@article {pmid41269417,
year = {2025},
author = {Yuan, M and Han, XJ and Luo, CQ and Pan, HL and Zhou, HY},
title = {PSMD4 Alleviates Aβ1-42-Induced Mitochondrial Dysfunction and Oxidative Stress via the PGC-1α/Nrf Axis in Alzheimer's Disease Models.},
journal = {Molecular neurobiology},
volume = {63},
number = {1},
pages = {117},
pmid = {41269417},
issn = {1559-1182},
support = {2024SSY06081//the Jiangxi Province Key Laboratory of Neurology/ ; 2023ZD001//The Key Science and Technology Innovation Project of Jiangxi Provincial Health Commission/ ; 82071245, 82360238//the National Natural Science Foundation of China/ ; 20202ACB215003, 20232ACB205008//Jiangxi Province Natural Science Foundation/ ; },
mesh = {Animals ; *Alzheimer Disease/metabolism/pathology ; *Oxidative Stress/drug effects ; *Mitochondria/metabolism/drug effects/pathology ; *Amyloid beta-Peptides/toxicity ; *Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha/metabolism ; Disease Models, Animal ; Mice, Transgenic ; *Peptide Fragments/toxicity ; Reactive Oxygen Species/metabolism ; *Nuclear Respiratory Factor 1/metabolism ; *Proteasome Endopeptidase Complex/metabolism ; Mice ; Membrane Potential, Mitochondrial/drug effects ; Signal Transduction/drug effects ; Hippocampus/pathology/metabolism ; },
abstract = {This study aimed to investigate the role of 26S proteasome non-ATPase regulatory subunit 4 (PSMD4) in regulating mitochondrial function and oxidative stress in Alzheimer's disease (AD) and to explore its potential molecular mechanism in Aβ-induced neurotoxicity. An in vitro AD model was established by treating Neuro-2a cells with Aβ1-42, and PSMD4 was overexpressed using a lentiviral vector. Flow cytometry was employed to assess reactive oxygen species (ROS) generation and mitochondrial membrane potential (ΔΨm). Quantitative PCR and Western blotting were utilized to examine the expression of mitochondrial biogenesis-associated regulators, including PGC-1α, Nrf1, Nrf2, and TFAM. For the in vivo study, APP/PS1 double-transgenic mice served as the AD model. Histological analyses (HE and Nissl staining), immunofluorescence, and Western blotting were performed to evaluate hippocampal neuronal morphology and the expression of PSMD4 and mitochondrial marker TOM20. Aβ1-42 significantly increased ROS levels, reduced ΔΨm, and downregulated the expression of PGC-1α, Nrf1, Nrf2, and TFAM in Neuro-2a cells. PSMD4 overexpression attenuated these changes, suggesting a protective role against mitochondrial dysfunction and oxidative stress. In APP/PS1 mice, hippocampal neurons showed morphological damage with reduced Nissl substance and decreased PSMD4 and TOM20 expression. Immunofluorescence revealed cytoplasmic PSMD4 localization and enhanced co-localization with MAP2, TOM20, and Aβ1-42 in transgenic mice. PSMD4 is downregulated in AD models, and its overexpression ameliorates Aβ-induced oxidative stress and mitochondrial impairment, potentially by promoting mitochondrial biogenesis. These findings suggest that PSMD4 may serve as a novel therapeutic target for AD intervention.},
}

Animals
*Alzheimer Disease/metabolism/pathology
*Oxidative Stress/drug effects
*Mitochondria/metabolism/drug effects/pathology
*Amyloid beta-Peptides/toxicity
*Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha/metabolism
Disease Models, Animal
Mice, Transgenic
*Peptide Fragments/toxicity
Reactive Oxygen Species/metabolism
*Nuclear Respiratory Factor 1/metabolism
*Proteasome Endopeptidase Complex/metabolism
Mice
Membrane Potential, Mitochondrial/drug effects
Signal Transduction/drug effects
Hippocampus/pathology/metabolism

@article {pmid41269410,
year = {2025},
author = {Chen, M and Ning, Y and Yang, H and Jia, J},
title = {Trofinetide Improves Cognitive Function in APP/PS1 Mice by Suppressing Inflammation and Apoptosis.},
journal = {Molecular neurobiology},
volume = {63},
number = {1},
pages = {129},
pmid = {41269410},
issn = {1559-1182},
support = {No.2021ZD0201802//the STI2030-Major Projects/ ; U20A20354//the Key Project of the National Natural Science Foundation of China/ ; Z201100005520016, Z201100005520017//Beijing Brain Initiative from Beijing Municipal Science & Technology Commission/ ; CX23YZ15//the grant from the Chinese Institutes for Medical Research/ ; 31627803//the National Key Scientific Instrument and Equipment Development Project/ ; },
mesh = {Animals ; *Apoptosis/drug effects ; Mice, Transgenic ; *Inflammation/drug therapy/pathology ; *Cognition/drug effects ; Mice ; Microglia/drug effects/metabolism/pathology ; Amyloid beta-Peptides/metabolism ; *Amyloid beta-Protein Precursor/metabolism/genetics ; Alzheimer Disease/drug therapy/pathology ; Neurons/drug effects/metabolism/pathology ; *Presenilin-1/metabolism ; Hippocampus/pathology/drug effects ; Neuroprotective Agents/pharmacology/therapeutic use ; Male ; Amyloid Precursor Protein Secretases/metabolism ; },
abstract = {Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by cognitive impairment, neuroinflammation, and neuronal apoptosis. Trofinetide, an analog of insulin-like growth factor 1 (IGF-1), has shown neuroprotective effects in various neurological disorders, but its role in AD remains unclear. Six-month-old APP/PS1 transgenic mice received intraperitoneal trofinetide for 2 months. Cognitive function was assessed using the Morris water maze (MWM) test. Immunohistochemistry (IHC) and immunofluorescence (IF) evaluated β-amyloid (Aβ) pathology, microglial activation, and neuronal loss. In vitro, BV2 microglial cells and HT22 hippocampal neurons were treated with trofinetide against AβO-induced cytotoxicity. Western blot (WB) was used to analyze inflammation and apoptosis-related proteins. Trofinetide significantly improved cognitive deficits, reduced Aβ plaque deposition, and decreased microglial activation and neuronal loss in APP/PS1 mice. In vitro, it rescued AβO-induced cytotoxicity, suppressed inflammatory cytokines (TNF-α, IL-6, IL-1) in BV2 cells, and inhibited apoptosis in HT22 cells. Mechanistically, trofinetide upregulated PPAR-γ, reduced BACE1, suppressed NF-κB phosphorylation, inhibited caspase-3 activation, and restored Bax/Bcl-2 balance, alleviating neuroinflammation and apoptosis. This study provides the first evidence that trofinetide improves cognitive function and mitigates Aβ pathology, neuroinflammation, and apoptosis in APP/PS1 mice and AβO-treated cells, highlighting its therapeutic potential for AD.},
}

Animals
*Apoptosis/drug effects
Mice, Transgenic
*Inflammation/drug therapy/pathology
*Cognition/drug effects
Mice
Microglia/drug effects/metabolism/pathology
Amyloid beta-Peptides/metabolism
*Amyloid beta-Protein Precursor/metabolism/genetics
Alzheimer Disease/drug therapy/pathology
Neurons/drug effects/metabolism/pathology
*Presenilin-1/metabolism
Hippocampus/pathology/drug effects
Neuroprotective Agents/pharmacology/therapeutic use
Male
Amyloid Precursor Protein Secretases/metabolism

@article {pmid41269403,
year = {2025},
author = {Jin, J and Hand, R and Meltzer, M and Abate, C and Geva, M and Hayden, MR and Ross, CA},
title = {Sigma-2 Receptor Antagonism Enhances the Neuroprotective Effects of Pridopidine, a Sigma-1 Receptor Agonist, in Huntington's Disease.},
journal = {Molecular neurobiology},
volume = {63},
number = {1},
pages = {121},
pmid = {41269403},
issn = {1559-1182},
mesh = {*Receptors, sigma/antagonists & inhibitors/agonists/metabolism ; *Huntington Disease/drug therapy/pathology/metabolism ; Animals ; *Neuroprotective Agents/pharmacology/therapeutic use ; Sigma-1 Receptor ; *Piperidines/pharmacology/therapeutic use ; Mice ; Humans ; Neurons/drug effects/metabolism/pathology ; Huntingtin Protein/metabolism ; },
abstract = {Pridopidine is a selective sigma-1 receptor (S1R) agonist in clinical development for Huntington's Disease (HD) and Amyotrophic Lateral Sclerosis (ALS). Activation of the S1R by pridopidine is neuroprotective in multiple preclinical models of neurodegenerative disease. The sigma-2 receptor (S2R) is evolutionarily and structurally unique from the S1R. Nevertheless, the S1R and S2R share an overlapping yet distinct ligand binding profile. Inhibition of the S2R is neuroprotective and S2R antagonists are in clinical development for Alzheimer's Disease (AD), ⍺-synucleinopathies, and dry age-related macular degeneration. In this study, we hypothesized that simultaneous activation of the S1R by pridopidine and inhibition of the S2R by the selective S2R antagonist FA10 might provide enhanced protection against mutant huntingtin (mHTT) expression in an in vitro model of neurodegeneration. Consistent with previous studies, pridopidine reduced neuronal cell death in a mouse primary neuron mHTT model. Similarly, we found that inhibition of the S2R by FA10 was also sufficient to protect against mHTT induced neurodegeneration in this model. The combination treatment of pridopidine and FA10 achieved greater efficacy than either compound alone, even at lower concentrations. The combination of these compounds may allow for lower efficacious doses leading to improved safety profiles and reduced off-target effects. This novel combinatorial approach, in which the S1R is activated while simultaneously inhibiting the S2R may prove to be a highly effective therapeutic strategy for HD and other neurodegenerative diseases.},
}

*Receptors, sigma/antagonists & inhibitors/agonists/metabolism
*Huntington Disease/drug therapy/pathology/metabolism
Animals
*Neuroprotective Agents/pharmacology/therapeutic use
Sigma-1 Receptor
*Piperidines/pharmacology/therapeutic use
Mice
Humans
Neurons/drug effects/metabolism/pathology
Huntingtin Protein/metabolism

@article {pmid41269384,
year = {2025},
author = {Di Domenico, F and Greco, V and Tramutola, A and Rataj-Baniowska, M and Barone, E and Lanzillotta, C and Pieroni, L and Butterfield, DA and Herault, Y and Pagnotta, S and Cassano, T and Head, E and Urbani, A and Perluigi, M},
title = {Proteome Signature of Alzheimer-Like Phenotypes in Frontal Cortices From Young and Old Individuals With Down Syndrome.},
journal = {Molecular neurobiology},
volume = {63},
number = {1},
pages = {126},
pmid = {41269384},
issn = {1559-1182},
support = {RM11916B78D5711A//Sapienza Università di Roma/ ; RG12117A75C98BE3//Sapienza Università di Roma/ ; 2022KP5LKS//Ministero dell'Istruzione, dell'Università e della Ricerca/ ; M4C2-I1.3 Project PE_00000019 "HEAL ITALIA" CUP: D73C22001230006//Ministero dell'Istruzione, dell'Università e della Ricerca/ ; #2280-2023b//Fondation Jérôme Lejeune/ ; APAFIS#15187- 201805221519333v3//Ministère de l'Enseignement supérieur et de la Recherche/ ; R01HD064993/NH/NIH HHS/United States ; BFF17_0008//BrightFocus Foundation/ ; 2022-23 Anna Tramontano//Istituto Pasteur-Fondazione Cenci Bolognetti/ ; },
mesh = {Humans ; *Down Syndrome/metabolism/pathology ; *Alzheimer Disease/metabolism/pathology ; *Frontal Lobe/metabolism/pathology ; *Proteome/metabolism ; Phenotype ; Male ; Female ; Middle Aged ; *Aging/metabolism/pathology ; Aged ; Adult ; Proteomics/methods ; Young Adult ; Aged, 80 and over ; },
abstract = {Down syndrome (DS) stands out as the most prevalent genetic contributor to intellectual disability, marked by the presence of an extra copy of chromosome 21 (HSA21). Notably, individuals with DS exhibit significant neuropathological changes for a diagnosis of Alzheimer's disease (AD), typically by the age of 50 years. To search for and identify biomarkers crucial for detecting and understanding the mechanisms involved in DS neuropathology, we conducted a protein expression analysis of post-mortem brain samples. We evaluated the frontal cortex of post-mortem brain samples from patients with DS both before and after the onset of AD pathology (DSAD), in comparison with age-matched healthy patients (CTRY and CTRO). Employing a comprehensive label-free shotgun proteomics approach, we sought to gain a deeper understanding of the intricate protein profiles associated with DS and its progression into DSAD. Collected results have been analyzed using specific databases and bioinformatics analysis software to understand relevant pathways, networks, and functions related to the experimental data. Our data support a genotype effect in DS at young and old ages that promotes specific proteome signatures associated with AD development. Notably, the affected signalling pathways encompass energy-related processes, synaptic transmission, and stress response. With aging, the dynamic shift in protein expression contributes to accelerating the neurodegenerative process, culminating in the manifestation of the AD phenotype.},
}

Humans
*Down Syndrome/metabolism/pathology
*Alzheimer Disease/metabolism/pathology
*Frontal Lobe/metabolism/pathology
*Proteome/metabolism
Phenotype
Male
Female
Middle Aged
*Aging/metabolism/pathology
Aged
Adult
Proteomics/methods
Young Adult
Aged, 80 and over

@article {pmid41269303,
year = {2025},
author = {Xin, H and He, L and Zhu, B},
title = {Ecological Insights into Gut Microbiota Networks Across Cognitive States in Alzheimer's Disease.},
journal = {Microbial ecology},
volume = {},
number = {},
pages = {},
doi = {10.1007/s00248-025-02662-6},
pmid = {41269303},
issn = {1432-184X},
support = {No. 202212691//Jiangxi Provincial Health Commission/ ; },
abstract = {The ecological mechanisms governing gut microbial community stability during Alzheimer's disease (AD) progression remain poorly understood. This study employed an ecological network to investigate microbial interactions and stability across cognitively normal controls (CK), individuals with mild cognitive impairment (MCI), and AD patients. We observed a stepwise decline in network complexity across groups, characterized by reduced clustering coefficients and average degree, from CK to AD. While the MCI group exhibited intermediate structural complexity, it displayed the highest vulnerability and lowest robustness, indicating a critical transitional state. Keystone taxa analysis revealed a significant shift in microbial community, with the CK network was enriched with diverse, potentially beneficial keystone taxa, whereas the AD network retained only connector species, and the MCI network showed a complete absence of keystone taxa. Cohesion analysis revealed a non-linear trajectory of microbial interactions, with negative cohesion peaking in MCI. Our findings demonstrate that cognitive decline is associated with a fundamental reorganization of the gut microbial ecosystem. This reorganization pattern reveals a resilient state in health, a vulnerable phase in MCI, and a stable yet dysbiotic configuration in AD, with keystone taxa serving as pivotal regulators of community stability. Community assembly analysis showed a shift from deterministic to stochastic processes during cognitive decline, with weakened host regulatory mechanisms. These findings advance our understanding of the gut microbial ecology in neurodegenerative disease and reveal the mechanism by which microbial communities reorganize network to maintain stability in different cognitive states.},
}

@article {pmid41269248,
year = {2025},
author = {Maggi, S and Fulöp, T and De Vita, E and Limongi, F and Pizzol, D and Di Gennaro, F and Veronese, N},
title = {Association between vaccinations and risk of dementia: a systematic review and meta-analysis.},
journal = {Age and ageing},
volume = {54},
number = {11},
pages = {},
doi = {10.1093/ageing/afaf331},
pmid = {41269248},
issn = {1468-2834},
mesh = {Humans ; *Dementia/epidemiology/prevention & control/diagnosis ; *Vaccination ; Aged ; Incidence ; Risk Factors ; Middle Aged ; Risk Assessment ; Cognitive Dysfunction/epidemiology/prevention & control ; Pneumococcal Vaccines ; Influenza Vaccines/administration & dosage ; },
abstract = {IMPORTANCE: Dementia is a highly prevalent issue in older people. Whilst the prevention of dementia is a public health priority, the role of vaccinations is still largely unexplored.

OBJECTIVE: The aim of this systematic review is to evaluate whether common adult vaccinations are associated with a reduced risk of dementia.

DATA SOURCES: PubMed, Embase and Web of Science were searched from inception to 1 January 2025.

STUDY SELECTION: Observational studies comparing dementia and mild cognitive impairment incidence between vaccinated and unvaccinated adults aged ≥50 years.

DATA EXTRACTION AND SYNTHESIS: Four reviewers independently extracted data and assessed study quality using the Newcastle-Ottawa Scale. Risk ratios (RRs) and 95% confidence intervals (CIs) were pooled using a random-effects model.

MAIN OUTCOMES AND MEASURES: Incidence of dementia, including its subtypes.

RESULTS: Twenty-one studies (n = 104 031 186 participants) were included. Vaccination against herpes zoster was associated with a reduced risk of any dementia (RR 0.76, 95% CI 0.69-0.83) and Alzheimer's disease (RR 0.53, 95% CI 0.44-0.64). Influenza vaccination was linked to a reduction in dementia risk (RR 0.87, 95% CI 0.77-0.99), as was pneumococcal vaccination (RR 0.64, 95% CI 0.47-0.87) for Alzheimer's disease. Tetanus, diphtheria, pertussis (Tdap) vaccination was also associated with a significant reduction for any dementia (RR 0.67, 95% CI 0.54-0.83).

CONCLUSIONS AND RELEVANCE: Adult vaccinations, particularly against herpes zoster, influenza, pneumococcus and Tdap, are associated with a lower risk of dementia. Vaccination strategies should be incorporated into public health initiatives for dementia prevention.

REGISTRATION: https://osf.io/x3d4f/.},
}

Humans
*Dementia/epidemiology/prevention & control/diagnosis
*Vaccination
Aged
Incidence
Risk Factors
Middle Aged
Risk Assessment
Cognitive Dysfunction/epidemiology/prevention & control
Pneumococcal Vaccines
Influenza Vaccines/administration & dosage

@article {pmid41269127,
year = {2025},
author = {Linton, KF},
title = {A Quasi-Experimental Study Comparing a VR, Computer-Based, and Face-to-Face Alzheimer's Embodiment Education Scenario, "Beatriz.},
journal = {The Gerontologist},
volume = {},
number = {},
pages = {},
doi = {10.1093/geront/gnaf251},
pmid = {41269127},
issn = {1758-5341},
abstract = {BACKGROUND AND OBJECTIVES: Effective education on Alzheimer's disease (AD) requires methods fostering empathy, confidence, and knowledge. Artificial intelligence (AI)-enhanced virtual reality (VR) provides immersive experiences potentially superior to traditional modalities. No previous studies have compared VR immersive learning experiences to analogous computer-based or in-person embodiment exercises. This quasi-experimental study compared the efficacy of an AI-enhanced VR scenario, "Beatriz," with computer-based and face-to-face methods in improving students' confidence, empathy, and knowledge of AD.

RESEARCH DESIGN AND METHODS: A quasi-experimental design included 173 undergraduate health science students assigned to AI-enhanced VR, computer-based, or face-to-face modalities depicting early, middle, and late AD stages. Confidence, empathy, and knowledge were measured via pre-post surveys. Repeated measures ANOVAs determined significant differences.

RESULTS: All groups significantly improved confidence across AD stages post-intervention. The VR group showed greater improvement specifically in early-stage confidence. VR also significantly increased empathy compared to other modalities. No modality significantly improved factual knowledge of AD symptoms.

DISCUSSION AND IMPLICATIONS: AI-enhanced VR effectively improved empathy and early-stage confidence, suggesting strong benefits for dementia education. However, it did not surpass traditional methods in improving factual knowledge. AI-driven VR has promising implications for enhancing therapeutic and caregiving practices for aging populations. Further research should explore long-term impacts and direct older adult care applications.},
}

@article {pmid41269125,
year = {2025},
author = {Singh, RK and Bekena, S and Zhu, Y and Adkins-Jackson, PB and Ances, BM and Babulal, GM},
title = {Sleep Quality as a Modifier of Plasma pTau217 and GFAP Associations with Cognitive Function.},
journal = {The journals of gerontology. Series A, Biological sciences and medical sciences},
volume = {},
number = {},
pages = {},
doi = {10.1093/gerona/glaf259},
pmid = {41269125},
issn = {1758-535X},
abstract = {BACKGROUND: Plasma biomarkers, such as neurofilament light chain (NfL), glial fibrillary acidic protein (GFAP), phosphorylated tau (pTau217), and total tau (tTau), are associated with cognitive decline. However, the role of sleep quality in modifying these associations remains unclear. This study examines whether subjective sleep quality, as measured by the Pittsburgh Sleep Quality Index (PSQI), modifies the associations between plasma biomarkers and cognitive performance.

METHODS: We analyzed cross-sectional data from 491 adults aged 36 years or older in the Aging Adult Brain Connectome study. Plasma levels of NfL, GFAP, pTau217, and total tTau were measured. Cognitive performance was assessed using the Montreal Cognitive Assessment (MoCA) and the Preclinical Alzheimer's Cognitive Composite (PACC). Sleep quality was measured using the Pittsburgh Sleep Quality Index (PSQI). Generalized linear models were used to test main and moderation effects while adjusting for demographics. Sensitivity analyses included APOE ε4 status and body mass index.

RESULTS: Higher plasma levels of NfL, GFAP, and pTau217 were associated with lower cognitive performance on both MoCA and PACC (all P < 0.05). Poorer sleep quality was independently associated with worse PACC outcomes. Critically, significant moderation effects were observed: PSQI moderated the negative associations between GFAP and both PACC (β = 0.0003, P = 0.039) and MoCA (β = 0.0019, P = 0.021), and between pTau217 and MoCA (β = 0.0299, P = 0.004), indicating a synergistic relationship between sleep quality and glial/amyloid-related pathology in cognitive aging.

CONCLUSION: Sleep quality modifies biomarker-cognition associations, highlighting its potential as a behavioral target to support brain health.},
}

@article {pmid41268975,
year = {2025},
author = {Saxena, V and Garg, S},
title = {Engineered Commensals as Next-Generation Drug Delivery Agents for Nose-to-Brain Therapeutics in Neurological Disorders.},
journal = {ACS chemical neuroscience},
volume = {},
number = {},
pages = {},
doi = {10.1021/acschemneuro.5c00874},
pmid = {41268975},
issn = {1948-7193},
abstract = {Central nervous system (CNS) disorders such as Alzheimer's diseases, Parkinson's diseases, stroke, and glioma remain among the most challenging to treat, largely due to the restrictive nature of the blood-brain barrier (BBB). In recent years, intranasal administration has emerged as a noninvasive route for CNS drug delivery. Due to its anatomical advantage over the traditional route, the nose-to-brain route can easily bypass the BBB and deliver drugs directly to the brain. Parallel advances in the interface of synthetic biology and materials engineering have led to the development of engineered living materials (ELMs) dynamic structures that embed mammalian cells, bacteria, or viruses within self-renewing or engineered matrices. These bioengineered systems have been developed as next-generation therapeutic platforms for various biomedical applications, utilizing intrinsic or engineered capabilities such as disease-targeted migration, localized therapeutic production, adaptive delivery, immune activation, and metabolic regulation. Therefore, developing a bioengineered commensal based delivery system that uses the intranasal route to effectively deliver drug across the BBB could represent a transformative strategy for treating CNS disorder and advancing neurotherapeutic research.},
}

@article {pmid41268926,
year = {2025},
author = {},
title = {Cyrus A. Raji, MD, PhD, is the recipient of the 2025 Mark A. Smith Alzheimer Award.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {106},
number = {4},
pages = {1217-1218},
doi = {10.1177/13872877251361092},
pmid = {41268926},
issn = {1875-8908},
}

@article {pmid41268856,
year = {2025},
author = {Andrews, SJ and Tolosa-Tort, P and Jonson, C and Fulton-Howard, B and Renton, AE and Yokoyama, JS and Yaffe, K and , },
title = {The role of genomic-informed risk assessments in predicting dementia outcomes.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21},
number = {11},
pages = {e70826},
doi = {10.1002/alz.70826},
pmid = {41268856},
issn = {1552-5279},
support = {5U24AG072122//National Alzheimer's Coordinating Center New Investigator Award/ ; R35AG071916/NH/NIH HHS/United States ; U19AG069701/NH/NIH HHS/United States ; /AG/NIA NIH HHS/United States ; Z01ZIAAG000534/HH/HHS/United States ; /NS/NINDS NIH HHS/United States ; },
mesh = {Humans ; Male ; Female ; *Dementia/genetics/epidemiology/diagnosis ; Risk Assessment ; Aged ; Apolipoproteins E/genetics ; *Genomics ; Risk Factors ; Disease Progression ; Alzheimer Disease/genetics ; Aged, 80 and over ; Genetic Predisposition to Disease ; Middle Aged ; },
abstract = {INTRODUCTION: By integrating genetic and clinical risk factors into genomic-informed dementia risk reports, healthcare providers can offer patients detailed risk profiles to facilitate understanding of individual risk and support the implementation of personalized strategies for promoting brain health.

METHODS: We constructed an additive score comprising the modified Cardiovascular Risk Factors, Aging, and Incidence of Dementia Risk Score (mCAIDE), family history of dementia, apolipoprotein E (APOE) genotype, and an Alzheimer's disease (AD) polygenic risk score in National Alzheimer's Coordinating Center (NACC) and Alzheimer's Disease Neuroimaging Iniative (ADNI), and assessed its association with progression to all-cause dementia.

RESULTS: A total of 81% of participants had at least one high-risk indicator for dementia, with each additional risk indicator linked to a 34% increase in the hazard of dementia onset.

DISCUSSION: We found that most participants in memory and aging clinics had at least one high-risk indicator for dementia. Furthermore, we observed a dose-response relationship where a greater number of risk indicators was associated with an increased risk of incident dementia.

HIGHLIGHTS: Compiled genomic-informed dementia risk report of genetic and clinical risk factors. Most memory clinic patients have at least one high-risk indicator for dementia. A higher risk indicator burden is associated with a greater dementia risk.},
}

Humans
Male
Female
*Dementia/genetics/epidemiology/diagnosis
Risk Assessment
Aged
Apolipoproteins E/genetics
*Genomics
Risk Factors
Disease Progression
Alzheimer Disease/genetics
Aged, 80 and over
Genetic Predisposition to Disease
Middle Aged

@article {pmid41268805,
year = {2025},
author = {Suemoto, CK and Paradela, R and Leite, REP and Paes, VR and Pasqualucci, CA and Ferriolli, E and Zatz, M and do Nascimento Santos, G and de Alexandria, MALS and Pereira, AC and Fortea, J and Naslavsky, M and Grinberg, LT},
title = {Apolipoprotein E and Alzheimer's disease pathology in a diverse autopsy study.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21},
number = {11},
pages = {e70927},
doi = {10.1002/alz.70927},
pmid = {41268805},
issn = {1552-5279},
support = {2020/14339-3//the Sao Paulo Research Foundation/FAPESP/ ; 2024/03917-7//the Sao Paulo Research Foundation/FAPESP/ ; INT21/00073 PI20/01473//the Instituto de Salud Carlos III (Ministerio de Asuntos Económicos y Transformación Digital, Gobierno de España/ ; PI23/01786//the Instituto de Salud Carlos III (Ministerio de Asuntos Económicos y Transformación Digital, Gobierno de España/ ; //the Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas CIBERNED Program 1/ ; //by Fondo Europeo de Desarrollo Regional, Unión Europea, Una Manera de Hacer Europa/ ; R01 AG056850//the National Institutes of Health/ ; R21 AG056974/AG/NIA NIH HHS/United States ; R01 AG061566//the National Institutes of Health/ ; R01 AG081394/AG/NIA NIH HHS/United States ; R61AG066543//the National Institutes of Health/ ; 1RF1AG080769-01//the National Institutes of Health/ ; IIBSP-DOW-2020-151//the Departament de Salut de la Generalitat de Catalunya, Fundación Tatiana Pérez de Guzmán el Bueno/ ; H2020-SC1-BHC-2018-2020//the Horizon 2020-Research and Innovation Framework Programme from the European Union/ ; //BrightFocus/ ; //and Life Molecular Imaging/ ; 24CBIDR-1185483//the Alzheimer's Association/ ; AARG-20-678884//the Alzheimer's Association/ ; AARGD-22-972378//the Alzheimer's Association/ ; 24CBIDR-1185483//the Alzheimer's Association/ ; AARG-20-678884//the Alzheimer's Association/ ; AARGD-22-972378//the Alzheimer's Association/ ; //the Sanford J. Grossman Charitable Trust/ ; //the Brian and Tania Higgins Charitable Foundation/ ; //Carolyn and Eugene Mercy Research Gift/ ; //the Karen Strauss Cook Research Scholar Award/ ; //Alzheimer's New Jersey/ ; //the Robert J. and Claire Pasarow Foundation/ ; //the Marvin and Judith Herb Family/ ; },
mesh = {Humans ; *Alzheimer Disease/genetics/pathology ; Female ; Male ; Aged ; Autopsy ; Cross-Sectional Studies ; Brazil ; Aged, 80 and over ; *Brain/pathology ; *Apolipoprotein E4/genetics ; *Apolipoproteins E/genetics ; Genotype ; },
abstract = {INTRODUCTION: Apolipoprotein E allele 4 (APOE ε4) is the main genetic risk factor for late-onset Alzheimer's disease (AD), but most evidence comes from White populations in high-income countries. We investigated APOE and AD pathology in an ethnically diverse Brazilian autopsy cohort.

