@article {pmid41144113,
year = {2025},
author = {Dunk, MM and Huang, H and Wang, J and Dove, A and Sakakibara, S and Guo, J and Carballo-Casla, A and Bennett, DA and Xu, W},
title = {The association between a pro-inflammatory diet and brain age in middle-aged and older adults.},
journal = {European journal of epidemiology},
volume = {},
number = {},
pages = {},
pmid = {41144113},
issn = {1573-7284},
abstract = {Pro-inflammatory diets are associated with cognitive decline and dementia, but their impact on brain aging is unclear. We investigated the association between a pro-inflammatory diet and brain age, taking into account age, genetic risk for dementia, and systemic inflammation. UK Biobank participants (N = 21,473) aged 40-70 years and free of neurological disorders were included. The Dietary Inflammatory Index (DII) was calculated from participants' average intake of 31 nutrients, assessed up to five times via 24-h recalls. Participants were categorized into four DII groups (group 1, anti-inflammatory, DII < -2; group 2, DII -2 to < 0; group 3, DII 0 to < 2; group 4, DII ≥ 2), with group 4 reflecting the most pro-inflammatory diet. Brain age was estimated using a machine learning model based on 1079 structural and functional MRI measures, obtained approximately 9 years after baseline. We calculated brain age gap (BAG; brain age minus chronological age), where BAG > 0 reflects a biologically older brain than chronological age. An Alzheimer's disease polygenic risk score (PRSAD), APOE4 status, and a composite score of systemic inflammation (INFLA-score) were determined from baseline blood samples. More pro-inflammatory diets were associated with increasingly greater BAG, with advanced brain age by [Formula: see text]=0.50 [95% CI 0.20, 0.80] years among those in group 4. There were no interactions between DII and age, PRSAD, or APOE4 in relation to BAG, but associations were stronger among adults ≥ 60 years. INFLA-score mediated 8% of the DII-BAG association. These findings suggest that a pro-inflammatory diet may accelerate brain aging, especially in older adults.},
}

@article {pmid41143963,
year = {2025},
author = {Yang, H and You, X and Yue, C and Yu, X and Yue, X and Zheng, X and Yan, X and Li, J and Bi, J and Zhang, L and Wang, P},
title = {Uncovering the cytophenotypic and transcriptomic features of natural killer cells derived from peripheral blood of patients with Alzheimer's disease.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877251390553},
doi = {10.1177/13872877251390553},
pmid = {41143963},
issn = {1875-8908},
abstract = {BackgroundAlzheimer's disease (AD) has been recognized as the most common neurodegenerative disease. Despite immunodysregulation being involved in AD pathogenesis, the systematic and detailed dissection of the cellular and transcriptomic characteristics of natural killer cells (NKs) in peripheral blood of AD patients is largely obscure.ObjectiveTo investigate the cytophenotypic and transcriptomic features of NKs in peripheral blood of AD patients.MethodsWe used flow cytometry assay, co-culturing, RNA-SEQ, multifaceted bioinformatics analyses (e.g., GSEA, GO, KEGG, PCA), and ELISA and qRT-PCR analysis for the comparison of the cytophenotypic and transcriptomic signatures of heathy donors-NKs (HD-NKs) and AD-NKs.ResultsCompared with HD-NKs, AD-NKs showed increase in the content of NKs in peripheral blood mononuclear cells (PBMCs). After a 14-day ex vivo expansion and activation, the content of AD-NKs also revealed a significant increase. Expanded AD-NKs exhibited higher cellular viability and cytotoxicity than HD-NKs. Both HD-NKs and AD-NKs revealed conservations in gene expression profiling and genetic variations, yet with multifaceted variations in diverse gene sets and the concomitant biological processes (e.g., nerve structural organization, negative regulation of immune, Wnt signaling pathway, cytotoxicity against tumor cell lines). Compared to HD-NKs, AD-NKs revealed abnormally high levels of neuroinflammation-related gene expression and cytokine secretion.ConclusionsCollectively, our data indicated the similarities and variations between HD-NKs and AD-NKs both at the cellular and transcriptomic levels, which would supply new references for further dissecting the pathogenesis of AD from the aspect of NKs and benefiting the development of novel therapeutic regimens in the future.},
}

@article {pmid41143929,
year = {2025},
author = {Moreau, A and Tisserand, A and Sanna, L and Botzung, A and Blanc, F and Philippi, N},
title = {Neural correlates of neurovisual deficits in prodromal and mild dementia with Lewy bodies: A voxel-based morphometry study.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877251389634},
doi = {10.1177/13872877251389634},
pmid = {41143929},
issn = {1875-8908},
abstract = {BackgroundDementia with Lewy bodies (DLB) is one of the main degenerative dementias after Alzheimer's disease and is characterized by neurovisual deficits. Volumetric MRI data on these deficits and their neuro-anatomical correlates are lacking.ObjectiveWe propose a volumetric analysis of the neuro-anatomical substrates of neurovisual deficits in DLB, as assessed by subtests of the Visual Object and Space Perception (VOSP) battery and the Rey-Osterrieth Complex Figure (ROCF).MethodsSeventy patients with prodromal to mild DLB were included in the study, along with 23 healthy elderly subjects (NCT01876459). We used VOSP's incomplete letters (LET) for object perception, and dot counting (DOT) for space perception. The ROCF copy was used to assess visuoconstruction. Correlation analyses were performed in voxel-based morphometry (VBM).ResultsVBM analyses showed a positive correlation between LET performance and the left cerebellar hemisphere (p < 0.05, family-wise error). Positive correlations between LET performance and bilateral occipitotemporal cortex were also demonstrated (p < 0.001 uncorrected). VBM analyses showed a positive correlation between DOT performance and both occipitoparietal cortex and cerebellum (p < 0.001 uncorrected). ROCF performance was positively correlated with frontoparietal cortex (p < 0.001 uncorrected).ConclusionsVisuoperceptive performance (i.e., on LET) was associated with the occipitotemporal cortex, corresponding to the "what" pathway, while performance involving visuospatial skills (i.e., on DOT and ROCF) was associated with the occipitoparietal cortex, corresponding to the "where" pathway. The cerebellum also appears to be involved, predominantly in visuoperception (LET). This exploratory work suggests the involvement of the cerebellum in the neurovisual impairment of DLB, alongside other regions classically involved in visuoperception.},
}

@article {pmid41143926,
year = {2025},
author = {Shi, Y and Ma, H and Li, H and Wang, Y and Wang, C and Zhang, N and Luo, G and Wang, Y and Gao, X},
title = {Sennoside A alleviating cognitive impairment in APP/PS1 mice via balancing microbiome metabolism.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877251389922},
doi = {10.1177/13872877251389922},
pmid = {41143926},
issn = {1875-8908},
abstract = {BackgroundThe progression of Alzheimer's disease (AD) is associated with constipation, potentially mediated by gut microbiota. Laxatives have shown potential in improving the cognitive function of AD, but the specific mechanism remains underexplored. Sennoside A (SA), a well-established laxative, is commonly used for treating constipation.ObjectiveThis work used SA as a probe to explore the therapeutic effects and potential mechanisms of laxatives on AD via the gut-brain axis.MethodsFollowing a two-month treatment, behavioral experiments were used to assess the cognitive function. The central pathologies and neuroinflammation were evaluated by histopathology and ELISA. 16S rRNA sequencing, fecal microbiota transplantation and antibiotic treatment were conducted to verify whether SA exerts anti-AD effects via gut microbiota. Further, non-targeted metabolomics coupled with Spearman correlation analysis was employed to elucidate the underlying mechanisms.ResultsSA significantly countered cognitive dysfunction and central pathological damage in APP/PS1 mice. Besides, SA ameliorated gut dysbiosis and affected the metabolic functions of the flora. Furthermore, the therapeutic effects of SA decrease with the depletion of gut microbes and could be transferred with the microbiota. Intriguingly, amino acid metabolism and aminoacyl-tRNA biosynthesis were the main metabolic pathways regulated by SA, consistent with the predicted functions of gut bacteria. Finally, correlation analysis revealed a strong correlation between gut microbes, fecal metabolites, and cognitive ability affected by SA.ConclusionsThe study investigated the efficacy and mechanisms of laxatives represented by SA for AD from the perspective of the gut-brain axis.},
}

@article {pmid41143877,
year = {2025},
author = {Shao, JY and Shen, Y and Li, R and Xiang, XF and Li, CH and Sun, ZY and Chen, S and Zhang, JW},
title = {Relationship between striatal dopaminergic depletion and cognitive milestone in Parkinson's disease: A comprehensive analysis of striatal subregions, laterality, and nonlinear relationships.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877251386839},
doi = {10.1177/13872877251386839},
pmid = {41143877},
issn = {1875-8908},
abstract = {BackgroundIn Parkinson's disease (PD), striatal dopaminergic degeneration follows a posterior-anterior gradient, with asymmetric involvement and an exponential decline in early disease stages. Previous investigations of the relationship between striatal dopamine transporter (DAT) availability and cognitive impairment in PD have been insufficient, especially in longitudinal studies.ObjectiveTo examine the longitudinal associations between baseline DAT availability and cognitive milestone (CogM) from the perspectives of striatal subregions, laterality, and nonlinear threshold effects.MethodsA total of 467 patients with early, sporadic PD without CogM and with available striatal DAT data at baseline were included from the Parkinson's Progression Markers Initiative database. Annual follow-up data over eight years were analyzed. Standard multivariable Cox and restricted cubic spline (RCS) Cox models were used to assess the associations between DAT uptake and CogM. Two-piecewise Cox regression was used to explore potential threshold effects.ResultsThe 8-year cumulative probability of being CogM-free was 66.0%. In multivariable Cox models, DAT uptake in the ipsilateral, but not contralateral, caudate and putamen was inversely associated with CogM. RCS Cox models revealed a linear negative association for the ipsilateral caudate, but an L-shaped association for the ipsilateral putamen. Two-piecewise Cox regression identified a threshold effect at a DAT uptake of 1.04 in the ipsilateral putamen, below which the risk of CogM increased significantly.ConclusionsBaseline ipsilateral caudate DAT uptake shows a linear inverse relationship with CogM, highlighting its potential as an early predictive biomarker. The L-shaped association observed for ipsilateral putamen DAT warrants further mechanistic investigation.},
}

@article {pmid41143875,
year = {2025},
author = {Saak, TM and Tervo, JP and Motter, JN and Overdevest, JB},
title = {Expanding the scope of olfactory evaluation in Alzheimer's disease and related dementias (ADRD): A narrative review of the role for odor memory and recognition in AD/ADRD.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877251389113},
doi = {10.1177/13872877251389113},
pmid = {41143875},
issn = {1875-8908},
abstract = {Olfactory dysfunction (OD) is a well-characterized feature of Alzheimer's disease (AD) and is often one of the earliest functional biomarkers in the disease course. As such, olfactory evaluation shows promise as an important tool in AD screening and may provide insight into pathologic underpinnings and potential treatment pathways. The National Plan to Address Alzheimer's Disease emphasizes the importance of including Alzheimer's disease related dementias (ADRD) in research efforts, and while olfaction is also associated with ADRD, this association is relatively understudied. Additionally, there have been efforts to expand the evaluation of olfactory function to include assessments beyond key domains, such as odor threshold, odor discrimination, and odor identification, which have been the primary focus of most olfaction research in AD/ADRD. Odor recognition memory assessments have been developed primarily for their utility in identifying and stratifying individuals along the AD continuum, although a wide variety of methods have been reported in the literature. In this narrative review, we provide an overview of odor identification, odor threshold, and odor discrimination in AD/ADRD with a specific focus on providing a centralized guide detailing odor recognition memory methods and their utility in AD/ADRD.},
}

@article {pmid41143873,
year = {2025},
author = {Tikkanen, V and Paajanen, TI and Heikkinen, AL and Solje, E and Katisko, K and Kokkola, T and Kärkkäinen, S and Herukka, SK and Huber, N and Haapasalo, A and Hänninen, T and Hublin, C and Koivisto, AM and Virkkala, J and Saari, TT and Portaankorva, AM and Krüger, J},
title = {Combining a computerized cognitive test with serum biomarkers improves detection of early-onset neurodegenerative disorders.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877251389224},
doi = {10.1177/13872877251389224},
pmid = {41143873},
issn = {1875-8908},
abstract = {BackgroundEarly diagnosis of early-onset dementia (EOD) is often challenging. Executive dysfunction is a common symptom in EOD, including Alzheimer's disease (AD). Currently, no specific tools for screening EOD at the primary health care exist. The availability of neuropsychological assessment and biomarker analyses is often limited to specialized memory clinics. However, recent advances in blood-biomarkers and better accessible computerized cognitive tests provide new opportunities.ObjectiveTo investigate the ability of serum biomarkers neurofilament light chain and glial fibrillary acidic protein, combined with a novel computerized Flexible Attention Test (FAT) to distinguish early-onset neurodegenerative disorders from other conditions resulting cognitive symptoms in a diagnostically challenging memory clinic population.MethodsCohort consisted of 206 participants with symptom onset ≤65 years and followed up to 24 months: EOD (n = 54, including 29 AD cases), neurological mild cognitive impairment (MCI-n, n = 34), MCI due to other causes (n = 104), and subjective cognitive decline (n = 14). Serum biomarkers were analyzed using single-molecule array, and discriminative accuracy of individual and combined tests was assessed using Receiver Operating Characteristic and discriminant analyses. FAT was compared to traditional neuropsychological tests.ResultsCombining serum biomarkers with cognitive tests were more accurate in detecting EOD and MCI-n from other conditions (area under the curve, AUC = 0.872) compared to each method individually (AUC = 0.633-0.783). Combination of the FAT and serum biomarkers reached 82.1% accuracy, comparable to traditional neuropsychological tests and biomarkers together (82.3%).ConclusionsIntegrating serum biomarkers with computerized FAT offers a promising strategy for screening EOD early and identifying patients for further evaluation.},
}

@article {pmid41143863,
year = {2025},
author = {Zheng, N and Zhou, Q and Chen, Z and Xie, L and Yang, X and Chen, Z and Wang, F and Sun, Q and Du, J and Lin, J and Li, L and Li, B},
title = {Cuproptosis: mechanisms and links with Alzheimer's Disease.},
journal = {Journal of neurophysiology},
volume = {},
number = {},
pages = {},
doi = {10.1152/jn.00370.2025},
pmid = {41143863},
issn = {1522-1598},
support = {2021B1515140011 & 2022A1515010638 & 2022A1515140067//| National Natural Science Foundation of China-Guangdong Joint Fund (-)/ ; JCYJ20220530150211026//Shenzhen Municipal Science and Technology Innovation Council | Shenzhen Science and Technology Innovation Program ()/ ; },
abstract = {Copper, an essential trace element in the human body, plays a crucial role in various metabolic processes, and its homeostasis imbalance is increasingly recognized as being associated with the pathology of Alzheimer's disease (AD). Notably, elevated levels of serum free copper are linked to cognitive decline in AD patients and may actively contribute to the disease process by promoting Aβ aggregation, tau protein hyperphosphorylation, and oxidative stress. A recent groundbreaking discovery identified a novel, copper-dependent form of regulated cell death-"cuproptosis"-characterized by lipoylated protein aggregation and loss of iron-sulfur clusters. This finding provides a new and compelling mechanistic link between copper overload and neuronal loss in AD. This article reviews the pathogenesis of cuproptosis, its relationship with copper homeostasis in the body, and its role in the pathogenesis of AD, including the regulatory functions of cuproptosis-related genes (CRGs) in AD. Additionally, it explores potential therapeutic strategies aimed at correcting copper imbalance in AD, including the use of copper chelators, lipid peroxidation inhibitors, and antioxidants. These treatments aim to restore copper homeostasis and prevent cuproptosis in Alzheimer's disease. However, the clinical application of these strategies remains challenging due to issues such as poor bioavailability, significant side effects, and insufficient targeting. Therefore, developing an ideal copper chelator for clinical use remains a distant goal. Elucidating the role of cuproptosis in AD not only deepens our understanding of its pathogenesis but also opens innovative avenues for therapeutic intervention, representing a significant frontier in future AD research.},
}

@article {pmid41143676,
year = {2025},
author = {Kim, S and Fields, N},
title = {Video Family Visit for Persons Living with Dementia in Long-Term Service and Support Settings: A Family Perspective.},
journal = {Clinical gerontologist},
volume = {},
number = {},
pages = {1-14},
doi = {10.1080/07317115.2025.2579127},
pmid = {41143676},
issn = {1545-2301},
abstract = {OBJECTIVES: This study explored family perspectives on a six-week video family visit intervention for persons living with dementia in long-term service and support settings, focusing on its barriers and benefits.

METHODS: Semi-structured interviews were conducted with five family members. A conventional content analysis was performed to analyze transcript narratives and identify shared meanings of their experiences during the intervention.

RESULTS: Four themes emerged: (1) Facilitating family connections and emotional well-being; (2) Technology as a barrier and a bridge; (3) The need for structured support; and (4) Adaptability in scheduling. Families noted that video family visits provided opportunities to bridge physical distance and maintain family relationships.

CONCLUSIONS: Video family visits can serve as a valuable tool to facilitate family connections in long-term service and support settings. By addressing technological barriers, incorporating structured support, and adapting to the specific needs of families and persons living with dementia, video family visits can enhance the quality of life for both patients and their families.

