
author = {Dallora, AL and Alexander, J and Palesetti, PP and Guenot, D and Selvander, M and Berglund, JS and Behrens, A},
title = {Hyperspectral retinal imaging to detect Alzheimer's disease in a memory clinic setting.},
journal = {Alzheimer's research & therapy},
volume = {17},
number = {1},
pages = {232},
pmid = {41153055},
issn = {1758-9193},
mesh = {Humans ; *Alzheimer Disease/diagnostic imaging/diagnosis/cerebrospinal fluid ; Male ; Female ; *Retina/diagnostic imaging ; Aged ; Cross-Sectional Studies ; Prospective Studies ; Amyloid beta-Peptides/cerebrospinal fluid ; *Hyperspectral Imaging/methods ; Middle Aged ; Aged, 80 and over ; Cohort Studies ; Sweden ; },
abstract = {BACKGROUND: Previous literature indicate retinal hyperspectral imaging as a non-invasive method with the potential for identifying amyloid-beta (Aβ) protein deposits. Current diagnostic methods, such as cerebrospinal fluid analysis or positron emission tomography, are costly, invasive, and non-scalable. Hyperspectral imaging offers a potentially accessible alternative for early detection of Alzheimer's disease. The aim of this study is to investigate the potential of retinal hyperspectral imaging in identifying Aβ-positive patients within a clinical cohort from a memory clinic.

METHODS: A prospective cross-sectional cohort study was conducted between January 2023 and May 2024 at a single memory clinic in Sweden. The study recruited 57 patients (35 Aβ-positive and 22 Aβ-negative) who underwent lumbar puncture as part of their diagnostic workup for cognitive complaints. Retinal hyperspectral images were captured from all participants at the time of their lumbar puncture and again 2-4 weeks later. Data was collected from five anatomical regions of the retina (Superior 1, Superior 2, Inferior 1, Inferior 2, and the center of the Fovea).The main outcome was the Aβ status (Aβ-positive or Aβ-negative). Catboost machine learning models were trained on hyperspectral imaging data to predict Aβ status. A nested cross-validation approach was used to train and evaluate classification models. Performance metrics included area under the curve (AUC), accuracy, sensitivity, and specificity.

RESULTS: The best-performing model used the combination of regions Superior 1, Superior 2, and center of the fovea, achieving a mean AUC of 0.77 (0.05), mean accuracy of 0.66 (0.03), and mean sensitivity of 0.73 (0.13) and mean specificity of 0.55 (0.12). Performance was consistent across outer folds. Models using all five regions or less-informative combinations yielded lower and more variable results.

CONCLUSIONS: Retinal hyperspectral imaging combined with the Catboost algorithm demonstrated significant potential as a non-invasive biomarker for detecting Alzheimer's disease in a consecutive clinical cohort. Further studies should validate these findings in larger, more diverse populations and explore the integration of hyperspectral imaging with other diagnostic modalities. Limited sample size and imaging constraints highlight the need for validation in diverse clinical settings.

TRIAL REGISTRATION: ClinicalTrials.gov, ID: NCT05604183 (registration date: 2022-10-27).},
}

Humans
*Alzheimer Disease/diagnostic imaging/diagnosis/cerebrospinal fluid
Male
Female
*Retina/diagnostic imaging
Aged
Cross-Sectional Studies
Prospective Studies
Amyloid beta-Peptides/cerebrospinal fluid
*Hyperspectral Imaging/methods
Middle Aged
Aged, 80 and over
Cohort Studies
Sweden