METHODS: This cross-sectional study used Biobank for Aging Studies (BAS) data. AD pathology was evaluated with Braak, Consortium to Establish a Registry for Alzheimer's Disease, and Thal criteria. APOE genotypes were obtained from blood or brain tissue. Regression models were adjusted for age, sex, race, and education; interaction with race was tested.

RESULTS: Among 1391 participants (mean age 75.1 ± 12.4 years, 50% women, 64% White), APOE ε4showed a dose response with greater AD pathological burden and higher odds of AD diagnosis, while APOE ε2/X was protective. APOE ε4/ε4 did not show full penetrance across age groups. Associations were similar in White and Black individuals.

DISCUSSION: APOE ε4was strongly associated with AD pathology, with consistent associations across racial groups.

HIGHLIGHTS: APOE ε4 increased AD neuropathological burden in Brazilians. APOE ε2/εX was protective against AD pathology. APOE ε4/ε4did not show full penetrance across age groups. Associations between APOE and AD pathology were similar by race. Large multiethnic autopsy study expands evidence beyond high-income country studies.},
}

Humans
*Alzheimer Disease/genetics/pathology
Female
Male
Aged
Autopsy
Cross-Sectional Studies
Brazil
Aged, 80 and over
*Brain/pathology
*Apolipoprotein E4/genetics
*Apolipoproteins E/genetics
Genotype

@article {pmid41268794,
year = {2025},
author = {Zhang, H and Ya, J and Liao, X and Du, X and Zhao, C and Ren, J and Qu, X},
title = {In Situ Activatable Hydrogen-Bonded Organic Framework-Based Nanozyme as NADH Peroxidase Mimic Restoring Homeostasis for Treatment of Alzheimer's Disease.},
journal = {Small (Weinheim an der Bergstrasse, Germany)},
volume = {},
number = {},
pages = {e09547},
doi = {10.1002/smll.202509547},
pmid = {41268794},
issn = {1613-6829},
support = {2022YFA1205804//National Key R&D Program of China/ ; T249526//National Natural Science Foundation of China/ ; 22437006//National Natural Science Foundation of China/ ; 22237006//National Natural Science Foundation of China/ ; },
abstract = {Nicotinamide adenine dinucleotide (NAD) serves as a vital regulator in metabolic networks, and the decrease in the level of its oxidized form, NAD+, is closely related to Alzheimer's disease (AD). However, unsatisfactory efficacy, non-targeted and imprecise treatment, along with interconnected pathogenic factors in AD, constrain the therapeutic efficacy of current AD therapeutic strategies. Herein, in lieu of complex multi-module treatments for pathogenesis, a bespoke in situ activatable hydrogen-bonded organic framework (HOF)-based nanozyme (denoted as NADH@Pre-Cu-HOF@KD8) has been constructed to modulate multiple interconnected homeostatic imbalances in AD. Benefiting from the specific organic monomers, 2,2'-bipyridine-5,5'-dicarboxylic acid, NADH@Pre-Cu-HOF@KD8 can sequester neurotoxic Cu[2+] from amyloid-β (Aβ)-Cu[2+] by competitive binding. The segregation of Cu[2+] from Aβ mitigated the generation of reactive oxygen species, Aβ toxicity, and alleviated the activation of microglia cells. Moreover, HOF-based nanozyme possessed NADH peroxidase (NPX)-like catalytic activity after binding Cu[2+], which can reduce oxidative stress and elevate compromised NAD+ levels, thereby restoring mitochondrial impairment and adenosine triphosphate (ATP) production. Spatiotemporally precise intervention is enabled through targeted delivery mediated by peptide modification and lesion-specific activation. Notably, cognitive deficits, neuropathology, and homeostatic markers in a 3xTg-AD mouse model are ameliorated upon treatment. By employing a facile HOF platform to modulate multiple interconnected pathological homeostatic imbalances in AD-copper toxicity, NAD[+] depletion, oxidative stress, and Aβ toxicity-this strategy offers a paradigm for ameliorating AD-associated homeostatic imbalances.},
}

@article {pmid41268793,
year = {2025},
author = {Morgan, A and Durkin, C and Tari, B and Squires, E and Young, S and Bauermeister, J and Bauermeister, S and Gallacher, J},
title = {Dementia Data Landscape 1. Cohorts.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21},
number = {11},
pages = {e70901},
doi = {10.1002/alz.70901},
pmid = {41268793},
issn = {1552-5279},
support = {//Alzheimer's Disease Data Enablement Fund/ ; //Gates Ventures/ ; },
mesh = {Humans ; *Dementia/epidemiology ; Cohort Studies ; *Metadata ; },
abstract = {INTRODUCTION: Understanding and maximizing complex health data is crucial for accelerating discovery, translational research, funding priorities, and improving data management. Rapid, cost-effective progress can be made by repurposing datasets. This work explores the dementia cohort landscape, identifies cohorts relevant to dementia translation, and highlights areas to strengthen health cohort infrastructure.

METHOD: PubMed was searched for publications utilizing dementia-related cohorts (1970-2024), supplemented by international dementia data platforms. A template aligned with the C-Surv data model was used to summarize administrative details and the presence of measurements across 17 themes.

RESULTS: From 4596 publications and 11 data platforms, 883 cohorts were identified (558 population and 325 clinical). Of these, 74% indicated data availability for future research, though metadata reporting varied. Cohort metadata are accessible via the landscape tool.

DISCUSSION: This work reveals extensive global dementia-related data for repurposing and identifies priority areas for improvement, including metadata transparency, data accessibility, and locations to prioritize for future research.

HIGHLIGHTS: A total of 883 cohorts were identified globally (1970 to 2024): 558 population and 325 clinical The Global South is substantially underrepresented Seventy-four percent of cohorts offer data access, but protocols and metadata quality vary widely Only 45% of cohorts were discoverable via existing data platforms The online landscape tool enables strategic discovery and reuse of dementia data.},
}

Humans
*Dementia/epidemiology
Cohort Studies
*Metadata

@article {pmid41268790,
year = {2025},
author = {Coburn, MA and Eskandari-Sedighi, G and Hasselmann, J and England, W and Shabestari, SK and Mansour, K and McQuade, A and Mgerian, MA and Chadarevian, JP and Tu, C and Silva, J and Beck, J and Keulen, Z and Spitale, RC and Davtyan, H and Blurton-Jones, M},
title = {Human microglia differentially respond to β-amyloid, tau, and combined Alzheimer's disease pathologies in vivo.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21},
number = {11},
pages = {e70930},
doi = {10.1002/alz.70930},
pmid = {41268790},
issn = {1552-5279},
support = {//Cure Alzheimer's Fund/ ; Discovery23-10//Alzheimer Society of Canada/ ; //The Larry L. Hillblom Foundation : 2024-A-023-FEL and 2025-A-175-FEL/ ; A2025007F//BrightFocus Postdoctoral Fellowship Program in Alzheimer's/ ; P30CA-062203//NIH / ; 1S10RR025496-01//NIH / ; 1S10OD010794-01//NIH / ; 1S10OD021718-01//NIH / ; 2024-A-023-FEL//NIH / ; NS082174//NIH Training Grant/ ; AG000096//NIH Training Grant/ ; //Susan Scott Foundation/ ; ADSF-21-829655-C/ALZ/Alzheimer's Association/United States ; },
mesh = {*Microglia/metabolism/pathology ; *Alzheimer Disease/pathology/metabolism ; Animals ; Humans ; Mice ; *Amyloid beta-Peptides/metabolism ; Disease Models, Animal ; *tau Proteins/metabolism ; Plaque, Amyloid/pathology/metabolism ; Mice, Transgenic ; Neurofibrillary Tangles/pathology/metabolism ; },
abstract = {INTRODUCTION: Recent studies have identified important species-dependent differences in the response of microglia to β-amyloid (Aβ) pathology. Yet, whether human microglia also interact differently with the pathognomonic combination of amyloid and tau pathologies that occur in Alzheimer's disease (AD) remains unclear.

METHODS: We generated a xenotolerant mouse model of AD that develops both plaque and tangle pathologies, transplanted stem cell-derived microglial progenitors and examined the interactions between human microglia and AD pathologies with scRNA sequencing, immunohistochemistry, and in vitro modeling.

RESULTS: The combined amyloid and tau pathologies induced robust type-I interferon and proinflammatory cytokine responses, as well as an increased adoption of a distinct "rod" morphology in human microglia. The rod morphology could be induced with type-I interferon treatment in vitro.

DISCUSSION: We provide new insights into human microglial responses to combined AD pathologies and a novel platform to investigate and manipulate human microglia in vivo.

HIGHLIGHTS: Amyloid pathology promotes the rapid development of neurofibrillary tangles and neuronal loss in a novel chimeric model of AD. Combined Alzheimer's disease pathologies lead to an expansion of disease-associated microglia (DAM) and exacerbate Interferon-responsive and cytokine/chemokine-enriched states in xenotransplanted human microglia. The combination of amyloid and tau promotes the development of a distinctive rod microglial phenotype that closely correlates with tau pathology and neurodegeneration. Rod morphology and transcriptional changes can be modeled in vitro by treatment of induced pluripotent stem cells (iPSC) -microglia with type-I interferons.},
}

*Microglia/metabolism/pathology
*Alzheimer Disease/pathology/metabolism
Animals
Humans
Mice
*Amyloid beta-Peptides/metabolism
Disease Models, Animal
*tau Proteins/metabolism
Plaque, Amyloid/pathology/metabolism
Mice, Transgenic
Neurofibrillary Tangles/pathology/metabolism

@article {pmid41268784,
year = {2025},
author = {Ghanbarian, E and Qian, T and Khorsand, B and Zheng, L and Sajjadi, SA and Grill, JD and Rabin, LA and Lipton, RB and Sperling, RA and Ezzati, A},
title = {Prognostic value of plasma glial fibrillary acidic protein in cognitively unimpaired older adults: Results from the A4 study.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21},
number = {11},
pages = {e70948},
doi = {10.1002/alz.70948},
pmid = {41268784},
issn = {1552-5279},
support = {NIA K23 AG063993/NH/NIH HHS/United States ; R01 AG080635/NH/NIH HHS/United States ; R01AG095017/NH/NIH HHS/United States ; SG-24-988292(ISAVRAD)/ALZ/Alzheimer's Association/United States ; //Cure Alzheimer's Fund/ ; },
mesh = {Humans ; *Glial Fibrillary Acidic Protein/blood ; Female ; Male ; Aged ; Biomarkers/blood ; Prognosis ; *Alzheimer Disease/blood/diagnosis ; *Cognitive Dysfunction/blood/diagnosis ; Cross-Sectional Studies ; Disease Progression ; Aged, 80 and over ; Cognition ; Neuropsychological Tests ; },
abstract = {INTRODUCTION: Plasma glial fibrillary acidic protein (GFAP), a marker of astrocytic activation, has been linked to Alzheimer's disease; however, its prognostic value in cognitively unimpaired (CU) individuals remains unclear.

METHODS: We included 949 CU older adults from the A4 preclinical AD trial and its companion LEARN cohort. Baseline plasma GFAP was measured, and associations with cognitive decline (Preclinical Alzheimer's Cognitive Composite [PACC]), Clinical Dementia Rating (CDR) progression, and imaging biomarkers were assessed over 240 weeks.

RESULTS: Baseline plasma GFAP was higher in females and in A4 (amyloid-positive) versus LEARN (amyloid-negative) participants. Cross-sectionally, elevated GFAP was associated with lower cognitive performance and greater amyloid burden. Longitudinally, higher GFAP predicted faster cognitive decline, increased risk of CDR progression, AD-related cortical atrophy, and amyloid conversion, with stronger effects in females.

DISCUSSION: Plasma GFAP is a prognostic biomarker in CU older adults, predicting cognitive and biological changes, with stronger associations observed in females, highlighting a possible sex-specific vulnerability.

HIGHLIGHTS: Elevated plasma glial fibrillary acidic protein (GFAP) predicted faster cognitive decline measured by Preclinical Alzheimer's Cognitive Composite (PACC). GFAP was associated with increased risk of progression to mild cognitive impairment. GFAP predicted conversion to amyloid positivity in amyloid-negative subjects. Higher baseline GFAP was associated with cortical atrophy in Alzheimer's disease (AD) -signature areas. Associations of GFAP with cognition and AD biomarkers were stronger in females.},
}

Humans
*Glial Fibrillary Acidic Protein/blood
Female
Male
Aged
Biomarkers/blood
Prognosis
*Alzheimer Disease/blood/diagnosis
*Cognitive Dysfunction/blood/diagnosis
Cross-Sectional Studies
Disease Progression
Aged, 80 and over
Cognition
Neuropsychological Tests

@article {pmid41268768,
year = {2025},
author = {Dacey, R and Hou, L and Gurnani, A and Han, X and Paller-Moore, MR and Chung, J and Durape, S and Rosenthaler, M and Uretsky, M and Abdolmohammadi, B and Lee, AJ and Brickman, AM and Hohman, TJ and Cuccaro, ML and Bennett, DA and Crane, PK and Kamboh, MI and Kukull, WA and Jun, G and Stein, TD and McKee, AC and Haines, JL and Pericak-Vance, MA and Wang, LS and Schellenberg, GD and Mayeux, R and Lunetta, KL and Farrer, LA and Mez, J},
title = {Alzheimer's disease multi-ancestry genome-wide interaction and stratified study with smoking.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21},
number = {11},
pages = {e70922},
doi = {10.1002/alz.70922},
pmid = {41268768},
issn = {1552-5279},
support = {U24-AG021886/AG/NIA NIH HHS/United States ; U01-AG016976/AG/NIA NIH HHS/United States ; U24-AG041689/AG/NIA NIH HHS/United States ; U24-AG074855/AG/NIA NIH HHS/United States ; U01-AG068057/AG/NIA NIH HHS/United States ; R01-AG059716/AG/NIA NIH HHS/United States ; U19-AG068753/AG/NIA NIH HHS/United States ; R01-AG048927/AG/NIA NIH HHS/United States ; U54-AG052427/AG/NIA NIH HHS/United States ; U01-AG058654/AG/NIA NIH HHS/United States ; U01-AG032984/AG/NIA NIH HHS/United States ; RF1-AG057519/AG/NIA NIH HHS/United States ; U01-AG062602/AG/NIA NIH HHS/United States ; P30-AG072978/AG/NIA NIH HHS/United States ; U24-AG074855/AG/NIA NIH HHS/United States ; U01-AG068057/AG/NIA NIH HHS/United States ; R01-AG059716/AG/NIA NIH HHS/United States ; U19-AG066567/AG/NIA NIH HHS/United States ; P30-AG066468/AG/NIA NIH HHS/United States ; P30-AG10161/AG/NIA NIH HHS/United States ; P30-AG72975/AG/NIA NIH HHS/United States ; R01-AG17917/AG/NIA NIH HHS/United States ; R01-AG015819/AG/NIA NIH HHS/United States ; U01-AG072572/AG/NIA NIH HHS/United States ; U01-AG046152/AG/NIA NIH HHS/United States ; U01-AG046152/AG/NIA NIH HHS/United States ; },
mesh = {Humans ; *Alzheimer Disease/genetics ; *Genome-Wide Association Study ; Polymorphism, Single Nucleotide/genetics ; Male ; Female ; *Smoking/genetics ; White People/genetics ; Aged ; *Gene-Environment Interaction ; Genetic Predisposition to Disease ; Quantitative Trait Loci ; Middle Aged ; Brain/metabolism ; Black or African American/genetics ; White ; },
abstract = {INTRODUCTION: Alzheimer's disease (AD) has genetic and environmental risk factors, including cigarette smoking. Gene-environment interactions may explain AD missing heritability.

METHODS: Lifetime smoking data from 22,032 European ancestry and 3126 African ancestry participants from the Alzheimer's Disease Genetic Consortium and the Framingham Heart Study were used to conduct genome-wide single nucleotide polymorphism (SNP)-by-smoking interaction and smoking-stratified association studies. For top-ranked loci, brain-derived bulk and single nuclei RNA-sequencing were used for differential expression and colocalization analyses.

RESULTS: Among smokers only, there was a genome-wide significant association in the APAF1/ANKS1B region (rs12368451; odds ratio = 1.19, 95% confidence interval: [1.12, 1.27], p = 3.0 × 10[-8]). Rs12368451 had expression quantitative trait locus (eQTL) activity that differed by smoking status and brain cell types but showed the most significant posterior probability (PP = 0.15) for being causal via ANKS1B expression in oligodendrocytes among smokers.

DISCUSSION: Potentially causal in smokers via eQTL activity, the top SNP may alter expression of ANKS1B, which encodes amyloid beta precursor protein intracellular domain associated-1, known to regulate amyloid beta plaques.

HIGHLIGHTS: Among smokers only, a novel chromosome 12 single nucleotide polymorphism (SNP) near ANKS1B was associated with Alzheimer's disease. Evidence came from European and African ancestry cohorts. RNA-sequencing analyses implicated the top SNP as causal via ANKS1B expression in oligodendrocytes. A genome-wide African ancestry-specific significant SNP-smoking interaction was observed on chromosome 6 in SLC22A23.},
}

Humans
*Alzheimer Disease/genetics
*Genome-Wide Association Study
Polymorphism, Single Nucleotide/genetics
Male
Female
*Smoking/genetics
White People/genetics
Aged
*Gene-Environment Interaction
Genetic Predisposition to Disease
Quantitative Trait Loci
Middle Aged
Brain/metabolism
Black or African American/genetics
White

@article {pmid41268764,
year = {2025},
author = {Valipour, MA and Abdollahi, E and Yadegar, A and Morad, H and Sheibani, M and Noori, M and Valipour, M},
title = {Therapeutic Potential of Trolox and Its Synthetic Derivatives as Multifunctional Bioactive Molecules in Periodontal Disease Management.},
journal = {Drug development research},
volume = {86},
number = {8},
pages = {e70200},
doi = {10.1002/ddr.70200},
pmid = {41268764},
issn = {1098-2299},
support = {//The authors received no specific funding for this work./ ; },
mesh = {Humans ; *Periodontal Diseases/drug therapy ; *Chromans/therapeutic use/pharmacology/chemistry ; *Antioxidants/therapeutic use/pharmacology/chemistry ; Animals ; Anti-Inflammatory Agents/therapeutic use/pharmacology ; Oxidative Stress/drug effects ; },
abstract = {Periodontal disease is a chronic inflammatory problem that has destructive effects on the tooth-supporting tissues. This disease affects a large portion of the population, influencing overall health and quality of life, and significant socioeconomic burden. Therefore, efforts to more effectively manage the problems caused by this disease are a necessity. This review describes the therapeutic potential of Trolox (a water-soluble analogue of vitamin E) and its modified derivatives as potential candidates for managing periodontal disease, highlighting their multifaceted pharmacological properties. Unlike the lipophilic molecule vitamin E, Trolox can be formulated into aqueous solutions, gels, mouthwashes, or rinses, ensuring optimal bioavailability at sites of inflammation and infection in the oral cavity. This compound can also help treat periodontal disease by combating oxidative stress, where its antioxidant properties neutralize harmful reactive oxygen species (ROS), reducing tissue damage and bone loss caused by undesired conditions such as bacterial imbalance. In addition to antioxidant and anti-inflammatory properties, Trolox and its derivatives exhibit various pharmacological activities against diabetes, Alzheimer's disease, Plasmodium falciparum malaria infection, and periodontopathogens, all of which are associated with the development of periodontal disease. In conclusion, this review suggests that Trolox and some of its derivatives with favorable activity/toxicity profiles have significant potential to be considered as new drug candidates for combating periodontal diseases.},
}

Humans
*Periodontal Diseases/drug therapy
*Chromans/therapeutic use/pharmacology/chemistry
*Antioxidants/therapeutic use/pharmacology/chemistry
Animals
Anti-Inflammatory Agents/therapeutic use/pharmacology
Oxidative Stress/drug effects

@article {pmid41268707,
year = {2025},
author = {Xu, K and Wang, L and Lv, T and Jin, C and Wu, Q and Zhou, Y and Xu, G and Duan, Z and Luo, K and Yang, J},
title = {Nanomedicines Against Mitochondrial Dysfunction-Induced Metabolic Diseases.},
journal = {Advanced science (Weinheim, Baden-Wurttemberg, Germany)},
volume = {},
number = {},
pages = {e14522},
doi = {10.1002/advs.202514522},
pmid = {41268707},
issn = {2198-3844},
support = {2023YFB3810004//National Key Research and Development Program of China/ ; 32271445//National Natural Science Foundation of China/ ; 52203182//National Natural Science Foundation of China/ ; 82300663//National Natural Science Foundation of China/ ; 82370624//National Natural Science Foundation of China/ ; 23ZDYF2182//the Key R&D Projects of Sichuan Province/ ; ZYGD23026//1·3·5 project for disciplines of excellence, West China Hospital, Sichuan University/ ; ZYGD24002//1·3·5 project for disciplines of excellence, West China Hospital, Sichuan University/ ; },
abstract = {Mitochondrial dysfunction is a common pathology for metabolic diseases such as obesity, diabetes, non-alcoholic fatty liver disease, atherosclerosis, Alzheimer's disease (AD), and Parkinson's disease (PD). Nanomedicines provide a revolutionary strategy for mitochondrial function repair. They can realize targeted delivery, responsive release, and integration of multimodal therapies through nanotechnology and engineering and overcome limitations of traditional therapeutic methods, such as insufficient targeting, low bioavailability, and toxic side effects. In this article, the pathological characteristics of mitochondria are first introduced, and the relationship between mitochondrial dysfunction and metabolic diseases are illustrated. Structural features and design strategies of nanomedicines targeting mitochondrial dysfunction are summarized, with particular elaboration on targeting strategies and response mechanisms for diseased organs and subcellular organelles such as the liver, adipose tissue, atherosclerotic plaques, the brain, and mitochondria. The application and clinical translation of nanomedicines in obesity, atherosclerosis, diabetes, non-alcoholic fatty liver disease (NAFLD), and brain metabolic disorders are detailed. This article is concluded with a summary and outlook of the current research status, challenges, and future development directions.},
}

@article {pmid41268687,
year = {2025},
author = {Chen, J and Liu, B and Yao, X and Yang, X and Sun, J and Yi, J and Xue, F and Zhang, J and Shen, Y and Chen, B and Sun, H},
title = {AMPK/SIRT1/PGC-1α Signaling Pathway: Molecular Mechanisms and Targeted Strategies From Energy Homeostasis Regulation to Disease Therapy.},
journal = {CNS neuroscience & therapeutics},
volume = {31},
number = {11},
pages = {e70657},
doi = {10.1111/cns.70657},
pmid = {41268687},
issn = {1755-5949},
support = {32130060//National Natural Science Foundation of China/ ; 82401633//National Natural Science Foundation of China/ ; BK20232023//Natural Science Foundation of Jiangsu Province/ ; 24KJA310007//Natural Science Research Projects in Universities of Jiangsu Province/ ; 24KJB310013//Natural Science Research Projects in Universities of Jiangsu Province/ ; SYW2024048//Suzhou Science and Technology Development Program/ ; },
mesh = {Humans ; *Sirtuin 1/metabolism ; *Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha/metabolism ; Animals ; *Signal Transduction/physiology ; *AMP-Activated Protein Kinases/metabolism ; *Homeostasis/physiology ; *Energy Metabolism/physiology ; },
abstract = {BACKGROUND: The AMPK/SIRT1/PGC-1α pathway serves as a central regulator of cellular energy homeostasis, coordinating metabolic stress responses, epigenetic modifications, and transcriptional programs. Its dysfunction is implicated in the pathogenesis of a wide spectrum of complex modern diseases, spanning neurodegeneration, metabolic syndromes, and chronic inflammatory conditions. This review examines the pathway's role as an integrative hub and its potential as a therapeutic target.

METHODS: We synthesize current mechanistic evidence from molecular, cellular, and preclinical studies to elucidate the pathway's operational logic and the consequences of its dysregulation. The analysis is structured around key disease paradigms-including Alzheimer's disease, Parkinson's disease, diabetes, cardiovascular injury, stroke, and chronic kidney disease-to dissect its tissue-specific pathophysiological impacts.

RESULTS: The AMPK/SIRT1/PGC-1α axis operates through a core positive feedback loop: AMPK activation elevates NAD+, thereby activating SIRT1, which in turn deacetylates and activates PGC-1α to drive mitochondrial biogenesis and function, further reinforcing SIRT1 activity. Disruption of this cascade manifests in disease-specific mechanisms: promoting Aβ production via BACE1/γ-secretase in Alzheimer's; impairing α-synuclein clearance in Parkinson's; disrupting GLUT4 translocation and insulin signaling in diabetes; exacerbating oxidative damage and mitochondrial dysfunction in cardiovascular and neuronal injury; and accelerating fibrosis and sustained inflammation in renal and pulmonary diseases via NLRP3 and TGF-β/Smad3 signaling.