CLINICAL IMPLICATIONS: Healthcare professionals can adapt video family visits to support psychosocial well-being of persons living with dementia and their families. Appropriate training for facilitators and families is important for meaningful and quality video family visits.},
}

@article {pmid41143250,
year = {2025},
author = {Dongre, P and Ramesh, M and Govindaraju, T and Inamdar, MS},
title = {Asrij/OCIAD1 contributes to age-associated microglial activation and neuroinflammation in mice.},
journal = {Frontiers in aging neuroscience},
volume = {17},
number = {},
pages = {1674136},
pmid = {41143250},
issn = {1663-4365},
abstract = {Aging is characterized by chronic low-grade neuroinflammation, which increases the risk of neurodegenerative disorders. Neuroinflammation, driven by the activation of astrocytes and microglia, underlies age-associated cognitive deficits. Amplified neuroinflammatory responses to immune challenges are attributed to microglial activation in the aged brain. Despite extensive clinical and experimental evidence linking neuroinflammation to aging, the molecular players that control age-associated neuroinflammatory responses in the brain are not fully understood. Genome-wide association studies (GWAS), proteomics, and transcriptomic datasets have revealed that Asrij/OCIAD1 is a novel aging and Alzheimer's disease (AD)-associated factor. Asrij levels are increased in patients with AD and are known to promote amyloid-beta (Aβ) pathology and microglia-mediated neuroinflammation, which are associated with cognitive dysfunction in AD. Increased levels of Asrij are also reported in the brains of aged wild-type (WT) mice; however, whether this may promote neuroinflammation or be a protective response during aging is not known. To test this, we used young and aged WT and asrij KO mice and showed that normal aging is associated with increased microgliosis and astrocyte activation in WT mice. While young asrij KO mice do not display any differences in glial activation, aged KO mice have reduced microglial and astrocytic activation compared to aged WT mice. This is accompanied by reduced levels of pro-inflammatory mediators and downregulation of STAT3 and NF-κB signaling in the cortex and hippocampus of aged asrij KO mice. Additionally, asrij depletion inhibits LPS-induced microglial activation and neuroinflammation in aged mice. This indicates that Asrij is essential for the neuroinflammatory responses in the brains of aged mice. We propose that identifying pharmaceutical modulators of Asrij could provide novel means to control microglial activation and neuroinflammation during normal aging.},
}

@article {pmid41143248,
year = {2025},
author = {Zhang, HE and Xiao, ML and Ji, JJ and Cheng, YR and Lu, F},
title = {Deciphering Alzheimer's disease transcriptomics: exploration and validation of core genes in tau and Aβ pathological models toward novel therapeutic targets.},
journal = {Frontiers in aging neuroscience},
volume = {17},
number = {},
pages = {1621153},
pmid = {41143248},
issn = {1663-4365},
abstract = {INTRODUCTION: To decode the pathology of Alzheimer's disease (AD), this study employs multi-omics approaches and bioinformatics analyses to explore AD-associated differentially expressed genes (DEGs), dissect the underlying mechanisms, and thereby facilitate the identification of core genes as well as the development of targeted therapeutic strategies.

METHODS: Six independent AD datasets were collected from the Gene Expression Omnibus (GEO) database, and data were processed and normalized using the R software. The evaluation of relationships between differentially expressed genes (DEGs) and AD encompassed differential expression analysis, expression quantitative trait loci (eQTL) analysis, and Mendelian randomization (MR) analysis. Additionally, gene set enrichment analysis (GSEA), immune cell correlation analysis, and Gene Ontology (GO)/Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses were employed to investigate the functional roles and pathways of these genes. Machine learning approaches were applied to identify potential genes from differentially expressed genes (DEGs) associated with AD. The diagnostic performance of these candidate genes was assessed using a nomogram and receiver operating characteristic curves. The expression levels of the identified genes were further validated via quantitative real-time polymerase chain reaction (qRT-PCR).

RESULTS: Differential gene analysis identified 294 highly expressed genes and 330 lowly expressed genes, and MR analysis identified 10 significantly co-expressed genes associated with AD, specifically METTL7A, SERPINB6, VASP, ENTPD2, CXCL1, FIBP, FUCA1, TARBP1, SORCS3, and DMXL2. Noteworthy observations naive CD4[+] T cells in AD, with this distinct from CIBERSORT analysis included the presence of unique immune cell subset further underscoring the critical role of immune processes in the pathogenesis and progression of the disease. METTL7A, SERPINB6, VASP, ENTPD2, FIBP, FUCA1, TARBP1, SORCS3, and DMXL2 were selected for nomogram construction and machine learning-based assessment of diagnostic value, demonstrating considerable diagnostic potential. Furthermore, the significance of the identified key genes was corroborated using both the GEO validation set and qRT-PCR.

CONCLUSION: METTL7A, SERPINB6, VASP, ENTPD2, FIBP, FUCA1, TARBP1, SORCS3, and DMXL2 may regulate the progression of AD. These findings not only deepen our mechanistic understanding of AD pathology but also provide potential candidate genes for the development of targeted therapeutic strategies against AD.},
}

@article {pmid41143243,
year = {2025},
author = {Allué, JA and Sarasa, L and Fandos, N and Gonzalo, R and Sabido-Vera, R and Loscos, J and Romero, J and Sánchez, A and Terencio, J and Matias-Guiu, JA and Piñol-Ripoll, G and Pascual-Lucas, M},
title = {Clinical validation of a plasma-based antibody-free LC-MS method for identifying CSF amyloid positivity in mild cognitive impairment.},
journal = {Frontiers in aging neuroscience},
volume = {17},
number = {},
pages = {1681516},
pmid = {41143243},
issn = {1663-4365},
abstract = {BACKGROUND: The recent approval of monoclonal antibodies for the treatment of Alzheimer's disease (AD) in several countries has accelerated the need for affordable, simple and scalable methods to identify patients who are eligible for treatment with the new disease-modifying therapies (DMT). Blood-based biomarkers offer less invasive alternatives to established gold standards. We have clinically validated a predictive model combining plasma Aβ42/Aβ40, apolipoprotein E (APOE) genotype and age, in two independent real-world cohorts to identify brain amyloid deposition.

METHODS: We conducted a clinical validation study involving 450 patients with mild cognitive impairment (MCI) from two real-world cohorts (HCSC, Madrid, Spain and HUSM, Lleida, Spain). Plasma Aβ42/Aβ40 was measured by ABtest-MS, an antibody-free liquid chromatography-mass spectrometry method. CSF Aβ42/Aβ40 and p-tau181/Aβ42 (gold standards) were quantified with the Lumipulse[®] platform. The model was trained in the HCSC cohort and validated in the HUSM cohort. Finally, an overall analysis in the combined population was performed. A dual cutoff approach was used to classify the patients as positive or negative. Statistical analysis included bootstrap resampling and model calibration.

RESULTS: In the HCSC, HUSM, external validation and combined analysis, AUCs were 0.89 (95% confidence intervals-CI: 0.84-0.93), 0.88 (0.84-0.93), 0.88 (0.83-0.92) and 0.88 (0.84-0.91), with corresponding accuracies of 82.3, 81.6, 82.3, and 81.1%, respectively. After the combined analysis, positive and negative predictive values (PPV and NPV) were established at 87.5%, resulting in cutoff values of 0.30 and 0.67 for the likelihood of amyloid negativity and positivity, respectively, for a prevalence of 62%. Probability values lower than 0.30 indicate low probability of brain amyloid deposition, while values greater than 0.67 indicate high probability. Less than 28% of the participants fell into the intermediate zone. Additional cutoffs were derived for different prevalence values. Predictive model calibration showed excellent agreement with observed data, confirming accurate predictions (slope = 0.98, intercept = -0.01).

CONCLUSION: This predictive model has demonstrated high accuracy for the identification of brain amyloid deposition in patients with MCI. Derived cutoffs enabled over 70% reduction in invasive testing, supporting efficient and cost-effective identification of candidates for DMTs.},
}

@article {pmid41143147,
year = {2025},
author = {Calderone, A and De Luca, R and Calapai, R and Mirabile, A and Quartarone, A and Calabrò, RS},
title = {Beauty in the shadow of neurodegenerative disease: a narrative review on aesthetic experience, neural mechanisms, and therapeutic frontiers.},
journal = {Frontiers in human neuroscience},
volume = {19},
number = {},
pages = {1658617},
pmid = {41143147},
issn = {1662-5161},
abstract = {Neuroaesthetics, an emerging field at the intersection of neuroscience, psychology, and the arts, offers new perspectives on the biological and cognitive mechanisms of aesthetic experience. This narrative review explores the convergence of neuroaesthetics and neurodegenerative disorders, focusing on Alzheimer's disease, Parkinson's disease, frontotemporal dementia, and Huntington's disease. Drawing on evidence from neuroimaging, neuropsychology, and clinical studies, we examine how neurodegenerative processes differentially disrupt the neural systems of the "aesthetic triad": sensory-motor, emotion-valuation, and meaning-knowledge. Such disruptions not only impair patients' ability to perceive and create art but may also reveal unexpected creative capacities. We discuss the therapeutic potential of arts-based interventions, highlighting the benefits of personalized and technology-driven approaches, including immersive virtual reality and digital art platforms, to enhance neurorehabilitation and psychological wellbeing. The "Michelangelo effect," where engagement in meaningful aesthetic activities supports learning, motivation, and resilience, exemplifies this translational potential. Our synthesis underscores clinical, neuroscientific, and rehabilitative implications, while noting ongoing challenges such as the need for standardized outcomes and interdisciplinary collaboration. Integrating neuroaesthetic principles into neurorehabilitation may help preserve cognitive and motor functions and enrich quality of life and self-concept in people with neurodegenerative disease. Future research should optimize these approaches to ensure meaningful benefits for patients.},
}

@article {pmid41143078,
year = {2025},
author = {Parker, DM and Adams, JN and Kim, S and McMillan, L and Yassa, MA},
title = {NODDI-derived measures of microstructural integrity in medial temporal lobe white matter pathways are associated with Alzheimer's disease pathology and cognition.},
journal = {Imaging neuroscience (Cambridge, Mass.)},
volume = {3},
number = {},
pages = {},
pmid = {41143078},
issn = {2837-6056},
abstract = {Diffusion tensor imaging has traditionally been used to assess white matter (WM) integrity in Alzheimer's disease (AD). However, the tensor model is limited in modeling complex WM structure. Neurite Orientation Dispersion and Density Imaging (NODDI), a cutting-edge technique applied to multishell diffusion MRI, can offer more precise insights into microstructural features of WM integrity. We assessed whether NODDI more sensitively detects AD-related changes in medial temporal lobe (MTL) WM than traditional tensor metrics. In total, 199 older adults with multishell diffusion MRI from ADNI3 (mean age = 75 years; 60% female; cognitively unimpaired, n = 121; cognitively impaired MCI/dementia, n = 77) were analyzed. Tensor metrics of fractional anisotropy (FA) and mean diffusivity (MD), as well as NODDI metrics of Neurite Density Index (NDI) and orientation dispersion Index (ODI), were calculated for MTL WM tracts (JHU Atlas: hippocampal cingulum, fornix column/body, fornix/stria terminalis, and uncinate). A subset of participants received 18F-florbetapir or 18F-florbetaben to measure Aβ (n = 146; converted to Centiloids), 18F-flortaucipir to measure tau (n = 135), and neuropsychological testing including the Clinical Dementia Rating Sum of Boxes (CDR-SB) and memory composite score (ADNI-MEM). NODDI measures in MTL tracts were more strongly correlated with cognitive performance and AD pathology than standard tensor measures. For example, entorhinal tau was strongly associated with NDI in the cingulum hippocampus and the uncinate, and with ODI in the fornix ST. Both ODI and NDI across the majority of tracts were associated with CDR-SB and ADNI-MEM. In contrast, FA in any MTL tract was not significantly correlated with either tau or global amyloid-beta, while MD in MTL tracts showed limited correlations with pathology or cognition. NDI partially mediated the relationship between AD pathology (entorhinal tau, meta temporal tau, or Aβ) and the memory composite score. Random forest modeling showed that a combination of NODDI metrics and DTI had the strongest estimates of memory performance and clinical impairment. NODDI metrics offer more sensitive insights about MTL WM integrity in AD that could have been previously missed due to the limitations of DTI analyses. Additionally, combining NODDI with DTI yielded the strongest predictive performance for memory and clinical impairment, suggesting that the two approaches are complementary. The use of advanced diffusion acquisitions such as multishell which allows for analyses such as NODDI is crucial for the future development of disease identification and structural understanding.},
}

@article {pmid41142952,
year = {2025},
author = {Schu, G and Limberger, C and Brum, WS and De Bastiani, MA and Rodrigues, YE and de Azeredo, JC and Pascoal, TA and Benedet, AL and Mathotaarachchi, S and Rosa-Neto, P and Almeida, J and de Paula Faria, D and de Souza Duran, FL and Buchpiguel, CA and Coutinho, AM and Busatto, GF and Zimmer, ER and , },
title = {Stable brain PET metabolic networks using a multiple sampling scheme.},
journal = {Network neuroscience (Cambridge, Mass.)},
volume = {9},
number = {3},
pages = {1087-1109},
pmid = {41142952},
issn = {2472-1751},
abstract = {Interregional communication within the human brain is essential for maintaining functional integrity. A promising approach for investigating how brain regions communicate relies on the assumption that the brain operates as a complex network. In this context, positron emission tomography (PET) images have been suggested as a valuable source for understanding brain networks. However, such networks are typically assembled through direct computation without accounting for outliers, impacting the reliability of group representative networks. In this study, we used brain [[18]F]fluoro-2-deoxyglucose PET data from 1,227 individuals in the Alzheimer's disease (AD) continuum from the Alzheimer's Disease Neuroimaging Initiative cohort to develop a novel method for constructing stable metabolic brain networks that are resilient to spurious data points. Our multiple sampling scheme generates brain networks with greater stability compared with conventional approaches. The proposed method is robust to imbalanced datasets and requires 50% fewer subjects to achieve stability than the conventional method. We further validated the approach in an independent AD cohort (n = 114) from São Paulo, Brazil (Faculdade de Medicina da Universidade de São Paulo). This innovative method is flexible and improves the robustness of metabolic brain network analyses, supporting better insights into brain connectivity and resilience to data variability across multiple radiotracers for both health and disease.},
}

@article {pmid41142921,
year = {2025},
author = {Tare, M and D'Orsi, B and Singh, A},
title = {Editorial: Cell death mechanisms in neurodegenerative disorders.},
journal = {Frontiers in cell and developmental biology},
volume = {13},
number = {},
pages = {1694173},
pmid = {41142921},
issn = {2296-634X},
}

@article {pmid41142758,
year = {2025},
author = {Scherlo, M and Höveler, A and Mann, M and Gerwert, G and Güldenhaupt, J and Gerwert, K and Rudack, T and Kötting, C},
title = {Replacement of a single residue in an antibody abolishes cognate antigen binding, as predicted by theoretical methods.},
journal = {Computational and structural biotechnology journal},
volume = {27},
number = {},
pages = {4363-4372},
pmid = {41142758},
issn = {2001-0370},
abstract = {Structural insights into the interaction between antibodies and antigens at the atomic level are pivotal for understanding the molecular mechanisms of antigen binding. Despite the availability of structural models generated by recent artificial intelligence advancements, computational predictions require experimental validation to confirm their accuracy. Here, we demonstrate an approach that combines computational protein modeling with spectroscopic experiments to validate antibody-antigen interactions. As a case example we use solanezumab, a monoclonal antibody that targets amyloid-beta (Aβ), whose misfolding is the main factor responsible for Alzheimer's disease. For this antibody, we predicted a single mutation, G95A[HC], within the paratope of the heavy chain to disrupt antigen binding. This mutation, referred to as a "dead mutant", was experimentally validated using an immuno-infrared biosensor (iRS). Our results confirmed that the mutation abolished antigen binding without affecting the native structure of the antibody. The use of dead mutants enables precise differentiation between specific and nonspecific binding, which is particularly important in medical diagnostics. We applied this approach to analyze the binding of solanezumab to synthetically produced Aβ variants and Aβ catched by the iRS functionalized surface from cerebrospinal fluid, showcasing its utility in Alzheimer's disease diagnostics. These findings highlight the value of computational modeling and experimental validation in understanding antigen-antibody interactions, with significant implications for diagnostic and therapeutic applications.},
}

@article {pmid41142740,
year = {2025},
author = {Juengst, SB and Smith, ML and Wilmoth, K and Wright, B and Han, G and Supnet, C and Maestre, G},
title = {Problem-solving training to improve caregiver burden and depressive symptoms among dementia caregivers: personal and clinical factors of responders vs. non-responders.},
journal = {Frontiers in public health},
volume = {13},
number = {},
pages = {1682373},
pmid = {41142740},
issn = {2296-2565},
mesh = {Humans ; Female ; Male ; *Caregivers/psychology/education ; *Problem Solving ; *Depression/therapy/psychology ; Aged ; Middle Aged ; *Dementia/nursing ; *Caregiver Burden/therapy ; Aged, 80 and over ; Adult ; },
abstract = {INTRODUCTION: Metacognitive strategy training interventions, like Problem-Solving Training/Descubriendo Soluciones Juntos (PST/DSJ), have efficacy for improving caregiver burden and depressive symptoms. We previously demonstrated that PST/DSJ improved caregiver burden and depressive symptoms among caregivers of adults with Alzheimer's Disease and related dementias (ADRD), regardless of the number of sessions or boosters received. However, these results did not examine factors characterizing those who responded (improvement in caregiver burden or depressive symptoms) or did not respond to the intervention.

OBJECTIVE: To identify key personal and clinical factors associated with response to PST/DSJ. Personal factors included age, gender, race, Hispanic ethnicity, education, and employment status. Clinical factors included care recipient diagnosis and dementia severity, caregiver problem-solving skills at baseline, caregiving experiences (caregiver life social support, satisfaction and resentment with the caregiving role, anger toward the care recipient, and care recipient aggressive, depressive, and forgetful behaviors), and social disconnection, caregiver burden, and depressive symptoms.

METHOD: We conducted a 2 × 2 randomized controlled optimization trial to test remotely delivered PST/DSJ to ADRD caregivers (NCT04748666). Primary outcomes were caregiver burden, measured by the Zarit Burden Interview (ZBI), and depressive symptoms, measured by the Patient Health Questionnaire-8 (PHQ-8). Response to PST/DSJ was defined for each primary outcome as a clinically important change (defined as ≥1 point on ZBI and ≥3 on PHQ) from baseline to 6-month follow-up.