@article {pmid41153028,
year = {2025},
author = {Yim, S and Park, S and Lim, KY and Kang, H and Shin, D and Jang, H and Weiner, M and Zetterberg, H and Blennow, K and Gonzalez-Ortiz, F and Ashton, NJ and Kang, SH and Yun, J and Chun, M and Kim, E and Kim, H and Na, DL and Kim, JP and Seo, SW and Kwak, K and , },
title = {CT-derived brain volumes and plasma p-Tau217 for risk stratification of amyloid positivity in early-stage Alzheimer's disease.},
journal = {Alzheimer's research & therapy},
volume = {17},
number = {1},
pages = {233},
pmid = {41153028},
issn = {1758-9193},
support = {101053962//EU Horizon Europe/ ; #ALFGBG-71320//Swedish State Support for Clinical Research/ ; #201809-2016862//Alzheimer Drug Discovery Foundation/ ; #ADSF-21-831376-C, #ADSF-21-831381-C, #ADSF-21-831377-C, #ADSF-24-1284328-C//AD Strategic Fund and the Alzheimer's Association/ ; #22HLT07//European Partnership on Metrology/ ; JPND2021-00694//European Union Joint Programme - Neurodegenerative Disease Research/ ; UKDRI-1003//National Institute for Health and Care Research University College London Hospitals Biomedical Research Centre, the UK Dementia Research Institute at UCL/ ; (#2023-00356, #2022-01018 and #2019-02397//Swedish Research Council/ ; #FO2022-0270//Hjärnfonden, Sweden/ ; 860197 (MIRIADE)//European Union's Horizon 2020 research and innovation programme/ ; 2024-ER1003-01//Korea National Institute of Health/ ; RS-2020-KH106434//Korea Dementia Research Project/ ; RS-2025-02223212//Korea Health Technology R&D Project/ ; RS-2019-NR040057//National Research Foundation of Korea/ ; SMX1250081//Future Medicine 20*30 Project of Samsung Medical Center/ ; RS-2021-II212068//Institute of Information & Communications Technology Planning & Evaluation (IITP)/ ; },
mesh = {Humans ; *Alzheimer Disease/diagnostic imaging/blood/pathology ; Aged ; Male ; *tau Proteins/blood ; Female ; Aged, 80 and over ; Middle Aged ; *Brain/diagnostic imaging/pathology ; *Tomography, X-Ray Computed ; Cognitive Dysfunction/diagnostic imaging/blood/pathology ; *Amyloid beta-Peptides/metabolism ; Biomarkers/blood ; Positron-Emission Tomography ; Cohort Studies ; Risk Assessment ; },
abstract = {BACKGROUND: Early detection of amyloid-β (Aβ) pathology is critical for timely intervention in Alzheimer's disease (AD). While Aβ positron emission tomography (PET) and cerebrospinal fluid (CSF) biomarkers are accurate, their high cost and limited accessibility hinder routine use. We developed a computed tomography (CT)-based, two-stage workflow combining CT-derived atrophy patterns with plasma phosphorylated tau 217 (p-Tau217) to predict Aβ PET positivity.

METHODS: In this cohort of 616 participants (521 with mild cognitive impairment (MCI], 95 with early dementia of Alzheimer's type (DAT]; age 60-93 years), CT, p-Tau217 assays, and Aβ PET were performed. A random forest model incorporating CT-derived regional W-scores and apolipoprotein E ε4 (APOE ε4) status stratified individuals into low-, intermediate-, and high-risk groups. p-Tau217 testing was reserved for the intermediate-risk group.

RESULTS: At a 95% sensitivity/specificity threshold, CT-based stratification yielded a low-risk negative predictive value (NPV) of 95.8% (93.0-98.6%) and a high-risk positive predictive value (PPV) of 98.4% (96.8-100.0%), with 28.2% classified as intermediate-risk. Targeted plasma testing of intermediate-risk group improved the overall PPV to 92.8% (88.5-97.1%) and the overall NPV to 88.9% (78.6-99.2%), achieving an overall accuracy of 95.8% (94.2-97.4%). The CT-based workflow's accuracy was non-inferior to our MRI-based method (area under the curve 0.96 vs. 0.95; p = 0.14).

CONCLUSIONS: This CT-based, two-stage approach is a cost-effective, scalable alternative to MRI-based strategies, leveraging routine CT and selective p-Tau217 testing to enhance early AD detection and optimize resource utilization in clinical practice.},
}

Humans
*Alzheimer Disease/diagnostic imaging/blood/pathology
Aged
Male
*tau Proteins/blood
Female
Aged, 80 and over
Middle Aged
*Brain/diagnostic imaging/pathology
*Tomography, X-Ray Computed
Cognitive Dysfunction/diagnostic imaging/blood/pathology
*Amyloid beta-Peptides/metabolism
Biomarkers/blood
Positron-Emission Tomography
Cohort Studies
Risk Assessment