CONCLUSIONS: The AMPK/SIRT1/PGC-1α pathway represents a cornerstone target at the intersection of metabolism, aging, and disease. Current therapeutic strategies-including pharmacological activators (e.g., metformin, SRT1720), natural compounds (e.g., resveratrol), lifestyle interventions (e.g., exercise, caloric restriction), and emerging technologies (e.g., gene editing, exosomal miRNAs)-offer multidimensional avenues for intervention. Future research must prioritize elucidating tissue-specific regulatory mechanisms, such as AMPK isoform diversity and PGC-1α interactome dynamics, to enable precision therapeutics and successful clinical translation for a range of complex disorders.},
}

Humans
*Sirtuin 1/metabolism
*Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha/metabolism
Animals
*Signal Transduction/physiology
*AMP-Activated Protein Kinases/metabolism
*Homeostasis/physiology
*Energy Metabolism/physiology

@article {pmid41268645,
year = {2025},
author = {Kang, K and Wu, Z and Qian, X and Song, X and Zhu, H},
title = {Federated double machine learning for high-dimensional semiparametric models.},
journal = {Biometrics},
volume = {81},
number = {4},
pages = {},
doi = {10.1093/biomtc/ujaf150},
pmid = {41268645},
issn = {1541-0420},
support = {12301368//National Natural Science Foundation of China/ ; 2024A04J4505//Guangzhou Science and Technology Programme/ ; },
mesh = {*Machine Learning ; Humans ; *Models, Statistical ; Alzheimer Disease/diagnostic imaging ; Computer Simulation ; Neuroimaging/statistics & numerical data ; Biometry/methods ; Multicenter Studies as Topic/statistics & numerical data ; },
abstract = {Federated learning enables the training of a global model while keeping data localized; however, current methods face challenges with high-dimensional semiparametric models that involve complex nuisance parameters. This paper proposes a federated double machine learning framework designed to address high-dimensional nuisance parameters of semiparametric models in multicenter studies. Our approach leverages double machine learning (Chernozhukov et al., 2018a) to estimate center-specific parameters, extends the surrogate efficient score method within a Neyman-orthogonal framework, and applies density ratio tilting to create a federated estimator that combines local individual-level data with summary statistics from other centers. This methodology mitigates regularization bias and overfitting in high-dimensional nuisance parameter estimation. We establish the estimator's limiting distribution under minimal assumptions, validate its performance through extensive simulations, and demonstrate its effectiveness in analyzing multiphase data from the Alzheimer's Disease Neuroimaging Initiative study.},
}

*Machine Learning
Humans
*Models, Statistical
Alzheimer Disease/diagnostic imaging
Computer Simulation
Neuroimaging/statistics & numerical data
Biometry/methods
Multicenter Studies as Topic/statistics & numerical data

@article {pmid41268620,
year = {2025},
author = {Sun, L and Wang, J and Zhang, L},
title = {The Role of Sphingomyelin Synthase 2 in Lipid Metabolism and Its Implications in Diseases.},
journal = {Cell biology international},
volume = {},
number = {},
pages = {},
doi = {10.1002/cbin.70103},
pmid = {41268620},
issn = {1095-8355},
support = {//This study was supported by National Natural Science Foundation of China (82272306), Taishan Scholars Program (tstp20221142), and Joint Innovation Team for Clinical & Basic Research [202409]./ ; },
abstract = {Sphingomyelin synthase 2 (SMS2) is a crucial enzyme predominantly localized to the plasma membrane, playing an essential role in sphingomyelin metabolism and signaling. SMS2 catalyzes the final step in the biosynthesis of sphingomyelin by transferring phosphocholine from phosphatidylcholine to ceramide, resulting in the production of sphingomyelin and diacylglycerol. This enzymatic activity dynamically regulates the intracellular levels of ceramide, diacylglycerol, and phosphatidylcholine, thereby influencing several critical cellular processes. SMS2 is integral to multiple signaling pathways, including TGF-β/Smad, NF-κB, and CXCL12/CXCR4, which are involved in cancer progression and platelet activation. SMS2 displays versatile enzymatic activities, including phospholipase C activity and ceramide phosphoethanolamine synthesis. Dysregulation of SMS2 is associated with various pathological conditions, such as skin barrier dysfunction, skeletal disorders, inflammatory diseases, and different types of cancer. Targeting SMS2 through inhibition or modulation demonstrates therapeutic potential in treating multiple conditions, including pancreatic cancer, Alzheimer's disease, and atherosclerosis, by impacting tumor growth dynamics and cellular migration. Given its multifaceted role in diverse pathological processes and its promise as a therapeutic target, further research on SMS2 is essential for the development of innovative treatment strategies aimed at cancer therapy, inflammation regulation, and overcoming drug resistance.},
}

@article {pmid41268476,
year = {2025},
author = {Villaman, C and Cartas-Espinel, I and Saez, M and Martin, AJM},
title = {Gaining insights into Alzheimer's disease by predicting chromatin spatial organization.},
journal = {Bioinformatics advances},
volume = {5},
number = {1},
pages = {vbaf268},
pmid = {41268476},
issn = {2635-0041},
abstract = {MOTIVATION: CTCF is a conserved protein involved in the establishment and maintenance of topologically associating domains (TADs) and loops. Alzheimer's disease (AD) represents the most common form of dementia, affecting over 50 million elderly individuals. Epigenetic alterations are a hallmark of AD, and epigenetic disruptions are able to affect CTCF binding and looping. Understanding the dynamics of CTCF loops behind AD may lead to new, undiscovered contributions of CTCF to the etiology of AD. To understand the dynamics behind CTCF loops, we developed a CTCF loop predictor using different genomic and epigenomic features, such as CTCF motif information, CTCF protein binding information, and different histone marks.

RESULTS: We obtained F-scores of over 0.9 in GM12878 and K562 cell lines. We reported the importance of each feature in classification, and compared the results with other loop predictors. After testing the predictor, we predicted loops in control and AD data, reported a score of loop disruption and selected the top disrupted loops on AD which were all previously linked with AD in bibliography. Our study contributes to a better understanding of the role of CTCF binding and CTCF loops in gene regulation, and highlights new clues about CTCF in the etiology and development of AD.

The method can be found in https://github.com/networkbiolab/jalpy.},
}

@article {pmid41268324,
year = {2025},
author = {Thakur, DK and Padole, S and Sarkar, T and Arumugam, S and Chattopadhyay, S},
title = {Liquid-Liquid Phase Separation: Mechanisms, Roles, and Implications in Cellular Function and Disease.},
journal = {FASEB bioAdvances},
volume = {7},
number = {11},
pages = {e70054},
pmid = {41268324},
issn = {2573-9832},
abstract = {Liquid-liquid phase separation is a basic biophysical process that creates essential membraneless organelles that support different cellular activities, including chromatin organization and gene expression. The malfunction of liquid-liquid phase separation (LLPS) plays a critical role in numerous diseases, such as neurodegenerative disorders, including amyotrophic lateral sclerosis (ALS) and Alzheimer's disease (AD), which involve TDP-43 and Tau, various cancers that utilize SPOP and YAP/TAZ proteins, and viral infections where pathogens use LLPS to replicate and avoid immune detection. This review brings together the fast-growing knowledge about LLPS across multiple scientific fields. The paper examines the physiological functions of LLPS along with its disease pathogenesis mechanisms and presents various experimental techniques (e.g., advanced microscopy, FRAP, FCS) for its investigation. It introduces new therapeutic approaches such as PTM modulation, small molecules like 1,6-hexanediol and Lipoamide, and advanced genetic tools including CRISPR and PROTACs like PSETAC, which also explores diagnostic applications. The thorough integration of knowledge presented here is essential to connect separate scientific findings while propelling research forward and turning LLPS discoveries into new biomedical developments.},
}

@article {pmid41268269,
year = {2025},
author = {Benavides, ED and Fuentes, MDM and Bell, L and Benedicenti, L and Galban, EM and Niggel, JK and Murgiano, L and Lenz, JA and Miska, JM and Amankulor, NM and Panek, WK},
title = {The role of regulatory T cells in central nervous system diseases in dogs: fighting with a double-edged sword toward translational discoveries.},
journal = {American journal of translational research},
volume = {17},
number = {10},
pages = {8222-8242},
pmid = {41268269},
issn = {1943-8141},
abstract = {Regulatory T cells (Tregs) are a recently discovered subpopulation of immunosuppressive T cells critical for sustaining immune homeostasis and self-tolerance. Depending on the disease, Tregs can alter immune responses by exerting their effects on various immunological functions. Evidence reveals that altered Treg homeostasis plays an important role in the development and progression of several central nervous system (CNS) diseases in humans. There have been positive outcomes in trials aimed at restoring Treg balance, but their clinical success has been limited. This could partly be due to a lack of an animal model to recapitulate the complex immune alterations that occur as the disease progresses. Therefore, there is a need for naturally occurring, immune-competent disease models to serve as the next critical step in translating therapy from murine models to human clinical trials. Several CNS diseases have canine analogs due to high inter-species homology of molecular signatures and clinicopathologic features. Human multiple sclerosis, Alzheimer's disease, glioblastoma, and meningioma parallel canine granulomatous meningoencephalomyelitis (GME), canine cognitive dysfunction (CCD), high-grade glioma (HGG), and canine meningioma, respectively. In addition, pet dogs share the same living environment and therefore may offer a compelling model faithfully recapitulating these diseases. This review discusses the current knowledge of Treg homeostasis and dysregulation mechanisms within canine CNS diseases, their analogous diseases in humans, and the ongoing clinical trials aimed at restoring normal Treg function. Collectively, comparative translational research investigating Treg homeostasis is needed to bridge well-designed pre-clinical canine studies with early-phase human clinical trials, ultimately benefiting the health of both species.},
}

@article {pmid41268264,
year = {2025},
author = {Chen, J and Zhao, J and Fan, Y and Jin, Y and Mi, R and Wang, H and Yu, S and Feng, X and Zhang, Y and Ren, G},
title = {Predictive value of beta amyloid, phosphorylated Tau, neurofilament light chain, and glial fibrillary acidic protein for depression in Alzheimer's disease.},
journal = {American journal of translational research},
volume = {17},
number = {10},
pages = {7789-7802},
pmid = {41268264},
issn = {1943-8141},
abstract = {OBJECTIVES: To investigate differences in biochemical markers and their association with depressive symptoms in patients with Alzheimer's disease (AD) with and without concurrent depression.

METHODS: In this retrospective case-control study, 329 AD patients admitted to Beijing Panjiayuan TCM-Western Integrated Hospital between May 2019 and May 2022 were included. Patients were categorized into a comorbid depression group (n=167) and a non-depression group (n=162) based on Cornell Scale for Depression in Dementia (CSDD) scores. Biochemical markers, including β-amyloid proteins (Aβ1-42, Aβ1-40), phosphorylated Tau proteins (p-Tau181, p-Tau217), neurofilament light chain protein (NfL), glial fibrillary acidic protein (GFAP), and inflammatory cytokines, were measured and statistically analyzed.

RESULTS: High-density lipoprotein cholesterol (HDL-C) was significantly lower in the comorbid depression group (P<0.001). Levels of Aβ1-42 (P=0.012), Aβ1-40 (P=0.006), p-Tau181 (P=0.003), p-Tau217 (P=0.003), NfL (P<0.001), and GFAP (P=0.008) were significantly elevated in the depression group compared to the non-depression group. Additionally, interleukin-10 (P=0.004) and interleukin-6 (P=0.047) levels were higher, while interleukin-1β (P<0.001) was lower in the comorbid depression group. Receiver operating characteristic curve identified HDL-C (area under the curve [AUC]=0.602), p-Tau217 (AUC=0.595), NfL (AUC=0.692), GFAP (AUC=0.580), and IL-1β (AUC=0.600) as significant predictors of depression severity.

CONCLUSIONS: Specific biochemical markers, including HDL-C, Aβ42/40, p-Tau217, NfL, GFAP, and IL-1β, are independently associated with depression in AD patients. A combined biomarker model may improve prediction of comorbid depression in AD and provide guidance for personalized treatment.},
}

@article {pmid41268178,
year = {2025},
author = {Zhu, N and Altuna, M and Arranz, J and Rodriguez-Baz, Í and Sanchez-Saudinós, MB and Videla, L and Valldeneu, S and Carrera-Vega, M and Romero, S and Fortea, J and Lleó, A and Giménez, S and Alcolea, D},
title = {Sleep-related changes in astrocytic biomarkers are modulated by APOE ε4 genotype in cognitively unimpaired adults.},
journal = {Brain communications},
volume = {7},
number = {6},
pages = {fcaf437},
pmid = {41268178},
issn = {2632-1297},
abstract = {Astrocytes are key regulators of sleep and neuroinflammatory responses. However, the relationship between objective sleep parameters and astrocytic fluid biomarkers in cognitively unimpaired individuals remains unclear. We examined how sleep architecture relates to astrocytic, neuroaxonal and Alzheimer's disease-related fluid biomarkers in cognitively unimpaired adults and whether age, sex and APOE ε4 moderate these associations. This cross-sectional study included 51 cognitively unimpaired participants from the Sant Pau Initiative on Neurodegeneration cohort. One-night in-lab polysomnography was used to quantify sleep architecture, fragmentation, slow-wave activity and respiratory parameters. CSF biomarkers included glial fibrillary acidic protein (GFAP), chitinase-like-3 protein 1 (YKL-40), Aβ42, Aβ40, pTau181 and tTau; plasma biomarkers included GFAP and neurofilament light chain (NfL). Associations were analysed using Spearman correlations, multiple linear regression, and moderation models, adjusting for age, sex, body mass index, APOE ε4 status and sleep apnoea. Lighter and more fragmented sleep, characterized by longer N1 duration, increased wake after sleep onset, frequent stage transitions and elevated cortical arousal, was associated with higher CSF YKL-40, Aβ40, pTau181 and tTau (ρ = 0.32-0.62, all P < 0.05). In contrast, deeper, more consolidated sleep, indicated by longer total time of sleep, greater N3 duration and higher slow-wave activity, was associated with lower CSF GFAP and YKL-40 (ρ = -0.35 to -0.44, all P < 0.05). These associations remained significant in adjusted regression models. Plasma GFAP and NfL exhibited an inverse profile, with positive associations with deeper sleep (β: 0.16-0.18, P < 0.05) and negative associations with lighter sleep stages (β: -0.23 to -0.29, P < 0.01). Rapid eye movement (REM) sleep was also associated with astrocytic fluid biomarkers, with negative correlations for CSF and plasma GFAP (ρ = -0.49 and ρ = -0.28, respectively, all P < 0.05), while in regression models, REM duration remained a negative predictor of plasma GFAP (β = -0.23, P = 0.003) and a positive predictor of CSF YKL-40 (β = 0.12, P = 0.037). Notably, APOE ε4 consistently moderated associations between sleep and CSF YKL-40 and GFAP, while age and sex influenced plasma GFAP and CSF YKL-40, respectively (all P < 0.05). In cognitively unimpaired adults, sleep architecture is differentially associated with central and peripheral biomarkers of astrocytic activation, neuroaxonal integrity and Alzheimer's disease-related proteins. These findings support the importance of considering sleep as a key factor in the early pathophysiology of neurodegenerative disease.},
}

@article {pmid41268140,
year = {2025},
author = {Doza, A and Lin, P and Rodriguez, GM and Cigolle, C and Mahmoudi, E},
title = {Identifying Likely Incidents of Traumatic Spinal Cord Injury and Elevated Risk of Alzheimer's Disease and Related Dementia: Health Care Cost Institute Data.},
journal = {Topics in spinal cord injury rehabilitation},
volume = {31},
number = {4},
pages = {188-198},
pmid = {41268140},
issn = {1945-5763},
mesh = {Humans ; *Alzheimer Disease/epidemiology/etiology ; Male ; Female ; *Spinal Cord Injuries/epidemiology/complications ; Case-Control Studies ; Middle Aged ; *Dementia/epidemiology/etiology ; Aged ; Longitudinal Studies ; Adult ; Incidence ; Risk Factors ; },
abstract = {OBJECTIVES: To examine the association between incident traumatic spinal cord injury (TSCI) and the risk of Alzheimer's disease and related dementia (ADRD).

METHODS: This is a longitudinal case-control study. We used 2012-2019 commercial insurance claims data from the Health Care Cost Institute (HCCI) and applied semi-parametric Cox survival models to compute hazard ratio (HR) for ADRD diagnosis comparing cases with incident TSCI with their controls without TSCI, adjusting for age, sex, a set of comorbid conditions, and any use of 6 classes of prescription medications. To reduce potential selection bias, we conducted a probability matching between cases (n = 251) and controls (n = 2480) using a 1:10 ratio without replacement based on age, sex, diagnosed chronic conditions, and index year of the TSCI diagnosis.

RESULTS: Cases with incident TSCI had a higher HR of 2.39 (95% CI 1.19-4.80) for ADRD compared to their matched controls. Our sensitivity analysis of removing cases with traumatic brain injury at the index TSCI date or afterward did not change the results (HR 2.21, 95% CI 1.06-4.62).

CONCLUSION: Incident TSCI is associated with an increased risk of ADRD. Clinical guidelines for people with TSCI should consider the early and regular use of cognitive screening.},
}

Humans
*Alzheimer Disease/epidemiology/etiology
Male
Female
*Spinal Cord Injuries/epidemiology/complications
Case-Control Studies
Middle Aged
*Dementia/epidemiology/etiology
Aged
Longitudinal Studies
Adult
Incidence
Risk Factors

@article {pmid41268048,
year = {2025},
author = {Moczygemba, W and Bradley, D and Carmona, R and Celano, V and Farley, L and Valverde, S and Sampley, A and Stratton, L},
title = {Perspectives on meaningful dementia treatment and care from those with lived experience.},
journal = {Alzheimer's & dementia (New York, N. Y.)},
volume = {11},
number = {4},
pages = {e70175},
doi = {10.1002/trc2.70175},
pmid = {41268048},
issn = {2352-8737},
abstract = {UNLABELLED: The ongoing conversations surrounding the importance of minimal clinically important differences and descriptions of meaningful impacts must include the voices of those living with Alzheimer's disease and related dementias. To provide this perspective, members of the Alzheimer's Association Early Stage Advisory Group were asked to describe what matters most to them, their experiences with treatment, how they define meaningful care, and what would provide them with feelings of progress and hope. Responses offer differing yet complementary definitions of a quality life, ways in which clinicians and providers can recognize and support the person behind the diagnosis, and how participating in clinical trials can bring hope - both now and for the future. By centering on the lived experiences and perspectives of those people living with dementia, this article provides insight for those seeking to develop novel treatments and provide care and support, both now and in the future.

HIGHLIGHTS: Maintaining independence, purposeful living, and social connection are among what matter most to those living with dementia.Meaningful treatment and care are person-centered and responsive to the needs and wants of the person living with dementia.Participating in clinical trials can have meaningful physical, cognitive, and psychosocial impacts for those living with dementia.},
}

@article {pmid41267917,
year = {2025},
author = {Kim, S and Jang, EH and Lee, S},
title = {Effects of the MIND Diet on the Cognitive Function of Older Adults: A Systematic Review.},
journal = {Clinical nutrition research},
volume = {14},
number = {4},
pages = {318-328},
pmid = {41267917},
issn = {2287-3732},
abstract = {The Mediterranean-DASH Intervention for Neurodegenerative Delay (MIND) diet is a brain-focused dietary pattern designed to prevent cognitive decline in older adults. This systematic review, conducted in accordance with Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines, aimed to examine the association between the MIND diet and cognitive function in older adults. Relevant studies published between 2015 and 2024 were identified through comprehensive searches of PubMed and the Cochrane Library using keywords including "MIND diet," "cognitive performance," and "older adults." From a total of 138 records screened, 11 studies met the inclusion criteria after excluding reviews, meta-analyses, editorials, and those incorporating other lifestyle interventions such as physical activity or education. These studies included 7 prospective cohort studies, 2 cross-sectional studies, 1 randomized controlled trial (RCT), and 1 case-control study, comprising a total of 17,201 participants aged 57-91 years. Across studies, at least 57% of participants were women, and in the 5 studies reporting race, more than 75% were White. Dietary intake and MIND adherence were assessed primarily via food frequency questionnaires, while cognitive outcomes were evaluated using validated instruments including the Montreal Cognitive Assessment, global cognition scores, Consortium to Establish a Registry for Alzheimer's Disease tests, and magnetic resonance imaging. Six cohort and two cross-sectional studies reported significant associations between higher MIND adherence and better cognitive outcomes. One cohort study and the single RCT showed no effect. Excluding 2 studies with short durations (≤ 3 years), the remaining nine studies suggest consistent cognitive benefits of MIND adherence. Future studies should include systematic reviews and large-scale RCTs focusing on Asian populations.},
}

@article {pmid41267905,
year = {2025},
author = {Valdevila Figueira, JA and Ramírez, A and Yambay-Bautista, XR and Carvajal Parra, ID and Valdevila Santiestevan, R and Altamirano Cárdenas, LF and Pico Cucalón, MJ and Rodas, JA},
title = {Epidemiology of dementia in an Ecuadorian mental health institution.},
journal = {Journal of Alzheimer's disease reports},
volume = {9},
number = {},
pages = {25424823251396049},
pmid = {41267905},
issn = {2542-4823},
abstract = {BACKGROUND: This study examines the prevalence and incidence of dementia in Ecuador, with a focus on understanding demographic and social factors associated with increased risk. Data were obtained from the Institute of Neurosciences of Guayaquil, covering patient records from 2010 to 2022.

OBJECTIVE: The purpose was to identify prevalence trends and key risk factors to inform targeted prevention and early intervention efforts in high-risk groups.

METHODS: This observational, correlational study analyzed patient data to estimate dementia prevalence and incidence. Statistical analyses included descriptive statistics to calculate overall and age-specific prevalence rates, while incidence was calculated per 1000 person-years. Correlations and chi-square analyses were used to evaluate associations between dementia and potential risk factors, including age, gender, education level, and marital status.

RESULTS: The overall prevalence of dementia was 3.1%, with higher rates among women (1.8%) compared to men (1.3%). Dementia incidence was calculated at 2.4 per 1000 person-years. Prevalence increased significantly with age, from 1.2% in individuals aged 65-69 to 54.8% in those aged 95 and older. Advanced age, female gender, lower education levels, and lack of a marital partner were associated with higher dementia prevalence.

CONCLUSIONS: These findings highlight a rising dementia prevalence in Ecuador, particularly among women and older individuals, with social and educational factors contributing to increased risk. The results underscore the need for tailored dementia prevention and early intervention strategies, especially as prevalence rates continue to rise across Latin America.},
}

@article {pmid41267904,
year = {2025},
author = {Zhao, F and Li, Y and Yi, C and Li, X and Huang, G and Chen, X and Li, Y and Zhang, J},
title = {Global, regional, and national burdens of early-onset Alzheimer's disease and other dementias in women, 1990 to 2021.},
journal = {Journal of Alzheimer's disease reports},
volume = {9},
number = {},
pages = {25424823251395223},
pmid = {41267904},
issn = {2542-4823},
abstract = {BACKGROUND: Alzheimer's disease and other dementias disproportionally impacts women. Novel treatment makes understanding of early-onset cases unprecedentedly important.

OBJECTIVE: We aimed to examine Alzheimer's disease and other dementias incidence, DALYs, trends, and risk factors among women aged under 65 years from 1990 to 2021.

METHODS: Using Global Burden of Diseases Study, we estimated the trend of Alzheimer's diseases and other dementias age-standardized incidence and disability-adjusted life-years (DALYs) among women aged under 65 years by social development index (SDI) worldwide during 1990 to 2021.

RESULTS: Globally, in 2021 there were 4.3 million prevalent cases among middle-aged women, with the incident cases doubled from 0.4 million to 0.8 million during 1990-2021. The largest increases in incidence and DALYs were found in high-middle SDI countries (0.27%/year) and low-middle SDI countries (0.19%/year), respectively. The incidence rate doubled once with every five years of age increase. The two contributors, which were high body mass index and high fasting plasma glucose, rapidly grew from 1990 to 2021.

CONCLUSIONS: The substantial increase of early-onset Alzheimer's disease and other dementias among middle-aged women requires attention, especially targeted at the increasing reversible lifestyle risk factors.},
}

@article {pmid41267903,
year = {2025},
author = {Bergamino, M and Nelson, MR and Keeling, E and Stokes, AM and , },
title = {Assessment of microstructural changes in white matter hyperintensities in aging and mild cognitive impairment revealed by advanced diffusion MRI.},
journal = {Journal of Alzheimer's disease reports},
volume = {9},
number = {},
pages = {25424823251395938},
pmid = {41267903},
issn = {2542-4823},
abstract = {BACKGROUND: White matter hyperintensities (WMHs) are common in older adults and appear as abnormal signal on T2-weighted or fluid-attenuated inversion recovery (FLAIR) magnetic resonance imaging (MRI). They are often linked to demyelination, axonal damage, and gliosis, as well as vascular changes. WMHs occur in both normal aging and mild cognitive impairment (MCI), where they may contribute to cognitive decline.

OBJECTIVE: The study objectives were to determine whether advanced diffusion MRI (dMRI) techniques can detect distinct microstructural changes within WMHs in individuals with MCI compared to healthy controls and to evaluate relationships between these measures and cognitive performance.

METHODS: Advanced dMRI techniques were used to assess WMH microstructural changes in normal aging (n = 55) and MCI (n = 46) participants from the ADNI database. WMHs and their surrounding penumbra were identified using an automated approach. Microstructural characteristics, derived from free-water (FW) diffusion tensor imaging and diffusion kurtosis imaging, were evaluated between groups and white matter regions. Associations between these measures and cognitive performance (assessed by the Mini-Mental State Exam) were examined.

RESULTS: Across both groups, WMHs showed higher FW and lower FW-fractional anisotropy and kurtosis metrics compared to normal-appearing white matter, indicating widespread microstructural alterations. No groupwise microstructural differences were observed within corresponding tissue types. In the MCI group, kurtosis metrics within WMHs correlated with cognitive performance.

CONCLUSIONS: These findings highlight the complexity of WMH-related microstructural changes and suggest that advanced dMRI biomarkers may offer valuable insights into the role of white matter changes in aging and cognitive decline.},
}

@article {pmid41267515,
year = {2025},
author = {Ünal, D and Sarıköse Özgüven, A},
title = {Exosomes: New Biomarker and Therapeutic Candidates in Autism Spectrum Disorder Research.},
journal = {Acta neuropsychiatrica},
volume = {},
number = {},
pages = {1-47},
doi = {10.1017/neu.2025.10047},
pmid = {41267515},
issn = {1601-5215},
abstract = {BACKGROUND: There is no recognized cure or specific biomarker for autism spectrum disorder (ASD). Exosomes are small vesicles that carry proteins, lipids, and nucleic acids. They have been investigated for diseases such as Parkinson's and Alzheimer's. As the conclusions were on the biological utility of exosomes as a non-invasive brain biopsy, some animal, human, and in vitro exosome studies have also been presented in the ASD field. The purpose of this review is to compile the studies that have established a relationship between ASD and exosomes so far and discuss their potential for linking the gap between the laboratory and clinic.

METHODS: In this systematic review, 31 PubMed articles were identified using the keywords "exosomal," "exosome," and "autism spectrum disorder." After excluding 16 reviews, 4 irrelevant studies, and 1 preprint, and adding 5 relevant articles, 15 research articles were included based on PRISMA criteria. The articles were investigated and reviewed by both authors. Their methodology and results are also discussed according to two main streams in studies.

RESULTS: Numerous studies have identified potential biomarkers, including mitochondrial DNA (mtDNA7S), cytokines including IL-1β, TNF-α, and IL-6, and different types of RNAs by comparing the exosomal contents of ASD patients or models with controls. In studies that focused on treatment, behavioral improvements were shown in ASD model mice.

CONCLUSION: Since there are presently no reliable biomarkers or effective treatments for ASD, exosome-based research offers a promising avenue for early diagnosis and the creation of tailored therapies.},
}

@article {pmid41267138,
year = {2025},
author = {Zafari, R and Goudarzi, N and Kamroo, A and Tafti, MF and Ghorbani, A and Talebian, N and Najafi, S and Shahbazian, S and Rahmanian, M and Parvardeh, S and Dargahi, L and Nassiri-Asl, M},
title = {The effects of polyphenols on gut microbial metabolites and composition in neurodegenerative diseases: a systematic review.},
journal = {Nutrition & metabolism},
volume = {22},
number = {1},
pages = {142},
pmid = {41267138},
issn = {1743-7075},
}

@article {pmid41266915,
year = {2025},
author = {Veloso-Luis, A and Diaconu, S and Mendes, M and Ferreira, JJ},
title = {Towards effective interventions: scoping review on prevention and modifiable risk factors of neurodegenerative diseases.},
journal = {Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology},
volume = {},
number = {},
pages = {},
pmid = {41266915},
issn = {1590-3478},
abstract = {BACKGROUND: Life expectancy is increasing with help of modern medicine, but well-being is not always guaranteed for elderly, especially when affected by diseases that hinder autonomy and to which there is still no cure. Amongst late-life related diseases are those affecting cognition, such as dementias and Alzheimer's Disease, which occurrence has been reported as one of the top Global Burden of Disease with prospective exponential growth for the next 30 years. Other reasons for dependency of elderly are health conditions affecting movement. Some of these are associated with neurodegenerative diseases (NDD), such as Parkinson's Disease, whose rise in prevalence is equally concerning and attending a pandemic status.