RESULTS: Ninety-one caregivers were included in responder analysis, with 55 (60.4%) demonstrating a clinically meaningful improvement in caregiver burden and/or depressive symptoms. No personal factors were associated with being a Responder (vs. Non-Responder). Clinical factors associated with being a Responder were greater care recipient dementia severity (FAST score, p < 0.01), lower baseline caregiver life satisfaction (p = 0.05), higher baseline caregiver overload (p = 0.05), higher baseline caregiver burden (p = 0.01), and more baseline depressive symptoms (p < 0.01).

CONCLUSION: Most caregivers demonstrated a clinically meaningful improvement in caregiver burden and/or depressive symptoms after receiving PST/DSJ. Notably, those who responded had higher symptoms of distress, including caregiver burden and overload and depressive symptoms and lower life satisfaction, and had care recipients with more severe dementia, indicating that those benefiting from the intervention were those most in need of this support.

CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov, identifier is NCT04748666.},
}

Humans
Female
Male
*Caregivers/psychology/education
*Problem Solving
*Depression/therapy/psychology
Aged
Middle Aged
*Dementia/nursing
*Caregiver Burden/therapy
Aged, 80 and over
Adult

@article {pmid41142236,
year = {2025},
author = {Yuan, Q and Liu, C and Zhang, Z and Chen, F and Xiao, Q and Zhang, L and Pan, X and He, F and Xiao, M},
title = {Pharmacological advances of the chlorogenic acids family: current insights and future research directions.},
journal = {Frontiers in pharmacology},
volume = {16},
number = {},
pages = {1613048},
pmid = {41142236},
issn = {1663-9812},
abstract = {Phenolic acids are considered an important source for developing natural drugs due to their extensive biological activities. The chlorogenic acids (CGAs) family is the most widely distributed botanical drug in the phenolic acid group and is also commonly found in various traditional Chinese medicine (TCM) extracts. The diverse structural variations of naturally occurring chlorogenic acids result in distinct functions and mechanisms. Recent studies have demonstrated that chlorogenic acid can reduce Aβ plaques in Alzheimer's disease model mice by 37%, indicating its neuroprotective potential. Similarly, CGAs offer protection to the cardiovascular system, gastrointestinal tract, kidneys, and liver, while additionally preventing metabolic syndrome and displaying anticancer and antimicrobial capabilities. The key signaling pathways and factors involved in these effects include PI3K/AKT, NF-κB, JNK, NLRP3, and Keap1/Nrf2. This review, for the first time, provides a comparative analysis of six typical CGAs, systematically reviewing their specific distribution characteristics in traditional Chinese medicinal metabolites, biosynthetic pathways, biological targets, and pharmacological activities. This review provides a reference for the research and rational development and utilization of CGAs.},
}

@article {pmid41141907,
year = {2025},
author = {Blazquez-Folch, J and Limones Andrade, M and Calm, B and Auñón García, JM and Alegret, M and Muñoz, N and Cano, A and Fernández, V and García-Gutiérrez, F and De Rojas, I and García-González, P and Olivé, C and Puerta, R and Capdevila-Bayo, M and Muñoz-Morales, Á and Bayón-Buján, P and Miguel, A and Montrreal, L and Espinosa, A and Sanz-Cartagena, P and Rosende-Roca, M and Zaldua, C and Gabirondo, P and Cantero-Fortiz, Y and Gurruchaga, MJ and Tarraga, L and Boada, M and Ruiz, A and Marquié, M and Valero, S},
title = {Federated learning for cognitive impairment detection using speech data.},
journal = {Frontiers in artificial intelligence},
volume = {8},
number = {},
pages = {1662859},
pmid = {41141907},
issn = {2624-8212},
abstract = {INTRODUCTION: In Alzheimer's disease (AD) research, clinical, neuroimaging, genetic, and biomarker data are vital for advancing its understanding and treatment. However, privacy concerns and limited datasets complicate data sharing. Federated learning (FL) offers a solution by enabling collaborative research while preserving data privacy.

METHODS: This study analyzed data from patients assessed at the Memory Unit of the Ace Alzheimer Center Barcelona who completed a standardized digital speech protocol. Acoustic features extracted from these recordings were used to distinguish between cognitively unimpaired (CU) and cognitively impaired (CI) individuals. The aim was to evaluate how data heterogeneity impacted the FL model performance across three scenarios: (1) equal contributions and class ratios, (2) unequal contributions, and (3) imbalanced class ratios. In each scenario, the performance of local models trained using an MLP feed-forward neural network on institutional data was analyzed and compared to a global model created by aggregating these local models using Federated Averaging (FedAvg) and Iterative Data Aggregation (IDA).

RESULTS: The cohort included 2,239 participants: 221 CU individuals (mean age 66.8, 64.7% female) and 2,018 CI subjects, comprising 1,219 with mild cognitive impairment (mean age 74.3, 61.9% female) and 799 with mild AD dementia (mean age 80.8, 64.8% female). In scenarios 1 and 3, FL provided modest gains in accuracy and AUC. In scenario 2, FL markedly improved performance for the smaller dataset (balanced accuracy rising from 0.51 to 0.80) while preserving 0.86 accuracy in the larger dataset, highlighting scalability across heterogeneous conditions.

CONCLUSION: These findings demonstrate the potential of FL to enable collaborative modeling of speech-based biomarkers for cognitive impairment detection, even under conditions of data imbalance and institutional disparity. This work highlights FL as a scalable and privacy-preserving approach for advancing digital health research in neurodegenerative diseases.},
}

@article {pmid41141840,
year = {2025},
author = {Sumbal, A and Sumbal, R and Ikram, A and Taimuri, MA},
title = {Rising heart failure mortality in Alzheimer's patients: A CDC wonder database analysis of trends and disparities from 1999 to 2020.},
journal = {American heart journal plus : cardiology research and practice},
volume = {59},
number = {},
pages = {100634},
pmid = {41141840},
issn = {2666-6022},
abstract = {INTRODUCTION: Alzheimer's disease and heart failure are two of the most prevalent disorders in the elderly. While AD-HF comorbidity has been described, the impact of HF on mortality in AD patients is less well characterized. Understanding these trends is vital, as HF-related mortality may represent a preventable contributor with important implications for prognosis, clinical care, and healthcare planning. This study aims to analyze national trends in HF-related mortality in AD patients across demographic and geographical subgroups in the United States from 1999 to 2020.

METHODS: A retrospective analysis of CDC WONDER data was conducted. Age-adjusted mortality rates (AAMRs) and crude mortality rates (CMRs) were calculated. Joinpoint regression analysis assessed annual percent change (APC) in mortality trends, with stratification by sub-groups like age, sex, race/ethnicity, and geographic region (including census, rural-urban and state level).

RESULTS: A total of 88,481 HF-related deaths were recorded in AD patients. An almost double increase in AAMR was noted, from 6.5 in 1999 to 12.1 in 2020. Female gender (overall AAMR: 10.2) and NH whites (overall AAMR: 9.8) exhibited the highest overall AAMRs. Geographically, higher mortality was observed in the West (overall AAMR: 10.9) and rural regions (overall AAMR: 11.9). Additionally, people aged 80-84 demonstrated the highest overall CMR (overall CMR: 11.9).

CONCLUSION: HF-related deaths in Alzheimer's patients have risen sharply over two decades, disproportionately affecting older adults, women, NH Whites, and rural residents. These findings highlight the urgent need for targeted interventions to address rising mortality in this vulnerable population.},
}

@article {pmid41141733,
year = {2025},
author = {Granzotto, A and Fullone, R and Miccoli, L and Bomba, M and Di Marzio, C and Delli Pizzi, S and Floresta, G and Sensi, SL},
title = {Potential Off-Target Interaction of the Amyloid PET Imaging Tracer PiB with Acetylcholinesterase.},
journal = {ACS omega},
volume = {10},
number = {41},
pages = {48544-48550},
pmid = {41141733},
issn = {2470-1343},
abstract = {Pittsburgh compound B (PiB) is a widely used Positron Emission Tomography (PET) tracer for detecting amyloid-β (Aβ) deposits in Alzheimer's disease (AD). While PiB is assumed to bind selectively to Aβ, emerging evidence suggests off-target interactions that may complicate PET signal interpretation. Here, we report that PiB can interact with acetylcholinesterase (AChE), a key enzyme in the cholinergic system. Similarity screening identified the AChE ligand thioflavin T (ThT) as the top structural analogue of PiB. Docking studies and molecular dynamics simulations showed that PiB stably binds the peripheral anionic site (PAS) of AChE, with binding energies comparable to ThT and clinically relevant AChE inhibitors. In vitro fluorescence-based assays confirmed this interaction and suggest an involvement of the PAS. These findings indicate a plausible, stable off-target interaction between PiB and AChE with implications for interpreting PiB-PET signals in AD, particularly in reference regions with altered AChE expression or under AChE inhibitor therapy.},
}

@article {pmid41141728,
year = {2025},
author = {Larralde, C and Pradeau-Phélut, L and Alvès, S and Percevault, F and Primig, M and Huclier-Markai, S and Garnier, C},
title = {Natural L-Hexapeptides with Therapeutic Potential for Alzheimer's Disease and Tauopathies.},
journal = {ACS omega},
volume = {10},
number = {41},
pages = {48531-48543},
pmid = {41141728},
issn = {2470-1343},
abstract = {Alzheimer's disease and tauopathies are partly caused by tau protein fibrillation. The tau's PHF6/β1 sequence 306VQIVYK311 plays a central role in protein self-assembly, acting as a nucleation center. We aimed to identify new therapeutic hexapeptides that inhibit tau fibrillation by targeting the 306VQIVYK311 nucleation site. We designed hexapeptide batches derived from PHF6, with varying sequences but preserving key amino acid positions involved in the tau nucleation process. These hexapeptides were characterized and classified using a newly optimized biochemical method that we developed. Soluble hexapeptides were preselected because of their therapeutic potential and were selected by using the in vitro PHF6/β1 fibrillation model. Hexapeptides strongly inhibiting fibrillation rates at substoichiometric levels were selected as leads. Unlike related peptides classified as amyloids, the leads were found to be completely innocuous to neuroblastoma cell lines, even at high concentrations. Hexapeptides selected as leads are promising candidates for therapeutic purposes and can be used to develop molecules for biochemical diagnosis and probes for positron emission tomography (PET) imaging in the context of tauopathies, particularly Alzheimer's disease.},
}

@article {pmid41141721,
year = {2025},
author = {Barbosa, DB and de Oliveira, LMG and Mendes, GO and Costa Junior, DB and de Oliveira, TA and da Silva, MP and Damázio, LCM and Maia, EHB and Falkoski, DL and de S Marra, IF and Valle, MS and da Silva, AM and Taranto, AG and da Silva, VDA and de Carvalho, PB and Leite, FHA},
title = {Silodosin as a Novel Inhibitor of Acetylcholinesterase, Butyrylcholinesterase, and BETA-Secretase 1: In Vitro and In Silico Studies.},
journal = {ACS omega},
volume = {10},
number = {41},
pages = {48887-48899},
pmid = {41141721},
issn = {2470-1343},
abstract = {Alzheimer's Disease (AD) is a progressive neurodegenerative disorder and the leading cause of cognitive decline in older adults. Several biomarkers of AD have been identified, but its pathogenesis has not yet been completely elucidated. One of the most relevant hypotheses proposed to explain the cognitive impairment caused by this disease is the cholinergic hypothesis, which postulates that loss of cholinergic neurons is one of its causes and that the subsequent reduction of acetylcholine levels in the synaptic cleft can be compensated through the inhibition of acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE). Another well-known hypothesis is the amyloid-beta hypothesis, which explains the disease as being caused by the formation and accumulation of amyloid plaques in a cascade of enzymatic events starting with the cleavage of an amyloid precursor protein (APP) by beta-secretase 1 (BACE-1). Previous studies have shown that silodosin has the structural requirements for the inhibition of those three enzymes (AChE, BuChE, and BACE-1), which suggests that it can be useful as a multitarget candidate to treat Alzheimer patients. This study aims to assess the effect of silodosin on cellular viability, measure the inhibitory activity against AChE, BuChE, and BACE-1, and evaluate the molecular behavior of all three inhibitor-enzyme systems by molecular dynamics (MD) simulations. Cell viability assays through the MTT method showed that silodosin concentrations of less than 10 μM are safe to be used. Enzymatic assays revealed AChE inhibitory activity at high micromolar levels (IC50 >500.0 μM) but inhibited BuChE at low micromolar levels (IC50 = 3.02 ± 0.05 μM). BACE-1 inhibition assays have shown significant reduction at three micromolar. MD simulations demonstrated that silodosin promotes late stabilization of the AChE complex, but the simulations involving BuChE and BACE-1 revealed that the compound promotes system stabilization at early stages and has the structural requirements to inhibition.},
}

@article {pmid41141642,
year = {2025},
author = {Francis, F and Chettri, D and Nair, D},
title = {AMPA receptors in the evolving synapse: structure, function, and disease implications.},
journal = {Frontiers in synaptic neuroscience},
volume = {17},
number = {},
pages = {1661342},
pmid = {41141642},
issn = {1663-3563},
abstract = {Synapses, once considered static conduits for neuronal signals, are now recognized as dynamic, multifunctional structures critical to brain function, plasticity, and disease. This evolving understanding has highlighted the tripartite nature of synapses, including pre-synaptic terminals, post-synaptic compartments, and regulatory glial elements. Among excitatory synapses, glutamatergic transmission dominates, with AMPA receptors (AMPARs) playing a central role in fast synaptic signaling. AMPARs are tetrameric, ligand-gated ion channels that mediate rapid depolarization and are tightly regulated by subunit composition, trafficking, and interactions with scaffolding and signaling proteins. Their activity-dependent modulation underpins key processes such as long-term potentiation and depression, central to learning and memory. Importantly, dysfunctions in AMPAR expression, localization, or signaling are increasingly linked to neurological and psychiatric disorders including autism spectrum disorders, epilepsy, schizophrenia, and Alzheimer's disease. This review discusses AMPAR biology in the context of synaptic organization, highlighting recent advances and ongoing challenges in understanding their roles in health and disease.},
}

@article {pmid41141360,
year = {2025},
author = {Oh, C and Kim, IS and Feltis, A},
title = {Affective prosody and cortical activation in dementia of the Alzheimer's type: an exploratory acoustic and fNIRS study.},
journal = {Frontiers in dementia},
volume = {4},
number = {},
pages = {1681602},
pmid = {41141360},
issn = {2813-3919},
abstract = {Affective prosody, the expression of emotion via speech, is critical for successful communication. In dementia of the Alzheimer's type (DAT), impairments in expressive prosody may contribute to interpersonal difficulties, yet the underlying acoustic and neural mechanisms are not well understood. This exploratory study examined affective prosody production and cortical activation in individuals with DAT using a multimodal approach. Ten participants with DAT completed three speech tasks designed to elicit happy, sad, and neutral emotional tones. Acoustic features were extracted using Praat software, and cerebral hemodynamics were recorded using functional near-infrared spectroscopy (fNIRS), focusing on oxygenated (HbO) and total (HbT) hemoglobin levels across hemispheres. Multinomial logistic regression showed that initial fundamental frequency and speech rate significantly predicted emotional condition. Paired-sample t-tests revealed hemispheric differences in HbO and HbT during affective speech, particularly in the happy and neutral conditions. These findings suggest that individuals with DAT may exhibit reduced modulation of affective prosody and altered patterns of hemispheric activation during emotionally expressive speech. While preliminary and limited by the absence of a control group, this study highlights behavioral and neural features that may contribute to communication challenges in DAT and provides a foundation for future research on affective prosody as a potential target for intervention or monitoring.},
}

@article {pmid41141359,
year = {2025},
author = {Smith, J and Talon, B and Martinez, A and McCarrier, K and Aggarwal, J},
title = {Physician and professional caregiver perspectives on meaningful change in agitation behaviors in Alzheimer's dementia: Insights from qualitative interviews.},
journal = {Frontiers in dementia},
volume = {4},
number = {},
pages = {1607566},
pmid = {41141359},
issn = {2813-3919},
abstract = {BACKGROUND: Agitation is a common neuropsychiatric symptom of Alzheimer's dementia. Limited qualitative evidence is available to characterize the clinical meaningfulness of changes in agitation behaviors, as assessed by the Cohen-Mansfield Agitation Inventory (CMAI).

OBJECTIVE: To collect qualitative data to characterize the magnitude of change in CMAI scores required to represent a clinically meaningful improvement in agitation behaviors from the perspectives of physicians and professional caregivers.

MATERIALS AND METHODS: One-on-one qualitative interviews were conducted with 15 physicians treating Alzheimer's dementia and 15 professional caregivers. Nine patient vignettes depicting observed changes in CMAI score profiles over a 12-week study period were used as examples of different magnitudes of change in the CMAI total score.

RESULTS: The proportion of participants affirming clinical meaningfulness varied for both physicians and caregivers within and across the nine vignettes presented; however, the four vignettes corresponding to a CMAI total score reduction of 14 or greater were considered clinically meaningful to all participants. Most physicians (8/13) and caregivers (7/13) found a total score reduction of 5 to be clinically meaningful, and some participants (2 caregivers; 0 physicians) articulated that even minimal changes could be clinically meaningful depending on the type of behavior.