@article {pmid41152946,
year = {2025},
author = {Bali, ZK and Bruszt, N and Göntér, K and Hernádi, I},
title = {Differential cognitive enhancer effects of acetylcholinesterase inhibitors and memantine on age-related deficits in vigilance and sustained attention: a preclinical validation study.},
journal = {Behavioral and brain functions : BBF},
volume = {21},
number = {1},
pages = {35},
pmid = {41152946},
issn = {1744-9081},
support = {KK/492/2019//Gedeon Richter Plc., Budapest, Hungary/ ; RRF-2.3.1-21-2022-00015//National Research, Development and Innovation Office/ ; K 143816//National Research, Development, and Innovation Office of the Hungarian Government/ ; },
mesh = {Animals ; *Memantine/pharmacology ; Donepezil/pharmacology ; *Cholinesterase Inhibitors/pharmacology ; Galantamine/pharmacology ; *Attention/drug effects ; Rats ; Male ; *Nootropic Agents/pharmacology ; Psychomotor Performance/drug effects ; Reaction Time/drug effects ; *Aging/drug effects/psychology ; Cognition/drug effects ; *Arousal/drug effects ; Indans/pharmacology ; Cognitive Dysfunction/drug therapy ; },
abstract = {BACKGROUND: The psychomotor vigilance task (PVT) is a cognitive test commonly used to measure sustained attention and vigilance in humans in healthy and diseased states. Here, we aimed to utilize a recently designed rat version of the PVT to assess potential cognitive enhancer effects of various pharmacological compounds in a natural model of age-related cognitive decline. Therefore, we treated aged rats (> 28 months old) with different doses of three approved Alzheimer's disease drugs: donepezil, galantamine, and memantine.

RESULTS: Aged rats made significantly slower responses to the cue stimuli compared to young animals and fewer correct responses, mainly because of an increased number of missed trials (i.e., when the trial was not initiated by the rat). Donepezil improved the performance of aged rats by accelerating their responses at a dose of 0.03 mg/kg. However, galantamine treatment showed no beneficial effects on either reaction time or the number of correct trials. Furthermore, both donepezil (0.3 and 1.0 mg/kg) and galantamine (3.0 mg/kg) increased the reaction time and number of missed trials at high doses. Memantine did not affect the reaction time of aged rats, but it increased the number of correct responses at 0.1 and 0.3 mg/kg doses.

CONCLUSIONS: Here, we showed that PVT is suitable for addressing pharmacological effects on various cognitive domains in a single behavioral paradigm. Our findings also indicate that different cognitive enhancer compounds (even when their targets are thought to be the same) may differentially influence distinct cognitive domains and modulate task performance.},
}

Animals
*Memantine/pharmacology
Donepezil/pharmacology
*Cholinesterase Inhibitors/pharmacology
Galantamine/pharmacology
*Attention/drug effects
Rats
Male
*Nootropic Agents/pharmacology
Psychomotor Performance/drug effects
Reaction Time/drug effects
*Aging/drug effects/psychology
Cognition/drug effects
*Arousal/drug effects
Indans/pharmacology
Cognitive Dysfunction/drug therapy

@article {pmid41152873,
year = {2025},
author = {Zhang, L and Chen, K and Zeng, R and Bu, G and Chen, XF},
title = {Soluble CSF1R promotes microglial activation and amyloid clearance in alzheimer's disease.},
journal = {Journal of neuroinflammation},
volume = {22},
number = {1},
pages = {245},
pmid = {41152873},
issn = {1742-2094},
support = {LG-GG-202401-ADA010200//Lin Gang Laboratory/ ; ADB210200//Lin Gang Laboratory/ ; 32170952//National Natural Science Foundation of China/ ; 2024J01613120//Fujian Provincial Natural Science Foundation/ ; JCYJ20240813145512017//Shenzhen Science and Technology Program/ ; },
mesh = {Animals ; *Alzheimer Disease/metabolism/pathology/genetics ; *Microglia/metabolism ; Mice, Transgenic ; Mice ; Humans ; *Receptors, Granulocyte-Macrophage Colony-Stimulating Factor/metabolism/genetics ; *Amyloid beta-Peptides/metabolism ; Male ; Female ; Brain/metabolism/pathology ; Aged ; Cells, Cultured ; Mice, Inbred C57BL ; Receptor, Macrophage Colony-Stimulating Factor ; },
abstract = {BACKGROUND: The colony-stimulating factor 1 receptor (CSF1R) is a receptor tyrosine kinase essential for microglial development and homeostasis. While dysregulated CSF1R signaling has been implicated in Alzheimer's disease (AD), the biological function of its soluble ectodomain (sCSF1R)-generated by a disintegrin and metalloproteinase 17 (ADAM17)-mediated cleavage-remains poorly understood in neurodegeneration.