METHODS: This scoping review is based on selected systematic reviews of interventions for the prevention or risk reduction of NDD. It summarizes existing studies, their efficacy and limitations, the coverage of topics and diseases to which scientific evidence of protective effect has become available in the last decade.

RESULTS: 75 systematic reviews were included, from which 75% were dedicated to risks associated with cognitive disorders. Movement disorders are facing scarcity of studies on prevention cues. Although growing in number, studies remain cautious in concluding preventive efficacy.

CONCLUSIONS: Nevertheless, our synthesis reveals strong evidence supporting the protective role of several non-genetic factors in delaying NDD onset. This review provides a practical resource for clinicians and policymakers in developing integrated, community-level prevention strategies. Findings suggest that interdisciplinary, multifactorial approaches may offer the greatest potential for reducing the burden of neurodegenerative diseases.},
}

@article {pmid41266692,
year = {2025},
author = {Shafi, A and Akmal, M and Sethi, A and Chauhdary, Z},
title = {A mechanistic insight of neuro-inflammation signaling pathways and implication in neurodegenerative disorders.},
journal = {Inflammopharmacology},
volume = {},
number = {},
pages = {},
pmid = {41266692},
issn = {1568-5608},
abstract = {Neuroinflammation is a multifaceted and carefully regulated process within the central nervous system (CNS) that serves a dual function in both protecting neurons and contributing to neurodegenerative processes. This process is mainly driven by activated microglia, astrocytes, and immune cells that infiltrate in response to neuronal damage, infections, or toxic exposures. This review emphasizes the key molecular pathways involved in neuroinflammatory reactions, such as the JAK/STAT, NF-κB, NLRP3 inflammasome, and MAPK signaling pathways. Each of these pathways plays a role in the generation and release of pro-inflammatory substances that maintain and increase inflammation in the CNS. Furthermore, the review examines the significance of crucial pro-inflammatory cytokines interleukin-1β (IL-1β), interleukin-6 (IL-6), and tumor necrosis factor-alpha (TNF-α) as well as the chemokines CCL2 and CXCL10, which coordinate the recruitment of immune cells and contribute to neuronal injury. Gaining an understanding of the interactions among these signaling pathways and mediators sheds light on the molecular mechanisms connected to various neurodegenerative conditions such as Alzheimer's disease, Parkinson's disease, and multiple sclerosis. Targeting these inflammatory signaling networks may provide valuable therapeutic approaches to manage neuroinflammation and avert its long-lasting neurotoxic effects.},
}

@article {pmid41266616,
year = {2025},
author = {Heininger, H and Feng, X and Altunkaya, A and Zheng, F and Stockinger, F and Wefers, B and Müller, SA and Giesbertz, P and Tschirner, SK and Shqau, D and Adelsberger, H and Ponomarenko, A and Fenzl, T and Alzheimer, C and Lichtenthaler, SF and Huth, T},
title = {BACE1 regulates sleep-wake cycle through both enzymatic and non-enzymatic actions.},
journal = {EMBO reports},
volume = {},
number = {},
pages = {},
pmid = {41266616},
issn = {1469-3178},
support = {HU 2358/1-1//Deutsche Forschungsgemeinschaft (DFG)/ ; PO1799/6-1//Deutsche Forschungsgemeinschaft (DFG)/ ; EXC 2145 SyNergy - ID 390857198//Deutsche Forschungsgemeinschaft (DFG)/ ; FKZ161L0214C,ClinspectM//Bundesministerium für Bildung und Forschung (BMBF)/ ; },
abstract = {The β-secretase BACE1 has become a prime target in Alzheimer's disease (AD) therapy, because it drives the production of pathogenic amyloid β peptides. However, clinical trials with BACE1-targeting drugs were halted due to adverse effects on cognitive performance. We propose here that cognitive impairment by BACE1 inhibitors may be a corollary of a higher function of BACE1 related to proper sleep regulation. To address non-enzymatic effects of BACE1 on ion channels likely involved in the sleep-wake cycle, we analyze sleep patterns in both BACE1-KO mice and a newly generated transgenic line expressing a proteolysis-deficient BACE1 variant (BACE1-KI). We find that BACE1-KI and BACE1-KO mice display common and distinct sleep-wake disturbances. Compared with their respective wild-type littermates, both mutant lines sleep less during the light phase (when they preferentially rest). Furthermore, transition rates between wake and sleep states are altered, as are sleep spindles and EEG power spectra mainly in the gamma range. Thus, a better understanding of how BACE1 interferes with sleep-modulated behaviors is needed if clinical trials with BACE1-targeted inhibitors are to resume.},
}

@article {pmid41266593,
year = {2025},
author = {Trudel, L and Therriault, J and Macedo, AC and Woo, MS and Rahmouni, N and Aumont, É and Servaes, S and Hosseini, SA and Ferrari-Souza, JP and Bellaver, B and Ferreira, PL and Chan, T and Wang, YT and Fernandez-Arias, J and Zheng, Y and Hall, B and Stevenson, J and Hopewell, R and Hsiao, CH and Montembeault, M and Klostranec, J and Iturria-Medina, Y and Vitali, P and Karikari, TK and Benedet, AL and Ashton, NJ and Zimmer, E and Gauthier, S and Pascoal, TA and Zetterberg, H and Blennow, K and Rosa-Neto, P},
title = {APOE ε4 potentiates tau related reactive astrogliosis assessed by cerebrospinal fluid YKL40 in Alzheimer's disease.},
journal = {Communications medicine},
volume = {5},
number = {1},
pages = {484},
pmid = {41266593},
issn = {2730-664X},
support = {NIRG-12-92090, NIRP-12-259245/ALZ/Alzheimer's Association/United States ; },
abstract = {BACKGROUND: Glial responses are involved in neurodegenerative processes, with tau pathology often associated with increased glial inflammatory responses in Alzheimer's disease (AD). The apolipoprotein E (APOE) ε4 allele, the major genetic susceptibility gene for AD, might contribute to this process by modulating both tau pathology and inflammatory cascades in the brain.

METHODS: We used data from the Translational Biomarkers of Alzheimer's Disease (TRIAD) cohort (n = 137) to investigate the association between YKL-40, a marker of reactive astrogliosis, and tau burden measured with PET imaging, while also exploring the involvement of APOE ε4 carriership. Statistical analyses included correlation and regression models controlling for age and sex.

RESULTS: Here we show that tau pathology is positively associated with YKL-40 levels, reflecting regional patterns of astrocyte activity in the brain. Furthermore, this association is more widespread in individuals carrying the APOE ε4 allele, suggesting a genotype-specific modulation of the glial neuroinflammatory response.

CONCLUSIONS: Our findings demonstrate a link between tau accumulation and astrocyte-mediated neuroinflammation in AD and highlight the modulatory role of APOE ε4 in this process. Taken together, our findings help inform the multifaceted role of tau-associated neuroinflammation in the progression of AD.},
}

@article {pmid41266291,
year = {2025},
author = {Prasad, H},
title = {NHE9 and Endosomal pH: Converging Mechanisms in Neurodevelopmental, Psychiatric and Neurodegenerative Disorders.},
journal = {The European journal of neuroscience},
volume = {62},
number = {10},
pages = {e70334},
doi = {10.1111/ejn.70334},
pmid = {41266291},
issn = {1460-9568},
support = {ANRF/ECRG/2024/002999/LS//Prime Minister Early Career Research Grant/ ; //Centre for Brain Research/ ; },
mesh = {Humans ; *Sodium-Hydrogen Exchangers/metabolism/genetics ; *Endosomes/metabolism ; Animals ; *Neurodegenerative Diseases/metabolism/genetics ; Hydrogen-Ion Concentration ; *Mental Disorders/metabolism/genetics ; *Neurodevelopmental Disorders/metabolism/genetics ; },
abstract = {The Na[+](K[+])/H[+] exchanger NHE9 (SLC9A9), a key regulator of endosomal pH, is increasingly recognized as a contributor to a shared pathomechanism-endosomal dysfunction-across neurodevelopmental, psychiatric and neurodegenerative disorders. Enriched in the brain, NHE9 acts as a leak pathway for protons to balance vacuolar ATPase-driven acidification, fine-tuning luminal pH essential for synaptic, circuit and behavioural functions. Structurally, NHE9 operates as a dimer via an elevator-like transport mechanism. Functionally, it modulates neuronal and glial processes-such as presynaptic Ca[2+] dynamics, synaptic vesicle exocytosis, endocytic recycling and glutamate clearance-all critical to neurotransmission and synaptic plasticity. Consequently, NHE9 has been implicated in a range of brain disorders, including autism, schizophrenia and Alzheimer's disease. Genetic studies also associate NHE9 with interferon-β therapy response in multiple sclerosis and chronic pain, underscoring broader neurological significance. Despite growing evidence, mechanistic links between NHE9 dysfunction and clinical phenotypes across the neurodevelopmental-neurodegenerative continuum remain poorly defined. This narrative review synthesizes conceptual advances and findings from cellular models, animal studies and human genetics to construct a model positioning NHE9 dysfunction as an upstream pathogenic factor across diverse brain disorders. Critical knowledge gaps include genotype-phenotype correlations, isoform-specific roles and neuron-glia interactions. Patient-derived systems and in vivo models will be essential for elucidating mechanisms and developing targeted therapies. Identifying a convergent mechanism of endosomal pH dysregulation across disorders would enable pharmacological control of NHE9. Future research should define strategies to restore endosomal homeostasis, with potential to interrupt pathogenic feedforward loops that worsen symptoms and drive disease progression.},
}

Humans
*Sodium-Hydrogen Exchangers/metabolism/genetics
*Endosomes/metabolism
Animals
*Neurodegenerative Diseases/metabolism/genetics
Hydrogen-Ion Concentration
*Mental Disorders/metabolism/genetics
*Neurodevelopmental Disorders/metabolism/genetics

@article {pmid41266285,
year = {2025},
author = {Lee, ML and Choi, SE and Mukherjee, S and Scollard, P and Nakano, C and Gibbons, LE and Culhane, J and Gauthreaux, K and Chan, KCG and Biber, S and Stephens, K and Kukull, W and Trittschuh, E and Mez, J and Saykin, AJ and Turner, S and Archer, D and Durant, A and Dumitrescu, L and Hohman, T and Crane, PK},
title = {Bridging the gap: addressing NACC's evolving cognition batteries across UDS versions.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21},
number = {11},
pages = {e70832},
doi = {10.1002/alz.70832},
pmid = {41266285},
issn = {1552-5279},
support = {U24 AG072122/AG/NIA NIH HHS/United States ; P30 AG062429 (to J.B.)/AG/NIA NIH HHS/United States ; P30 AG066468 (to O.L.)/AG/NIA NIH HHS/United States ; P30 AG062421 (to B.H.)/AG/NIA NIH HHS/United States ; P30 AG066509 (to T.G.)/AG/NIA NIH HHS/United States ; P30 AG066514 (to M.S.)/AG/NIA NIH HHS/United States ; P30 AG066530 (to H.C.)/AG/NIA NIH HHS/United States ; P30 AG066507 (to M.A.)/AG/NIA NIH HHS/United States ; P30 AG066444 (to D.H.)/AG/NIA NIH HHS/United States ; P30 AG066518 (to L.S.)/AG/NIA NIH HHS/United States ; P30 AG066512 (to T.W.)/AG/NIA NIH HHS/United States ; P30 AG066462 (to S.S.)/AG/NIA NIH HHS/United States ; P30 AG072979 (to D.W.)/AG/NIA NIH HHS/United States ; P30 AG072972 (to C.D.)/AG/NIA NIH HHS/United States ; P30 AG072976 (to A.S.)/AG/NIA NIH HHS/United States ; P30 AG072975 (to J.A.S.)/AG/NIA NIH HHS/United States ; P30 AG072978 (to A.M.)/AG/NIA NIH HHS/United States ; P30 AG072977 (to R.V.)/AG/NIA NIH HHS/United States ; P30 AG066519 (to F.L.)/AG/NIA NIH HHS/United States ; P30 AG062677 (to R.P.)/AG/NIA NIH HHS/United States ; P30 AG079280 (to J.L.)/AG/NIA NIH HHS/United States ; P30 AG062422 (to G.R.)/AG/NIA NIH HHS/United States ; P30 AG066511 (to A.L.)/AG/NIA NIH HHS/United States ; P30 AG072946 (to L.V.E.)/AG/NIA NIH HHS/United States ; P30 AG062715 (to S.A.)/AG/NIA NIH HHS/United States ; P30 AG072973 (to R.S.)/AG/NIA NIH HHS/United States ; P30 AG066506 (to G.S.)/AG/NIA NIH HHS/United States ; P30 AG066508 (to S.S.)/AG/NIA NIH HHS/United States ; P30 AG066515 (to V.H.)/AG/NIA NIH HHS/United States ; P30 AG072947 (to S.C.)/AG/NIA NIH HHS/United States ; P30 AG072931 (to H.P.)/AG/NIA NIH HHS/United States ; P30 AG066546 (to S.S.)/AG/NIA NIH HHS/United States ; P30 AG086401 (to E.R.)/AG/NIA NIH HHS/United States ; P30 AG086404 (to G.R.)/AG/NIA NIH HHS/United States ; P20 AG068082 (to A.J.)/AG/NIA NIH HHS/United States ; P30 AG072958 (to H.W.)/AG/NIA NIH HHS/United States ; P30 AG072959 (to J.L.)/AG/NIA NIH HHS/United States ; },
mesh = {Humans ; Male ; Female ; *Neuropsychological Tests/standards ; Aged ; Magnetic Resonance Imaging ; Executive Function/physiology ; *Cognition/physiology ; Apolipoproteins E/genetics ; *Cognitive Dysfunction/diagnosis ; Reproducibility of Results ; },
abstract = {INTRODUCTION: The Uniform Data Set (UDS) version 3 neuropsychological battery replaced old tests used in UDS 1&2. Here, we validate domain scores for memory, executive functioning, and language co-calibrated across UDS eras.

METHODS: We compared co-calibrated and harmonized domain scores to traditional equipercentile equating in a crosswalk sample. We also validated domain scores by evaluating associations with magnetic resonance imaging (MRI) findings and APOE genotype across UDS eras.

RESULTS: We co-calibrated cognitive domain scores for 49,396 participants, about 25% of whom had data spanning UDS 1&2 and UDS 3 eras. Crosswalk sample (n = 955) correlations between UDS 1&2 and UDS 3 domain scores and equipercentile scores were similar. Harmonized domain scores had statistically significant associations in imaging (n = 2458) and APOE validity assessments (n = 27,857). Significant differences in domain scores were found across UDS eras.

DISCUSSION: Longitudinal co-calibrated and harmonized cognitive domain scores bridge the gap across UDS versions and are available from the National Alzheimer's Coordinating Center.

HIGHLIGHTS: Co-calibrated domain scores are validated in the NACC crosswalk sample. Co-calibrated domain scores are validated with neuroimaging measures. Co-calibrated domains scores are validated with APOE genotype. Co-calibrated domain scores reveal cognitive performance differences in enrollment visit depending on UDS era. Co-calibrated domain scores are readily available to investigators utilizing NACC's rich dataset.},
}

Humans
Male
Female
*Neuropsychological Tests/standards
Aged
Magnetic Resonance Imaging
Executive Function/physiology
*Cognition/physiology
Apolipoproteins E/genetics
*Cognitive Dysfunction/diagnosis
Reproducibility of Results

@article {pmid41266256,
year = {2025},
author = {Hoenig, MC and Dzialas, V and Doering, E and Bischof, GN and van Eimeren, T and Drzezga, A and , },
title = {Modifiable Factors Associated with the Longitudinal Increase and Spatial Extent of Tau Pathology in Alzheimer Disease.},
journal = {Journal of nuclear medicine : official publication, Society of Nuclear Medicine},
volume = {},
number = {},
pages = {},
doi = {10.2967/jnumed.125.270593},
pmid = {41266256},
issn = {1535-5667},
abstract = {There are 14 modifiable factors that are associated with a significantly lower risk of dementia. We tested the interactive effect of modifiable factors, genetic determinants, and initial pathologic burden on the spatial progression and local amplification of tau pathology. Methods: In total, 162 amyloid-positive individuals were included, for whom longitudinal [[18]F]AV-1451 PET scans, baseline information on global amyloid burden, ApoE4 status, body mass index (BMI), hypertension, education, neuropsychiatric symptom severity, and demographic information were available in the Alzheimer Disease Neuroimaging Initiative. All [[18]F]AV-1451 scans were intensity-standardized (reference: inferior cerebellum), z-transformed (control sample: 147 amyloid-negative subjects), thresholded (z score, >1.96), and converted to volume maps. Longitudinal tau changes were then assessed in terms of tau spatial extent (i.e., newly affected volume at follow-up) and tau level rise (i.e., tau increase in previously affected volume). These 2 measures were entered as dependent variables in linear mixed-effects models, including baseline modifiable risk factors (BMI, education, hypertension, neuropsychiatric symptom severity), global amyloid, tau volume or tau burden, ApoE4 status, clinical stage, sex, and age as predictors. Next, we tested the interactive effects between baseline amyloid or tau burden with the 4 modifiable factors on tau extent or tau level rise, respectively. Results: Greater tau extent was linked to higher BMI (β = 0.002; 95% CI, 0.0003-0.003), ApoE4 status (β = 0.024; 95% CI, 0.001-0.046), and baseline tau volume (β = 0.207; 95% CI, 0.107-0.308) across groups. In terms of tau level rise, we observed that absence of hypertension (β = 0.295; 95% CI, -0.477 to -0.114), dementia group (β = 0.305; 95% CI, 0.088-0.522), and BMI (β = 0.011; 95% CI, 0.00004-0.022) were linked to increased tau burden. A load-dependent effect of baseline amyloid and tau volume/burden was found for both tau extent (β = -0.005; 95% CI, -0.008 to -0.002) and tau level rise (β = -0.003; 95% CI, -0.005 to -0.001). Higher amyloid and BMI (β = 0.001; 95% CI, 0.0004-0.001) and lower education and higher tau burden (β = -0.035; 95% CI, -0.064 to -0.006) were linked to greater tau level rise. Conclusion: Education, BMI, and hypertension differentially influence tau's spatial extent and increase by its interaction with initial pathologic burden. Timely modification of these factors may overall slow tau progression.},
}

@article {pmid41265806,
year = {2025},
author = {Zhang, M and Wei, W and Zu, H},
title = {DHCR24 knockdown-induced cellular cholesterol deficiency triggers tau hyperphosphorylation at Thr181, Ser199 and Ser202/Thr205 via p38 MAPK/JNK signaling.},
journal = {Cellular signalling},
volume = {},
number = {},
pages = {112254},
doi = {10.1016/j.cellsig.2025.112254},
pmid = {41265806},
issn = {1873-3913},
abstract = {Cholesterol deficiency is implicated in Alzheimer's disease (AD) pathogenesis, yet its regulatory role in tau phosphorylation remains unclear. We investigated whether the loss of 24-dehydrocholesterol reductase (DHCR24), a key enzyme in cholesterol biosynthesis, drives tau hyperphosphorylation via p38 MAPK and JNK signaling pathways in SH-SY5Y neuroblastoma cells. Using lentiviral vectors encoding DHCR24-cDNA or DHCR24-shRNA, we established stable DHCR24-overexpression and DHCR24-knockdown SH-SY5Y cell models. Filipin III staining and UPLC-MS/MS demonstrated that DHCR24 knockdown significantly reduced cellular cholesterol levels, whereas overexpression raised cholesterol levels. Immunoblotting showed selective increases in tau phosphorylation at Thr181, Ser199 and Ser202/Thr205 under DHCR24 deficiency; total tau remained unchanged. Concomitantly, phospho-p38 and phospho-JNK rose 1.5- to 2.5-fold without alterations in total kinase levels, indicating pathway activation. To test causality, DHCR24-silenced cells were treated with escalating doses of the p38 inhibitor SB203580 (0-40 μM) or the JNK inhibitor SP600125 (0-40 μM). Both compounds restored tau phosphorylation to baseline in a concentration-dependent manner, with maximal suppression at 40 μM (SB203580) and 20-40 μM (SP600125). Collectively, these data establish DHCR24-controlled cholesterol homeostasis as a molecular rheostat of tau pathology through p38/JNK signaling, and nominate this axis for therapeutic intervention in AD.},
}

@article {pmid41265581,
year = {2025},
author = {Sun, T and Li, Z and Xiao, B and Yang, J and Han, M and Zhang, J and Liu, S and Ma, J and Wang, P},
title = {Structural modification of atractylenolides: synthesis and evaluation of derivatives with potent anti-Aβ aggregation and neuroprotective activities against Alzheimer's disease.},
journal = {Bioorganic & medicinal chemistry letters},
volume = {},
number = {},
pages = {130478},
doi = {10.1016/j.bmcl.2025.130478},
pmid = {41265581},
issn = {1464-3405},
abstract = {Alzheimer's disease (AD), a progressive neurodegenerative disorder characterized by β-amyloid (Aβ) deposition, hyperphosphorylated Tau tangles, and neuronal loss, lacks effective disease-modifying therapies. Herbal medicines like Atractylodes macrocephala (AM) offer promising candidates for AD drug development, given their structural diversity and neuroprotective potential. Our prior work involved systematic phytochemical isolation of AM and preliminary anti-AD activity evaluation, through which we identified atractylenolide A1 as a neuroprotective lead. To further optimize efficacy, we herein synthesized a small series of novel atractylenolide derivatives via structural modification of A1's exocyclic. Among derivatives, B7 exhibited the broadest activity such as inhibiting self- and Cu[2+]-induced Aβ aggregation, protecting neurons and microglia, and mitigating Aβ toxicity in vivo. The exocyclic ester of A1 proves a viable modification site, with B7 emerging as a promising multi-target lead for AD therapy.},
}

@article {pmid41265570,
year = {2025},
author = {Shi, Q and Hou, J and Peng, X and Xu, Z and Wang, Y and Cao, D},
title = {Magnetic Resonance Imaging Analysis for Alzheimer's Disease Diagnosis using Artificial Intelligence: Methods, Challenges, and Opportunities.},
journal = {Ageing research reviews},
volume = {},
number = {},
pages = {102943},
doi = {10.1016/j.arr.2025.102943},
pmid = {41265570},
issn = {1872-9649},
abstract = {Alzheimer's disease(AD) is the most common cause of dementia and affects millions of people worldwide. The early and accurate diagnosis of AD is crucial for timely intervention and disease management. Magnetic resonance imaging (MRI) is a widely used noninvasive technique for assessing brain structure and function in patients with AD. However, conventional MRI analysis methods are often subjective, time-consuming, and depend on expert knowledge. Artificial intelligence (AI), particularly deep learning (DL), has emerged as a powerful tool for extracting meaningful information from large and complex MRI data and providing an automated and reliable diagnosis of AD. In this review, we summarize the recent advances and challenges in AI MRI for AD diagnosis, focusing on the following aspects: (1) types and characteristics of MRI data used for AD diagnosis; (2) the main AI models and architectures applied to MRI data analysis; (3) performance and evaluation metrics of AI models for AD diagnosis; (4) potential applications and limitations of AI models for AD diagnosis in clinical practice; and (5) future research directions for AI MRI for AD diagnosis. This review aims to provide a comprehensive and updated overview of the field and stimulate further research and advancements in AI-aided MRI for the diagnosis of AD.},
}

@article {pmid41265552,
year = {2025},
author = {Sardari, M and Sahafi, OH and Rezayof, A},
title = {Mitochondria serve as indispensable components of neuron-glia crosstalk in the trajectory of Alzheimer's disease.},
journal = {Brain research},
volume = {},
number = {},
pages = {150040},
doi = {10.1016/j.brainres.2025.150040},
pmid = {41265552},
issn = {1872-6240},
abstract = {Alzheimer's disease (AD) is a multiplex and progressive neurodegenerative disorder commonly recognized by the accumulation of amyloid-β (Aβ) plaques, neurofibrillary tangles (NFTs), and dysfunction in the cholinergic and glutamatergic systems. At the early stages of AD, mitochondrion operates as a neuroprotective organelle in both neuronal and glial cells by compensating energy fluctuations. As the disease progresses, mitochondrial function in both neurons and glial cells deteriorates, culminating in impaired cellular metabolism and glial hyperactivation. This time-dependent hyperactivation of microglia and astrocytes sequentially promotes the release of pro-inflammatory cytokines, elevates reactive oxygen species, disrupts calcium homeostasis, and increases oxidative stress. Altogether, these processes drive neuroinflammation, which both influences and is influenced by mitochondrial activity. Additionally, mitochondrial dysfunction across the disease trajectory hampers communication between neurons and glial cells, promoting excitotoxicity in neurons. This review emphasizes the vital role of mitochondrial dynamics in AD pathophysiology across different stages and explores how cell-specific targeting of mitochondrial activity could mitigate neuroinflammation, restore neuronal function, and offer potential treatment benefits. Enhancing mitochondrial function in healthy neurons and glial cells, particularly in microglia as a compensatory mechanism, especially at the early stage of the disease or restoring mitochondrial function of surviving neurons at the later stages, may promote neuroprotection and improve neuron-glia interactions, thus offering a potential strategy for AD treatment.},
}

@article {pmid41265341,
year = {2025},
author = {Yuan, X and Gao, L and Peng, Y and She, T and Wang, J},
title = {A deep representation learning algorithm on drug-target interaction to screen novel drug candidates for Alzheimer's disease.},
journal = {Artificial intelligence in medicine},
volume = {171},
number = {},
pages = {103301},
doi = {10.1016/j.artmed.2025.103301},
pmid = {41265341},
issn = {1873-2860},
abstract = {Alzheimer's disease (AD) is a serious neurodegenerative brain disorder with complex pathophysiology. While currently available drugs can provide symptomatic benefits, they often fail to cure the disease. Thus, there is an urgent need to explore new therapeutic agents. In this study, we developed DTIP (Drug-Target Interaction Prediction), a machine learning-based approach to search novel drugs for AD by utilizing the information of drug-target interaction (DTI). By training a Skip-gram model on drug-target sequences derived from known DTI information, the algorithm learned the drug-target relationship embeddings and to predict potential drug candidates for diseases like AD. For AD, we compiled 917 risk genes and identified 292 potential drugs via the new algorithm. We further performed molecular docking by AutoDock Vina and conducted Inverted Gene Set Enrichment Analysis (IGSEA) on these drug candidates. Our results identified that several drugs could be promising for AD treatment, including human C1-esterase inhibitor, quetiapine, dasatinib, miconazole, aniracetam, chlorpromazine, hypericin, entrectinib, torcetrapib, bosutinib, sunitinib, aniracetam, rosiglitazone, tarenflurbil, milrinone, and MITO-4509. Results from this study also provided insights for understanding the molecular mechanisms underlying AD. As a systematic and versatile method, our approach can also be applied to identify efficacious therapies for other complex diseases.},
}

@article {pmid41265254,
year = {2025},
author = {Sun, T and Li, Z and Xiao, B and Yang, J and Han, M and Zhang, J and Liu, S and Ma, J and Sang, Z and Wang, P},
title = {Recent development in PDE4D-targeted inhibitors for Alzheimer's disease therapy.},
journal = {European journal of medicinal chemistry},
volume = {302},
number = {Pt 3},
pages = {118383},
doi = {10.1016/j.ejmech.2025.118383},
pmid = {41265254},
issn = {1768-3254},
abstract = {Alzheimer's disease (AD) is a complex neurodegenerative disorder primarily characterized by cognitive decline and memory impairment. Due to its elusive etiology, complex pathogenesis, and significant interindividual heterogeneity, current clinical interventions face substantial challenges. Therefore, exploring novel therapeutic targets and strategies remains a critical research focus. Phosphodiesterase-4 (PDE4), which specifically hydrolyzes cAMP, has shown potential as a therapeutic target for neurological disorders. However, the lack of subtype selectivity of existing PDE4 inhibitors often leads to dose-limiting adverse effects such as nausea and vomiting, compromising patient tolerance and hindering clinical translation. PDE4D, a key subtype of PDE4, is abundantly expressed in brain regions critical for cognitive function and is particularly involved in memory formation and learning processes. Recent studies indicate that selective inhibition of PDE4D can effectively circumvent these side effects. Consequently, PDE4D has emerged as a promising potential target in AD therapeutic research. This review aims to critically evaluate the regulatory role of PDE4D in neurodegeneration, assess its potential as a novel therapeutic target for AD, and discuss recent advances in the development of PDE4D inhibitors.},
}

@article {pmid41265212,
year = {2025},
author = {Patel, Y and Sharma, P and Kumar, A and Parmar, HS and Inwati, GK},
title = {Design, Ssynthesis, and biological evaluation of β-secretase inhibitors: An integrated study of molecular docking, dynamics, pharmacokinetics, quantum chemistry, and in-vitro analysis for Alzheimer's disease.},
journal = {Bioorganic chemistry},
volume = {167},
number = {},
pages = {109267},
doi = {10.1016/j.bioorg.2025.109267},
pmid = {41265212},
issn = {1090-2120},
abstract = {Present paper elicits the synthesis of a series of 2,2-dimethyl-2H-[1,3]dioxino[4,5-b]pyrrol-4(7H)-one derivatives as novel selective BACE1 inhibitors for the treatment of Alzheimer's disease (AD). A four-component, solvent-free condensation process, catalyzed by 10 mol% NiCl2·6H2O strategy was explored to achieve their synthesis. The structures of the synthesized compounds were ascertained using different spectroscopic techniques, including FT-IR, [1]H NMR, [13]C NMR, mass spectrometry, and elemental analysis. In silico molecular docking and molecular dynamics simulations suggest that these compounds exhibit strong potential as β-secretase (BACE1) inhibitors, demonstrating high interaction and binding energies compared to reference inhibitors AZD3293 and E2602. Notably, compounds 5p displayed significant inhibitory interactions, effectively suppressing the catalytic dyad (Asp A:228 and Asp A:32) of BACE1. To further validate the computational findings, in vitro BACE1 enzymatic inhibition assays were performed on the most interactive molecule 5p. Additionally, ADMET descriptors and density functional theory (DFT) calculations were employed to assess the pharmacokinetics, chemical stability, and binding affinity of the synthesized compounds. The findings from this study pave the way for future in vivo investigations to assess the reversal of Alzheimer's disease phenotypes, along with comprehensive safety and toxicity evaluations.},
}

@article {pmid41264725,
year = {2025},
author = {Stephan, AT and Chai, HW and Nicholson, JS and McVey, A and Phillips, CB and Ross, LA},
title = {Participant Motivation Typologies as Correlates of Study Participation and Retention in Randomized Controlled Trials Targeting Cognitive Aging Through Computerized Cognitive Training.},
journal = {The Gerontologist},
volume = {},
number = {},
pages = {},
doi = {10.1093/geront/gnaf252},
pmid = {41264725},
issn = {1758-5341},
abstract = {BACKGROUND AND OBJECTIVES: Participants' motivations may explain why they participate in Alzheimer's disease and related dementias (ADRD) research. Drawing on the Activator, Motivator, Outside mediator, Re-enforcer (AMOR) model of research engagement, the current study utilized a mixed methods design to 1) explore participants' reasons for participating and, in some cases, withdrawing from computerized cognitive training studies and 2) connect these reasons to study retention.