CONCLUSION: Participants who regularly treat people with Alzheimer's dementia described a significant burden associated with agitation behaviors and provided qualitative examples highlighting that even minor reductions in the frequency of such behaviors can have meaningful benefits for the patient's care and the burden on professional caregivers and family members.},
}

@article {pmid41141199,
year = {2025},
author = {Sorod, P and Chen, GI},
title = {Hearing All About Donepezil: Its Role in the Field of Auditory Processing.},
journal = {Cureus},
volume = {17},
number = {9},
pages = {e93143},
pmid = {41141199},
issn = {2168-8184},
abstract = {Donepezil is a central-acting acetylcholinesterase inhibitor aimed at increasing acetylcholine availability at the neuron synapses to enhance cholinergic transmission. It is often used to assist with cognitive function and is well-known as the first-line treatment for mild to severe dementia of several etiologies. However, its mechanism of action within "top-down" and "bottom-up" neurological pathways continues to be explored. This case reports on a 93-year-old woman in an ambulatory geriatrics clinic with moderate-to-severe dementia. Her significant history of hearing loss with auditory hallucination impressively responded to the initiation of donepezil. There may be potential benefits of donepezil within the peripheral pathways of neuro-cortical reorganization in the field of hearing loss and auditory processing.},
}

@article {pmid41140811,
year = {2025},
author = {Sim, MA and Rowsthorn, E and O'Brien, WT and Sun, M and Cribb, L and Franks, K and McDonald, SJ and Yiallourou, S and Cavuoto, M and Harding, IH and Chong, TTJ and Law, M and O'Brien, TJ and Vivash, L and Pase, MP},
title = {Plasma phosphorylated tau-217 correlates with brain atrophy, cognition, and cerebrospinal fluid biomarkers in a cognitively healthy community cohort.},
journal = {Brain communications},
volume = {7},
number = {5},
pages = {fcaf383},
pmid = {41140811},
issn = {2632-1297},
abstract = {Plasma biomarkers are promising for detecting Alzheimer's disease (AD) pathology, but their role in cognitively healthy individuals remains unclear. Plasma pTau-217 has high diagnostic accuracy for clinical and prodromal AD, yet its relevance in preclinical stages is underexplored. We examined if plasma biomarkers of AD, neurodegeneration, and neuroinflammation were associated with cognition, brain structure, and their cerebrospinal fluid (CSF) counterparts in dementia-free older adults. We studied community-based, dementia-free older adults from the Brain and Cognitive Health (BACH) cohort. Neuropsychological testing assessed global cognition (MMSE), memory (Logical Memory II), visual processing (Hooper Visual Organization Test), processing speed (Trail Making Test-A), and reasoning (Similarities). Paired plasma and CSF biomarkers [phosphorylated Tau-217 (pTau-217), phosphorylated Tau-181 (pTau-181), Glial fibrillary acidic protein (GFAP), neurofilament light chain (NfL), amyloid-beta 42/40 (Aβ42/40)] were measured using Single molecule arrays (SIMOA). Brain magnetic resonance imaging (MRI)-derived cortical thickness was used as a neurodegeneration marker. Multivariable linear regression assessed associations between log10-transformed plasma biomarker levels, cognition (adjusted for age, sex, education, hypertension, hyperlipidemia, diabetes), and cortical thickness (adjusted for age, sex, education, and intracranial volume). Pearson's correlations and Bland-Altman plots evaluated plasma-CSF agreement. There were 147 dementia-free participants [mean age ± standard deviation (SD): 66.7 ± 7.7 years; 56% women]. Higher plasma pTau-217 levels associated with lower global cognition scores (β -0.80, 95% C.I. -1.56, -0.03, P = 0.041) and abstract reasoning [β -0.86, 95% confidence interval (C.I.) -1.62, -0.09, P = 0.028]. Greater plasma pTau-217 also associated with lower global cortical thickness [βeta (β) -0.21, 95% confidence interval (C.I). -0.37, -0.06, per log unit change; P = 0.006]. Nfl associated with memory (β -1.38, 95% C.I. -2.65, -0.12, P = 0.033), while GFAP associated with global cognition (β -1.48, 95% C.I. -2.44, -0.52, P = 0.003) and memory (β -1.05, 95% C.I. -2.05, -0.04, P = 0.041). No associations were found between the plasma biomarkers and processing speed or visual processing (P > 0.05 for all). Among 47 participants with paired plasma-CSF biomarkers, plasma pTau-217 showed the strongest correlation with its CSF counterpart (R = 0.76, P < 0.0001), followed by GFAP (R = 0.66, P < 0.0001), pTau-181 (R = 0.61, P < 0.0001), NfL (R = 0.56, P < 0.0001), and Aβ42/40 (R = 0.53, P = 0.0001). In conclusion, plasma pTau-217 levels were associated with both cognition and cortical thickness in dementia-free older adults. All plasma biomarkers correlated significantly with their CSF counterpart. These findings reinforce the utility of plasma biomarkers, particularly pTau-217, as indicators of neurodegenerative processes, even in asymptomatic individuals.},
}

@article {pmid41140810,
year = {2025},
author = {You, Y and Ward, J and Ho, FK and Lyall, DM and Hastie, CE},
title = {Associations and interactions between APOE e4 genotype and lifestyle with brain structural phenotypes.},
journal = {Brain communications},
volume = {7},
number = {5},
pages = {fcaf350},
pmid = {41140810},
issn = {2632-1297},
abstract = {Apolipoprotein E gene (APOE) e4 allele is known as the strongest common genetic risk factor for Alzheimer's disease. Various lifestyle factors are reported to have multiple associations with brain health, including smoking, alcohol intake, diet, sedentary behaviour and physical activity. However, the associations and interactions of overall or individual modifiable lifestyle factors and APOE e4 genotype, on brain volumes and white matter tract integrity measured by diffusion tensor imaging and neurite orientation dispersion and density imaging (NODDI), remain incompletely understood. In this cross-sectional study, we used data from the UK Biobank MRI assessment (N = 24 912) participants living without dementia. They were classified as having 'favourable', 'moderate' and 'unfavourable' levels based on their lifestyle scores (0-10 points) being calculated by the magnitudes of adherence to five healthy lifestyle guidelines: two points for each healthy category, one point for moderate ones, and zero point for unhealthy ones. Neuroimaging markers, namely brain volumes and white matter tract integrity measures, were derived from MRI. Linear regression was performed to examine the associations and interactions of lifestyle levels, APOE e4 genotype and each lifestyle factor, with multiple brain structural MRI phenotypes. We found that compared with favourable-level lifestyle, moderate and unfavourable levels were significantly independently associated with smaller grey matter, hippocampus and total brain volumes (standardized β range 0.004-0.096 per unit). Significant associations were found between APOE e4 presence and smaller hippocampal volumes (β range 0.042-0.048 lower versus absence) and worse white matter tract integrity. Individual unhealthy lifestyle aspects were mostly associated with poorer brain structural markers, such as current smoking (β range -0.014 to 0.209), high-level drinking (β range -0.105 to 0.152) and grey matter and white matter, as well as both traditional white matter tract and NODDI metrics, in both individually and simultaneously modelled lifestyle-factor models. The interactions between lifestyle levels and APOE e4 status on brain metrics were generally non-significant. In conclusion, the presence of APOE e4 and non-favourable lifestyles were mostly associated with worse brain health, and this was largely linear rather than synergistic. The benefit of a healthy lifestyle on brain health does not vary by genetic risk for dementia.},
}

@article {pmid41140678,
year = {2025},
author = {Gutfilen, B and Ramirez-Fort, MK},
title = {Editorial: Women in science - nuclear medicine 2024.},
journal = {Frontiers in medicine},
volume = {12},
number = {},
pages = {1684663},
pmid = {41140678},
issn = {2296-858X},
}

@article {pmid41140436,
year = {2025},
author = {Matyi, MA and Rhodes, E and Emrani, S and Jin, HA and Irwin, DJ and McMillan, CT and Massimo, L},
title = {Racial/ethnic differences in neuropsychological test performance in frontotemporal degeneration.},
journal = {Alzheimer's & dementia (Amsterdam, Netherlands)},
volume = {17},
number = {4},
pages = {e70190},
pmid = {41140436},
issn = {2352-8729},
abstract = {BACKGROUND: Racial and/or ethnic differences in neuropsychological test performance are understudied in frontotemporal degeneration (FTD) but their identification is critical to identifying ways to improve care of representative FTD populations.

METHODS: Differences in cognitive scores between Black (n = 56) and Hispanic (n = 76) relative to White (n = 2281) participants and the likelihood of impairment status in cognitive test performance were evaluated.

RESULTS: Minoritized individuals had lower scores and/or greater likelihood of impairment on measures of lexical retrieval, processing speed, cognitive flexibility, and working memory but not global cognition, verbal recall, attention, and category fluency. Addition of severity, age (M = 65.18), sex (40% female), education (M = 15.62), and vascular comorbidities attenuated group differences.

DISCUSSION: Racial/ethnic differences on neuropsychological tests used in diagnosis and monitoring of FTD were substantially attenuated when accounting for potential contributing factors. To address these differences in FTD, future efforts must increase representative research participation of patients and understand social determinants of health.

HIGHLIGHTS: Racially/ethnically minoritized individuals with frontotemporal dementia are severely underrepresented in the National Alzheimer's Coordinating Center datasetRacially/ethnically minoritized individuals with frontotemporal dementia obtained lower scores and greater likelihood of impairment on common neuropsychological testsThe effect of racial/ethnic group on neuropsychological test scores was substantially attenuated when adjusting for disease severity, education level, sex, and age.},
}

@article {pmid41140221,
year = {2025},
author = {Mastrostefano, A and Alborghetti, M and Tiso, D and Davinelli, S and Medoro, A and Scapagnini, G},
title = {Pleiotropic Actions of Gastrodia Elata Glucosides in the Treatment of Painful Neuropathies and CNS Disorders: Focus on Mitochondrial Dysfunction and Modulation of Ion Channels.},
journal = {Current neuropharmacology},
volume = {},
number = {},
pages = {},
doi = {10.2174/011570159X402568251002112117},
pmid = {41140221},
issn = {1875-6190},
abstract = {Glycosides contained in Gastrodia elata have consistently shown neuroprotective and antiinflammatory activity in preclinical models of neurological disorders, including peripheral neuropathies, cerebrovascular disorders, and chronic neurodegenerative disorders. In a commercial product used in Italy, gastrodin has replaced α-lipoic, the use of which is now limited by unexpected adverse effects, such as severe hypoglycemia. The clinical efficacy of gastrodin in traditional Chinese medicine has been ascribed to a plethora of mechanisms, which involve the modulation of intracellular signaling pathways and membrane ion channels. Moving from the pathophysiology of diabetic neuropathy, Alzheimer's disease, and Parkinson's disease, we now focus on what we consider a key mechanism in the action of gastrodin, i.e., the regulation of mitochondrial quality control. Gastrodin is able to enhance mitochondrial fusion and biogenesis, as shown by the induction of specific biochemical markers, such as mitofusins and mitochondrial transcription factors. This supports mitochondrial health, preventing the loss of energy production and formation of reactive oxygen species associated with disorders of the central and peripheral nervous system. In addition, gastrodin physically interacts with, and restrains the expression and activity of, voltage-sensitive ion channels and acid-sensing ion channels, which play a central role in pain transmission and nociceptive sensitization. Thus, gastrodin and other constituents of Gastrodia elata show promising potential to support first-line treatments, based on preclinical evidence in models of neurological disease.},
}

@article {pmid41140219,
year = {2025},
author = {Devi, S and Singh, AP},
title = {Novel Therapeutic Approaches to Neuroinflammation in Neurodegenerative Disorders: Aptamers as Central Nervous System Agents.},
journal = {Central nervous system agents in medicinal chemistry},
volume = {},
number = {},
pages = {},
doi = {10.2174/0118715249392444251002135338},
pmid = {41140219},
issn = {1875-6166},
abstract = {INTRODUCTION: Neurodegenerative disorders (NDDs) like Alzheimer's, Parkinson's, and multiple sclerosis all begin with neuroinflammation. Neuroinflammation targeting has recently gained attention as a potential approach to treating several diseases affecting the central nervous system. The objective of this review is to explore the potential of aptamers as innovative therapeutic agents for targeting neuroinflammation in neurodegenerative disorders, offering a novel approach to CNS treatment.

METHODS: The use of aptamers, which are single-stranded nucleic acids, in diagnostic and therapeutic contexts may one day help overcome these obstacles. Myotrophic lateral sclerosis, Alzheimer's disease, Parkinson's disease, and other neurodegenerative disorders are linked to neuroinflammation. Important regulators of CNS inflammatory responses include microglia and astrocytes.

RESULTS: Neurotoxic (M1-phenotype microglia and A1-phenotype astrocytes) and neuroprotective (M2-phenotype microglia and A2-phenotype astrocytes) activation of microglia and astrocytes, respectively, is a diverse and complex process. There may be a lack of reflection of the diverse morphologies of microglia and astrocytes in this binary categorisation. In addition to the complexity of the relationships between these activated glial cells, the phenotypic distribution can vary as neurodegenerative illnesses progress.

DISCUSSION: To create effective treatments for neurodegenerative illnesses, a deeper knowledge of microglia and astrocyte functions is required. Drug efficacy, safety concerns, and pharmacokinetics are only a few of the topics covered, along with the enormous possibilities and enormous hurdles of employing aptamers as therapeutic agents.

CONCLUSION: This review highlights aptamers as a promising genetic tool for treating neuroinflammation and neurodegenerative diseases through targeted delivery to the central nervous system.},
}

@article {pmid41140215,
year = {2025},
author = {Behrouzinia, S and Afshar, M and Khanteymoori, A},
title = {Spectral Biomarkers of Functional Brain Network Alteration in Alzheimer's Disease.},
journal = {Current Alzheimer research},
volume = {},
number = {},
pages = {},
doi = {10.2174/0115672050434251251008104505},
pmid = {41140215},
issn = {1875-5828},
abstract = {INTRODUCTION: The primary objective of this study was to examine changes in brain network architecture across multiple frequency bands using spectral analysis of both weighted and binarized functional connectivity networks. This cross-sectional observational study, conducted as a secondary analysis of a publicly available EEG dataset, analyzed spectral coherence measurements from 25 patients with Alzheimer's disease (AD) and 25 age- and sex-matched healthy controls (HC). Nevertheless, the modest sample size and cultural homogeneity of the dataset may limit the statistical power and generalizability of the results. A data-driven thresholding approach was employed to generate binary networks, allowing a robust comparison of connectivity disruptions associated with AD.

METHOD: Brain network features derived from the graph Laplacian, including weighted Fiedler value, spectral range, and Middle Eigenvalue, were analyzed across seven frequency layers: delta, theta, alpha1, alpha2, beta1, beta2, and gamma. For binary networks, the Fiedler value was calculated after thresholding. Statistical group comparisons between AD and HC were performed using t-tests (p < 0.05), and each feature was assessed based on the number of frequency bands showing significant differences.

RESULTS: Among all features, the weighted Fiedler value was the most discriminative, showing significant reductions in AD patients within the alpha2 and beta1 bands. In binary networks, the Fiedler value remained significantly lower in AD within the alpha2 band, confirming topological degradation even without edge weight information. Other spectral features showed similar trends, but did not reach statistical significance in the binary networks.

DISCUSSION: The consistent decline in Fiedler value across both weighted and binary networks indicates a global reduction in connectivity characteristic of AD. These spectral markers offer a quantitative and interpretable framework for understanding the progressive disconnection syndrome in AD.

CONCLUSION: This study demonstrates significant alterations in Laplacian spectral features of brain networks between the AD and HC groups across specific frequency bands. These exploratory findings indicate that the spectral features, particularly the Fiedler value, consistently differentiate AD patients from healthy controls across frequency bands, suggesting its potential as a biomarker. However, larger and longitudinal studies are needed to confirm its diagnostic and prognostic utility. The combined use of weighted and binarized connectivity matrices enhances analytical sensitivity and facilitates the application of spectral graph theory for the early detection and monitoring of AD.},
}

@article {pmid41140214,
year = {2025},
author = {Shi, Y and Luo, W and Hu, Y and Chen, W},
title = {Low-Dimensional Nanomaterials in Alzheimer's Disease: Current Applications.},
journal = {Current Alzheimer research},
volume = {},
number = {},
pages = {},
doi = {10.2174/0115672050413838251014045255},
pmid = {41140214},
issn = {1875-5828},
abstract = {INTRODUCTION: Alzheimer's Disease (AD) is a common neurodegenerative disorder (NDD) driven by multifaceted pathologies, including β-amyloid (Aβ) aggregation, tau protein hyperphosphorylation, oxidative stress, metal ion dyshomeostasis, and neuroinflammation. Current therapeutic strategies remain limited by insufficient Blood-Brain Barrier (BBB) penetration, singletarget approaches, and inefficacy against nanoscale pathological aggregates. This review highlights the emerging potential of low-dimensional nanomaterials (LDNMs) as multi-target therapeutic platforms for AD.

METHOD: We systematically evaluate zero-dimensional (0D), one-dimensional (1D), and twodimensional (2D) nanostructures and establish a "nano-nano" interaction paradigm that demonstrates how LDNMs interact with AD core pathological factors. Supporting tables summarize experimental data quantifying the effects of LDNMs on Aβ and tau pathologies, oxidative stress, metal ion homeostasis, neuroinflammation, and the delivery of BBB-penetrant drugs.

RESULTS: LDNMs exhibit significant potential in mitigating core AD pathologies. They effectively inhibit Aβ aggregation and tau hyperphosphorylation, attenuate oxidative damage, restore metal ion homeostasis, reduce neuroinflammatory activity, and enable targeted drug delivery to the brain.

DISCUSSION: The multi-target functionality of LDNMs overcomes major limitations of single-target therapies. Their nanoscale dimensions and modifiable surfaces enable synergistic interactions with pathological factors, offering a holistic intervention strategy. Limitations and translational challenges are discussed for future research directions for clinical application.