METHODS: We quantified sCSF1R levels in the brain and cerebrospinal fluid (CSF) of 5×FAD transgenic mice and wild-type controls using ELISA and immunoblotting, and reanalyzed publicly available CSF proteomic datasets from three independent, clinically characterized AD cohorts. Functional studies were performed in primary microglial cultures and through hippocampal delivery of recombinant sCSF1R into 5×FAD mice to evaluate its effects on microglial activity and amyloid pathology.

RESULTS: In this study, we identify sCSF1R as a previously unrecognized, functionally active modulator of microglial responses in AD. Analysis of three independent clinical cohorts revealed significantly elevated sCSF1R levels in the CSF of AD patients, a finding recapitulated in both the brain and CSF of 5×FAD transgenic mice. Importantly, sCSF1R concentrations showed positive correlations with core AD biomarkers-including total tau, phosphorylated tau, and β-amyloid 1-42 (Aβ42)-and with measures of cognitive performance, highlighting its clinical significance and suggesting that sCSF1R may serve as a marker of disease-associated microglial responses. Functionally, recombinant sCSF1R enhanced microglial survival, migration, proinflammatory signaling, and Aβ phagocytosis in vitro. In vivo, administration of sCSF1R promoted microglial clustering around amyloid plaques, reduced Aβ deposition, and attenuated plaque-associated neuritic dystrophy in 5×FAD mice. Finally, we found that soluble TREM2 (sTREM2)-a CSF biomarker and potent activator of microglia-stimulates ADAM17-dependent cleavage of membrane-bound CSF1R, thereby driving the generation of sCSF1R. Collectively, these findings establish sCSF1R as a novel regulator of microglial function in AD and reveal a regulatory axis linking sTREM2, ADAM17 activity, and CSF1R shedding with potential implications for disease modulation.

CONCLUSIONS: These findings identify sCSF1R as a novel component of the neuroimmune signaling network in AD and highlight its dual potential as a CSF biomarker of beneficial microglial activation and a candidate therapeutic modulator of neuroinflammation and amyloid pathology.},
}

Animals
*Alzheimer Disease/metabolism/pathology/genetics
*Microglia/metabolism
Mice, Transgenic
Mice
Humans
*Receptors, Granulocyte-Macrophage Colony-Stimulating Factor/metabolism/genetics
*Amyloid beta-Peptides/metabolism
Male
Female
Brain/metabolism/pathology
Aged
Cells, Cultured
Mice, Inbred C57BL
Receptor, Macrophage Colony-Stimulating Factor