RESEARCH DESIGN AND METHODS: Our convenience sample included community-dwelling adults (N = 423) between 55-88 years (M = 67.45, SD = 7.22) from two randomized controlled trials involving computerized cognitive training (Everyday Function Intervention Trial, NCT04651582; Elucidating the Necessary Active Components of Training, NCT05366023). We analyzed participants' reasons for participating (shared via written responses) and, when relevant, stated reasons for withdrawing (ascertained via study personnel's notes in participant files) using inductive coding then theoretically-informed pattern coding. Associations between reasons for participation and study retention were examined using chi-square tests and logistic regression.

RESULTS: Primary reasons for participating in research included activating and motivating factors; reasons for withdrawing included outside contextual factors and re-enforcers. Re-enforcers were particularly relevant for withdrawals during the cognitive training phase. Participation reasons were not associated with reasons for, nor likelihood of, withdrawal.

DISCUSSION AND IMPLICATIONS: Findings support an adapted version of the AMOR model for explaining research engagement. Reasons for participating in and withdrawing from trials for computerized cognitive training are nuanced with participants considering multiple factors in their decisions. Refining and applying models outlining research engagement is critical for identifying and refining recruitment and retention efforts.},
}

@article {pmid41264616,
year = {2025},
author = {Ware, EB and Zhu, P and Noppert, G and Fu, M and Benbow, M and Kobayashi, LC and Ryan, LH and Bakulski, KM},
title = {Associations of perceived neighborhood factors and Alzheimer's disease polygenic score with cognition: Evidence from the Health and Retirement Study.},
journal = {PloS one},
volume = {20},
number = {11},
pages = {e0336403},
pmid = {41264616},
issn = {1932-6203},
mesh = {Humans ; *Alzheimer Disease/genetics/epidemiology/psychology ; Female ; Male ; Aged ; *Cognition/physiology ; Middle Aged ; *Multifactorial Inheritance ; *Cognitive Dysfunction/genetics/epidemiology ; *Neighborhood Characteristics ; Risk Factors ; *Residence Characteristics ; Proportional Hazards Models ; Aged, 80 and over ; Retirement ; },
abstract = {BACKGROUND: We examined the relationships between neighborhood characteristics, cumulative genetic risk for Alzheimer's disease (polygenic scores for Alzheimer's disease), and cognitive function using data from the Health and Retirement Study (2008-2020, age > 50).

METHODS: Baseline perceived neighborhood characteristics were combined into a subjective neighborhood disadvantage index. Cognitive function was assessed at baseline and measured biennially over a 10-year follow-up period. Analyses were stratified by genetic ancestry. Cox proportional hazard models analyzed associations between neighborhood characteristics, Alzheimer's disease polygenic scores, and their interactions on cognitive impairment.

RESULTS: In the European ancestries sample, a one standard deviation higher score on the subjective neighborhood disadvantage index was associated with a higher hazard of any cognitive impairment (HR:1.09; CI:1.03-1.15), cognitive impairment without dementia (HR:1.08; CI:1.03-1.14), and dementia (HR:1.13; CI:1.03-1.24). Similarly, a one standard deviation increase in Alzheimer's disease polygenic score was associated with a higher risk of cognitive impairment (HR:1.10; CI:1.05-1.16) and cognitive impairment without dementia (HR:1.10; CI:1.05-1.16) but not dementia (HR:1.05; CI:0.96-1.16). No significant interactions were found. Evidence in African ancestries were directionally similar but imprecise and inconclusive due to limited precision and cross-ancestry polygenic score transferability. Subjective neighborhood disadvantage index and Alzheimer's disease polygenic score were independently associated with incident cognitive impairment.

CONCLUSIONS: Preventing dementia by addressing modifiable risk factors is essential.},
}

Humans
*Alzheimer Disease/genetics/epidemiology/psychology
Female
Male
Aged
*Cognition/physiology
Middle Aged
*Multifactorial Inheritance
*Cognitive Dysfunction/genetics/epidemiology
*Neighborhood Characteristics
Risk Factors
*Residence Characteristics
Proportional Hazards Models
Aged, 80 and over
Retirement

@article {pmid41264543,
year = {2025},
author = {Wang, X and Shen, Y and Lei, C and Chai, J and Tan, Q and Qin, Y},
title = {Comprehensive Bibliometric Analysis of P-Tau in Alzheimer's Disease: Trends and Emerging Research Priorities (1991-2024).},
journal = {Dementia and geriatric cognitive disorders},
volume = {},
number = {},
pages = {1-20},
doi = {10.1159/000549394},
pmid = {41264543},
issn = {1421-9824},
abstract = {INTRODUCTION: As a major contributor to dementia burden worldwide, Alzheimer's disease (AD) pathogenesis involves critical phosphorylated tau (p-tau) abnormalities. This research employed bibliometric methods to systematically evaluate worldwide scientific trends, emerging foci, and international collaboration patterns regarding p-tau in AD research.

METHODS: Relevant publications spanning 1991-2024 from the Web of Science Core Collection were extracted. Bibliometric analysis was performed using R package "Bibliometrix" (v4.3.3), CiteSpace (v6.1.R2) and VOSviewer (v1.6.20).

RESULTS: A total of 2,685 publications were included. China led in publication volume (612, 22.8%), followed by the USA (586, 21.8%) and Sweden (212, 7.9%). University of London was the most productive institution (603 publications). Blennow Kaj stood out with publications and citations of 270 and 18,093. The Journal of Alzheimer's Disease and Neurology were the top-ranked journal, with the highest publications (321) and citations (6,446), respectively. Cluster analysis revealed four major clusters, including mechanisms underlying p-tau in AD, p-tau as biomarker in AD, diagnosis of AD using p-tau, and consensus in AD. Keyword burst analysis emphasized recent terms such as "neurofilament light", "dysfunction", "performance" and "biomarker".

CONCLUSION: This study systematically analyzed the researches on p-tau in AD. Research hotspots have evolved from the early focus on pathological features to the exploration of biomarkers-based diagnosis. Recently, the comprehensive assessment AD is emphasized, suggesting that future studies should pay more attention to regulatory mechanism of abnormal p-tau for identification of therapeutic targets and overcome the challenges of p-tau as biomarkers during clinical diagnosis.},
}

@article {pmid41264464,
year = {2025},
author = {Fauchier, L and Lenormand, T and Lochon, L and Bisson, A and Venier, S and Defaye, P},
title = {Memantine use and risk of cardiac arrhythmias in Alzheimer dementia A report from a global federated research network.},
journal = {Europace : European pacing, arrhythmias, and cardiac electrophysiology : journal of the working groups on cardiac pacing, arrhythmias, and cardiac cellular electrophysiology of the European Society of Cardiology},
volume = {},
number = {},
pages = {},
doi = {10.1093/europace/euaf299},
pmid = {41264464},
issn = {1532-2092},
}

@article {pmid41264165,
year = {2025},
author = {Gao, H and Cheng, F and Zhang, Z and Yan, B and Liao, P and Zhang, S and Li, D and Chen, F and Lei, P},
title = {Breaking the Alzheimer's Treatment Stalemate: Synergistic Application Strategies of Nanomaterials and Pharmaceutical Agents.},
journal = {Molecular neurobiology},
volume = {63},
number = {1},
pages = {107},
pmid = {41264165},
issn = {1559-1182},
support = {grant no. 82271401//National Natural Science Foundation of China/ ; },
mesh = {*Alzheimer Disease/drug therapy/diagnosis ; Humans ; *Nanostructures/therapeutic use ; Animals ; Drug Delivery Systems/methods ; Nanomedicine/methods ; },
abstract = {Alzheimer's disease (AD), the leading cause of dementia, is characterized by amyloid beta accumulation and tau pathology propagation. Nanomedicine, a discipline enabling targeted drug delivery with precision, holds significant promise in the treatment of neurodegenerative diseases. This review explores the diagnostic and therapeutic applications of nanomaterials in neurodegenerative diseases, particularly AD, emphasizing their properties and their role in modulating pathogenic proteins. Advances in the development of novel anti-AD nanomedicines and their clinical progress are also highlighted. Despite the growing potential of nanotechnology in AD therapy, a definitive cure remains elusive. The review further addresses the current challenges in the field of AD nanomedicines and outlines future research directions to propel their development.},
}

*Alzheimer Disease/drug therapy/diagnosis
Humans
*Nanostructures/therapeutic use
Animals
Drug Delivery Systems/methods
Nanomedicine/methods

@article {pmid41263813,
year = {2025},
author = {Grembecka, B and Kaczorowska, N},
title = {[Therapeutic potential of spermidine in neurodegenerative diseases].},
journal = {Postepy biochemii},
volume = {71},
number = {1},
pages = {50-60},
doi = {10.18388/pb.2021_589},
pmid = {41263813},
issn = {0032-5422},
mesh = {*Spermidine/therapeutic use/pharmacology ; Humans ; *Neurodegenerative Diseases/drug therapy ; Animals ; Autophagy/drug effects ; Oxidative Stress/drug effects ; },
abstract = {In recent years, a progressive increase in the incidence of neurodegenerative diseases has been observed. The etiology and pathophysiology of Parkinson's, Alzheimer's, and Huntington's diseases are diverse; however, universal mechanisms occurring during neurodegeneration warrant attention. Among the best-characterized are chronic inflammation, oxidative stress, and altered autophagy processes resulting from abnormal protein aggregation. Neuronal loss of structure and function is accompanied by impaired repair mechanisms. Given the lack of therapies capable of halting neurodegeneration progression, studies aimed at identifying substances that activate natural cellular repair mechanisms or mitigate factors promoting neurodegeneration are of significant importance. Recently, spermidine has attracted considerable interest from research teams worldwide. This study aims to present evidence confirming the broad spectrum of spermidine’s effects in models replicating degenerative changes in the central nervous system, highlighting its influence on mechanisms of neuronal cell death associated with neurodegenerative diseases.},
}

*Spermidine/therapeutic use/pharmacology
Humans
*Neurodegenerative Diseases/drug therapy
Animals
Autophagy/drug effects
Oxidative Stress/drug effects

@article {pmid41263803,
year = {2025},
author = {Ponamarczuk, H and Popielarski, M},
title = {[Meldonium: current and emerging therapeutic applications].},
journal = {Postepy biochemii},
volume = {71},
number = {2},
pages = {127-144},
doi = {10.18388/pb.2021_605},
pmid = {41263803},
issn = {0032-5422},
mesh = {Humans ; *Methylhydrazines/therapeutic use/pharmacology ; *Neurodegenerative Diseases/drug therapy ; Carnitine/biosynthesis ; Oxidative Stress/drug effects ; Animals ; },
abstract = {Meldonium functions as an inhibitor of γ-butyrobetaine hydroxylase, the enzyme responsible for catalyzing the biosynthesis of L-carnitine. By inhibiting mitochondrial β-oxidation of fatty acids under hypoxic conditions, meldonium exerts cytoprotective effects on cardiac, hepatic, and pulmonary tissues. Meldonium attenuates the deleterious effects of myocardial infarction, arrhythmias, and diabetes. It is recognized as a promising therapeutic agent for neurodegenerative disorders, including Alzheimer's disease, Parkinson's disease, and Huntington's disease, as well as painful neuropathies. Its neuroprotective properties are attributed to its ability to mitigate age-related alterations in the central nervous system by reducing oxidative stress and inflammation. Moreover, it inhibits neuronal apoptosis and facilitates cognitive functions, particularly learning and memory processes. Meldonium has been designated as a prohibited doping agent by the World Anti-Doping Agency (WADA), and its use is strictly banned in professional sports. Recent scientific investigations indicate that meldonium may exhibit additional therapeutic potential beyond its currently recognized clinical applications.},
}

Humans
*Methylhydrazines/therapeutic use/pharmacology
*Neurodegenerative Diseases/drug therapy
Carnitine/biosynthesis
Oxidative Stress/drug effects
Animals

@article {pmid41263800,
year = {2025},
author = {Stępkowski, D and Jarmuła, A},
title = {[Aging, β-amyloid, Alzheimer's - Opinion].},
journal = {Postepy biochemii},
volume = {71},
number = {2},
pages = {187-190},
doi = {10.18388/pb.2021_608},
pmid = {41263800},
issn = {0032-5422},
mesh = {*Alzheimer Disease/metabolism/drug therapy ; Humans ; *Amyloid beta-Peptides/metabolism ; *Aging/metabolism ; },
abstract = {For over 100 years, medicine has not developed an effective method for treating Alzheimer's disease (AD). Despite countless studies, successes have been rather modest. This situation requires a new approach. In the current article, the authors attempt to outline and propose, based on literature and their own research results, the directions of such an approach. We begin with the observation that the strongest risk factor for AD is the aging process of the body, organs, and cells. According to the Informational Theory of Aging, the process of amyloidogenesis, must be the result of earlier molecular events leading to epigenetic chaos. However, the use of anti-amyloid antibodies has shown some moderate successes. Economic considerations suggest, that use of antibodies will not solve the problem on a population-wide scale due to the very high cost. Therefore, small molecule inhibitors of amyloidogenesis are promising molecules for stopping AD dementia processes.},
}

*Alzheimer Disease/metabolism/drug therapy
Humans
*Amyloid beta-Peptides/metabolism
*Aging/metabolism

@article {pmid41263427,
year = {2025},
author = {Wang, Y and Wang, Y and Zhang, W and Xu, Y and Narayan, NS and Cheng, H and Yang, H and Huang, Y and Zhang, C and Wang, C},
title = {Development of a Novel PET Radioligand Targeting PKM2 for Brain Imaging and Alzheimer's Disease Characterization.},
journal = {Journal of medicinal chemistry},
volume = {},
number = {},
pages = {},
doi = {10.1021/acs.jmedchem.5c02549},
pmid = {41263427},
issn = {1520-4804},
abstract = {Targeting pyruvate kinase M2 (PKM2) offers a route to probe neuroinflammatory metabolism in Alzheimer's disease (AD). We report the radiosynthesis and preclinical evaluation of a PKM2-targeted PET radioligand, [[11]C]7d. [[11]C]7d was produced in 21.6-29.4% decay-corrected yield from trapped [[11]C]CH3I with >95% radiochemical purity. Whole-body PET (0-60 min) indicated predominantly hepatobiliary clearance with modest renal excretion. In wild-type mice, [[11]C]7d showed rapid brain entry followed by washout consistent with reversible kinetics. Pharmacological pretreatment with 7d reduced whole-brain AUC, indicating displaceable binding. Ex vivo autoradiography showed a 62.8% signal reduction with 7d and ∼20.1% higher binding in 5xFAD versus NonTg sections. In vivo, 5xFAD mice displayed higher uptake; cerebellum normalized SUVR(20-60 min) increased across multiple regions. PKM2 immunohistochemistry supported regional target engagement. These data support [[11]C]7d as a tool for noninvasive visualization of PKM2-linked glycolytic alterations in the living brain and motivate further quantitative and translational studies.},
}

@article {pmid41263380,
year = {2025},
author = {Haciosmanoglu Aldogan, E and Elibol, B and Korkmaz, ND and Karakayali, ZC and Yildiz, GB},
title = {Plasma Levels of Chitinase 3-Like 1 Protein Increase in Patients With Neurodegenerative Diseases: A Small Cohort Study.},
journal = {Geriatrics & gerontology international},
volume = {},
number = {},
pages = {},
doi = {10.1111/ggi.70253},
pmid = {41263380},
issn = {1447-0594},
abstract = {INTRODUCTION: Neuroinflammation, widely regarded as a chronic inflammatory response of the central nervous system, is thought to be a key player in the initiation of neurodegeneration. While there is a great effort in finding useful biomarkers for early detection of neurodegenerative diseases such as Alzheimer's disease (AD) or Parkinson's disease (PD), a precise biomarker capable of elucidating the disease progression and effectiveness of therapeutic interventions is needed.

METHODS: The plasma NLRP3, ASC, IL-1β, IL-6, IL-10, and CHI3L1 levels were measured in control subjects and patients with AD and PD by ELISA to evaluate whether these molecules can be biomarkers with a high diagnostic power.

RESULTS: While there is no significant difference in the levels of NLRP3, ASC, IL-1β, and IL-10, CHI3L1 was significantly elevated in the AD and PD patients compared to the healthy controls. In addition, in AD patients, IL-6 levels significantly increased and there was a positive correlation between IL-6 and CHI3L1 levels. In the PD patients, there was a negative correlation between IL-6 and CHI3L1. According to the ROC curves, the levels of CHI3L1 had better sensitivity and specificity than other parameters to distinguish AD and PD.

CONCLUSION: In summary, our results indicated that plasma CHI3L1 level can be useful as one of the biomarkers in AD and PD patients.},
}

@article {pmid41263026,
year = {2025},
author = {},
title = {Correction to "TNEA Regulates Hippocampal Oscillation by Improving Inhibitory Synaptic Plasticity to Ameliorates Cognitive Impairment in Alzheimer's disease".},
journal = {Advanced science (Weinheim, Baden-Wurttemberg, Germany)},
volume = {},
number = {},
pages = {e21837},
doi = {10.1002/advs.202521837},
pmid = {41263026},
issn = {2198-3844},
}

@article {pmid41262942,
year = {2025},
author = {Pfutzenreuter, KC and Losada-Baltar, A and Márquez-González, M and Falcão, DVDS},
title = {Psychometric properties of the Brazilian version of the "Caregiver Guilt Questionnaire" (CGQ-BR).},
journal = {Dementia & neuropsychologia},
volume = {19},
number = {},
pages = {e20250325},
pmid = {41262942},
issn = {1980-5764},
abstract = {UNLABELLED: The "Caregiver Guilt Questionnaire" CGQ was originally developed in Spain and contains 22 self-report items covering the following factors: guilt about doing wrong by the care recipient, guilt about failing to meet the challenges of caregiving, guilt about self-care, guilt over feeling negative emotions while caregiving, and guilt about neglecting other relatives.

OBJECTIVE: To analyze the psychometric properties of the Brazilian version of the CGQ.

METHODS: The sample was established for convenience, consisting of 153 family caregivers of people with Alzheimer's disease. The following measures were applied: a sociodemographic questionnaire, the CGQ, the Depression, Anxiety and Stress Scale (DASS-21), and the Life Satisfaction Scale. An exploratory factor analysis was performed for analyzing construct validity to obtain evidence of validity with internal structure and external correlation measures.

RESULTS: The exploratory factor analysis identified five factors with 22 items, which explained 71% of the total variance. Criterion validity was supported by positive associations between CGQ-BR scores and levels of depression, anxiety, and stress, and a negative association with life satisfaction. Good to excellent reliability indexes were found for the total score and subscales.

CONCLUSION: The psychometric properties of the CGQ-BR, when applied to a sample of family caregivers of people with Alzheimer's disease in the Brazilian population, proved to be a valid tool for measuring feelings of guilt. The findings suggest that this tool can be used in clinical and research settings with caregivers.},
}

@article {pmid41262771,
year = {2025},
author = {Fonseca, LM and Queiroz, UT and Queiroz, MT and Forlenza, OV},
title = {Inclusive research with individuals with Down syndrome at risk for dementia.},
journal = {Dementia & neuropsychologia},
volume = {19},
number = {Suppl 1},
pages = {e20240280},
pmid = {41262771},
issn = {1980-5764},
abstract = {Inclusive research is a relatively new concept that has received attention in recent years as a scientific priority to respond to health disparities and maximize the practical implications of research. This approach involves a partnership between academics and the individuals who are experiencing the problem to be investigated. Despite the high incidence of dementia and asymptomatic Alzheimer's disease in aging individuals with Down syndrome, inclusive research with this population or those with intellectual disability (ID) at risk of dementia is an area that is little approached and not well documented. Here, we describe the evolution of inclusive research on ID and dementia, some of the challenges and benefits of its implementation, and key aspects to consider when planning such studies. There is an urgent need for national and international guidelines to support inclusive research involving this population. Such frameworks should ensure accessibility, ethical rigor, the meaningful participation of co-researchers, ultimately advancing equity and scientific quality in this underrepresented field.},
}

@article {pmid41262682,
year = {2025},
author = {Romano, RR and Roby, D and Wilhoite, S and Velez, M and Jefferson, AL and Bolton, CJ},
title = {Developing educational materials to aid in Alzheimer's blood biomarker disclosure.},
journal = {Alzheimer's & dementia (New York, N. Y.)},
volume = {11},
number = {4},
pages = {e70182},
pmid = {41262682},
issn = {2352-8737},
abstract = {INTRODUCTION: A crucial step before clinical use of Alzheimer's disease (AD) blood biomarkers is the development of effective methods for disclosing results. This mixed-method study developed educational materials to disclose the dementia risk based on plasma phosphorylated tau (p-tau) results.

METHODS: Participants diagnosed with mild cognitive impairment (MCI; n = 8) and their care partners (n = 7) participated in focus groups discussing the utility of an educational tool and communication preferences. Focus groups were recorded, transcribed, and analyzed using NVivo, with two independent coders conducting thematic analysis.

RESULTS: Participants rated the materials highly regarding value and comprehension. Thematic analysis revealed confusion about dementia progression and terminology. Participants preferred varied communication modes. Participants found utility in these materials but sought additional information on risk reduction.

DISCUSSION: These findings highlight the utility of educational materials to aid in the disclosure of AD dementia risk based on plasma p-tau to individuals with MCI and their loved ones.

HIGHLIGHTS: Individuals with mild cognitive impairment (MCI) find value in receiving blood biomarker results.Additional risk reduction information is helpful when communicating dementia risk.Individuals prefer medical information communicated visually.},
}

@article {pmid41262573,
year = {2025},
author = {Demsey, LL and Burch, D and Lin, E and Quach, D and Podvin, S and Boyarko, B and Levey, AI and Weinshenker, D and Edland, S and Galasko, D and Jacobs, H and Bang, A and Neil, A and Silverman, J and Feldman, HH and Hook, V},
title = {Atomoxetine Drug Properties for Repurposing as a Candidate Alzheimer's Disease Therapeutic Agent.},
journal = {ACS pharmacology & translational science},
volume = {8},
number = {11},
pages = {3757-3772},
pmid = {41262573},
issn = {2575-9108},
abstract = {Ongoing Alzheimer's disease (AD) drug development research addresses the need for therapeutic agents that can ameliorate cognitive symptoms and attenuate the course of AD synaptic deficits and neurodegeneration. There is growing interest in evaluating FDA-approved drugs for repurposing as candidate AD therapeutics. Such drugs have the advantage that data are available about their pharmaceutical properties, including doses, pharmacokinetics, pharmacodynamics, biomarkers, metabolism, and safety, to inform the design of clinical drug trials. Importantly, the suitability of such drugs with properties needed for AD requires evaluation. In the early stage of AD, degeneration of the locus coeruleus (LC) brain region results in the reduction of noradrenergic neurons and the loss of the neurotransmitter norepinephrine (NE) that regulates cognition and degeneration. Elevation of extracellular NE through inhibition of the NE transporter (NET) is hypothesized to ameliorate AD deficits. Notably, the NET reuptake inhibitor atomoxetine, an FDA-approved drug for the treatment of attention deficit hyperactivity disorder (ADHD), provides an attractive candidate as an AD therapeutic agent because it may attenuate cognitive decline in AD patients, positively impact AD biomarkers, and reduce neuropathology. The goal of this review is to assess atomoxetine for repurposing in AD based on its ability to improve cognition, regulate NE, impact AD biomarkers, and preserve LC neuronal function, with suitable pharmacokinetics, drug metabolism, and safety based on analysis of clinical and preclinical studies. Evidence for neuroprotective effects of atomoxetine in the early stage of AD at clinically safe doses with suitable pharmaceutical properties supports its candidacy as a repurposed drug for AD therapeutics.},
}

@article {pmid41262391,
year = {2025},
author = {Latella, D and Calderone, A and Casella, C and De Luca, R and Gangemi, A and Impellizzeri, F and Caliri, S and Quartarone, A and Calabrò, RS},
title = {Cognitive behavioral therapy for insomnia in neurodegenerative disorders-targeting sleep disturbances in Alzheimer's and Parkinson's disease: a scoping review.},
journal = {Frontiers in psychology},
volume = {16},
number = {},
pages = {1700496},
pmid = {41262391},
issn = {1664-1078},
abstract = {INTRODUCTION: Insomnia is highly prevalent in neurodegenerative disorders, yet pharmacological options carry safety and tolerability concerns. This scoping review mapped contemporary evidence for cognitive behavioral therapy for insomnia (CBT-I) across Alzheimer's disease (AD), mild cognitive impairment (MCI), and Parkinson's disease (PD).