CONCLUSION: This review links the structure and drug loading of LDNMs to multi-targeted efficacy against core AD pathology. It establishes a mechanistic connection between nanomaterial size and multi-pathway efficacy that transcends the limitations of single-target strategies. Moreover, it also provides a comprehensive framework for designing LDNMs-based nanotherapeutics, highlighting their potential as multi-target platforms for AD therapy.},
}

@article {pmid41140213,
year = {2025},
author = {Zhao, R and Che, M and Cui, Y and Peng, J and Chen, M},
title = {The Role of Lipoprotein and Gut Microbiome in Alzheimer's Disease: A Review of Novel Findings and Potential Applications.},
journal = {Current Alzheimer research},
volume = {},
number = {},
pages = {},
doi = {10.2174/0115672050407276251014113234},
pmid = {41140213},
issn = {1875-5828},
abstract = {Alzheimer's disease (AD), a progressive neurodegenerative disorder, is inadequately comprehended, with hypotheses implicating amyloid-β, tau pathology, mitochondrial dysfunction, and epigenetic factors. Recent research underscores the significance of lipoproteins and the gut microbiota in the etiology of AD. Apolipoprotein E (ApoE), particularly the E4 subtype, emerges as a key genetic risk factor, influencing oxidative stress, synaptic defects, glucose metabolism, and amyloid-β clearance. Lipoprotein receptors, such as LRP-1, also influence the integrity of the blood-brain barrier, indicating potential for therapeutic applications. Novel therapies targeting lipoproteins, such as ALZ-801 and IDOL inhibitors, show promise in preclinical and clinical trials. Concurrently, the gut microbiome's impact on AD is increasingly recognized. Dysbiosis correlates with inflammation, mitochondrial oxidative stress, impaired autophagy, and neurotransmitter imbalances. Gut-derived metabolites, including phenylalanine and isoleucine, promote Th1 cell activation and microglial dysfunction, exacerbating AD pathology. Interventions, like probiotics, GV-971, and polyphenols, demonstrate efficacy in restoring microbial balance and mitigating cognitive decline. Crucially, bidirectional interactions between lipoproteins and the gut microbiome are implicated in AD. ApoE genotypes influence gut microbial composition, while microbiota- derived short-chain fatty acids and endotoxins modulate lipid metabolism and neuroinflammation. These interactions, mediated via the gut-brain axis, highlight novel therapeutic avenues. Current FDA-approved AD drugs face limitations in efficacy and side effects, underscoring the need for innovative strategies targeting lipoprotein-gut microbiome crosstalk. Integrating insights into lipoprotein biology and gut microbiota dynamics may offer transformative potential for AD treatment, emphasizing combinatorial approaches to modulate these interconnected pathways. Further research is warranted to elucidate mechanistic links and translate preclinical findings into clinical applications.},
}

@article {pmid41140062,
year = {2025},
author = {Abdel-Lah, ES and Hamad, N and Taha, AF and Mohamed, WH and Fawy, MA and Attaai, AH and Abbas, FYA and Sherkawy, HS and Abdelwarith, A and Gamea, MG},
title = {Neuroprotective Effect of Empagliflozin/Rivastigmine in Alzheimer's Disease Rat Model: Optimization of Multifaceted Mechanism of Action.},
journal = {Drug development research},
volume = {86},
number = {7},
pages = {e70180},
doi = {10.1002/ddr.70180},
pmid = {41140062},
issn = {1098-2299},
support = {//The authors received no specific funding for this work./ ; },
mesh = {Animals ; *Rivastigmine/pharmacology/administration & dosage ; *Glucosides/pharmacology/administration & dosage/therapeutic use ; *Neuroprotective Agents/pharmacology/administration & dosage ; *Alzheimer Disease/drug therapy/chemically induced/metabolism/pathology ; Male ; *Benzhydryl Compounds/pharmacology/administration & dosage/therapeutic use ; Rats ; Disease Models, Animal ; Oxidative Stress/drug effects ; Acetylcholinesterase/metabolism ; Glucose/metabolism ; Brain/drug effects/pathology/metabolism ; Rats, Wistar ; Sodium-Glucose Transporter 2 Inhibitors/pharmacology ; tau Proteins/metabolism ; Drug Therapy, Combination ; Lipid Peroxidation/drug effects ; },
abstract = {This study assessed the neuroprotective potential of empagliflozin (EMPA) as antidiabetic drug on glucose metabolism, comparing it to rivastigmine (RIVA) as standard treatment for Alzheimer's disease (AD), and their combination. Male rats were sorted into five groups. Group I served as the control, while groups II, III, IV, and V received the scopolamine plus heavy metal mixture for AD induction. Groups III and IV were administered RIVA and EMPA, respectively, and group V received both treatments. Cognitive function was evaluated behaviorally. Subsequently, glucose levels, acetylcholinesterase, oxidative stress, and inflammatory markers were assessed. Alongside the brain histopathological changes, the expression of phosphorylated tau protein was assessed. Moreover, glycolytic enzymes and glucose transporters were assessed using PCR analysis. The findings were attributed to a notable suppressive impact of EMPA on lipid peroxidation, acetylcholinesterase, glucose levels, phosphorylated tau protein, pro-inflammatory cytokines, and neuropathological changes, while enhancing antioxidant and interleukin-10 levels. It also improves glucose metabolism. The findings suggest that EMPA may be a viable candidate for future therapeutic exploration in AD, which has a multifaceted mechanism of action encompassing anti-neuroinflammation, antioxidant stress, and enhanced glucose metabolism, as well as decreased acetylcholinesterase activity and phosphorylated tau protein levels. Interestingly, combined treatment showed a superior effect than EMPA alone.},
}

Animals
*Rivastigmine/pharmacology/administration & dosage
*Glucosides/pharmacology/administration & dosage/therapeutic use
*Neuroprotective Agents/pharmacology/administration & dosage
*Alzheimer Disease/drug therapy/chemically induced/metabolism/pathology
Male
*Benzhydryl Compounds/pharmacology/administration & dosage/therapeutic use
Rats
Disease Models, Animal
Oxidative Stress/drug effects
Acetylcholinesterase/metabolism
Glucose/metabolism
Brain/drug effects/pathology/metabolism
Rats, Wistar
Sodium-Glucose Transporter 2 Inhibitors/pharmacology
tau Proteins/metabolism
Drug Therapy, Combination
Lipid Peroxidation/drug effects

@article {pmid41139981,
year = {2025},
author = {Yamakami, K and Matsubara, T and Fujita, K and Nakamura, K and Kihara, N and Sogawa, K and Nakao, R and Hanada, K and Yamamoto, Y and Haji, S and Otomi, Y and Harada, M and Izumi, Y},
title = {Identification of Hasegawa Dementia Scale-Revised Cutoff Scores Associated With Mini-Mental State Examination Thresholds for Anti-Amyloid β Therapies in Patients With Amnesia.},
journal = {Psychogeriatrics : the official journal of the Japanese Psychogeriatric Society},
volume = {25},
number = {6},
pages = {e70107},
doi = {10.1111/psyg.70107},
pmid = {41139981},
issn = {1479-8301},
support = {JP25dk0207068//Japan Agency for Medical Research and Development/ ; JP24re0122001//Japan Agency for Medical Research and Development/ ; JP18he1402001//Japan Agency for Medical Research and Development/ ; JP24K15767//Japan Society for the Promotion of Science/ ; },
mesh = {Humans ; Male ; Female ; Aged ; Cross-Sectional Studies ; Retrospective Studies ; *Mental Status and Dementia Tests/standards/statistics & numerical data ; *Amyloid beta-Peptides/cerebrospinal fluid/antagonists & inhibitors ; *Amnesia/diagnosis/cerebrospinal fluid/drug therapy ; Neuropsychological Tests ; Sensitivity and Specificity ; Aged, 80 and over ; Middle Aged ; *Alzheimer Disease/diagnosis/drug therapy/cerebrospinal fluid ; ROC Curve ; Positron-Emission Tomography ; },
abstract = {BACKGROUND: This study aimed to evaluate Hasegawa Dementia Scale-Revised (HDS-R) cutoff scores that correspond to Mini-Mental State Examination (MMSE) thresholds for identifying candidates for anti-amyloid β (Aβ) therapies. Additionally, we conducted exploratory analyses to examine the cognitive subdomains associated with Aβ status.

METHODS: This retrospective cross-sectional study included consecutive patients with amnesia who underwent neuropsychological examinations and Aβ assessment through cerebrospinal fluid analysis or positron emission tomography. Diagnostic accuracy for MMSE thresholds (≥ 20, ≥ 22 and ≥ 24) was assessed, and two HDS-R cutoffs (high-sensitivity, high-specificity) were determined for each threshold. We examined differences in cognitive subdomains between Aβ-positive and Aβ-negative patients with MMSE score ≥ 20.

RESULTS: Of 234 patients, 143 (61.1%) were Aβ-positive. The area under the receiver operating characteristic curve for predicting MMSE score ≥ 20, ≥ 22 and ≥ 24 was 0.92, 0.90 and 0.91, respectively. High-sensitivity cutoffs, defined as scores that maximised specificity while maintaining sensitivity ≥ 80%, were HDS-R score ≥ 16, ≥ 17 and ≥ 18. Conversely, high-specificity cutoffs, defined as scores that maximised sensitivity while maintaining specificity ≥ 80%, were HDS-R score ≥ 19, ≥ 20 and ≥ 21, respectively. Subdomain analysis of MMSE and HDS-R showed Aβ-positive patients had lower scores in delayed recall and higher scores in calculation than Aβ-negative patients (all p < 0.01). In HDS-R subdomains, visual memory scores were also lower in Aβ-positive patients than in Aβ-negative patients (p < 0.01).

CONCLUSIONS: The identified HDS-R cutoff scores were associated with MMSE-defined cognitive thresholds and may serve as a potential reference for identifying patients who could be eligible for anti-Aβ therapies. The cognitive profile observed in Aβ-positive patients was characterised by deficits in delayed recall and in visual memory and by relatively preserved calculation ability, suggesting a selective vulnerability pattern in early Alzheimer's disease.},
}

Humans
Male
Female
Aged
Cross-Sectional Studies
Retrospective Studies
*Mental Status and Dementia Tests/standards/statistics & numerical data
*Amyloid beta-Peptides/cerebrospinal fluid/antagonists & inhibitors
*Amnesia/diagnosis/cerebrospinal fluid/drug therapy
Neuropsychological Tests
Sensitivity and Specificity
Aged, 80 and over
Middle Aged
*Alzheimer Disease/diagnosis/drug therapy/cerebrospinal fluid
ROC Curve
Positron-Emission Tomography

@article {pmid41139734,
year = {2025},
author = {Fazio, S and Ribino, P and Gasparini, F and Marwan, N and Fazio, P and Gherardi, M and Mannone, M},
title = {K-operator for Modelling Neurodegeneration: Simulations, fMRI Application, Eigenvalue Analysis and Recurrence Plots.},
journal = {Journal of medical systems},
volume = {49},
number = {1},
pages = {144},
doi = {10.1007/s10916-025-02244-6},
pmid = {41139734},
issn = {1573-689X},
mesh = {Humans ; *Magnetic Resonance Imaging/methods ; *Neurodegenerative Diseases/physiopathology/diagnostic imaging ; Machine Learning ; *Brain/diagnostic imaging/physiopathology ; *Models, Neurological ; Computer Simulation ; },
abstract = {The brain network damage provoked by a neurological disease can be modelled as the result of the action of an operator, K, acting on the brain, inspired by physics. Here, we explore the matrix formulation of K, analysing eigenvalues and eigenvectors, with heuristic considerations on different techniques to approximate it. The primary objective of this paper is to lay the foundational groundwork for an innovative framework aimed at the development of predictive models regarding the progression of neurodegenerative diseases. This endeavour will leverage the potential of integrating these novel representations of brain damage with advanced machine-learning techniques. A case study based on real-world data is presented here to support the proposed modelling.},
}

Humans
*Magnetic Resonance Imaging/methods
*Neurodegenerative Diseases/physiopathology/diagnostic imaging
Machine Learning
*Brain/diagnostic imaging/physiopathology
*Models, Neurological
Computer Simulation

@article {pmid41139712,
year = {2025},
author = {Li, H and Xie, Z and Tian, Y and Zhou, R and Yang, Y and Lin, B and Chen, S and Wu, J and Deng, Z and Li, J and Chen, M and Liu, X and Sun, Y and Wei, N and Huang, B and Ji, X},
title = {Genome-wide consensus transcriptional signatures identify synaptic pruning linking Alzheimer's disease and epilepsy.},
journal = {Molecular psychiatry},
volume = {},
number = {},
pages = {},
pmid = {41139712},
issn = {1476-5578},
support = {82201629//National Science Foundation of China | Young Scientists Fund/ ; },
abstract = {Alzheimer's disease (AD) and epilepsy (EP) share a complex bidirectional relationship, yet the molecular mechanisms underlying their comorbidity remain insufficiently explored. To identify potential transcriptional programs across animal models and human patients with AD and EP, we conducted a comprehensive genome-wide transcriptomic analysis. Our investigation included mouse models of temporal lobe epilepsy (pilocarpine- and kainic acid-induced; n = 280), AD transgenic models (7 transgenic models expressing human tau or amyloid pathology; n = 257), and performed cross-species validation in human cohorts (EP: n = 182; AD: n = 301). We identified a highly conserved immune-related module across all models and patient cohorts. The hub consensus signatures of this module were centered around a microglial synaptic pruning pathway involving TYROBP, TREM2, and C1Q complement components. Gene regulatory network analysis identified TYROBP as the key regulatory signature. These signatures showed consistent up-regulation in both conditions and diagnostic potential. Differential expression analyses revealed their predominant expression in specific microglial subpopulations associated with complement-mediated synaptic pruning and immune activation. Neural circuit modeling further demonstrates the asymmetric sensitivity of synaptic pruning to network dynamics. Loss of inhibitory synapses has a disproportionately significant impact on neural network excitation/inhibition balance and synchronization. Our findings support microglial complement-mediated synaptic pruning as a conserved central pathway linking neurodegeneration to epileptogenesis, suggesting a promising therapeutic target for AD and EP comorbidity.},
}

@article {pmid41139687,
year = {2025},
author = {Li, X and Singh, S and DeVries, A and Gurwitz, JH},
title = {Lecanemab Therapy Use Patterns for Alzheimer's Disease Among Early Initiators in a Large National Health Plan.},
journal = {Journal of the American Geriatrics Society},
volume = {73},
number = {10},
pages = {3203-3207},
doi = {10.1111/jgs.70010},
pmid = {41139687},
issn = {1532-5415},
support = {3R33AG057806-07S1/AG/NIA NIH HHS/United States ; K01AG073651/AG/NIA NIH HHS/United States ; },
mesh = {Humans ; *Alzheimer Disease/drug therapy ; Female ; Aged ; Male ; United States ; Medicare Part C/statistics & numerical data ; Magnetic Resonance Imaging ; *Antibodies, Monoclonal, Humanized/therapeutic use/administration & dosage ; Aged, 80 and over ; },
abstract = {BACKGROUND: Lecanemab, an anti-amyloid monoclonal antibody, has been approved for treatment of early Alzheimer's disease. However, real-world data remain limited regarding use.

METHODS: Using data from a large national health plan with primarily Medicare Advantage enrollees, we characterized demographic and clinical characteristics in the 6 months preceding the initial infusion among individuals who initiated lecanemab between 1/1/2023 and 06/30/2024. We also characterized the patterns of infusions and the timing of MRIs for safety monitoring following the initial infusion among initiators who had ≥ 3 months of follow-up. We further assessed trends in lecanemab use between 1/1/2023 and 12/31/2024.

RESULTS: Of the 195 lecanemab initiators, the average age was 74.6 (SD = 5.5) years, 62.1% were female, 87.7% were White, 4.1% were Black, 1.5% were Hispanic, and 98.5% were on a Medicare Advantage plan. Almost all initiators resided in nonrural areas (96.4%); 2.6% used anticoagulants, and 1.5% used antiplatelets. Among the 119 initiators who had ≥ 3 months of follow-up, 40 (33.6%) received 7 total infusions, the expected number of infusions based on the recommended schedule of every 2 weeks. From the initial infusion, the average number of days to the first MRI was 47.1 (SD = 15.8), and to the second MRI scan was 73.4 (SD = 12.0) days, consistent with the recommended schedule. During 2023-2024, there were 526 patients who had ever received lecanemab. The increase in new initiators was modest over 2024, with only 43 more initiators during the final (n = 137) versus the first quarter (n = 94) of 2024.

CONCLUSIONS: This study demonstrated slow uptake of lecanemab among Medicare Advantage beneficiaries. Adherence to the ideal treatment schedule was less than recommended. Early lecanemab users were not representative of the population likely eligible for treatment nationally. Further research is warranted to track longer-term trends in utilization, as well as reasons for treatment interruption or discontinuation in real-world populations.},
}

Humans
*Alzheimer Disease/drug therapy
Female
Aged
Male
United States
Medicare Part C/statistics & numerical data
Magnetic Resonance Imaging
*Antibodies, Monoclonal, Humanized/therapeutic use/administration & dosage
Aged, 80 and over

@article {pmid41139428,
year = {2025},
author = {Justo-Henriques, SI and Lemos, R and Rahmatpour, P and Silva, RCG and Carvalho, JO and Ribeiro, O},
title = {Effectiveness of Individual Cognitive Stimulation on Cognition in Mild Alzheimer's Disease: A Multicenter RCT.},
journal = {Psychogeriatrics : the official journal of the Japanese Psychogeriatric Society},
volume = {25},
number = {6},
pages = {e70109},
doi = {10.1111/psyg.70109},
pmid = {41139428},
issn = {1479-8301},
mesh = {Humans ; *Alzheimer Disease/therapy/psychology ; Female ; Male ; Aged ; *Executive Function/physiology ; Neuropsychological Tests ; Treatment Outcome ; *Cognition/physiology ; Aged, 80 and over ; *Cognitive Behavioral Therapy/methods ; Memory ; Portugal ; *Cognitive Dysfunction/therapy ; },
abstract = {BACKGROUND: Alzheimer's Disease (AD) is characterised by impairments across several neurocognitive domains, including memory and executive function. The study explored the effectiveness of a 3-month individual Cognitive Stimulation (iCS) program in older adults with mild AD.

METHODS: A multicenter randomised controlled trial was conducted with 62 Portuguese older adults with mild AD. Participants were randomly assigned to either iCS (n = 33; 53%) or treatment as usual (TAU, n = 29; 47%). Cognitive outcomes were assessed at baseline, post-intervention, and 12-week follow-up using standardised tests for global cognition, memory and executive function.

RESULTS: The iCS group showed a significant improvement in memory and executive function compared to the TAU group. The analysis of subscales revealed significant improvements in encoding and semantic memory (Memory Alteration Test) and free delayed recall (Free and Cued Selective Reminding Test). Adherence and engagement with the intervention were high.