@article {pmid41152868,
year = {2025},
author = {Ceyzériat, K and Badina, AM and Abjean, L and Meyer, L and Bouteldja, F and Balkota, M and Amossé, Q and Prudhomme, O and Middleton, RJ and Liu, GJ and Banati, RB and Zilli, T and Lathuiliere, A and Owen, D and Maechler, P and Garibotto, V and Tsartsalis, S and Millet, P and Tournier, BB},
title = {TSPO contributes to neuropathology and cognitive deficits in Alzheimer's disease.},
journal = {Journal of neuroinflammation},
volume = {22},
number = {1},
pages = {248},
pmid = {41152868},
issn = {1742-2094},
mesh = {Animals ; *Alzheimer Disease/pathology/metabolism/genetics/complications ; Humans ; *Receptors, GABA/genetics/metabolism ; Mice ; Mice, Transgenic ; Hippocampus/pathology/metabolism ; Astrocytes/metabolism/pathology ; Male ; Mice, Knockout ; Disease Models, Animal ; Mice, Inbred C57BL ; Amyloid beta-Peptides/metabolism ; Female ; *Cognition Disorders/pathology/metabolism/etiology/genetics ; tau Proteins/metabolism/genetics ; Aged ; },
abstract = {The 18kDa translocator protein (TSPO) is increased in neurodegenerative diseases. In Alzheimer's disease (AD) animal models, TSPO's upregulation is detected first in astrocytes, then in microglia. However, the role of TSPO in the pathophysiology and symptoms characteristic of the disease remains unknown. In the human postmortem hippocampus, we show here that TSPO correlated positively with reactive astrocyte-associated genes and negatively with genes involved in glycolytic pathways. In addition, we observed that TSPO deletion in 3 × TgAD mice reversed the reduction in glucose uptake and reduced astrocyte reactivity. We observed a decrease of poorly and highly aggregated forms of Tau (-44% and -82%, respectively) and Aβ42 (-25% and -95%, respectively) at 9 months of age. In 5 × FAD mice, we confirmed the association between TSPO, astrocyte reactivity and Aβ. Functionally, Tau over-expression in the hippocampus induced a memory decline in WT animals, prevented in TSPO[-/-] mice. Altogether, these data demonstrate that TSPO plays an important role in the active progression of AD. This identifies TSPO as a potential therapeutic target and highlights the importance of astrocyte metabolism in the pathogenesis of the disease.},
}

Animals
*Alzheimer Disease/pathology/metabolism/genetics/complications
Humans
*Receptors, GABA/genetics/metabolism
Mice
Mice, Transgenic
Hippocampus/pathology/metabolism
Astrocytes/metabolism/pathology
Male
Mice, Knockout
Disease Models, Animal
Mice, Inbred C57BL
Amyloid beta-Peptides/metabolism
Female
*Cognition Disorders/pathology/metabolism/etiology/genetics
tau Proteins/metabolism/genetics
Aged

@article {pmid41152649,
year = {2025},
author = {Kang, KM and Park, C and Byun, MS and Yi, D and Nam, H and Ryu, J and Jung, JH and Jung, G and Ahn, H and Lee, JY and Lee, YS and Kim, YK and Sohn, CH and Lee, DY and , },
title = {APOE4 modulates the association between DTI-ALPS index and Alzheimer's pathologies.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21},
number = {10},
pages = {e70837},
doi = {10.1002/alz.70837},
pmid = {41152649},
issn = {1552-5279},
support = {//New Faculty Startup Fund from Seoul National University/ ; //National Research Foundation of Korea/ ; RS-2022-00165636//Ministry of Science and ICT/ ; 2014M3C7A1046042//Ministry of Science and ICT/ ; RS-2023-KH136195//Ministry of Science and ICT/ ; //Korea Health Technology R&D Project/ ; HI18C0630//Ministry of Health and Welfare, Republic of Korea/ ; HI19C0149//Ministry of Health and Welfare, Republic of Korea/ ; //Korea Dementia Research Project/ ; //Ministry of Health and Welfare/ ; //Basic Science Research Program/ ; RS-2023-00210380//Ministry of Education/ ; U01AG072177/AG/NIA NIH HHS/United States ; 03-2023-0330//SNUH Research Fund/ ; RS-2025-00518633//Korean government (MSIT)/ ; 2021R1C1C1006407//Korean government (MSIT)/ ; },
mesh = {Humans ; *Apolipoprotein E4/genetics/metabolism ; Aged ; *Alzheimer Disease/genetics/pathology/diagnostic imaging/metabolism ; Male ; Female ; Positron-Emission Tomography ; Amyloid beta-Peptides/metabolism ; tau Proteins/metabolism ; *Diffusion Tensor Imaging ; *Glymphatic System/diagnostic imaging/pathology/metabolism ; Aniline Compounds ; Thiazoles ; Aged, 80 and over ; Middle Aged ; *Brain/pathology/diagnostic imaging/metabolism ; },
abstract = {INTRODUCTION: Diffusion-tensor imaging (DTI) analysis along the perivascular space (ALPS) has emerged as a non-invasive marker of glymphatic function. Preclinical studies suggest that apolipoprotein E4 (APOE4), a major genetic risk factor for Alzheimer's disease, may exacerbate glymphatic dysfunction-related accumulation of beta-amyloid (Aβ) and tau, but human evidence is lacking. This study examined whether APOE4 moderates the relationship between glymphatic dysfunction, estimated by the ALPS index, and Aβ or tau deposition.