METHODS: Following a preregistered protocol (OSF DOI: 10.17605/OSF.IO/8VP3F), we searched PubMed, Cochrane Library, Web of Science, and Scopus for studies published 2015-2025. We screened English-language studies in adults and applied dual independent review with consensus resolution. Of 105 records, 70 were screened after de-duplication, and 8 met eligibility criteria.

RESULTS: Across randomized trials, pilot and feasibility studies, and single-case experimental designs, CBT-I-delivered in person or via telehealth-consistently reduced insomnia severity and improved sleep quality, with frequent ancillary gains in mood, anxiety, and daytime functioning. Remote and digitally augmented delivery appeared feasible and acceptable for cognitively vulnerable adults and caregivers. Early signals suggested potential cognitive benefits in prodromal populations (AD/MCI), and exploratory observations linked improved sleep with plausible neurobiological mechanisms such as amyloid-beta dynamics. In PD, findings aligned with a mechanistic pathway in which presleep cognitive arousal, safety behaviors, and dysfunctional sleep beliefs are modifiable targets. Non-pharmacological comparators (e.g., mindfulness, therapeutic exercise, neuromodulation) also showed benefits, helping contextualize where CBT-I may offer disorder-relevant leverage on insomnia outcomes.

DISCUSSION: The overall strength of evidence is tempered by small samples, heterogeneity in comparators and dosing, short follow-up, and inconsistent reporting of clinically meaningful change. Priorities include multicenter randomized trials with standardized sleep and cognitive endpoints, longer observation, head-to-head comparative effectiveness with economic evaluation, adaptive protocols tailored to PD-specific disruptors, and mechanistic studies integrating digital phenotyping and biomarkers to test durability and downstream clinical impact.},
}

@article {pmid41262332,
year = {2025},
author = {Rahm, KK and Kinghorn, BS and Moody, MJ and Stone, BC and Strong, KC and Kim, BS and Chang, YJ and Sleight, SN and Nitz, AA and Hansen, DV and Bailey, MH},
title = {Cellf-deception: human microglia clone 3 (HMC3) cells exhibit more astrocyte-like than microglia-like gene expression.},
journal = {Frontiers in bioinformatics},
volume = {5},
number = {},
pages = {1681811},
pmid = {41262332},
issn = {2673-7647},
abstract = {INTRODUCTION: Recent advances in Alzheimer's research suggest that the brain's immune system plays a critical role in the development and progression of this devastating disease. Microglial cells are vital as immune cells in the brain's defense system. Human Microglia Clone 3 (HMC3) is a cell line developed as a promising experimental model to understand the role of microglial cells in human diseases including Alzheimer's and other neurodegenerative diseases. The frequency of HMC3 cell usage has increased in recent years, with the idea that this cell line could serve as a convenient model for human microglial cell functions.

METHODS: We utilized gene-pair ratios from bulk and single-cell RNA sequencing (scRNA-seq) expression data to create predictive models of cell-type origins.

RESULTS: Our model reveals that the HMC3 cell line represents various cell types, with the highest cell similarity score relating to astrocytes, not microglia.

DISCUSSION: These findings suggest that the HMC3 cell line is not a reliable human microglia model and that extreme caution should be taken when interpreting the results of studies using the HMC3 cell line.},
}

@article {pmid41262225,
year = {2025},
author = {Bayram, E},
title = {Sex and gender differences in Lewy body dementia: a narrative review.},
journal = {Equity neuroscience},
volume = {1},
number = {2},
pages = {},
pmid = {41262225},
issn = {3050-8401},
abstract = {Lewy body dementia (LBD), including Parkinson's disease dementia and dementia with Lewy bodies, is one of the most prevalent and burdensome type of dementias. Clinical diagnostic accuracy during life remains limited and there are currently only symptomatic therapy options without disease modification. However, recent advances in biomarkers and clinical trials are promising. Literature so far showed sex and gender differences in older adults without cognitive changes, people with all-cause dementia, Alzheimer's disease, and Parkinson's disease. While the number of studies in LBD are lower, understanding sex and gender differences and the underlying reasons can improve both diagnosis and treatment for LBD. Accordingly, the aim of this narrative review is to provide a summary of the literature for sex and gender differences in LBD. Majority of the studies for LBD investigating sex/gender differences so far focused on sex, with sex and gender terms being misused at times. Experiences of people in non-binary categories for sex or gender have yet to be investigated. While more research is needed, findings so far outline sex differences in prevalence, risk factors, biomarkers, symptoms, progression, treatment, daily life, and pathology for LBD. Sex-specific risk factors have also been reported, emphasizing the value of sex-stratified analyses and investigating female/male-specific factors such as sex hormones, menopause, and sex chromosomes. Lack of adequate research representation for females and women, as well as people from non-binary categories, is an important limitation that should be addressed to obtain more applicable findings in LBD.},
}

@article {pmid41262081,
year = {2025},
author = {Jamalinia, M and Zare, F and Lonardo, A},
title = {Liver Fibrosis and Risk of Incident Dementia in the General Population: Systematic Review With Meta-Analysis.},
journal = {Health science reports},
volume = {8},
number = {11},
pages = {e71530},
pmid = {41262081},
issn = {2398-8835},
abstract = {BACKGROUND AND AIMS: The relationship between liver fibrosis and the risk of developing dementia remains unclear, with studies yielding inconsistent results. This systematic review and meta-analysis seek to synthesize the available evidence.

METHODS: We systematically searched PubMed, Scopus, Embase, and Web of Science from their respective inception through October 2024 to identify observational studies diagnosing liver fibrosis non-invasively or via histology. The primary outcome was new-onset dementia. Risk of bias was evaluated using the Newcastle-Ottawa Scale (NOS), and pooled estimates of hazard ratios (HRs) with 95% confidence intervals (CIs) were calculated using a random-effects model.

RESULTS: Eight longitudinal cohorts, including 1,115,759 middle-aged individuals (31,129 with liver fibrosis at baseline), identified 29,923 new dementia cases over a mean follow-up of 14 years. Liver fibrosis exhibited a 32% increased risk of developing all-cause dementia (pooled HR: 1.32, 95% CI: 1.08-1.61; I² = 76.06%). Dementia risk increased with fibrosis severity: HR 1.06 (95% CI: 0.67-1.68) in ≥F2, HR 1.32 (95% CI: 1.06-1.64) in ≥F3, and HR 1.69 (95% CI: 1.01-2.83) in F4. Geographically, the risk appeared higher in Western than Eastern countries. Women had a greater risk, and vascular dementia was more strongly associated with fibrosis than Alzheimer's disease. Sensitivity analyses confirmed the robustness of the findings, and no publication bias was observed.

CONCLUSION: Liver fibrosis is linked to a 32% increased long-term dementia risk, independent of common demographic, social, anthropometric, and cardiometabolic factors. Fibrosis severity further increases this risk. Based on our findings, healthcare professionals should recognize the moderately increased risk of developing dementia in individuals with liver fibrosis and perform close surveillance of these patients to enable early detection and timely intervention.},
}

@article {pmid41261930,
year = {2025},
author = {Sutnikiene, V and Pakulaite-Kazliene, G and Audronyte, E and Kuzmickaite, J and Kaubrys, G},
title = {Time/Movement Estimation and Mental Rotation Tasks as Early Cognitive Markers in Alzheimer's Disease.},
journal = {Brain and behavior},
volume = {15},
number = {11},
pages = {e71077},
doi = {10.1002/brb3.71077},
pmid = {41261930},
issn = {2162-3279},
mesh = {Humans ; *Alzheimer Disease/diagnosis/physiopathology/psychology ; Male ; Female ; Aged ; Cross-Sectional Studies ; *Cognitive Dysfunction/diagnosis/physiopathology ; Neuropsychological Tests ; *Time Perception/physiology ; Aged, 80 and over ; Middle Aged ; Rotation ; Cognition/physiology ; },
abstract = {INTRODUCTION: Cognitive impairments, including memory decline and executive dysfunction, are well-documented in Alzheimer's disease (AD); however, distortions in temporal judgment, motion perception and mental rotation in the early stages remain underexplored. Existing research has predominantly relied on verbal time-estimation tasks, with a limited investigation into alternative paradigms, such as time reproduction or bisection tasks. This study investigated the diagnostic utility of time-movement estimation and mental rotation tasks from the psychology experiment building language (PEBL) test battery for identifying early cognitive impairment. Moreover, it assessed correlations among task performance, cognitive test scores, and demographic variables.

METHODS: This cross-sectional study included 28 patients with mild dementia (MD), 27 with amnestic mild cognitive impairment (MCI), and 26 with normal cognitive function as the control cohort (CC). Participants completed the mini-mental state examination, clinical dementia rating assessments, Alzheimer's disease assessment scale-cognitive subscale 13 (ADAS-Cog 13), and PEBL-based Time-Wall and mental rotation tasks.

RESULTS: Time-Wall task inaccuracy scores exhibited strong diagnostic accuracy in distinguishing between the CC and early AD (MCI and MD), with an AUC of 0.9, and effectively differentiated CC from MCI, with an AUC of 0.86. Conversely, the mental rotation task exhibited weaker diagnostic properties, with AUC values of 0.75 for distinguishing CC from early AD and 0.71 for distinguishing CC from MCI. The multinomial logistic regression model accurately categorized 75.3% of participants (CC = 92.3%, MCI = 59.3%, and MD = 75%), utilizing demographic data and ADAS-Cog 13 and Time-Wall inaccuracy scores as predictors. Both ADAS-Cog 13 and Time-Wall task inaccuracy scores were statistically significant predictors (X[2] = 49.41, p < 0.001; X[2] = 9.24, p = 0.01, respectively). Time-Wall task inaccuracy scores did not notably correlate with age.

CONCLUSIONS: The Time-Wall task showed strong diagnostic utility in identifying early AD, independent of age. The mental rotation task exhibited low sensitivity and requires further investigation regarding its potential to reflect compensatory brain network functions.},
}

Humans
*Alzheimer Disease/diagnosis/physiopathology/psychology
Male
Female
Aged
Cross-Sectional Studies
*Cognitive Dysfunction/diagnosis/physiopathology
Neuropsychological Tests
*Time Perception/physiology
Aged, 80 and over
Middle Aged
Rotation
Cognition/physiology

@article {pmid41261682,
year = {2025},
author = {Huang, X and Wang, X and Yang, Y and Chen, H},
title = {Assessing the potential causal influence of myasthenia gravis on neurodegenerative diseases via multivariable Mendelian randomization.},
journal = {Medicine},
volume = {104},
number = {44},
pages = {e45340},
pmid = {41261682},
issn = {1536-5964},
mesh = {Humans ; Mendelian Randomization Analysis ; *Myasthenia Gravis/genetics/complications/epidemiology ; Genome-Wide Association Study ; *Neurodegenerative Diseases/genetics/etiology/epidemiology ; Amyotrophic Lateral Sclerosis/genetics ; Alzheimer Disease/genetics/epidemiology/etiology ; Parkinson Disease/genetics ; Genetic Predisposition to Disease ; Risk Factors ; },
abstract = {Myasthenia gravis (MG), an autoimmune condition known for impairing neuromuscular signaling, has increasingly been implicated in broader neurological dysfunctions. Recent studies point toward a possible connection between autoimmune and neurodegenerative processes. However, whether MG contributes causally to the onset of major neurodegenerative disorders such as Alzheimer disease (AD), Parkinson disease (PD), and amyotrophic lateral sclerosis (ALS) remains unclear. This study utilizes Mendelian randomization (MR) to explore the potential causal influence of MG on these disorders from a genetic standpoint. A univariable Mendelian randomization (UVMR) framework was employed using summary-level data from genome-wide association studies (GWAS) to evaluate the effect of MG on the risk of AD, PD, and ALS. To confirm the robustness of the association between MG and AD, 2 independent AD GWAS datasets were incorporated for external replication, followed by a meta-analysis to combine the evidence. Additionally, multivariable Mendelian randomization (MVMR) was conducted to adjust for smoking behavior as a potential confounding factor. The UVMR analysis revealed a statistically significant causal relationship between MG and increased susceptibility to AD (odds ratio (OR): 1.037; 95% confidence interval (CI): 1.007-1.068; P = .016). No significant causal effects were observed for PD (OR: 1.019; 95% CI: 0.964-1.077; P = .509) or ALS (OR: 1.055; 95% CI: 0.977-1.140; P = .171). The association between MG and AD was consistently validated in 2 independent datasets (ieu-a-297: OR = 1.084; 95% CI: 1.017-1.156; P = .013; ieu-b-2: OR = 1.054; 95% CI: 1.006-1.104; P = .027). Meta-analysis reinforced the evidence supporting MG as a risk factor for AD (OR: 1.047; 95% CI: 1.023-1.072; P < .001). Furthermore, MVMR adjusting for smoking confirmed that MG independently contributes to AD risk (OR: 1.037; 95% CI: 1.006-1.069; P = .020). This study provides robust genetic evidence suggesting that MG is a causal and independent risk factor for AD. These findings highlight a novel link between autoimmunity and neurodegeneration, offering new directions for mechanistic and therapeutic research.},
}

Humans
Mendelian Randomization Analysis
*Myasthenia Gravis/genetics/complications/epidemiology
Genome-Wide Association Study
*Neurodegenerative Diseases/genetics/etiology/epidemiology
Amyotrophic Lateral Sclerosis/genetics
Alzheimer Disease/genetics/epidemiology/etiology
Parkinson Disease/genetics
Genetic Predisposition to Disease
Risk Factors

@article {pmid41261525,
year = {2025},
author = {Wu, S and Chen, L and He, Y and Liu, J and Deng, Z and Chen, Y and Sheng, Z and Xia, B and Tan, Y and Pan, S and Lu, N and Yu, W and Lü, Y},
title = {MIND diet adherence and cognitive function in Alzheimer's disease: Mediating roles of neural oscillatory markers from resting-state EEG.},
journal = {Psychiatry and clinical neurosciences},
volume = {},
number = {},
pages = {},
doi = {10.1111/pcn.13923},
pmid = {41261525},
issn = {1440-1819},
support = {CYB240194//Chongqing Municipal Education Commission/ ; KJZD-K202200405//Chongqing Municipal Education Commission/ ; cstc2022ycjh-bgzxm0184//Chongqing Municipal Education Commission/ ; 2021ZD0201802//National Natural Science Foundation of China/ ; CYYY-BSYJSKYCXXM202439//Chongqing Medical University/ ; W0166//Chongqing Medical University/ ; },
abstract = {AIM: Adherence to the Mediterranean-dietary approaches to stop hypertension (DASH) intervention for neurodegenerative delay (MIND) diet has been associated with a reduced risk of dementia, yet clinical and mechanistic evidence is limited. This study aims to explore the relationship between MIND diet adherence and cognitive function in Alzheimer's disease (AD), with a specific focus on resting-state EEG to investigate the underlying mechanisms.

METHODS: We evaluated 841 memory clinic participants: 119 cognitively normal, 255 with mild cognitive impairment, and 467 with AD. Cognitive, dietary, neuropsychiatric, and functional data were collected. EEG from 204 participants was analyzed for spectral and connectivity features.

RESULTS: MIND scores were significantly lower in the AD group (P < 0.001). Higher MIND adherence was linked to better global cognition, lower dementia severity, fewer mood symptoms, and greater daily functioning (P < 0.05). Individuals in the lowest adherence tertile had 6.78 times higher odds of cognitive impairment compared to those in the highest tertile (OR = 6.78, 95% CI: 4.54-10.13, P < 0.001). EEG analyses revealed that greater MIND adherence was associated with increased alpha power, reduced occipital theta/beta and delta/alpha ratios, and stronger frontoparietal connectivity. Mediation analysis indicated that frontal and global alpha power partially mediated the associations between MIND diet adherence and dementia severity, mood symptoms, and functional status.

CONCLUSIONS: High MIND adherence is associated with improved cognitive and functional outcomes in AD. EEG signatures may partially mediate these effects, highlighting the clinical potential of the MIND diet for early intervention and neurophysiological monitoring.},
}

@article {pmid41261494,
year = {2025},
author = {Yang, HJ and Song, JM and Park, JH},
title = {Independent Role of White Matter Hyperintensity Volume and Location in Alzheimer's Disease Risk Beyond Hippocampal Atrophy.},
journal = {Psychiatry investigation},
volume = {},
number = {},
pages = {},
doi = {10.30773/pi.2025.0127},
pmid = {41261494},
issn = {1738-3684},
abstract = {OBJECTIVE: Increases in white matter hyperintensities (WMH) observed on brain MRI are associated with the onset of Alzheimer's disease (AD) and cognitive decline. Recent hypotheses suggest that the impact of WMH on cognition may differ by their distance from the ventricular surface. This study aimed to investigate the effects of WMH volume and location, classified by distance from the ventricular surface, on cognitive function in individuals with AD.

METHODS: A total of 112 normal cognition (NC) individuals and 171 patients with AD underwent clinical evaluation, volumetric MRI, and neuropsychological testing using the Korean version of the Consortium to Establish a Registry for Alzheimer's Disease. WMH volume was categorized as juxtaventricular (JVWMH, <3 mm from ventricle), periventricular (PVWMH, 3-13 mm), and deep (DWMH, >13 mm).

RESULTS: The mean WMH volume was significantly higher in AD group (20.7±18.2 mL) than in the NC group (6.8±8.1 mL, p<0.001). A tenfold increase in WMH volume led to a 5.967-fold increased risk of AD (95% confidence interval [CI]=1.550-22.986). A similar risk association was observed for PVWMH (OR=4.021, 95% CI=1.592-10.156), and DWMH showed a significant risk association (OR= 2.873, 95% CI=1.227-6.731). Total WMH, JVWMH, and PVWMH were associated with poorer performance in verbal fluency and memory tasks, while DWMH showed no significant cognitive association.

CONCLUSION: WMH volume and location independently contribute to AD risk and cognitive decline, with PVWMH and JVWMH particularly affecting executive and memory functions, regardless of hippocampal atrophy.},
}

@article {pmid41261421,
year = {2025},
author = {Etani, H and Takatori, S and Wang, W and Omi, J and Amiya, Y and Akahori, A and Watanabe, H and Sonn, I and Okano, H and Hara, N and Hasegawa, M and Miyashita, A and Kikuchi, M and Ikeuchi, T and Morishima, M and Saito, Y and Murayama, S and Saito, T and Saido, TC and Takai, T and Ohwada, T and Aoki, J and Tomita, T},
title = {Selective agonism of GPR34 stimulates microglial uptake and clearance of amyloid β fibrils.},
journal = {Alzheimer's research & therapy},
volume = {17},
number = {1},
pages = {248},
pmid = {41261421},
issn = {1758-9193},
mesh = {*Microglia/metabolism/drug effects ; Animals ; *Amyloid beta-Peptides/metabolism ; Humans ; Mice ; *Receptors, G-Protein-Coupled/agonists/metabolism ; Alzheimer Disease/metabolism/pathology ; Phagocytosis/drug effects ; Mice, Transgenic ; Male ; Mice, Inbred C57BL ; Cells, Cultured ; },
abstract = {BACKGROUND: Microglia play a crucial role in brain homeostasis through phagocytosis of amyloid-β (Aβ) fibrils, a hallmark of Alzheimer disease (AD) pathology. The balance between Aβ production and clearance is critical for AD pathogenesis, with impaired clearance mechanisms potentially contributing to disease progression. G-protein coupled receptor 34 (GPR34), a microglia-enriched Gi/o-coupled receptor, is highly expressed in homeostatic microglia and may regulate phagocytic functions, yet its role in Aβ clearance remains poorly understood.

METHODS: Using flow cytometry-based assays, we investigated the effect of a selective GPR34 agonist (M1) on Aβ uptake in mouse primary microglia and human induced pluripotent stem cell-derived microglia. We evaluated uptake specificity across different Aβ species and phagocytic substrates, and measured intracellular cyclic adenosine monophosphate (cAMP) levels to determine the signaling mechanism. We performed in vivo studies using human amyloid precursor protein knock-in mice with intrahippocampal M1 injections. Additionally, we analyzed GPR34 expression in Japanese AD patient brain samples using single-nucleus RNA sequencing and examined age-dependent expression changes across multiple datasets.

RESULTS: M1 specifically enhanced uptake of Aβ fibrils through reduction of intracellular cAMP levels, without affecting monomeric or oligomeric Aβ internalization. Gpr34 knockdown experiments confirmed GPR34 as the molecular target of M1. An intrahippocampal injection of M1 significantly increased microglial Aβ uptake in vivo, an effect that required functional TREM2 signaling. GPR34 expression was significantly reduced in microglia from AD patients and showed age-dependent decline in both humans and mice.

CONCLUSIONS: Our findings identify GPR34 as a promising therapeutic target for enhancing microglial Aβ clearance and highlight the potential of GPR34 agonists for AD treatment. The age-dependent decline in GPR34 expression may contribute to reduced Aβ clearance efficiency in aging brains, exacerbating amyloid accumulation. Pharmacological activation of GPR34 represents a novel strategy to counteract impaired Aβ clearance in both aging and AD brains, potentially modifying disease progression through enhancement of microglial phagocytic function.},
}

*Microglia/metabolism/drug effects
Animals
*Amyloid beta-Peptides/metabolism
Humans
Mice
*Receptors, G-Protein-Coupled/agonists/metabolism
Alzheimer Disease/metabolism/pathology
Phagocytosis/drug effects
Mice, Transgenic
Male
Mice, Inbred C57BL
Cells, Cultured

@article {pmid41261328,
year = {2025},
author = {İlhan, N and Şahin, E and Ildız, S and Samancı, B and Sordu, P and Alaylıoğlu, M and Bilgiç, B and Hanağası, HA and Gürvit, İH and Dursun, E and Gezen-Ak, D},
title = {The CSF Levels of Mitochondrial Phosphoenolpyruvate Carboxykinase 2 as a Novel Biomarker in Alzheimer's Disease.},
journal = {Molecular neurobiology},
volume = {63},
number = {1},
pages = {98},
pmid = {41261328},
issn = {1559-1182},
support = {22AG017 - APYOK2//Türkiye Bilimsel ve Teknolojik Araştırma Kurumu/ ; TYL-2023-37292//Istanbul Üniversitesi-Cerrahpasa/ ; },
mesh = {Humans ; *Alzheimer Disease/cerebrospinal fluid/enzymology ; Biomarkers/cerebrospinal fluid ; Male ; Female ; Aged ; *Mitochondria/enzymology ; Amyloid beta-Peptides/cerebrospinal fluid ; Middle Aged ; Cognitive Dysfunction/cerebrospinal fluid ; ROC Curve ; },
abstract = {Studies have shown that the expression patterns of neurons and glia can be altered by the Aβ fragments. We hypothesized that genes regulated by Aβ-affected transcription factors (TFs) are most impacted by amyloid pathology, leading to significant expression changes. To test this, we focused on three key TFs namely, Jun, Fos, and RELA, and identified 13 common genes they regulate. Given AD-related neurodegeneration disrupts essential cellular processes like mitochondrial function and glucose metabolism, we selected PCK2 as a biomarker candidate from these 13 common genes. The present study included core CSF biomarker validated 154 AD, 41 non-AD MCI patients, and 16 individuals with subjective cognitive impairment. We measured the PCK2 levels in CSF of the cases and controls with ELISA. The PCK2 levels were significantly lower in the CSF of AD cases compared to SCI or non-AD MCI cases. The PCK2 levels of A - individuals were significantly lower than that of A + individuals. Similarly, T - or (N) - individuals exhibit significantly lower levels of CSF PCK2 compared to their + counterparts. Each area under the curve for the ROC analysis of CSF pTau(181)/CSF PCK2 ratio in SCI vs. AD, non-AD MCI vs. AD, A - vs. A + , T - vs. T + and (N) - vs. (N) + were higher than 84%. The sensitivity and specificity of each analysis were at least 76% and 83%; respectively. A positive correlation was determined between CSF PCK2 and Aβ1-42 in AD. PCK2, along with other mitochondrial proteins, could be utilized as a mitochondrial biomarker for neurodegeneration, and PCK2 levels should be investigated in large cohorts for verification.},
}

Humans
*Alzheimer Disease/cerebrospinal fluid/enzymology
Biomarkers/cerebrospinal fluid
Male
Female
Aged
*Mitochondria/enzymology
Amyloid beta-Peptides/cerebrospinal fluid
Middle Aged
Cognitive Dysfunction/cerebrospinal fluid
ROC Curve

@article {pmid41261326,
year = {2025},
author = {Li, S and Wang, D and Li, A and Wang, T and Chen, X and Li, H and Wang, T and Xie, Y and Liang, J and Cai, X},
title = {ZuoGui Pill Ameliorates Alzheimer's Disease-Like Pathology in 3xTg-AD Mice by Targeting Aβ Production, Tau Phosphorylation, Synaptic Loss, and Neuroinflammation.},
journal = {Molecular neurobiology},
volume = {63},
number = {1},
pages = {96},
pmid = {41261326},
issn = {1559-1182},
support = {No. LH2022H059//Heilongjiang University of Chinese Medicine/ ; No. 2021GZ57//Public Welfare Application Research Project of the Huzhou Municipal Science and Technology Bureau/ ; },
mesh = {Animals ; *Alzheimer Disease/drug therapy/pathology/metabolism ; *tau Proteins/metabolism ; *Amyloid beta-Peptides/metabolism/biosynthesis ; *Drugs, Chinese Herbal/pharmacology/therapeutic use ; Mice, Transgenic ; Phosphorylation/drug effects ; *Synapses/drug effects/pathology/metabolism ; *Neuroinflammatory Diseases/drug therapy/pathology/metabolism ; Mice ; Hippocampus/drug effects/pathology/metabolism ; Disease Models, Animal ; Male ; },
abstract = {Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by amyloid-β (Aβ) accumulation, tau hyperphosphorylation, synaptic dysfunction, and chronic neuroinflammation. Current single-target interventions fail to halt disease progression, highlighting the need for multi-target strategies. This study investigates the therapeutic potential and mechanisms of ZuoGui Pill (ZGP), a traditional Chinese medicine formula, in a transgenic AD mouse model. 3xTg-AD mice were treated with ZGP for 60 days. Behavioral performance was assessed using the Morris water maze, novel object recognition, and open field test. Aβ deposition, tau phosphorylation, and synaptic integrity were evaluated via immunohistochemistry, Western blotting, RT-qPCR, and Golgi staining. Neuroinflammation and RAGE/NF-κB signaling were analyzed by ELISA and protein expression profiling. Statistical analyses included ANOVA with post hoc Tukey or Bonferroni tests following Shapiro-Wilk and Bartlett's validation. ZGP significantly improved cognitive performance, reduced hippocampal Aβ deposition and BACE1 expression, and suppressed tau phosphorylation at multiple pathological sites (T205, S396, S404). Synaptic markers (Syn, PSD95) were restored, accompanied by increased dendritic spine density. ZGP also reduced hippocampal IL-1β, IL-6, and TNF-α levels and inhibited the RAGE/p-NF-κB pathway. ZGP exerts multi-target neuroprotective effects in 3xTg-AD mice by modulating Aβ and tau pathologies, preserving synaptic structure, and attenuating RAGE-mediated neuroinflammation. These findings support ZGP as a promising integrative therapeutic strategy for AD.},
}