CONCLUSIONS: A 3-month iCS program showed preliminary benefits in specific cognitive domains (memory and executive function) in older adults with mild AD, warranting further research with larger samples and longer follow-up.

TRAIL REGISTRATION: Clinicaltrials.gov ID: NCT05433493; Effect of Individual Cognitive Stimulation on Memory and Executive Function in Older Adults With Alzheimer's Disease.},
}

Humans
*Alzheimer Disease/therapy/psychology
Female
Male
Aged
*Executive Function/physiology
Neuropsychological Tests
Treatment Outcome
*Cognition/physiology
Aged, 80 and over
*Cognitive Behavioral Therapy/methods
Memory
Portugal
*Cognitive Dysfunction/therapy

@article {pmid41139170,
year = {2025},
author = {Cai, X and Luo, X and Guo, L and Gu, Y and Yang, Q and Li, Y and Zhang, M and Wu, J and He, Q and Zhang, X and Huang, P and Zhang, H},
title = {Probabilistic maps of white matter hyperintensity in a Chinese aging cohort and application for clinical diagnosis.},
journal = {European radiology},
volume = {},
number = {},
pages = {},
pmid = {41139170},
issn = {1432-1084},
support = {2022ZD0209000//STI 2030-Major Projects/ ; ZJ2018-ZD-012//Major Projects of Special Development Funds in Zhangjiang National Independent Innovation Demonstration Zone, Shanghai/ ; JCYJ-SHFY-2022-014//Shanghai Pilot Program for Basic Research/ ; NMED2021ZD-01-001//Open Research Fund Program of National Innovation Center for Advanced Medical Devices/ ; KCXFZ20211020163408012//Shenzhen Science and Technology Innovation Program/ ; CIFMS, 2019-I2M-5-082//Chinese Academy of Medical Sciences (CAMS) Innovation Fund for Medical Science/ ; 21PJ1421400//Shanghai Pujiang Program/ ; 62131015//National Natural Science Foundation of China/ ; U23A20295//National Natural Science Foundation of China/ ; },
abstract = {OBJECTIVES: White matter hyperintensities (WMH) are abnormalities in brain imaging that contribute to cognitive decline and diseases. This study aimed to build WMH probability maps (WPMs) and normative data of WMH volume from a Chinese aging cohort, to offer valuable insights for diagnosis.

MATERIALS AND METHODS: We developed WPMs from a comprehensive dataset across six age groups (20-29, 30-39, 40-49, 50-59, 60-69, and 70-79 years), encompassing 735 participants. WMH segmentation was performed with a deep learning approach, and the resulting masks were registered to the standard space for WPM construction. We explored how WMH volume changed with age and established normative data for different age groups. Additionally, we examined whether WMH volume moderates the relationship between aging and cognitive decline. The practical utility of WPMs was then validated with a separate patient cohort with mild cognitive impairment and Alzheimer's disease.

RESULTS: WPMs and the normative data of WMH volume were constructed for six age groups. As age increased, both the likelihood and spatial coverage of WMH grew. All types of WMH (total, periventricular, and deep white matter hyperintensities) quadratically increased with age. Deep white matter hyperintensities moderated the decline of general cognitive abilities related to aging. The two patient groups had significantly higher ratios of abnormal WMH than typical aging adults.

CONCLUSION: We successfully built WPMs and WMH normative data for Chinese adults and demonstrated their clinical diagnostic values.

KEY POINTS: Question Current diagnostic tools lack population-specific references for white matter hyperintensities (WMH)in Chinese aging adults, limiting accurate discrimination between pathological neurodegeneration and typical aging patterns. Findings These Chinese WMH probability maps show quadratic age-related growth, with deep WMH moderating cognitive decline. Mild cognitive impairment/Alzheimer's Disease (MCI/AD) patients exhibited significantly higher WMH volumes. Clinical relevance These population-specific WMH references enable clinicians to quantitatively identify abnormal aging and early neurodegeneration in Chinese patients, addressing the critical need for ethnically tailored diagnostic tools in Alzheimer's disease and vascular cognitive impairment.},
}

@article {pmid41139132,
year = {2025},
author = {Sonwani, A and Pathak, A and Jain, K},
title = {Development and characterization of multifunctional dendrimeric nanoconjugates for delivery of rutin: in vitro characterization for potential neuroprotective application.},
journal = {Nanomedicine (London, England)},
volume = {},
number = {},
pages = {1-14},
doi = {10.1080/17435889.2025.2576463},
pmid = {41139132},
issn = {1748-6963},
abstract = {AIM: In the present research work, multifunctional dendrimeric nanoconjugates were developed, where poly(amidoamine) dendrimer generation 4.0 (G4.0) was conjugated with folic acid and N-acetyl cysteine simultaneously to deliver rutin for potential neuroprotective applications.

METHODS: G4.0 was functionalized with folic acid and N-acetyl cysteine by carbodiimide coupling chemistry, and the conjugation was confirmed using [1]H NMR and FTIR spectroscopy. Further, rutin was incorporated within the conjugate, and the rutin-loaded dendrimeric conjugate was evaluated for size, drug release, cytotoxicity, cellular uptake, and antioxidant activity.

RESULTS: The results of FTIR and [1]H NMR confirmed the conjugation of folic acid and N-acetyl cysteine over the dendrimeric surface. The particle size of NAC-FA-G4.0 was 163.4 ± 16.63 nm, which was increased to 229.76 ± 14.05 nm following the rutin incorporation. The in vitro drug release study showed an initial burst release of rutin, i.e. 44.27 ± 6.4% from dendrimeric conjugate within 4 h, followed by sustained release up to 72 h. The safety and biocompatibility of the developed nanoconjugate were confirmed by the hemolytic toxicity and cytotoxicity studies.

CONCLUSION: The developed rutin-loaded dendrimeric conjugate showed improved antioxidant activity and acetylcholinesterase inhibition, suggesting promising neuroprotection properties and hence may be further explored for the treatment of neurodegenerative diseases, including Alzheimer's disease.},
}

@article {pmid41139043,
year = {2025},
author = {Yu, C and Liu, L and Lu, Z and Chen, M and Yang, N and Li, Z and Bai, L and Li, C and Zhou, X},
title = {A new approach for treating AD: Guifu Dihuang Pills improves brain insulin resistance by promoting NrCAM to activate the EGFR/PI3K/Akt signaling pathway.},
journal = {Journal of ethnopharmacology},
volume = {},
number = {},
pages = {120642},
doi = {10.1016/j.jep.2025.120642},
pmid = {41139043},
issn = {1872-7573},
abstract = {Guifu Dihuang Pills (GFDHP), a classical Chinese herbal formula originally recorded in the Synopsis of the Golden Chamber (Jingui Yaolüe), significantly ameliorate cognitive dysfunction in patients with Alzheimer's disease (AD). However, the precise molecular mechanisms underlying its therapeutic effects, particularly those involving the regulation of cerebral insulin resistance (IR), are not yet fully elucidated.

AIM OF THE STUDY: This study systematically investigated the neuroprotective mechanism of the traditional Chinese medicine (TCM) compound GFDHP in alleviating AD by integrating RNA-seq transcriptomics, surface plasmon resonance (SPR) analysis, and bioinformatic analysis. The aim was to clarify its key targets and signaling pathways involved in the modulation of cerebral IR by in vitro and in vivo experiments.

METHODS: The chemical components of GFDHP were characterized using ultra-performance liquid chromatography quadrupole time-of-flight mass spectrometry (UPLC-Q-TOF/MS). An AD model with cerebral IR was established by an intracerebroventricular streptozotocin (ICV-STZ) injection. Cognitive function was assessed using the Morris water maze (MWM) test, while hippocampal damage was evaluated by histological staining. The insulin level in hippocampal tissues was quantified using enzyme-linked immunosorbent assay (ELISA). AD-related proteins were analyzed using immunohistochemistry and western blot. Integrated transcriptome sequencing, AlphaFold3 prediction, and SPR analysis confirmed the interaction between neuronal cell adhesion molecule (NrCAM) and epidermal growth factor receptor (EGFR). In vitro experiments were performed using HT22 cells treated with dexamethasone (DXM) to induce an IR model, followed by evaluation of IR and AD-related markers. Lentivirus-mediated shRNA knockdown of NrCAM was performed to systematically examine its regulatory effect on the EGFR/PI3K/Akt signaling pathway and GFDHP's therapeutic intervention.

RESULTS: GFDHP significantly attenuated ICV-STZ-induced IR and AD-related neuropathological alterations. SPR analysis further revealed that NrCAM mediated the neuroprotective effect through the specific binding to EGFR, thereby activating the downstream PI3K/Akt signaling cascade. NrCAM silencing not only exacerbated both IR and AD pathology but also suppressed the EGFR/PI3K/Akt pathway and reduced the therapeutic effect of GFDHP.

CONCLUSIONS: This study demonstrated that GFDHP alleviated IR by upregulating NrCAM expression and subsequently activating the EGFR/PI3K/Akt signaling pathway, thereby ameliorating AD. This is the first report identifying NrCAM as the key molecular target mediating the neuroprotective effect of this herbal formulation, providing a novel therapeutic strategy for AD treatment.},
}

@article {pmid41138967,
year = {2025},
author = {Kim, KJ and Villegas, AL and Kelley, AR and Labut, EM and Hagen, TM and Magnusson, KR and Kloefkorn, H},
title = {Sex differences in sleep fragmentation in 5xFAD mice.},
journal = {Neuroscience},
volume = {589},
number = {},
pages = {118-127},
doi = {10.1016/j.neuroscience.2025.10.035},
pmid = {41138967},
issn = {1873-7544},
abstract = {Sleep alterations have long been associated with Alzheimer's disease (AD), but whether it is an early symptom or only develops later in the pathological progression remains unknown. To study this, 5xFAD heterozygous (Het) mice, a transgenic model of amyloid overexpression, and wild-type (WT) littermates at 1, 2, 3, 4 and 6 months of age were assessed within instrumented home cages to noninvasively score 3-state sleep using respirations and gross body movements during the dark cycle. Progressive alterations in dark cycle sleep architecture were identified in Het animals as early as 1 month of age. Compared to WT littermates, Het mice exhibited increased sleep fragmentation and more microarousals. These effects were more pronounced in females than in males. Across ages, Het mice showed increased time awake and decreased sleep time, latency to rapid eye movement (REM) and total time in REM, although percent sleep time spent in REM did not differ significantly from WT controls. Most genotype differences widened by 6 months of age. Female mice exhibited shorter total time in non-REM relative to males. Additionally, females spent a greater proportion of time in wake, findings consistent with prior literature on WT sex differences in sleep vulnerability. Given that transgene expression was evidenced by day 15 of the 5xFAD Het and escalated with age, the observed early sleep dysregulation was likely reflective of the accumulation of soluble amyloid-beta oligomers. These results highlight early, sex-specific disruptions in dark cycle sleep that may serve as preclinical markers of AD-related pathology.},
}

@article {pmid41138884,
year = {2025},
author = {Xu, Y and Peng, Y and Zhi, F and Yang, Y and Li, J and Fan, L and Xia, Y and Shao, N},
title = {Delta-opioid receptor ameliorates microglia-induced synapse loss by regulating C1q in Alzheimer disease pathology.},
journal = {Brain, behavior, and immunity},
volume = {},
number = {},
pages = {106149},
doi = {10.1016/j.bbi.2025.106149},
pmid = {41138884},
issn = {1090-2139},
abstract = {While previous studies have well established δ-opioid receptor (DOR)-mediated neuroprotection against Alzheimer's pathology, the underlying mechanisms remain poorly understood. Our present work reveals a strong negative correlation between DOR and the classical complement pathway (CCP) initiator C1q, confirming their direct binding both in vitro and in APP/PS1 transgenic mice. Activating DOR with the specific agonist UFP-512 in aged APP/PS1 mice reduced cerebral C1q levels, while increasing DOR-C1q binding affinity. This interaction subsequently suppressed CCP activation, ameliorated complement-dependent synaptic engulfment by microglia, prevented synaptic protein loss, and consequently improved cognitive performance of these Alzheimer's disease (AD) mice. Consistent with these findings, overexpressing microglial DOR effectively inhibited its shift towards a phagocytotic phenotype and protected co-cultured neurons from lipopolysaccharide (LPS) -induced injury. Collectively, our findings demonstrate a critical role of DOR in restricting complement-mediated synaptic elimination during neurodegeneration, highlighting its potential as a new therapeutic target for AD.},
}

@article {pmid41138840,
year = {2025},
author = {Mazahir, F},
title = {Active Immunization: A Novel Therapeutic Strategy for Treating Alzheimer's Disease.},
journal = {European journal of pharmacology},
volume = {},
number = {},
pages = {178288},
doi = {10.1016/j.ejphar.2025.178288},
pmid = {41138840},
issn = {1879-0712},
abstract = {Alzheimer's disease is an age-dependent chronic neurodegenerative disorder characterised by progressive and chronic neurodegenerative disorder leading to cognitive decline and dementia. FDA-approved drugs only treat Alzheimer's disease, not cure it. Monoclonal antibodies (passive immunotherapy) target the pathological forms of amyloid β, improve cognitive function, and slow down the progression of Alzheimer's disease. Moreover, inconsistent therapeutic outcomes with the use of monoclonal antibodies led the doubts about their therapeutic effectiveness and the amyloid β cascade hypothesis. Recently, active immunotherapy has shown efficacy by producing antibodies against disease-related amyloid β and multiple phosphorylation sites of tau. CAD 106, a first second-generation vaccine, showed no incidence of amyloid β-specific T-cell response, meningoencephalitis, and CNS inflammation. However, no vaccine has been licensed for clinical practice. In this review, we described different hypotheses explaining the development of Alzheimer's disease, available therapy, and their limitations, and different active immunotherapeutic agents, their mechanisms, preclinical and clinical outcomes, challenges in the development, and future perspectives.},
}

@article {pmid41138838,
year = {2025},
author = {Yuan, Y and Wang, S and Lian, P and Yu, Z and Gao, X and Duan, Y and Mao, L and Zhou, Y},
title = {From plasma proteomics Mendelian Randomization to neuropathological validation: The potential role of CTSH-GRN-TMEM106B and TREM2-IL-34 networks of microglia in Alzheimer's disease.},
journal = {European journal of pharmacology},
volume = {},
number = {},
pages = {178297},
doi = {10.1016/j.ejphar.2025.178297},
pmid = {41138838},
issn = {1879-0712},
abstract = {BACKGROUND: Alzheimer's disease (AD) has complex pathophysiological features, and the interaction between peripheral and central systems has recently been considered to contribute to its occurrence and development. The complexity of the disease may not be fully captured by currently available exploration methods, such as biomarkers, which are limited by correlation associations. Comprehensive analytical methods are necessary to elucidate the association networks between different tissues, thereby further understanding the potential mechanisms of this disease.

METHODS: This study used a bidirectional Mendelian randomization (MR) framework to establish causal relationships between peripheral biomarkers and AD. It examined 734 plasmas and 151 cerebrospinal fluid (CSF) proteins as exposure factors, compared to AD diagnosis (causal relationship from peripheral to AD). In reverse, the study also explored 1296 brain protein outcomes using an AD genetic risk tool (causal relationship from AD to brain pathology). Additionally, this study integrated single-cell transcriptome data from prefrontal cortex specimens and validated findings in AD postmortem human brain tissue through immunohistochemistry and immunofluorescence, followed by protein-protein interaction (PPI) analysis using the STRING database to construct networks.

RESULTS: The bidirectional MR analysis revealed different proteomic characteristics, including elevated levels of cathepsin H (CTSH), signal regulatory protein alpha (SIRPA), and transmembrane protein 106B (TMEM106B) in plasma, and increased bone sialoprotein (BSP), interleukin-34 (IL-34), and immunoglobulin-like transcript 2 (ILT-2) in CSF, all exhibiting a positive correlation with AD risk. In contrast, higher plasma granulin (GRN), triggering receptor expressed on myeloid cells 2 (TREM2), sialic acid-binding immunoglobulin-like lectin-9 (SIGLEC9), and CSF SIGLEC7 exhibited protective effects. Reverse MR analysis revealed that AD is associated with the upregulation of CTSH, SIRPA, TMEM106B, IL-34, GRN, TREM2, SIGLEC9, and SIGLEC7 expression in the brain. Neuropathological validation confirmed the cortical overexpression of CTSH, GRN, TMEM106B, SIGLEC9, and TREM2 in AD specimens, consistent with MR analysis. According to the PPI network analysis, the regulatory networks of CTSH-GRN-TMEM106B and TREM2-IL-34 may be closely linked to AD.