METHODS: We analyzed 423 older adults (mean age 70.5  ±  8.1 years) with varying cognitive profiles who underwent DTI to calculate the ALPS index and [[1] [1]C] Pittsburgh Compound B (PiB) positron emission tomography (PET) for Aβ deposition. Additionally, 132 underwent [[1]⁸F] AV-1451 PET for tau imaging.

RESULTS: A significant interaction between APOE4 status and ALPS index was observed for Aβ deposition, but not for tau. A lower ALPS index was associated with higher Aβ only in APOE4-positive individuals.

DISCUSSION: APOE4 enhances the association between glymphatic dysfunction and Aβ burden.

HIGHLIGHTS: Apolipoprotein E4 (APOE4) status moderates the link between analysis along the perivascular space (ALPS) index and cerebral beta-amyloid. Lower ALPS index is associated with higher beta-amyloid (Aβ) only in APOE4 carriers. No significant moderation by APOE4 on ALPS-tau association was found. ALPS index may offer non-invasive glymphatic marker for beta-amyloid burden.},
}

Humans
*Apolipoprotein E4/genetics/metabolism
Aged
*Alzheimer Disease/genetics/pathology/diagnostic imaging/metabolism
Male
Female
Positron-Emission Tomography
Amyloid beta-Peptides/metabolism
tau Proteins/metabolism
*Diffusion Tensor Imaging
*Glymphatic System/diagnostic imaging/pathology/metabolism
Aniline Compounds
Thiazoles
Aged, 80 and over
Middle Aged
*Brain/pathology/diagnostic imaging/metabolism

@article {pmid41152510,
year = {2025},
author = {Devi, A and Saini, CS and Shiven, A and Kumar, A and Sharma, A and Joshi, N and Kour, S and Khan, ZA and Dewangan, H and Dwibedi, V},
title = {Unconventional Non-rodent Models in Neurological Research: Exploring New Paths to Translational Insights.},
journal = {Journal of molecular neuroscience : MN},
volume = {75},
number = {4},
pages = {145},
pmid = {41152510},
issn = {1559-1166},
mesh = {Animals ; Humans ; *Disease Models, Animal ; *Translational Research, Biomedical/methods ; *Nervous System Diseases ; Caenorhabditis elegans ; Zebrafish ; },
abstract = {Neurological disorders such as Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), Schizophrenia (SCZ), and epilepsy pose a significant global health challenge, particularly among the ageing population. With Alzheimer's cases projected to double in the next 30 years, the lack of effective treatments presents a critical concern, leading to substantial social and economic burdens. While rodent models have been instrumental in elucidating disease mechanisms and identifying therapeutic targets, their limited translational success necessitates exploring alternative model systems. This review highlights the increasing integration of non-rodent models, including invertebrates (Drosophila melanogaster and Caenorhabditis elegans), lower vertebrates (Danio rerio), and higher-order mammals (non-human primates), alongside emerging approaches such as Octopus models, 2D and 3D cell culture systems, computational models, and in silico methodologies. These alternative models provide unique advantages in studying neural development, function, and pathology, offering improved translational relevance. By leveraging the complementary strengths of these systems, researchers can refine therapeutic strategies and advance our understanding of complex neurological disorders.},
}

Animals
Humans
*Disease Models, Animal
*Translational Research, Biomedical/methods
*Nervous System Diseases
Caenorhabditis elegans
Zebrafish