Animals
*Alzheimer Disease/drug therapy/pathology/metabolism
*tau Proteins/metabolism
*Amyloid beta-Peptides/metabolism/biosynthesis
*Drugs, Chinese Herbal/pharmacology/therapeutic use
Mice, Transgenic
Phosphorylation/drug effects
*Synapses/drug effects/pathology/metabolism
*Neuroinflammatory Diseases/drug therapy/pathology/metabolism
Mice
Hippocampus/drug effects/pathology/metabolism
Disease Models, Animal
Male

@article {pmid41261317,
year = {2025},
author = {Zhou, R and Tian, G and Yu, J and Wang, R and Peng, N and Guo, X and Li, R},
title = {Echinacoside Improves Memory Function and Bone Mineral Density in the Aged SAMP8 Mouse Model.},
journal = {Molecular neurobiology},
volume = {63},
number = {1},
pages = {102},
pmid = {41261317},
issn = {1559-1182},
mesh = {Animals ; Male ; Mice ; *Bone Density/drug effects ; *Aging/drug effects/pathology ; Disease Models, Animal ; *Memory/drug effects ; *Glycosides/pharmacology/therapeutic use ; Osteoporosis/drug therapy ; },
abstract = {Alzheimer's disease (AD) and osteoporosis (OP) are prevalent age-related degenerative diseases that often coexist. Echinacoside (ECH) has been extensively studied for its potential to mitigate AD and bone mineral density (BMD) loss. This study aimed to evaluate the simultaneous therapeutic effects of ECH on AD-OP comorbidity using the senescence-accelerated mouse-prone 8 (SAMP8) model, which exhibits both age-related memory deficits and bone metabolism abnormalities. Six-month-old male SAMP8 mice (n = 8-9) were used as the model group, while age-matched senescence-accelerated mouse resistant 1 (SAMR1) mice served as normal controls. SAMP8 mice were administered ECH intragastrically (100 mg/kg/day) for 10 weeks, while control groups received saline. Behavioral tests, including the open field test (OFT), novel object recognition test (NORT), and Morris Water Maze (MWM), assessed locomotor ability, emotionality, and cognitive functions. Bone microstructure was evaluated using micro-computed tomography (micro-CT), and pathological changes in the brain were analyzed via Western blotting and immunofluorescence. As compared to SAMR1 mice, SAMP8 mice exhibited significant locomotor activity issues, impaired memory (P < 0.05), glial activation (P < 0.01), reduced trabecular bone number (P = 0.007), and altered trabecular separation (P = 0.040). ECH treatment improved memory function and inhibited glial activation (P < 0.05). Bone-related parameters showed that ECH intervention had a trend of improvement in bone health, but this did not reach statistical significance. The SAMP8 model exhibits key features of both AD and OP, making it a valuable tool for investigating their comorbidity and underlying mechanisms. ECH improves cognitive functions and alleviates bone loss, indicating its potential as a therapeutic candidate for AD-OP comorbidity.},
}

Animals
Male
Mice
*Bone Density/drug effects
*Aging/drug effects/pathology
Disease Models, Animal
*Memory/drug effects
*Glycosides/pharmacology/therapeutic use
Osteoporosis/drug therapy

@article {pmid41261299,
year = {2025},
author = {Zhang, R and Wu, K and Yang, Q and Kong, M and Guo, L and You, Q},
title = {Hyperprolactinemia and Brain Health: Exploring the Gut-Brain Axis and Therapeutic Strategies.},
journal = {Molecular neurobiology},
volume = {63},
number = {1},
pages = {101},
pmid = {41261299},
issn = {1559-1182},
mesh = {Humans ; *Hyperprolactinemia/therapy/metabolism ; *Brain/pathology/metabolism ; Animals ; *Gastrointestinal Tract ; Gastrointestinal Microbiome/physiology ; Prolactin/metabolism ; *Brain-Gut Axis/physiology ; },
abstract = {Prolactin is a pituitary anterior lobe hormone that plays a crucial role in milk secretion from the mammary glands. Hyperprolactinemia is a common endocrine disorder characterized by abnormally elevated levels of prolactin in the serum. Recent research findings indicate that prolactin also exerts important physiological effects beyond lactation, including effects on brain health and the central nervous system. The gut-brain axis has become an important area of neuroscience research, providing insights into the complex interactions between the gastrointestinal system and the central nervous system. Future research may involve developing new probiotic therapies or optimizing the gut microbiota through dietary and lifestyle interventions. In addition, understanding the mechanisms by which hyperprolactinemia contributes to various neurological disorders and targeting prolactin for treatment are crucial areas of research. Therefore, this study aimed to investigate the correlation between hyperprolactinemia and brain health from the perspective of the gut-brain axis, with the goal of discovering new approaches for preventing and treating neurodegenerative and mental health conditions. This synthesis highlights potential strategies for future therapeutic interventions.},
}

Humans
*Hyperprolactinemia/therapy/metabolism
*Brain/pathology/metabolism
Animals
*Gastrointestinal Tract
Gastrointestinal Microbiome/physiology
Prolactin/metabolism
*Brain-Gut Axis/physiology

@article {pmid41261295,
year = {2025},
author = {Kritika, and Sood, R and Sanjay, and Lee, HJ},
title = {Nobiletin Reduces LPS-Induced Neuroinflammation through TLR4/MyD88/NF-κB and Oxidative Stress via Nrf2/HO-1 Signaling in Human Microglial HMC3 Cells.},
journal = {Molecular neurobiology},
volume = {63},
number = {1},
pages = {103},
pmid = {41261295},
issn = {1559-1182},
support = {GCU-202401020001//Gachon University research fund of 2023 (GCU-202401020001)/ ; (project No. RS-2022-RD010230)//Cooperative Research Program for Agriculture Science and Technology Development (project No. RS-2022-RD010230), Rural Development Administration, Republic of Korea./ ; },
mesh = {Humans ; *Oxidative Stress/drug effects ; *Myeloid Differentiation Factor 88/metabolism ; *NF-E2-Related Factor 2/metabolism ; *Toll-Like Receptor 4/metabolism ; *Signal Transduction/drug effects ; Lipopolysaccharides ; *NF-kappa B/metabolism ; *Microglia/drug effects/metabolism/pathology ; *Heme Oxygenase-1/metabolism ; *Flavonols/pharmacology ; *Neuroinflammatory Diseases/metabolism/drug therapy/chemically induced/pathology ; *Flavones/pharmacology ; Cell Line ; Inflammation/metabolism/drug therapy ; Reactive Oxygen Species/metabolism ; },
abstract = {Neuroinflammation and oxidative stress (OS) are the major contributors to the onset and progression of neurodegenerative diseases (NDs), where microglial activation and dysregulated inflammatory signaling exacerbate neuronal injury. Nobiletin (NOB), a polymethoxylated flavonoid abundant in citrus fruits, has been reported to possess excellent bioactivities; however, its effects in combating inflammation and OS in human microglial cells (HMC3) have not been comprehensively examined. In this study, we investigated the effects of NOB on lipopolysaccharide (LPS)-induced inflammatory and oxidative responses in HMC3 cells. The HMC3 cells exposed to LPS (1 µg/mL) in the presence/absence of NOB (5, 10, 20, and 40 µM) for 24 h showed that NOB could attenuate LPS-induced cytotoxicity. NOB treatment attenuated LPS-induced upregulation of pro-inflammatory cytokines including interleukin (IL)-1β, and IL-6, and suppressed activation of the toll-like receptor 4/myeloid differentiation primary response 88/nuclear factor kappa-light-chain-enhancer of activated B (TLR4/MyD88/NF-κB) pathway. NOB enhanced the protein expression levels of TLR10, a negative regulator of TLR4-mediated inflammatory signaling. In addition, NOB increased the nuclear factor erythroid 2-related factor 2 (Nrf2) and heme oxygenase-1 (HO-1) expression, along with other antioxidants including catalase (CAT), glutathione peroxidase (GPx), and superoxide dismutase (SOD), leading to reduced intracellular reactive oxygen species (ROS). These findings suggest that NOB has promising anti-inflammatory and antioxidant effects in an in vitro model of LPS-induced neuroinflammation, potentially through modulation of TLR4/MyD88/NF-κB and Nrf2/HO-1 signaling pathways. However, further in vivo studies are needed to validate these effects and explore NOB's potential as a candidate for therapeutic development in NDs.},
}

Humans
*Oxidative Stress/drug effects
*Myeloid Differentiation Factor 88/metabolism
*NF-E2-Related Factor 2/metabolism
*Toll-Like Receptor 4/metabolism
*Signal Transduction/drug effects
Lipopolysaccharides
*NF-kappa B/metabolism
*Microglia/drug effects/metabolism/pathology
*Heme Oxygenase-1/metabolism
*Flavonols/pharmacology
*Neuroinflammatory Diseases/metabolism/drug therapy/chemically induced/pathology
*Flavones/pharmacology
Cell Line
Inflammation/metabolism/drug therapy
Reactive Oxygen Species/metabolism

@article {pmid41261291,
year = {2025},
author = {Singh, L},
title = {Paeonol Mitigates Neurodegeneration: Molecular Insights into Its Anti-inflammatory, Antioxidant, and Synaptoprotective Mechanisms.},
journal = {Molecular neurobiology},
volume = {63},
number = {1},
pages = {94},
pmid = {41261291},
issn = {1559-1182},
mesh = {Humans ; Animals ; *Anti-Inflammatory Agents/pharmacology/therapeutic use ; *Neuroprotective Agents/pharmacology/therapeutic use ; *Acetophenones/pharmacology/therapeutic use ; *Antioxidants/pharmacology/therapeutic use ; *Neurodegenerative Diseases/drug therapy/metabolism/pathology ; *Synapses/drug effects/metabolism/pathology ; Signal Transduction/drug effects ; },
abstract = {Neurodegeneration is the gradual atrophy of the structure and functionality of the neurons, which culminates in the death of the neurons. This pathological process is central to numerous neurodegenerative diseases such as Alzheimer's disease and Parkinson's disease. The global prevalence of neurodegenerative diseases is increasing rapidly, posing a significant public health burden. The various interconnected molecular pathways are disrupted in the pathogenesis of neurodegenerative diseases. Among them, TLR/MyD88/NF-κB and MAPK/NF-κB signaling cascades are critical ones that activate neuroinflammation. Whereas, NLRP3 inflammasome-mediated pyroptosis contributes to inflammatory cell death. Moreover, the BDNF/Trk-B-mediated PI3K/Akt/mTOR pathway controls the synaptic plasticity that is necessary in the learning and memory processes. In addition, caspase and AIF-mediated apoptotic signaling pathways are disrupted in neurodegenerative diseases. Till now, various natural phenolic compounds have shown high potential in combating different neurodegenerative diseases. Paeonol is a 2'-hydroxy-4'-methoxyacetophenone, commonly found in the root bark of Paeonia suffruticosa and other Paeonia species. It possesses diverse pharmacological actions, including neuroprotection, anti-inflammatory, antioxidant and cardioprotective. Various cell lines and preclinical reports have documented that paeonol confers neuroprotection through modulation of various mediators, including TLR4, MAPK, PI3K, mTOR, BDNF, NF-κB, ROS, AMPK, NLRP3, apoptotic proteins and inflammatory mediators, among others. Given that paeonol can modulate these mediators, the current study was designed to investigate the mechanistic interactions that underlie its neuroprotective effects. Examining these interrelated pathways will give future researchers the fundamental knowledge to fill the existing gaps and better understand the potential of paeonol in neurodegenerative diseases.},
}

Humans
Animals
*Anti-Inflammatory Agents/pharmacology/therapeutic use
*Neuroprotective Agents/pharmacology/therapeutic use
*Acetophenones/pharmacology/therapeutic use
*Antioxidants/pharmacology/therapeutic use
*Neurodegenerative Diseases/drug therapy/metabolism/pathology
*Synapses/drug effects/metabolism/pathology
Signal Transduction/drug effects

@article {pmid41261263,
year = {2025},
author = {Peng, XQ and Yang, ZK and Guo, HS and Wu, XY and Ruganzu, JB and Liu, ZZ and Wu, SD and Yang, WN},
title = {TREM2 Alleviates Neuroinflammation and Improves Neurogenesis in ApoE[-/-] Mice by Regulating M1/M2 Microglial Polarization.},
journal = {Molecular neurobiology},
volume = {63},
number = {1},
pages = {105},
pmid = {41261263},
issn = {1559-1182},
support = {2024003//Open Project Program of Xi'an Key Laboratory for Innovation and Translation of Neuroimmunological Diseases/ ; 2023-JC-YB-735; 2024JC-YBMS-615//Natural Science Basic Research Plan in Shaanxi Province of China/ ; },
mesh = {Animals ; *Microglia/metabolism/pathology ; *Neurogenesis/physiology ; *Receptors, Immunologic/metabolism ; Doublecortin Protein ; *Neuroinflammatory Diseases/pathology/metabolism ; *Membrane Glycoproteins/metabolism ; Mice ; *Apolipoproteins E/deficiency ; *Cell Polarity ; Mice, Inbred C57BL ; Hippocampus/pathology/metabolism ; Phosphatidylinositol 3-Kinases/metabolism ; Mice, Knockout ; Male ; Signal Transduction ; },
abstract = {Triggering receptor expressed on myeloid cells 2 (TREM2) is an innate immune receptor abundantly expressed in microglia in the brain. Our previous study indicated that TREM2 promoted microglia polarization to the M2 phenotype in APP/PS1 transgenic mice and BV2 cells. It is reported that M2 microglia release brain-derived neurotrophic factor (BDNF) to enhance adult neurogenesis in the hippocampus. However, the role of TREM2 in hippocampal neurogenesis and the underlying mechanism are still less known. Apolipoprotein E knockout (ApoE[-/-]) mice exhibit cholinergic dysfunction, tau hyperphosphorylation, synaptic loss and dysfunction that may affect brain function and simulate Alzheimer's disease (AD). In this study, overexpression of TREM2 significantly increased the number of minichromosome maintenance 2 (MCM2) and doublecortin (DCX) cells in the subgranular zone (SGZ) of ApoE[-/-] mice. Additionally, the protein levels of MCM2 and DCX showed a similar trend. Furthermore, we found that overexpression of TREM2 promoted a phenotypical switch from M1 to M2 in microglia, as the levels of tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β), and CD86 were decreased, whereas the levels of IL-4, Arginase-1(Arg-1), BDNF, and CD206 were increased. Importantly, overexpression of TREM2 activated the phosphatidylinositol 3-kinase/protein kinase B (PI3K/Akt) and extracellular signal-regulated protein kinase 1 and 2 (ERK1/2) signaling pathways. In vitro, overexpression of TREM2 in primary microglia increased the production of anti-inflammatory factors (IL-4, Arg-1) and BDNF, while decreasing the production of pro-inflammatory factors (TNF-α, IL-1β). Furthermore, conditioned medium (CM) from TREM2 overexpressing primary microglia facilitated neural stem cells (NSCs) proliferation and differentiation into neurons. Moreover, the mechanistic study indicated that overexpression of TREM2 modulated microglial M2 polarization and promoted the proliferation and differentiation of NSCs partly via the PI3K/Akt and ERK1/2 signaling pathways. Collectively, these findings revealed that TREM2 may modulate microglial M2 polarization to inhibit neuroinflammation and increase the M2 microglia-derived BDNF to rescue hippocampal neurogenesis in ApoE[-/-] mice, and TREM2 can be considered a promising therapeutic factor to promote neurogenesis in AD and other brain diseases.},
}

Animals
*Microglia/metabolism/pathology
*Neurogenesis/physiology
*Receptors, Immunologic/metabolism
Doublecortin Protein
*Neuroinflammatory Diseases/pathology/metabolism
*Membrane Glycoproteins/metabolism
Mice
*Apolipoproteins E/deficiency
*Cell Polarity
Mice, Inbred C57BL
Hippocampus/pathology/metabolism
Phosphatidylinositol 3-Kinases/metabolism
Mice, Knockout
Male
Signal Transduction

@article {pmid41261258,
year = {2025},
author = {Rahmani, D and Chodari, L and Kakallahpour, M and Niknam, Z},
title = {Therapeutic Potential of Sodium Butyrate in Neurological and Psychiatric Disorders.},
journal = {Molecular neurobiology},
volume = {63},
number = {1},
pages = {90},
pmid = {41261258},
issn = {1559-1182},
mesh = {Humans ; *Mental Disorders/drug therapy ; Animals ; *Butyric Acid/therapeutic use/pharmacology ; *Nervous System Diseases/drug therapy ; Histone Deacetylase Inhibitors/therapeutic use/pharmacology ; },
abstract = {Neurodegenerative diseases (NDDs), such as Alzheimer's disease (AD), Parkinson's disease (PD), and Huntington's disease (HD), are characterized by progressive neuronal loss associated with neuroinflammation, oxidative stress, and epigenetic dysregulation. Emerging evidence suggests that histone deacetylases (HDACs) are overexpressed in these conditions, making HDAC inhibitors (HDACIs) like sodium butyrate (NaB) promising candidates for therapeutic intervention. In addition, NaB has shown beneficial effects in various psychiatric disorders, including depression, anxiety, and schizophrenia, suggesting a broader neurotherapeutic potential. This review synthesizes findings from various in vitro and in vivo studies investigating the mechanisms and therapeutic applications of NaB, in both neurological and psychiatric disorders. We focus on its role as an HDACI, its impact on histone acetylation and gene expression, its ability to modulate gut microbiota, and its capacity to cross the blood-brain barrier (BBB) to exert neuroprotective effects. NaB demonstrates anti-inflammatory, antioxidant, anti-apoptotic, and neurotrophic properties, contributing to improved cognitive, motor, and behavioral outcomes in multiple models of central nervous system (CNS) dysfunction. Accumulating evidence supports its efficacy not only in NDDs but also in mental health disorders, highlighting its potential as a complementary treatment alongside conventional therapies. Given its multifaceted mechanisms and favorable safety profile, NaB holds promise as a novel therapeutic agent across a spectrum of neurological and psychiatric conditions. Further clinical investigation is warranted to fully establish its translational value.},
}

Humans
*Mental Disorders/drug therapy
Animals
*Butyric Acid/therapeutic use/pharmacology
*Nervous System Diseases/drug therapy
Histone Deacetylase Inhibitors/therapeutic use/pharmacology

@article {pmid41261002,
year = {2025},
author = {Canney, M and Bouchoux, G and Carpentier, A and De Rossi, P},
title = {Repeated blood-brain barrier opening using low-intensity pulsed ultrasound mitigates amyloid pathology.},
journal = {Ultrasound in medicine & biology},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.ultrasmedbio.2025.10.008},
pmid = {41261002},
issn = {1879-291X},
abstract = {OBJECTIVE: The delivery of large molecules to the pathological brain is one of the main obstacles in the development of disease-modifying drugs. This is partly due to the presence of the blood-brain barrier (BBB), which blocks the free passage of lipophobic molecules and those larger than 400 Da. One strategy to bypass this natural barrier is to use low-intensity pulsed ultrasound to oscillate circulating micro-sized microbubbles, which then exert mechanical stress on the vessel walls. This procedure allows for temporary disruption of the BBB and enhanced local delivery of therapeutics from the blood to the brain parenchyma. In this study, the effect of repeated BBB opening on neuroinflammation in a healthy mouse model was first explored, followed by the effect of repeated opening on amyloid-beta (Aβ) pathology in an Alzheimer's disease model.

METHODS: A cohort of wild-type mice was used to determine the effect of a single BBB opening session mediated by ultrasound/microbubbles (US/MBs) on the inflammatory profile via real-time quantitative polymerase chain reaction on brain extracts at 2, 4, 8 and 15 d post-opening. A second cohort of ARTE10 mice, a mouse model for Aβ pathology, was treated with a different sequence of repeated US/MB-mediated BBB opening to explore the effect on Aβ pathology. Tissues were also analyzed for immune cell infiltration, microglia and astrocyte activation, as well as inflammatory response.

RESULTS: Our results demonstrate that opening the BBB leads to a mild inflammatory response in wild-type animals. However, repeated opening of the BBB in the ARTE10 model resulted in a mild decrease in Aβ pathology, along with a mild increase in growth factor.

CONCLUSION: Altogether, this study suggests that sonication is not only a safe method to deliver therapeutics to the brain but could also have synergistic effects in the treatment of neurodegenerative disease.},
}

@article {pmid41260778,
year = {2025},
author = {Yue, C and Chen, B and Chen, L and Xiong, L and Gong, C and Wang, Z and Liu, G and Li, W and Wang, R and Tang, Y},
title = {KG-CNNDTI: a knowledge graph-enhanced prediction model for drug-target interactions and application in virtual screening of natural products against Alzheimer's disease.},
journal = {Chinese journal of natural medicines},
volume = {23},
number = {11},
pages = {1283-1292},
doi = {10.1016/S1875-5364(25)60980-0},
pmid = {41260778},
issn = {1875-5364},
mesh = {*Alzheimer Disease/drug therapy ; *Biological Products/chemistry/pharmacology/therapeutic use ; Humans ; Neural Networks, Computer ; Machine Learning ; Drug Discovery/methods ; Algorithms ; Drug Evaluation, Preclinical/methods ; },
abstract = {Accurate prediction of drug-target interactions (DTIs) plays a pivotal role in drug discovery, facilitating optimization of lead compounds, drug repurposing and elucidation of drug side effects. However, traditional DTI prediction methods are often limited by incomplete biological data and insufficient representation of protein features. In this study, we proposed KG-CNNDTI, a novel knowledge graph-enhanced framework for DTI prediction, which integrates heterogeneous biological information to improve model generalizability and predictive performance. The proposed model utilized protein embeddings derived from a biomedical knowledge graph via the Node2Vec algorithm, which were further enriched with contextualized sequence representations obtained from ProteinBERT. For compound representation, multiple molecular fingerprint schemes alongside the Uni-Mol pre-trained model were evaluated. The fused representations served as inputs to both classical machine learning models and a convolutional neural network-based predictor. Experimental evaluations across benchmark datasets demonstrated that KG-CNNDTI achieved superior performance compared to state-of-the-art methods, particularly in terms of Precision, Recall, F1-Score and area under the precision-recall curve (AUPR). Ablation analysis highlighted the substantial contribution of knowledge graph-derived features. Moreover, KG-CNNDTI was employed for virtual screening of natural products against Alzheimer's disease, resulting in 40 candidate compounds. 5 were supported by literature evidence, among which 3 were further validated in vitro assays.},
}

*Alzheimer Disease/drug therapy
*Biological Products/chemistry/pharmacology/therapeutic use
Humans
Neural Networks, Computer
Machine Learning
Drug Discovery/methods
Algorithms
Drug Evaluation, Preclinical/methods

@article {pmid41260674,
year = {2025},
author = {Finn, Q and Pascual, B and Schultz, PE and Masdeu, JC},
title = {β-amyloid PET signal reduction in prior ARIA-E regions after anti-amyloid therapy for Alzheimer's disease.},
journal = {AJNR. American journal of neuroradiology},
volume = {},
number = {},
pages = {},
doi = {10.3174/ajnr.A9111},
pmid = {41260674},
issn = {1936-959X},
abstract = {BACKGROUND AND PURPOSE: The relationship between regional brain edema caused by anti-amyloid monoclonal antibodies (ARIA-E) and the degree of regional β-amyloid (Aβ) positron emission tomography (PET) signal reduction is unknown.

MATERIALS AND METHODS: In patients with moderate or severe ARIA-E, we quantified changes in Aβ PET signal before and after ARIA-E resolution, comparing regions affected by ARIA-E with unaffected regions.

RESULTS: In four of five patients treated with lecanemab or donanemab and who had moderate or severe ARIA-E, Aβ PET signal decreased significantly more in regions that had been involved with ARIA-E.

CONCLUSIONS: Greater regional Aβ PET signal reduction in areas affected by ARIA-E may reflect enhanced local Aβ clearance, reduced tracer binding site availability, impaired glymphatic flow from immune complex deposition, or other mechanisms. The finding of greater regional Aβ PET signal reduction in ARIA-E regions refines the characterization of ARIA-E and raises the possibility that its occurrence may have beneficial as well as adverse implications.

ABBREVIATIONS: ARIA＝ amyloid related imaging abnormalities; Aβ＝ β-amyloid; SUVR = standard uptake value ratio.},
}

@article {pmid41260654,
year = {2025},
author = {Horiuchi, K and Ishikawa, K and Nunomura, S},
title = {Cognitive Impairment and Central Sleep Apnea Secondary to Tortuous Vertebral Artery Compression of the Medulla, Mimicking Alzheimer's Disease: A Case Report.},
journal = {Internal medicine (Tokyo, Japan)},
volume = {},
number = {},
pages = {},
doi = {10.2169/internalmedicine.6282-25},
pmid = {41260654},
issn = {1349-7235},
abstract = {We report the case of a man in his 60s, who was previously diagnosed with Alzheimer's disease and presented with acute respiratory failure. Investigations revealed severe hypercapnia and central sleep apnea. Imaging revealed a tortuous right vertebral artery compressing the ventral medulla. Cerebrospinal fluid analysis showed a normal amyloid-β 1-42/1-40 ratio, and he exhibited pyramidal and autonomic signs of brainstem involvement. Despite microvascular decompression, the patient remained ventilator dependent. This case illustrates that medullary compression can cause central hypoventilation that mimics a neurodegenerative disorder, with cognitive decline driven by chronic hypoxia rather than by Alzheimer's pathology.},
}

@article {pmid41260559,
year = {2025},
author = {Peng, D and Wu, L and Zhang, L and Chen, H and Hu, B and Zhang, Q and Huang, Y},
title = {haFGF14-154 attenuates Aβ1-42-induced neurotoxicity by facilitating BDNF maturation in a neuron-astrocyte co-culture system.},
journal = {Molecular and cellular neurosciences},
volume = {},
number = {},
pages = {104056},
doi = {10.1016/j.mcn.2025.104056},
pmid = {41260559},
issn = {1095-9327},
abstract = {haFGF14-154 improves cognitive impairment in animal models of Alzheimer's disease (AD), but the effects and mechanisms of astrocytes on the neuroprotection mediated by haFGF14-154 remain unclear. Here, a neuron-astrocyte co-culture system was established to investigate the functions of astrocytes. The results showed that astrocytes strengthened the protective effect of haFGF14-154 on Aβ1-42-treated neurons. This enhanced protective function of haFGF14-154 correlates with phenotypic transition in astrocytes, as demonstrated by the suppression of Aβ1-42-induced A1-like genes and the elevation of A2-like markers in vitro. These observations are consistent with the reduction of GFAP and C3 levels in the hippocampus and prefrontal cortex of APP/PS1 mice treated with haFGF14-154. haFGF14-154 modified the function of astrocytes by activating the AKT/CREB/BDNF pathway, thereby promoting neurite growth. Moreover, haFGF14-154 up-regulated the expression of Furin and MMP9 in astrocytes, leading to the processing of pro-BDNF. This effect was replicated in APP/PS1 mice administered with haFGF14-154. Compared to the Aβ group, the BDNF level in the co-culture system supernatant was increased, while the IL-1β level was decreased following haFGF14-154 treatment. Additionally, haFGF14-154 inhibited neuronal apoptosis in the co-culture system, as evidenced by a decrease in pro-BDNF/P75[NTR], an increase in Bcl-2, and a reduction of Bad and Cleaved-caspase-3. In conclusion, current results demonstrate that astrocytes are crucial for mediating the protective effect of haFGF14-154 against neuronal damage, and underline the importance of the AKT/CREB/BDNF pathway in promoting neurite growth and attenuating neuronal apoptosis.},
}

@article {pmid41260522,
year = {2025},
author = {Park, JK and Kim, HG and Lee, JS and Joo, JH and Yoo, HR},
title = {Traditional Herbal Medicine Ga-Mi Gongjindan Improves Muscarinic Cholinergic Dysfunction through Regulation of BDNF/CREB Signaling Pathway Using a Scopolamine-Induced Cognitive Impairment of Mouse Model.},
journal = {Brain research bulletin},
volume = {},
number = {},
pages = {111644},
doi = {10.1016/j.brainresbull.2025.111644},
pmid = {41260522},
issn = {1873-2747},
abstract = {BACKGROUND: Neurodegenerative diseases, such as Alzheimer's disease (AD), are characterized by progressive memory loss and cognitive dysfunction, often linked to cholinergic system deterioration and hippocampal oxidative stress. Current pharmacological treatments offer only modest symptomatic relief and are often accompanied by adverse effects. In traditional Korean medicine, Ga-Mi Gongjindan (GJD), a modified formulation of Gongjindan, has long been used for enhancing cognitive function, but its neuropharmacological basis remains largely unexplored.