CONCLUSIONS: This study established a connection between peripheral biomarkers and the central system, validated in AD postmortem human brain tissue samples, revealing a microglial CTSH-GRN-TMEM106B and TREM2-IL-34-related networks that may be involved in AD occurrence and development.},
}

@article {pmid41138654,
year = {2025},
author = {Ha, TY and Kim, Y and Lim, SM and Hong, Y and Chang, KA},
title = {GPR40 agonist ameliorates neurodegeneration by regulating mitochondria dysfunction and NLRP3 inflammasome in Alzheimer's disease animal models.},
journal = {Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie},
volume = {192},
number = {},
pages = {118678},
doi = {10.1016/j.biopha.2025.118678},
pmid = {41138654},
issn = {1950-6007},
abstract = {Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by mitochondrial dysfunction and chronic neuroinflammation. G-protein coupled receptor 40 (GPR40), primarily known for its role in metabolic regulation, has recently emerged as a modulator of neuronal activity and inflammatory signaling. In this study, we investigated the therapeutic potential of the selective GPR40 agonist TUG469 in both in vitro and in vivo models of AD. Treatment with amyloid-β oligomers (AβO) induced mitochondrial dysfunction in primary hippocampal neurons, as evidenced by disrupted mitochondrial morphology and membrane potential. TUG469 treatment restored mitochondrial integrity and membrane potential. Moreover, TUG469 significantly reduced AβO-induced reactive oxygen species (ROS) production. In the 5xFAD mouse model of AD, TUG469 administration improved cognitive performance and reduced Aβ plaque burden. Furthermore, TUG469 rescued impaired autophagy flux, as demonstrated by the regulation of LC3, p62, and LAMP1 expression, and attenuated neuroinflammatory responses by inhibiting NLRP3 inflammasome activation and modulating microglial reactivity. These findings indicate that GPR40 activation mitigates mitochondrial dysfunction and neuroinflammation, thereby alleviating AD-related pathology. Our results highlight the therapeutic potential of TUG469 as a multi-target modulator for AD.},
}

@article {pmid41138336,
year = {2025},
author = {Waheed, R and Mostafa, Z and Emad, M and Darwish, SS and Purgatorio, R and Miniero, DV and De Palma, A and Cheng, TP and Wang, TY and Chen, YC and El Kerdawy, AM and Gabr, M and Catto, M and Abadi, AH and Hwang, TL and Abdel-Halim, M},
title = {Revisiting COX-2 inhibitors for Alzheimer's disease as multitargeted ligands: Development of 4-hydrazono-pyrazolidinediones with tuned COX selectivity profile and improved cellular potency.},
journal = {European journal of medicinal chemistry},
volume = {302},
number = {Pt 1},
pages = {118261},
doi = {10.1016/j.ejmech.2025.118261},
pmid = {41138336},
issn = {1768-3254},
abstract = {Herein, we expand on our previously synthesized 4-hydrazono-pyrazolidinedione COX-2 inhibitors as multitargeted agents for Alzheimer's disease (AD). Structural modifications of the 4-phenylhydrazono group led to the identification of several highly potent COX-2 inhibitors, with compound 3 exhibiting the strongest COX-2 inhibition (IC50 = 0.07 μM), with a balanced COX-2/COX-1 profile, suggesting lower cardiovascular risk. Compounds 2 and 9 showed high potency and selectivity shift toward COX-1 and displayed strong antiplatelet activity. Several derivatives showed 4-7 times improved submicromolar cellular potency, significantly inhibiting PGE2 release in LPS-stimulated THP-1 cells. Compounds 2, 3, 7, and 9 maintained the multitarget profile and inhibited Aβ and tau aggregation. Compounds 2, 3, and 7 protected against Amyloid-beta (Aβ)- and H2O2-induced cytotoxicity, confirming their neuroprotective activity with high potential for BBB permeability demonstrated via PAMPA and MDCK-MDR1 assays. These results support the potential of multitargeted COX-2 inhibitors as AD therapeutics and suggest a re-evaluation of their role in neurodegenerative disease treatment.},
}

@article {pmid41138148,
year = {2025},
author = {Meller, AH and Siepker, KL and Fields, NL and Fantus, S and Jang, S},
title = {Informal Caregiver Outcomes in Home-Based Dyadic Dementia Interventions: A Scoping Review.},
journal = {Journal of evidence-based social work (2019)},
volume = {},
number = {},
pages = {1-35},
doi = {10.1080/26408066.2025.2576705},
pmid = {41138148},
issn = {2640-8074},
abstract = {PURPOSE OF THE STUDY: This scoping review aims to map the range of outcomes reported in studies of informal caregivers delivering home-based interventions to people with dementia, using the stress process model as a guiding framework.

MATERIALS AND METHODS: We followed the Arskey & O'Malley framework to conduct a scoping review. Data from nine databases were descriptively synthesized to map intervention types, caregiver roles, and outcome domains.

RESULTS: An initial database search yielded 3,977 studies of which 22 were included in this review. Results revealed a high degree of heterogeneity in research with ten different types of home-based interventions delivered by informal caregivers to persons living with dementia at home. Nine out of 10 types showed some positive benefits for the caregivers. No intervention had only negative impacts on caregivers.

DISCUSSION: Home-based, dyadic interventions for persons living with dementia showed promise in improving care recipient outcomes, but caregiver outcomes were mixed and often modest. Interventions that are flexible, feasible, and person-centered tend to be better received, yet challenges such as caregiver burden, intervention complexity, and lack of cultural inclusivity persist.

CONCLUSION: This scoping review underscores the impact of home-based, dyadic interventions on caregivers of persons living with dementia, highlighting that benefits for care recipients do not always translate into caregiver well-being. Future research should prioritize longitudinal, culturally responsive, and scalable studies to optimize outcomes for both caregivers and care recipients.},
}

@article {pmid41138063,
year = {2025},
author = {Ross, D and Chang, F and Edwards, L and Thomas, KR and Bangen, KJ and , },
title = {Cognitive dispersion is associated with white matter hyperintensities in amyloid positive older adults.},
journal = {The Clinical neuropsychologist},
volume = {},
number = {},
pages = {1-18},
doi = {10.1080/13854046.2025.2570301},
pmid = {41138063},
issn = {1744-4144},
abstract = {Objective: White matter hyperintensities (WMH), imaging markers of small vessel cerebrovascular disease, are associated with risk of dementia, including Alzheimer's disease (AD). Cognitive intraindividual variability (IIV) has emerged as a sensitive measure of future decline. We examined associations between IIV-dispersion, beta-amyloid (Aß) positivity, and WMH in older adults. Method: We included 819 participants (mean age = 72.01) without dementia from the Alzheimer's Disease Neuroimaging Initiative. IIV-dispersion was calculated as the intraindividual standard deviation across 6 neuropsychological scores. WMH volume was quantified on T2-weighted fluid attenuated inversion recovery images. Regression models examined interactions between IIV-dispersion and Aß status on WMH, adjusting for age, sex, and education. Results: Amyloid status moderated associations between IIV-dispersion and WMH, such that higher IIV-dispersion was associated with greater WMH in Aß+ individuals whether WMH was examined as a continuous (B = 0.30, ß = 0.13, p = .006) or a dichotomous variable based on quartiles (odds ratio [OR] = 2.41, p < .001). Sensitivity analyses to adjust for the effects of individual mean cognition in the models modified findings such that greater IIV-dispersion was again associated with greater WMH in Aß+ individuals when WMH was examined dichotomously (OR = 2.13, p = .018) but the effect was attenuated for continuous WMH. Conclusions: Greater IIV-dispersion was associated with greater WMH among Aß+ individuals. IIV-dispersion may be an early marker of cerebrovascular changes in AD although future research is needed to further establish its incremental utility.},
}

@article {pmid41138018,
year = {2025},
author = {Hu, L and Qi, L and Lin, Z and Zhu, J and Zhang, M},
title = {Research progress of single cell RNA sequencing in nervous system.},
journal = {Molecular biology reports},
volume = {53},
number = {1},
pages = {9},
pmid = {41138018},
issn = {1573-4978},
support = {82271747//National Natural Science Foundation of China/ ; },
mesh = {Humans ; *Single-Cell Analysis/methods ; *Sequence Analysis, RNA/methods ; *Nervous System/metabolism ; Transcriptome/genetics ; *Nervous System Diseases/genetics ; Animals ; Gene Expression Profiling/methods ; },
abstract = {Single-cell RNA sequencing (scRNA-seq) and its integration with multi-omics technologies such as epigenomics and spatial transcriptomics are revolutionizing our traditional understanding of cellular heterogeneity and the microenvironment in the nervous system. While technical reviews abound, translating multi-omics data into biological and clinical insights remains a challenge. This review comprehensively outlines the latest advancements in scRNA-seq technology and its integration with multi-omics approaches and artificial intelligence. We systematically summarize its applications across neuroscience, from unraveling neurodevelopment and evolution to deciphering the mechanisms of neurological diseases such as Alzheimer's disease, Parkinson's disease, and gliomas. By deeply resolving cell-specific expression differences in neurological disorders, scRNA-seq has enabled the discovery of novel cell subtypes and revealed intercellular regulatory mechanisms, thereby facilitating the deconstruction of disease pathogenesis and the identification of new potential therapeutic targets. Furthermore, this technology has demonstrated significant value in drug screening, efficacy evaluation, and the development of novel treatment strategies. However, scRNA-seq still faces multiple technical limitations. Future efforts should focus on reducing its application costs, addressing clinical ethical concerns, and progressively advancing the clinical translation of scRNA-seq technology.},
}

Humans
*Single-Cell Analysis/methods
*Sequence Analysis, RNA/methods
*Nervous System/metabolism
Transcriptome/genetics
*Nervous System Diseases/genetics
Animals
Gene Expression Profiling/methods

@article {pmid41137894,
year = {2025},
author = {Gu, X and Yu, SP and Jiang, MQ and Zhong, W and Sastry, A and Wei, L},
title = {Preventive Memantine Treatment at the Preclinical Stage in the Alzheimer's Disease Model of the 5xFAD Mouse.},
journal = {Neuroscience bulletin},
volume = {},
number = {},
pages = {},
pmid = {41137894},
issn = {1995-8218},
abstract = {Neuronal and NMDA receptor (NMDAR) hyperactivities are common pathophysiology in Alzheimer's disease (AD). We recently identified that the deficiency of NMDAR regulatory subunit GluN3A (NR3A) cultivated early psychological and olfactory symptoms, followed by cognitive decline and deferred endogenous amyloid/tau pathologies. NMDAR antagonist memantine (MEM) prevented AD-like progression in GluN3A knockout (KO) mice. We tested the hypothesis that AD development of the 5xFAD mouse can be antagonized by the preemptive MEM treatment. MEM (10 or 20 mg/kg per day in drinking water for 3 months) was started in wild-type (WT) and 5xFAD mice at 3 months old. In this preclinical stage, the 5xFAD mouse displayed psychological and olfactory symptoms, yet exhibited no significant cognitive deficits or Aβ42 deposition. The MEM treatment antagonized early symptoms, abated cognitive decline, and amyloid/tau pathology. Early and persistent maintenance of normal neuronal/NMDAR activities in individuals carrying AD risk factors should be considered as a preventive and a possible disease-modifying therapy.},
}

@article {pmid41137750,
year = {2025},
author = {Noh, B and Lee, HJ and Lee, J and Lee, JE and Joo, B and Jung, YH and Park, M and Kang, S and Oh, S and Hwang, JW and Kang, DS and Jeon, Y and Lee, SM and Hoe, HS and Koo, JW and Choi, KC},
title = {Color Dependence of OLED Phototherapy for Cognitive Function and Beta-Amyloid Reduction through ADAM17 and BACE1.},
journal = {ACS biomaterials science & engineering},
volume = {},
number = {},
pages = {},
doi = {10.1021/acsbiomaterials.5c01162},
pmid = {41137750},
issn = {2373-9878},
abstract = {Previous studies have reported that 40 Hz visual stimulation (acute white light exposure) reduced Aβ levels in Alzheimer's disease (AD) mouse model. However, whether different light colors distinctly regulate AD pathologies has not been well characterized. In the present study, an optimized organic light-emitting diode (OLED)-based visual stimulation platform was developed to provide uniform illumination without blind spots, and the color-dependent effects on cognitive function and amyloid-β (Aβ) pathology were investigated in 5xFAD mice, an Aβ-overexpressing AD model. Acute exposure to white or red OLED light (1 h/day for 2 days) significantly improved cognitive function, reduced hippocampal Aβ plaque accumulation via increasing ADAM17 activity, and downregulated proinflammatory cytokine IL-1β levels in 3-month-old 5xFAD mice, whereas green or blue OLED light did not produce these effects. In addition, chronic white and red OLED stimulation (1 h/day for 2 weeks) was shown to enhance recognition memory; however, only red light further diminished Aβ plaque deposition by upregulating ADAM17 activity and suppressing BACE-1 activity without altering neuroinflammation in 6-month-old 5xFAD mice. Moreover, acute white and red OLED exposure (1 h, single session) was observed to enhance c-fos expression, which is associated with neural activation along the visual pathway, thereby suggesting a mechanistic link between light stimulation and cognitive enhancement. Taken together, these findings demonstrate that color-dependent visual stimulation may serve as a promising electroceutical strategy for AD, with red light uniquely combining memory enhancement, Aβ reduction via ADAM17 upregulation and BACE1 suppression, and anti-inflammatory effects.},
}

@article {pmid41137733,
year = {2025},
author = {Venkat, V and Clark, K and Jeng, XJ and Yao, TC and Tsai, HJ and Lu, TP and Hsiao, TH and Lin, CH and Holloway, S and Hoyo, C and Chou, SY and Wang, H and Lee, WP and Wang, LS and Tzeng, JY},
title = {Exploring Random Forest in Genetic Risk Score Construction.},
journal = {Genetic epidemiology},
volume = {49},
number = {8},
pages = {e70022},
pmid = {41137733},
issn = {1098-2272},
support = {//This work is partially supported by National Institutes of Health Grants RF1AG074328 and U24AG041689./ ; },
mesh = {Humans ; *Genetic Predisposition to Disease ; *Models, Genetic ; Polymorphism, Single Nucleotide ; Linkage Disequilibrium ; Alzheimer Disease/genetics ; Computer Simulation ; Epistasis, Genetic ; Body Mass Index ; Genome-Wide Association Study ; Risk Factors ; Genetic Risk Score ; Random Forest ; },
abstract = {Genetic risk scores (GRS) are crucial tools for estimating an individual's genetic liability to various traits and diseases, computed as a weighted sum of trait-associated allele counts. Traditionally, GRS models assume additive, linear effects of risk variants. However, complex traits often involve nonadditive interactions, such as epistasis, which are not captured by these conventional methods. In this study, we investigate the use of random forest (RF) models as a model-free approach for constructing GRS, leveraging RF's capacity to capture complex, nonlinear interactions among genetic variants. Specifically, we introduce two new RF-based GRS strategies to boost RF performance and to incorporate base data information if available, including (1) ctRF, which optimizes linkage disequilibrium (LD) clumping and p-value thresholds within RF; and (2) wRF, which adjusts the chance of SNP inclusion in tree nodes based on their association strength. Through simulation studies and real data applications of Alzheimer's disease, body mass index, and atopy, we find that ctRF consistently outperforms other RF-based methods and classical additive models when traits exhibit complex genetic architectures. Additionally, incorporating informative base data into RF-GRS construction can enhance predictive accuracy. Our findings suggest that RF-based GRS can effectively capture intricate genetic interactions, and offer a robust alternative to traditional GRS methods, especially for complex traits with nonlinear genetic effects.},
}

Humans
*Genetic Predisposition to Disease
*Models, Genetic
Polymorphism, Single Nucleotide
Linkage Disequilibrium
Alzheimer Disease/genetics
Computer Simulation
Epistasis, Genetic
Body Mass Index
Genome-Wide Association Study
Risk Factors
Genetic Risk Score
Random Forest

@article {pmid41137705,
year = {2025},
author = {Lanskey, JH and Jafarian, A and Karadag, M and Kocagoncu, E and Williams, RS and Yadav, P and Quinn, AJ and Pitt, J and Thayanandan, T and Lowe, S and Perkinton, M and Timmers, M and Raymont, V and Singh, KD and Woolrich, M and Nobre, AC and Henson, RN and Rowe, JB},
title = {Alzheimer's disease and its progression reduce pyramidal cell gain and connectivity.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21},
number = {10},
pages = {e70805},
pmid = {41137705},
issn = {1552-5279},
support = {//Dementias Platform UK/ ; SUAG/092 G116788/MRC_/Medical Research Council/United Kingdom ; SUAG/096G116788/MRC_/Medical Research Council/United Kingdom ; MC_UU_00030/14/MRC_/Medical Research Council/United Kingdom ; MR/T033371/1/MRC_/Medical Research Council/United Kingdom ; 220258/WT_/Wellcome Trust/United Kingdom ; NIHR203312//NIHR Cambridge Biomedical Research Centre/ ; NIHR203316//NIHR Oxford Health Biomedical Research Centre/ ; ARUK-PG2017B-19//Alzheimer's Research Trust/ ; },
mesh = {Humans ; *Alzheimer Disease/physiopathology/pathology ; Magnetoencephalography ; *Pyramidal Cells/physiology ; Male ; Female ; Disease Progression ; Aged ; Middle Aged ; Adult ; Bayes Theorem ; Reproducibility of Results ; },
abstract = {INTRODUCTION: Alzheimer's disease (AD) affects neurophysiology by loss of neurons, synapses, and neurotransmitters. A mechanistic understanding of the human disease will facilitate new treatments.

METHODS: Magnetoencephalography was recorded during an auditory mismatch negativity paradigm from healthy adults (n = 14) and people with symptomatic AD (n = 45, amyloid biomarker positive) at baseline and after 16 months. Fourteen people with AD had repeat magnetoencephalography at 2 weeks to assess test-retest reliability. Dynamic causal models were fitted to the evoked responses and analyzed using parametric empirical Bayes.

RESULTS: Sensor data confirmed that AD and its progression reduce the mismatch negativity amplitude, which had excellent test-retest reliability. Parametric empirical Bayes analyses confirmed that AD progressively reduces extrinsic connectivity between pyramidal cells and superficial pyramidal cell gain modulation.

DISCUSSION: Dynamic causal modeling revealed cellular-level causes of the neurophysiological deficits observed in AD. This approach may help facilitate experimental medicine studies of candidate treatments.