@article {pmid41152396,
year = {2025},
author = {Haudry, S and Lambert, N and Gaser, C and Thirion, B and Landeau, B and Gonneaud, J and Poisnel, G and Champetier, P and Lehodey, A and Marchant, NL and Klimecki, O and Collette, F and Vivien, D and de la Sayette, V and Lutz, A and Chételat, G},
title = {Impact of meditation on brain age derived from multimodal neuroimaging in experts and older adults from a randomized trial.},
journal = {Scientific reports},
volume = {15},
number = {1},
pages = {37710},
pmid = {41152396},
issn = {2045-2322},
support = {AS-SF-15b-002/ALZS_/Alzheimer's Society/United Kingdom ; 15.0336//Secrétariat d'état à la formation, à la recherche et à l'innovation/ ; },
mesh = {Humans ; *Meditation ; Aged ; Female ; Male ; *Brain/diagnostic imaging/physiology ; *Neuroimaging/methods ; *Aging/physiology ; Magnetic Resonance Imaging ; Middle Aged ; Aged, 80 and over ; Machine Learning ; Cognition ; Multimodal Imaging ; },
abstract = {Meditation is thought to promote healthy aging by improving mental health, preserving brain integrity and reducing Alzheimer's disease risk. We examined the impact of long-term meditation expertise and an 18-month meditation training on brain aging in older adults using machine learning. We included 25 Older Expert Meditators (OldExpMed) with > 20 years of practice and 135 Cognitively Unimpaired Older Adults (CUOA) from the Age-Well randomized controlled trial. CUOA were randomized (1:1:1) into an 18-month meditation training, a non-native language training, and a no intervention group. Brain age was predicted using a machine learning model trained on gray and white matter volume and glucose metabolism data from ADNI and replicated with a second model. Brain Predicted Age Difference (BrainPAD) was computed as the gap between predicted and chronological age. We assessed meditation expertise effects on BrainPAD, its links with meditation hours, cognitive, and affective measures, and the impact of 18-month training. Compared to CUOA, OldExpMed exhibited significantly lower/more negative BrainPAD, linked to meditation hours, mental imagery, and prosocialness. No significant effect of 18-month training was observed. Results were consistent across the replication model. Long-term meditation is associated with younger brain age, but 18-month training has no effect, emphasizing the need for sustained practice to support healthy brain aging.},
}

Humans
*Meditation
Aged
Female
Male
*Brain/diagnostic imaging/physiology
*Neuroimaging/methods
*Aging/physiology
Magnetic Resonance Imaging
Middle Aged
Aged, 80 and over
Machine Learning
Cognition
Multimodal Imaging

@article {pmid41152341,
year = {2025},
author = {Fujii, K and Koshidaka, Y and Yanagibashi, Y and Adachi, M and Matsuo, M and Kimura, K and Saito, T and Saido, TC and Takao, K},
title = {Ovariectomy attenuates phenotypes related to Alzheimer's disease in a preclinical mouse model and in C57BL/6 J mice.},
journal = {Scientific reports},
volume = {15},
number = {1},
pages = {36995},
pmid = {41152341},
issn = {2045-2322},
support = {22H04922//Japan Society for the Promotion of Science/ ; },
mesh = {Animals ; *Alzheimer Disease/metabolism/genetics/pathology/physiopathology ; *Ovariectomy ; Disease Models, Animal ; Female ; Mice ; Mice, Inbred C57BL ; Phenotype ; Amyloid beta-Protein Precursor/genetics/metabolism ; Mice, Transgenic ; Behavior, Animal ; Mutation ; Amyloid beta-Peptides/metabolism ; Fear ; Anxiety ; Gene Knock-In Techniques ; Memory ; },
abstract = {Women are at higher risk for Alzheimer's disease (AD) than men and hormonal changes during perimenopause are considered a risk factor. The relationship between ovarian hormones and AD has been explored using AD animal models, especially through ovariectomy (OVX) in established AD models. The link between early-stage AD and ovarian hormones, however, remains unclear, largely due to the lack of suitable animal models. Appropriate models for studying early-stage AD pathology, treatment, and prevention are critically needed. The App knock-in mouse model, which carries a single amyloid precursor protein (App) gene mutation, effectively reproduces early amyloid AD pathology. To elucidate the relationship between ovarian hormone deficiency and the behavioral phenotypes of a preclinical AD model, we applied a comprehensive behavioral test battery to this mouse model with bilateral OVX. The App mutation reduced anxiety-like behavior and impaired performance in the fear memory task. OVX restored the anxiety-like behavior of the App mutation mice to a level comparable to that in wild-type (WT) mice. Furthermore, OVX enhanced performance in a fear memory task in both genotypes and reduced amyloid-β staining in WT mice. Together, these findings suggest that OVX attenuates AD-related phenotypes in a preclinical AD model and in C57BL/6 J WT mice.},
}