OBJECTIVE: This study aimed to investigate the neuroprotective potential and underlying mechanisms of GJD in a murine model of scopolamine-induced cognitive impairment, which mimics aspects of muscarinic cholinergic dysfunction observed in Alzheimer's disease (AD).

METHODS: C57BL/6J mice were administered GJD or tacrine (positive control) for 14 days. Cognitive impairment was induced by a single intraperitoneal injection of scopolamine (2mg/kg), and behavioral analysis was assessed using the Morris Water Maze. Hippocampal tissues were analyzed for markers of oxidative stress, inflammation, cholinergic function, and neurotrophic signaling by focusing on the BDNF/CREB signaling pathway.

RESULTS: GJD treatment significantly improved spatial learning and memory performance. It restored cholinergic function by reducing acetylcholinesterase (AChE) activity and increasing choline acetyltransferase (ChAT) levels. GJD also suppressed oxidative stress and neuroinflammation and markedly enhanced hippocampal expression of brain-derived neurotrophic factor (BDNF), cAMP response element-binding protein (CREB), and their receptors (TrkA, TrkB, and M1 mAChR).

CONCLUSION: GJD exerted significant neuroprotective effects in a scopolamine-induced model of cognitive dysfunction, potentially via modulation of cholinergic and BDNF/CREB signaling pathways. These findings provide a scientific rationale for the traditional use of GJD in cognitive disorders and support its further development as a candidate for treating neurodegenerative diseases such as AD.},
}

@article {pmid41260441,
year = {2025},
author = {Hu, K and Mecca, T and Sabatino, G and Satriano, C and Brambilla, L and Dattilo, S and Giglio, V and Di Natale, G and Castiglioni, C and Cunsolo, F and Pappalardo, G},
title = {Functionalizing cryogels with the GPGKLVFF peptide for amyloid-β binding: A comparative study of two synthetic pathways.},
journal = {International journal of biological macromolecules},
volume = {},
number = {},
pages = {149079},
doi = {10.1016/j.ijbiomac.2025.149079},
pmid = {41260441},
issn = {1879-0003},
abstract = {Macroporous cryogels (Cry) represent a versatile class of scaffolds with broad applicability in biomedical fields, including biomolecular immobilization, diagnostic sensing, and tissue engineering. More recently, their application in neuroscience has gained increasing interest as a viable alternative to conventional systems for drug delivery and neural tissue regeneration. A novel aspect of this work is the design and synthesis of cryogels functionalized with a peptide sequence capable of selectively binding β-amyloid (Aβ) peptides, key biomarkers of Alzheimer's Disease (AD). The peptide GPGKLVFF (KL), was covalently linked into the cryogel matrix using two distinct chemical protocols. The first, a one-step procedure, involves the simultaneous polymerization of a 2-hydroxyethyl methacrylate (HEMA)-N,N'-methylenebisacrylamide (MBAA) and different amounts of a methacrylate-conjugate peptide (maa-KL), enabling precise control over the degree of functionalization. The second, a two-step procedure, involves peptide grafting onto a preformed poly-methacrylic acid (pMAA) cryogel, resulting in significantly higher functionalization yields, albeit with less homogeneity in the material. Successful peptide incorporation was confirmed by infrared (IR) and Raman spectroscopy. A straightforward quantification protocol based on comparing the intensities of selected Raman marker bands was developed, allowing detection of grafted peptides even at low concentrations. The morphology of the cryogels was characterized by scanning electron microscopy (SEM) and atomic force microscopy (AFM). The ability of the functionalized cryogels to reversibly bind and release Aβ40 was assessed by electrospray-ionization mass spectrometry (ESI-MS). This study represents a crucial first step toward developing a diagnostic platform for the early detection of β-amyloid proteins in AD.},
}

@article {pmid41260424,
year = {2025},
author = {Yi, L and Tian, Q and Xu, B and Pang, Y and Dong, Z},
title = {Targeting the PS1-ELK1 protein-protein interaction with a peptide-based inhibitor reduces Aβ production and alleviates memory decline in Alzheimer's disease.},
journal = {International journal of biological macromolecules},
volume = {},
number = {},
pages = {149074},
doi = {10.1016/j.ijbiomac.2025.149074},
pmid = {41260424},
issn = {1879-0003},
abstract = {Alzheimer's disease (AD) is a common neurodegenerative disorder among the elderly. Our recent research revealed that increased ELK1 (E-twenty-six (ETS)-like protein 1) in AD competitively binds to the C-terminal fragment of presenilin-1 (PS1-CTF), thereby inhibiting E3 ubiquitin ligase synoviolin (SYVN1)-mediated ubiquitination and degradation of PS1, ultimately aggravating pathological progression. However, the precise molecular interface of this interaction and the therapeutic potential of its targeted disruption remain unknown. In the present study, we identified the critical ELK1-binding epitope within PS1 (amino acids 408-429) and, based on this discovery, developed Tat-PS1408-429, a cell-penetrating peptide containing this sequence that specifically disrupts pathological PS1-ELK1 interaction. Tat-PS1408-429 competitively bound to ELK1, attenuating its interaction with PS1 and promoting SYVN1-mediated PS1 degradation. Importantly, disruption of the PS1-ELK1 interaction with Tat-PS1408-429 substantially diminished amyloidogenic processing of amyloid-β (Aβ) precursor protein (APP), leading to reduced Aβ accumulation and improved cognitive and synaptic function in APP23/PS45 double transgenic AD model mice. Collectively, these findings demonstrate that ELK1 interacts with the PS1408-429 domain and disruption of this interaction by Tat-PS1408-429 can alleviate AD-related neuropathology and memory deficits, highlighting its potential as a promising therapeutic peptide for AD.},
}

@article {pmid41260404,
year = {2025},
author = {Lan, S and Gao, F and Ji, R and Wang, Z and Zang, Z and Wei, Y and Kuang, H and Wang, Z},
title = {Bushen Yinao pill improves cognitive function in Alzheimer's disease rats by regulating PI3K/Akt pathway and intestinal microbiota.},
journal = {Fitoterapia},
volume = {},
number = {},
pages = {106999},
doi = {10.1016/j.fitote.2025.106999},
pmid = {41260404},
issn = {1873-6971},
abstract = {Bushen Yinao Pill (BSYN), a traditional Chinese medicine (TCM), is commonly employed to treat forgetfulness and kidney deficiency. The objective of this research was to explore the curative effect of BSYN in Alzheimer's disease (AD) rats and to delve into its underlying mechanism of action. The chemical composition of BSYN was examined by means of UPLC-Q-TOF-MS/MS. The rat model of AD was established using Aβ1-42, alumina, and D-galactose. Through the Morris Water Maze test (MWM), cognitive function was evaluated. To observe the pathological changes in the hippocampus, Hematoxylin and eosin (HE) staining was applied. The oxidative stress level and cholinergic nerve factors were measured using the enzyme-linked immunosorbent assay (ELISA). Moreover, Western blot was utilized for detecting proteins related to the PI3K/Akt pathway. Gut microbiota composition was analyzed using 16S rDNA sequencing. In total, 203 compounds of BSYN were identified. BSYN significantly improved cognitive performance, reduced hippocampal histopathological damage, and restored markers of oxidative stress. Additionally, BSYN modulated the PI3K/Akt pathway by enhancing p-PI3K and p-Akt expression and downregulating GSK-3β. Gut microbiota analysis revealed that BSYN restored microbial diversity and composition, increasing beneficial bacteria such as Lactobacillus while reducing pro-inflammatory genera like Lachnospiraceae NK4A136. In conclusion, the study revealed that BSYN can improve AD-like pathology in rats by modulating several aspects. These findings provide a mechanistic basis for BSYN's therapeutic potential in AD and support its further development as a novel intervention for neurodegenerative diseases.},
}

@article {pmid41260370,
year = {2025},
author = {Xiao, K and Sayed, H and Xing, J and Zhang, XY and Ai, J and Kirichek, E and Le, GH and Wong, S and Valentino, K and Teopiz, KM and Vinberg, M and Rosenblat, JD and Lo, HKY and Zhang, MC and McIntyre, RS},
title = {The effects of Lithium on Beta-amyloid deposition and tau phosphorylation: A systematic review.},
journal = {Journal of affective disorders},
volume = {},
number = {},
pages = {120721},
doi = {10.1016/j.jad.2025.120721},
pmid = {41260370},
issn = {1573-2517},
abstract = {BACKGROUND: Current anti-amyloid treatments often cause amyloid-related imaging abnormalities in the treatment of Alzheimer's disease (AD). Lithium demonstrates neuroprotective and neurotrophic effects, and preclinical studies indicate it reduces intracerebral amyloid deposition and tau phosphorylation. This systematic review evaluates lithium's effects on beta-amyloid, tau, and cognitive deficits in major neurocognitive disorders.

METHODS: A systematic review of primary research was conducted using Embase, PsycInfo, MEDLINE, and PubMed databases from inception to September 2024, following PRISMA criteria. Animal and adult human studies evaluating lithium monotherapy's effects on AD were included.

RESULTS: Long-term low-dose lithium treatment demonstrates inconsistent efficacy in lowering intracerebral amyloid deposition and reversing AD-related cognitive deficits in preclinical and clinical trials. Lithium potentially slows amyloid plaque formation in pre-plaque stages through increasing heat shock proteins and suppressing protein synthesis in preclinical trials. Intracerebral lithium concentrations above 1 mM reduced phosphorylated tau through promoting tau ubiquitination and inhibiting CDK5 signalling in preclinical trials.

LIMITATIONS: AD currently needs a comprehensive animal model accurately representing human AD symptoms and progression, and more clinical trials are needed. Several included studies utilize peripheral lithium administration, which complicates assessment of effective intracerebral concentrations.

CONCLUSIONS: Lithium potentially reduces intracerebral amyloid deposition and tau phosphorylation in AD animal models and may reverse associated cognitive deficits. Further research should seek to replicate similar findings in larger samples and explore lithium's optimal dosage range in promoting intracerebral amyloid clearance.},
}

@article {pmid41260337,
year = {2025},
author = {Katsinelos, T and Lövestam, S and Qi, C and Ryskeldi-Falcon, B and Macdonald, JA and Stephenson, G and Ghetti, B and McKee, A and Scheres, SHW and Goedert, M},
title = {Seeding biosensor cell line that reproduces the Alzheimer tau fold.},
journal = {The Journal of biological chemistry},
volume = {},
number = {},
pages = {110952},
doi = {10.1016/j.jbc.2025.110952},
pmid = {41260337},
issn = {1083-351X},
abstract = {The assembly of tau protein into amyloid filaments through templated seeding is believed to underlie the propagation of pathology in neurodegenerative diseases, such as Alzheimer's disease (AD) and other tauopathies. A commonly used model system for studying this process is through the induction of tau filament formation in cultured cells following the addition of tau seeds isolated from the human brain. However, little is known about the structures of seeded filaments; some biosensor cell lines are unable to reproduce the tau filament structures from AD, because they overexpress tau fragments that do not cover the whole of the ordered filament core. Here, we describe a novel tau seeding biosensor model in HEK293T cells that overexpress residues K297-E391 of human 4R human tau. The construct contains an N-terminal HA-tag, which allows the specific detection of the amplified template. The biosensor cells detected filaments seeded by material from sporadic 3R + 4R tauopathies, with little activity by seeds from 3R-only or 4R-only tauopathies. The sensitivity of seed detection from 3R + 4R tauopathies in our system was similar or higher than for previously reported biosensors. We also structurally characterised the AD-seeded tau filaments by electron cryo-microscopy (cryo-EM). Most of the cell-derived filaments consisted of two protofilaments with the Alzheimer fold, but with a 'head-to-head' inter-protofilament packing. Our results establish a sensitive biosensor cell line with specificity towards seeds from 3R + 4R tauopathies.},
}

@article {pmid41260286,
year = {2025},
author = {Altındağ, F and Bayır, MH and Alhalboosi, JKI and Yıldızhan, K},
title = {Syringic acid mitigates scopolamine-induced cognitive impairment by regulating PSD-95 and GSK-3β and by preventing neurodegeneration in an Alzheimer-like rat model.},
journal = {Experimental neurology},
volume = {},
number = {},
pages = {115556},
doi = {10.1016/j.expneurol.2025.115556},
pmid = {41260286},
issn = {1090-2430},
abstract = {Alzheimer's disease (AD) is a disorder characterized by progressive cognitive impairment. Syringic acid (SA) is a phenolic compound with many beneficial effects, such as antioxidant, anti-inflammatory, anti-diabetic, anti-carcinogenic, and neuroprotective. Our study aimed to investigate the effects of SA (50 mg/kg/day) on scopolamine (SCO)-induced AD-like condition in rats. Immunohistochemical evaluation was performed using antibodies to postsynaptic density protein 95 (PSD-95), Glycogen synthase kinase-3β (GSK-3β), TNF-α, and caspase-3. The hippocampus was stained with Hematoxylin-Eosin, and the total number of hippocampal neurons and hippocampal volume were calculated using the stereological method. The Y-maze task behavioral test was performed. SCO decreased PSD-95 expression while increasing GSK-3β, TNF-α, and caspase-3 expression. SA treatment increased PSD-95 expression while decreasing GSK-3β, TNF-α, and caspase-3 expression. Compared to the control group, the number of hippocampal neurons was significantly decreased in the Alzheimer's group, but the number of neurons in the SA group was significantly higher than in the Alzheimer's group. Hippocampal volume was lower in the Alzheimer's group, although there was no statistical difference between the groups. SA also improved SCO-induced cognitive impairment. Our study findings suggest that SA may mitigate SCO-induced cognitive impairment in the AD rat model, modulating PSD-95 and GSK-3β and decreasing neuroinflammation and apoptosis.},
}

@article {pmid41260167,
year = {2025},
author = {Wang, X and Li, W and Liu, X and Liang, J and Wang, L and Liu, G and Liu, Y and Song, M and Li, Z and Guo, Y and Li, S and Fu, N and Zhang, B},
title = {Celastrol as a neuroprotective drug: current status and challenges.},
journal = {International immunopharmacology},
volume = {168},
number = {Pt 2},
pages = {115846},
doi = {10.1016/j.intimp.2025.115846},
pmid = {41260167},
issn = {1878-1705},
abstract = {Neurological disorders are increasing worldwide, imposing a major social and economic burden. Therefore, there is an urgent need to explore effective treatment methods to alleviate neurological disorders. Celastrol, derived from the traditional Chinese medicine Tripterygium wilfordii Hook. f., has been shown in multiple studies to exhibit promising neuroprotective effects in neurodegenerative, including Parkinson's disease, Alzheimer's disease, and spinal cord injury. The targets or pathways through which celastrol exerts its neuroprotective effects are diverse. This paper primarily focuses on in vivo animal models (such as Parkinson's disease mouse models, Alzheimer's disease mouse models) and in vitro cell models (such as neuronal cell lines, primary cultured neurons) experiments to comprehensively summarize the molecular mechanisms underlying celastrol's neuroprotective effects. Celastrol exerts its neuroprotective effects through pathways such as reducing inflammation, activating the autophagy-lysosome pathway, and inhibiting ferroptosis. Additionally, we discuss the current challenges faced by celastrol and potential strategies to address them. Collectively, these findings highlight celastrol as a promising therapeutic candidate, although further pharmacokinetic optimization and clinical validation are essential.},
}

@article {pmid41260107,
year = {2025},
author = {Wang, Y and Li, Y and Zhang, C and Li, M and Zheng, Q},
title = {MRomicsNet: A morphomics-radiomics-driven adaptive topological model for AD diagnosis on clinically routine T1-weighted images.},
journal = {Computer methods and programs in biomedicine},
volume = {274},
number = {},
pages = {109160},
doi = {10.1016/j.cmpb.2025.109160},
pmid = {41260107},
issn = {1872-7565},
abstract = {BACKGROUND AND OBJECTIVE: Both morphomics and radiomics are typical features when constructing brain networks on the clinically routine T1-weighted images (T1WI) in Alzheimer's disease (AD) diagnosis but the integration was rarely reported. The study was to devise a morphomics-radiomics-driven adaptive topological model (MRomicsNet) by leveraging the strengths of morphomics and radiomics in AD representation.

METHODS: An experimental validation between morphomics and radiomics was conducted to clarify the individual strengths in capturing brain topology and brain region features. The MRomicsNet was then conducted by integrating the individual strengths via a deep learning framework. Specifically, the MRomicsNet consisted of a morphomics-based graph convolution channel (morphGCN channel) and a morphomics-radiomics-based graph convolution channel (mrGCN channel). The morphGCN channel was fed with morphomics-based brain network to establish a sparse brain topology by strengthening important inter-regional connections while suppressing irrelevant ones. Given the generated sparse topology and the brain region features by radiomics, the new graph was then established and fed into the mrGCN channel for AD diagnosis.

RESULTS: The MRomicsNet was validated on the ADNI and EDSD datasets with a 10-fold cross-validation strategy. The experimental results demonstrated that the MRomicsNet achieved a relatively large improvement of 5.27% to 13.79% on the ADNI dataset and 3.70% to 10.22% on the EDSD dataset in diagnostic accuracy when compared to the existing methods. The complementary mechanism of the morphomics- vs radiomics-based brain network in AD representation was also validated by a visualization result.

CONCLUSIONS: The MRomicsNet highlighted the potential value of the morphomics and radiomics integration in facilitating T1WI-based structural brain network establishment and its associated AD diagnosis.},
}

@article {pmid41260033,
year = {2025},
author = {Zhang, Q and Zhang, S and Cao, X and Zhi, Y and Guo, Y},
title = {The gut microbiota in post-stroke depression: A systematic review of microbial mechanisms and therapeutic targeting of neuroinflammation.},
journal = {Microbiological research},
volume = {303},
number = {},
pages = {128391},
doi = {10.1016/j.micres.2025.128391},
pmid = {41260033},
issn = {1618-0623},
abstract = {Post-stroke depression (PSD), a frequent and debilitating complication after stroke, severely hinders rehabilitation. Emerging evidence underscores the role of neuroinflammation and the gut microbiota in PSD pathogenesis. This review systematically elaborates the mechanisms by which gut dysbiosis contributes to PSD-related neuroinflammation via immune cell regulation (e.g., Treg/Th17 balance), microbial metabolites (e.g., SCFAs, tryptophan derivatives), and neural pathways (vagus nerve, HPA axis). A key focus is the comparative analysis of the gut microbiota in PSD against major depressive disorder (MDD) and Alzheimer's disease (AD), revealing a unique, stroke-induced microbial signature characterized by a loss of protective symbionts and a bloom of pro-inflammatory taxa. We further discuss the translational potential of microbiota-targeted interventions (e.g., probiotics, prebiotics) for PSD. By integrating clinical microbial ecology with mechanistic insights, this review synthesizes evidence suggesting that the gut microbiome may represent a promising diagnostic and therapeutic target for PSD, offering a distinct perspective from previous literature.},
}

@article {pmid41260015,
year = {2025},
author = {Zhao, S and Dong, Y and Jiang, B and Bai, Y and Wei, W and Wu, Y and Li, C and Chen, J and Wang, M},
title = {Cerebral phosphorus metabolite as imaging biomarkers in Alzheimer's disease: a [31]P magnetic resonance spectroscopy study.},
journal = {NeuroImage. Clinical},
volume = {48},
number = {},
pages = {103904},
doi = {10.1016/j.nicl.2025.103904},
pmid = {41260015},
issn = {2213-1582},
abstract = {This study employed phosphorus-31 magnetic resonance spectroscopic imaging (31P-MRSI) to characterize hippocampal and frontal metabolic alterations in Alzheimer's disease (AD) and to evaluate their associations with cognitive decline. We enrolled 30 patients with AD, 26 with amnestic mild cognitive impairment (aMCI), and 25 healthy controls (HC), all of whom underwent [31]P-MRSI using a 3.0 T MRI scanner with a dual-tuned [1]H/[31]P head coil. Spectroscopic data were acquired from the hippocampus, prefrontal gray matter, and prefrontal white matter regions for subsequent analysis.The results of this study indicate that compared to the HC groups, patients with AD showed a significantly reduced phosphocreatine to inorganic phosphate ratio in the hippocampal region (p = 0.018). Meanwhile, the phosphomonoesters to phosphodiesters (PME/PDE) ratio in both the hippocampus and prefrontal gray matter exhibited a progressive increase along the HC-aMCI-AD disease continuum(all p < 0.001), although the difference between the aMCI and HC groups did not reach statistical significance in the frontal gray matter. Further analysis revealed a association between the elevated PME/PDE ratios in these brain regions and the decline in cognitive function. These findings support the potential of [31]P-MRSI as a noninvasive imaging tool for detecting metabolic alterations associated with Alzheimer's disease, providing important insights for future clinical research and early diagnosis.},
}

@article {pmid41259985,
year = {2025},
author = {Lin, C and Li, Q and Liu, G and Xi, Z and Yan, X and Li, S and He, L and Bai, P},
title = {Fe3O4@MoS2@Au-Ag microsphere-based ultrasensitive immunobiosensor for the early diagnosis of Alzheimer's disease.},
journal = {Talanta},
volume = {299},
number = {},
pages = {129127},
doi = {10.1016/j.talanta.2025.129127},
pmid = {41259985},
issn = {1873-3573},
abstract = {Alzheimer's Disease (AD), a most common neurodegenerative disease, has aroused people's great attention. Amyloid-β 1-42 (Aβ42) from serum/plasma has been listed as Core 1 biomarker in diagnostic guide and explore an ultrasensitive detection method of Aβ42 is of great significance for early AD diagnosis and treatment. Herein, an ultrasensitive fluorescent biosensor for Aβ42 detection is designed, which is composed of Fe3O4@MoS2 microsphere and Au-Ag alloy. Compared with typical single gold nanoparticles in traditional fluorescent biosensor, alloy nanoparticles can generate a stronger electromagnetic field to enhance the fluorescence of quantum dots via surface plasmon resonance, achieve the effect of signal amplification. Importantly, our design significantly improved the limit of detection to 11 ag/mL, with a linear response ranging from 0.1 to 10[4] fg/mL. Moreover, by replacing the detection antibody in the biosensor, it can also be applied to other common AD biomarkers, such as Aβ40 (linear range: 0.1 to 10[5] fg/mL, LOD: 61 ag/mL) and total Tau protein (linear range: 0.1 to 10[5] fg/mL, LOD: 40 ag/mL). The biosensor exhibited excellent performance in both spiked and real serum samples. This fluorescent biosensor based on Au-Ag alloy strategy with ultra-sensitivity and good selectivity, provides a reliable solution for AD's early diagnosis.},
}

@article {pmid41259881,
year = {2025},
author = {Zuliani, G and Gianfredi, V and Veronese, N and Volpe, M and Maggi, S and Onder, G and Silano, M and Nucci, D and Zanetti, M and Benussi, A and Burgio, MI and Fadda, M and Guindani, P and Sollai, S and Cereda, E and Caffarra, P},
title = {Efficacy of Mediterranean diet for the prevention of neurological diseases: A systematic review and meta-analysis featured in the Italian National Guidelines "La Dieta Mediterranea".},
journal = {Nutrition (Burbank, Los Angeles County, Calif.)},
volume = {142},
number = {},
pages = {112990},
doi = {10.1016/j.nut.2025.112990},
pmid = {41259881},
issn = {1873-1244},
abstract = {BACKGROUND: Neurological diseases, including Alzheimer's disease, depression, and Parkinson's disease, pose a growing public health challenge. Dietary patterns, particularly the Mediterranean diet (MD), have been proposed as modifiable factors for prevention. The aim of this systematic review and meta-analysis was to evaluate the association between adherence to the MD and the risk or progression of neurological conditions.

METHODS: This review was conducted in accordance with PRISMA 2020 and MOOSE guidelines. A comprehensive search of PubMed/MEDLINE, Scopus, Embase, and Cochrane Library was performed up to February 28, 2024. Study quality was assessed using the Newcastle-Ottawa Scale, and the certainty of evidence was evaluated with the NUTRIGRADE approach. Pooled effect sizes were computed using a random-effects model and expressed as risk ratios (RR), hazard ratios, or odds ratios, as appropriate.

RESULTS: Forty-five studies involving over 730 000 participants were included. Higher MD adherence was associated with reduced risk or prevalence of Alzheimer's disease (odds ratios = 0.92), mild cognitive impairment (RR = 0.93), depression (RR = 0.96), and Parkinson's disease (RR = 0.90), with moderate certainty of evidence. Limited evidence suggested reduced anxiety and lower mortality among patients with Alzheimer's disease. No significant associations were observed for dementia prevalence or progression from mild cognitive impairment to dementia.

CONCLUSIONS: Greater adherence to the MD is consistently associated with a lower risk of several neurological and mental health conditions. These findings support the promotion of MD-based dietary patterns in clinical and public health strategies to prevent cognitive decline and enhance healthy aging.},
}

@article {pmid41260074,
year = {2025},
author = {Alzarea, SI and Alsaidan, OA and Qasim, S and Alhassan, HH and Alzarea, AI and Alsahli, TG and Alharbi, M and Almutairi, M},
title = {A network pharmacology and in silico approach to target NEU1-mediated microglial activation in neuroinflammation: Validation in an LPS-induced mouse model.},
journal = {Computers in biology and medicine},
volume = {199},
number = {},
pages = {111318},
doi = {10.1016/j.compbiomed.2025.111318},
pmid = {41260074},
issn = {1879-0534},
abstract = {BACKGROUND: Neuroinflammation is a critical driver of neurodegenerative diseases such as Alzheimer's and Parkinson's. Activation of microglia through Toll-like receptor 4 (TLR4) signaling contributes to neuronal dysfunction. Neuraminidase 1 (NEU1) enhances TLR4 activation via desialylation, amplifying inflammatory cascades. This study investigates the therapeutic potential of NEU1 inhibition using Osthole (OST), identified through integrated network pharmacology and in silico modeling, with subsequent in vivo validation.

METHODS: NEU1 inhibitors were predicted using network pharmacology, followed by analysis of NEU1-related neuroinflammatory pathways via protein-protein interaction (PPI) networks, Gene Ontology (GO), and KEGG enrichment. OST, the top-ranked candidate, was evaluated in an LPS-induced neuroinflammation mouse model through behavioral assessments (Locomotor Activity, Y-Maze, Morris Water Maze). qPCR was used to quantify NEU1, CD11b, and cytokines (TNF-α, IL-1β, IL-6) in the hippocampus and prefrontal cortex. Molecular docking and molecular dynamics (MD) simulations were performed to assess OST-NEU1 binding and interaction stability.

RESULTS: OST significantly improved spatial memory in LPS-treated mice, reduced escape latency, and enhanced Y-maze performance. It downregulated NEU1 and CD11b expression, attenuating microglial activation, and suppressed pro-inflammatory cytokine expression. Docking showed a strong binding affinity of OST to NEU1 (-17 kcal/mol), with stable interactions confirmed by MD simulations (low RMSD and residue fluctuations).

CONCLUSION: NEU1 inhibition via OST reduces neuroinflammation and cognitive deficits in vivo. Computational modeling supports OST's stable and specific binding to NEU1, highlighting its potential as a lead compound against neuroinflammation in neurodegenerative disorders.},
}