Animals
*Alzheimer Disease/metabolism/genetics/pathology/physiopathology
*Ovariectomy
Disease Models, Animal
Female
Mice
Mice, Inbred C57BL
Phenotype
Amyloid beta-Protein Precursor/genetics/metabolism
Mice, Transgenic
Behavior, Animal
Mutation
Amyloid beta-Peptides/metabolism
Fear
Anxiety
Gene Knock-In Techniques
Memory

@article {pmid41152204,
year = {2025},
author = {Arnold, D and Barros, RC and Ferrari-Souza, JP and de Bastiani, MA and Zimmer, ER and Borelli, WV},
title = {Stratifying dementia risk factors: A prediction model and hypothesis-driven analysis.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21},
number = {10},
pages = {e70870},
doi = {10.1002/alz.70870},
pmid = {41152204},
issn = {1552-5279},
support = {AACSFD-22-928689//the Alzheimer's Association/ ; 312410/2018-2//the Alzheimer's Association/ ; 435642/2018- 9//the Alzheimer's Association/ ; 312306/2021-0//the Alzheimer's Association/ ; 409066/2022-2//the Alzheimer's Association/ ; //ARD/ ; 21/2551- 0000673-0//the FAPERGS/ ; AARGD-21- 850670//the FAPERGS/ ; //CNPQ/ ; 16/2551- 0000475-7//PRONEX/ ; //Brazilian National Institute of Science/ ; 465671/2014-4//Technology in Excitotoxicity and Neuroprotection/ ; Serra-1912-31365//Instituto Serrapilheira/ ; R-2401-47242//Instituto Serrapilheira/ ; ALZ-NAN-22-928381//National Academy of Neuropsychology/ ; AARFD-23-1148735//National Academy of Neuropsychology/ ; 21/2551- 0000673-0//Fundação de Amparo à Pesquisa do Estado do Rio Grande do Sul/ ; 16/2551- 0000475-7//Conselho Nacional de Desenvolvimento Científico e Tecnológico/ ; AARFD-23-1148735/ALZ/Alzheimer's Association/United States ; },
mesh = {Humans ; Male ; Risk Factors ; Female ; *Dementia/epidemiology/diagnosis ; Aged ; Risk Assessment/methods ; Machine Learning ; Depression/epidemiology ; Aged, 80 and over ; Body Mass Index ; Cohort Studies ; Educational Status ; Age Factors ; },
abstract = {INTRODUCTION: Most older adults present multimorbidity, but dementia risk factors are typically analyzed individually. Direct methodological comparisons evaluating simultaneous multiple risk factors are essential to provide the realistic effects of multimorbidity. We aimed to compare hypothesis- and data-driven approaches for dementia risk stratification in a real-world cohort.

METHODS: We analyzed 9606 participants from the National Alzheimer's Coordinating Center (NACC) Uniform Data Set (2005-2023) using machine learning with interpretability analysis and survival models to simultaneously evaluate 13 risk factors for incident dementia conversion.

RESULTS: A total of 877 participants (9%) developed dementia over (mean ± SD, 6 ± 4.2) years of follow-up. Both approaches consistently identified four key predictors: age, depression, low education, and body mass index (protective). Convergent findings across methodologies demonstrated robust factor identification despite different analytical paradigms.

DISCUSSION: In this direct methodological comparison, age, depression, and low education emerge as major dementia risk factors regardless of analytical approach. Convergent interpretability of these approaches support simultaneous multifactorial risk assessment in clinical practice.

HIGHLIGHTS: Data- and hypothesis-driven approaches identified convergent key risk factors Age, depression, and low education are major risk factors for dementia Higher body mass index was unexpectedly protective against dementia conversion Multimorbidity requires simultaneous evaluation of multiple risk factors Real-world analysis reveals complex interactions between dementia risks.},
}

Humans
Male
Risk Factors
Female
*Dementia/epidemiology/diagnosis
Aged
Risk Assessment/methods
Machine Learning
Depression/epidemiology
Aged, 80 and over
Body Mass Index
Cohort Studies
Educational Status
Age Factors