HIGHLIGHTS: Magnetoencephalography scanning provides reliable biomarkers that are sensitive to Alzheimer's disease (AD) and its progression, and informative about disease mechanisms underlying cognitive decline. In vivo assays of pyramidal cell function during cognitive processes in humans improve our understanding of AD mechanisms. The amplitude of the mismatch negativity response is progressively reduced in AD. Reduced pyramidal cell gain and connectivity underlie this neurophysiological deficit. These measures are potential biomarkers for interventional studies.},
}

Humans
*Alzheimer Disease/physiopathology/pathology
Magnetoencephalography
*Pyramidal Cells/physiology
Male
Female
Disease Progression
Aged
Middle Aged
Adult
Bayes Theorem
Reproducibility of Results

@article {pmid41137629,
year = {2025},
author = {Sachs, BC and Latham, LA and Isom, S and Clark, LR and Craft, S and Duff, K and Espeland, MA and Farias, ST and Gaussoin, SA and Goldstein, FC and Hampstead, BM and Jayadev, S and Jicha, GA and Kukull, WA and Leng, XI and Mechanic-Hamilton, D and Neugroschl, J and Papp, KV and Saykin, AJ and Sewell, MC and Rapp, SR},
title = {Multi-site video-based assessment with the NACC UDS-Version 3 battery: Design and participant experience in the V-Cog study.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21},
number = {10},
pages = {e70842},
pmid = {41137629},
issn = {1552-5279},
support = {R01AG075959/AG/NIA NIH HHS/United States ; },
mesh = {Humans ; Female ; Aged ; Male ; *Cognitive Dysfunction/diagnosis ; *Video Recording ; *Alzheimer Disease/diagnosis ; *Neuropsychological Tests ; Aged, 80 and over ; COVID-19 ; Reproducibility of Results ; Feasibility Studies ; *Dementia/diagnosis ; },
abstract = {INTRODUCTION: Video-based cognitive testing is becoming more common. The 'VCog' study aims to evaluate the validity, feasibility, and acceptability of a standardized video-administered cognitive research battery.

METHODS: Twelve Alzheimer's Disease Research Centers (ADRCs) administered, in randomized order, an in-person and video-adapted Uniform Data Set Version 3 (UDSv3) cognitive assessment battery to participants with normal cognition (n = 156), mild cognitive impairment (MCI; n = 230), and dementia (n = 77). Acceptability of technology and participant experience completing video testing was assessed.

RESULTS: Of 463 participants (mean age 75.1 years, 52.5% female, and 25.5% non-White individuals), most rated video testing as easy (90.0%), convenient (95.3%) and would accept it in future visits (75.5%). Greater cognitive impairment was associated with more difficulty with setup and use of video. Staff rated most administrations as producing valid data (94.8%).

DISCUSSION: Video-based research cognitive testing with an adapted UDSv3 battery is feasible and well-accepted among older adults with and without cognitive impairment.

HIGHLIGHTS: The COVID-19 pandemic increased the need for video-administered cognitive assessments in Alzheimer's Disease Research Centers (ADRCs) . Feasibility, acceptability, and validity of video cognitive testing were evaluated. Participant experience and examiner evaluations of data validity were positive. Video assessment may extend the ADRCs reach to otherwise unreachable participants.},
}

Humans
Female
Aged
Male
*Cognitive Dysfunction/diagnosis
*Video Recording
*Alzheimer Disease/diagnosis
*Neuropsychological Tests
Aged, 80 and over
COVID-19
Reproducibility of Results
Feasibility Studies
*Dementia/diagnosis

@article {pmid41137626,
year = {2025},
author = {Valay, L and Potier, MC},
title = {Reviewing the possible connection between cerebral amyloid angiopathy and blood-brain barrier integrity in Down syndrome.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21},
number = {10},
pages = {e70814},
pmid = {41137626},
issn = {1552-5279},
support = {//Association France Alzheimer/ ; ED394//Sorbonne Université/ ; ANR-10-AIHU-06//Agence Nationale de la Recherche/ ; COEN-0002//Centre Of Excellence Neurodegenerative diseases Agence Nationale de la Recherche/ ; COEN-4024//Centre Of Excellence Neurodegenerative diseases Agence Nationale de la Recherche/ ; },
mesh = {*Down Syndrome/complications/pathology ; Humans ; *Cerebral Amyloid Angiopathy/pathology/metabolism ; *Blood-Brain Barrier/pathology/metabolism ; Amyloid beta-Protein Precursor/metabolism/genetics ; Amyloid beta-Peptides/metabolism ; },
abstract = {Individuals with Down syndrome (DS) have a higher risk of developing cerebral amyloid angiopathy (CAA), primarily because of the excessive production of amyloid beta (Aβ). However, the consequences of CAA on blood-brain barrier (BBB) integrity and the neurovascular unit (NVU) are still not well understood. Systematic search was conducted on PubMed using 12 targeted keywords related to CAA, BBB, and the NVU in combination with DS. Additional sources were identified and the research gap validated using Consensus and ChatGPT-assisted literature screening. Individuals with DS are vulnerable to cerebrovascular conditions across their lifespan. Despite pronounced Aβ pathology, CAA appears less frequent than in cases with microduplication of the APP locus, suggesting distinct vascular dynamics potentially influenced by chromosome 21 genes. Limited direct evidence on BBB integrity in DS highlights the need for mechanistic and longitudinal studies. DS offers a unique lens for exploring cerebrovascular resilience and CAA pathogenesis. HIGHLIGHTS: Down syndrome (DS) individuals overexpressing amyloid precursor protein (APP) are at risk for cerebral amyloid angiopathy (CAA) and lobar microbleeds. CAA is less severe in DS compared to APP microduplication (APPdup) cases. Intracerebral hemorrhage (ICH) is less common in DS than in APPdup cases. DS may have protective mechanisms against CAA and ICH involving BBB function. Few longitudinal studies examine BBB permeability in DS across the lifespan.},
}

*Down Syndrome/complications/pathology
Humans
*Cerebral Amyloid Angiopathy/pathology/metabolism
*Blood-Brain Barrier/pathology/metabolism
Amyloid beta-Protein Precursor/metabolism/genetics
Amyloid beta-Peptides/metabolism

@article {pmid41137623,
year = {2025},
author = {Soreq, E and Kolanko, MA and , and Ravindran, KKG and Della Monica, C and Revell, V and Daniels, S and Joffe, A and Lai, H and Golemme, M and Giovane, MD and Walsh, C and Wingfield, D and Nilforooshan, R and Stefanos, MA and Vittrant, B and de Villèle, P and Dijk, DJ and Sharp, DJ},
title = {Contactless longitudinal monitoring in the home characterizes aging and Alzheimer's disease-related night-time behavior and physiology.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21},
number = {10},
pages = {e70758},
pmid = {41137623},
issn = {1552-5279},
support = {7201//UK Dementia Research Institute/ ; 7206//UK Dementia Research Institute/ ; //Alzheimer's Research UK/ ; /MRC_/Medical Research Council/United Kingdom ; },
mesh = {Humans ; *Alzheimer Disease/physiopathology/complications ; Male ; Female ; Aged ; Longitudinal Studies ; *Aging/physiology ; *Sleep Wake Disorders/diagnosis/physiopathology/etiology ; Aged, 80 and over ; Disease Progression ; Sleep/physiology ; Monitoring, Physiologic/methods ; Machine Learning ; },
abstract = {INTRODUCTION: Disturbed sleep patterns are common in dementia but have not been objectively quantified over long periods.

METHODS: We compared a cohort of 83 Alzheimer's disease (AD) patients to 13,588 individuals from the general population. Sleep patterns, heart rate, and breathing rate data were acquired using a zero-burden contactless, under-mattress pressure sensor. Data reduction and explainable machine learning approaches were used to identify sleep phenotypes.

RESULTS: AD was characterized by longer time in bed, more bed exits, less snoring, and changes in estimated sleep states. We derived the Dementia Research Institute Sleep Index for Alzheimer's Disease (DRI-SI-AD), a digital biomarker quantifying sleep disturbances. DRI-SI-AD detected the effects of acute clinical events and dementia progression at the individual level.

DISCUSSION: Our approach may help bridge a gap in dementia care by providing a zero-burden method for longitudinal monitoring of health events, disease progression, and dementia risk.

HIGHLIGHTS: Continuous monitoring reveals dementia-specific nocturnal sleep disturbances. We developed a novel sleep biomarker, Dementia Research Institute Sleep Index (AD), for tracking Alzheimer's disease (AD) progression. We used contactless under-mattress sensors for low-burden, long-term data collection. Prolonged bedtimes and frequent exits were identified as key dementia-related sleep traits. We demonstrated the feasibility of in-home monitoring for dementia care and risk assessment.},
}

Humans
*Alzheimer Disease/physiopathology/complications
Male
Female
Aged
Longitudinal Studies
*Aging/physiology
*Sleep Wake Disorders/diagnosis/physiopathology/etiology
Aged, 80 and over
Disease Progression
Sleep/physiology
Monitoring, Physiologic/methods
Machine Learning

@article {pmid41137622,
year = {2025},
author = {Wisch, JK and McKay, NS and Zammit, M and Christian, BT and Schultz, SA and Millar, PR and Ryan, NS and Cash, DM and Belder, CRS and Chrem, P and Cruchaga, C and Ibanez, L and Jucker, M and Yakushev, I and Day, GS and Murphy, M and Llibre-Guerra, J and Aguillon, D and Roh, JH and Xiong, C and Wang, G and Li, Y and Schindler, SE and Jack, C and McDade, E and Bateman, RJ and Benzinger, TLS and Ances, BM and , and Betthauser, T and Gordon, B},
title = {Comparison of amyloid chronicity and EYO in autosomal dominant Alzheimer's disease.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21},
number = {10},
pages = {e70812},
pmid = {41137622},
issn = {1552-5279},
support = {U19AG032438/AG/NIA NIH HHS/United States ; R01 AG080766/AG/NIA NIH HHS/United States ; SG-20-690363-DIAN/ALZ/Alzheimer's Association/United States ; //German Center for Neurodegenerative Diseases (DZNE)/ ; //Raul Carrea Institute for Neurological Research(FLENI)/ ; //Japan Agency for Medical Research and Development/ ; //Ministry of Health & Welfare/ ; RS-2024-00344521//Ministry of Science and ICT/ ; //Spanish Institute of Health Carlos III (ISCIII)/ ; //UKDementia Research Institute at University College London/ ; //the Barnes-Jewish Hospital Foundation/ ; //the Charles F and Joanne Knight Alzheimer's Research Initiative/ ; //the Hope Center for Neurological Disorders/ ; //the Mallinckrodt Institute ofRadiology/ ; //the Paula and Rodger Riney fund/ ; //the Daniel J Brennan MD fund/ ; },
mesh = {Humans ; *Alzheimer Disease/genetics/diagnostic imaging/pathology/metabolism ; Male ; Female ; Positron-Emission Tomography ; Middle Aged ; Age of Onset ; Longitudinal Studies ; Aged ; Biomarkers ; Disease Progression ; *Amyloid/metabolism ; *Amyloid beta-Peptides/metabolism ; },
abstract = {INTRODUCTION: Preclinical Alzheimer's disease (AD) can be described relative to biomarker positivity onset time.

METHODS: We estimated time from amyloid positivity (A+) using sampled iterative local approximation (SILA) in a longitudinal autosomal dominant AD (ADAD) sample (N = 379) with amyloid positron emission tomography. We compared (1) predicted age at A+ to imputed age, (2) estimated age at A+ to estimated age at symptom onset, and (3) variance in cognitive performance explained.

RESULTS: Mean error between imputed and SILA-estimated age at A+ (N = 26) was 1.15 years. Age at A+ explained 39% of estimated years to symptom onset (EYO) variance. Time from A+ explained 19% of cognitive composite variance and 14% of Clinical Dementia Rating Sum of Boxes CDR-SB variance; EYO explained 43% and 57%, respectively.

DISCUSSION: SILA estimates A+ age in ADAD with reasonably good accuracy. SILA-estimated time from A+ describes the start of pathology, but the time from A+ onset to symptoms is variable in ADAD and better described by EYO.

HIGHLIGHTS: Amyloid chronicity predicts a 14-year preclinical AD phase in ADAD. SILA accurately estimates age at A+ (MAE < 2 years). EYO outperforms chronicity in predicting symptom onset. APP mutation carriers show atypical amyloid accumulation. Chronicity models help reveal AD heterogeneity in preclinical stages.},
}

Humans
*Alzheimer Disease/genetics/diagnostic imaging/pathology/metabolism
Male
Female
Positron-Emission Tomography
Middle Aged
Age of Onset
Longitudinal Studies
Aged
Biomarkers
Disease Progression
*Amyloid/metabolism
*Amyloid beta-Peptides/metabolism

@article {pmid41141948,
year = {2023},
author = {Sarko, L and Saha, K},
title = {Harnessing chimeric antigen receptor (CAR)-T cells as a potential treatment for Alzheimer's disease.},
journal = {Cell & gene therapy insights},
volume = {9},
number = {7},
pages = {1003-1010},
pmid = {41141948},
issn = {2059-7800},
abstract = {Alzheimer's disease (AD) significantly burdens global healthcare systems given limited treatment options to delay or stop disease progression. Chimeric antigen receptor (CAR) T cell therapy, an immunotherapeutic approach that has produced remarkably effective responses in cancer, offers a potential avenue for the treatment of AD. Here, we discuss three significant challenges of adapting CAR-T cell therapy for AD: (i) identifying a suitable antigen target; (ii) limited permeability of the blood-brain barrier; and (iii) long-term persistence and durability of manufactured CAR-T cell products. Potential strategies to overcome these hurdles provide an attractive opportunity to revolutionize the treatment for AD and potentially other neurodegenerative disorders.},
}

@article {pmid41137616,
year = {2025},
author = {Chan, D and de Weck, G and Jackson, BL and Suk, HJ and Milman, NP and Kitchener, E and Avalos, VSF and Quay, MJ and Aoki, K and Ruiz, E and Becker, A and Zheng, M and Philips, R and Firenze, R and Geigenmüller, U and Hammerschlag, B and Arnold, S and Kivisäkk, P and Brickhouse, M and Touroutoglou, A and Brown, EN and Boyden, ES and Dickerson, BC and Klerman, EB and Tsai, LH},
title = {Gamma sensory stimulation in mild Alzheimer's dementia: An open-label extension study.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21},
number = {10},
pages = {e70792},
doi = {10.1002/alz.70792},
pmid = {41137616},
issn = {1552-5279},
support = {//Freedom Together Foundation/ ; //Robert A. and Renee E. Belfer Family Foundation/ ; //Eleanor Schwartz Charitable Foundation/ ; //The Dolby Family/ ; //Che King Leo/ ; //Amy Wong and Calvin Chin/ ; //Kathleen and Miguel Octavio/ ; //the Degroof-VM Foundation/ ; //Halis Family Foundation/ ; //Chijen Lee/ ; //Eduardo Eurnekian/ ; //Larry and Debora Hilibrand/ ; //Gary Hua and Li Chen/ ; //Ko Han Family/ ; //Lester Gimpelson/ ; //David B. Emmes/ ; //Joseph P. DiSabato and Nancy E. Sakamoto/ ; //Donald A. and Glenda G. Mattes/ ; //Alan and Susan Patricof/ ; //Carol and Gene Ludwig Family Foundation/ ; //Alex Hu and Anne Gao/ ; //Elizabeth K. and Russell L. Siegelman/ ; //Marc Haas Foundation/ ; //Dave and Mary Wargo/ ; //James D. Cook, and the Nobert H. Hardner Foundation/ ; UDIW8172//NIH Loan Repayment Program/ ; 15367//Doris Duke Clinical Scientist Development Award/ ; //Picower Clinical Fellowship/ ; UL1 TR002541/TR/NCATS NIH HHS/United States ; },
mesh = {Humans ; *Alzheimer Disease/therapy/physiopathology/diagnostic imaging ; Female ; Aged ; Electroencephalography ; Magnetic Resonance Imaging ; Neuropsychological Tests ; Male ; Biomarkers/blood ; Brain/diagnostic imaging/physiopathology ; Aged, 80 and over ; tau Proteins/blood ; *Acoustic Stimulation/methods ; *Photic Stimulation/methods ; Cognition/physiology ; Mental Status and Dementia Tests ; },
abstract = {INTRODUCTION: We evaluated the long-term effects of daily 40 Hz (gamma frequency) audiovisual stimulation on cognition and biomarkers in five patients with mild Alzheimer's disease (AD).

METHODS: Over 2 years, patients received 1-h daily stimulation. Electroencephalography (EEG) was used to assess neural entrainment; magnetic resonance imaging (MRI) measured brain volumes; actigraphy monitored activity patterns; neuropsychological tests evaluated cognition; and S-PLEX assay measured plasma pTau217.

RESULTS: No adverse events occurred over the study period. Three female patients with late-onset AD (LOAD) retained strong EEG entrainment and showed less decline in Mini-Mental State Examination (MMSE), Clinical Dementia Rating (CDR), and Functional Assessment Scale (FAS) scores compared to matched controls from National Alzheimer's Coordinating Center (NACC), Alzheimer's Disease Neuroimaging Initiative (ADNI), and Longitudinal Early-Onset Alzheimer's Disease Study (LEADS). Plasma samples were available for only two of five participants - both with LOAD - and both showed pTau217 reductions of 47% and 19%.

DISCUSSION: These findings suggest that long-term 40 Hz audiovisual stimulation is safe, feasible, and may offer cognitive and biomarker benefits in some individuals with mild AD, supporting further investigation.

ClinicalTrials.gov (NCT04055376).

HIGHLIGHTS: Five mild Alzheimer's disease (AD) patients safely used daily 40 Hz audiovisual stimulation for 2 years. Late-onset AD (LOAD) patients showed increased 40 Hz electroencephalography (EEG) power and improved cognitive scores. National Alzheimer's Coordinating Center (NACC) data enhanced early-phase analysis and support precision medicine in AD studies. Plasma pTau217 declined in 2 LOAD patients after 2 years of daily use. This small pilot is the first to link long-term 40 Hz therapy to AD biomarker change.},
}

Humans
*Alzheimer Disease/therapy/physiopathology/diagnostic imaging
Female
Aged
Electroencephalography
Magnetic Resonance Imaging
Neuropsychological Tests
Male
Biomarkers/blood
Brain/diagnostic imaging/physiopathology
Aged, 80 and over
tau Proteins/blood
*Acoustic Stimulation/methods
*Photic Stimulation/methods
Cognition/physiology
Mental Status and Dementia Tests

@article {pmid41137556,
year = {2025},
author = {Geiger, AR and Guevara, JE and King, JB and Hoffman, JM and Duff, K},
title = {Using neuropsychological test scores to predict beta-amyloid deposition in older adults across the late-life cognitive continuum.},
journal = {Journal of clinical and experimental neuropsychology},
volume = {},
number = {},
pages = {1-9},
doi = {10.1080/13803395.2025.2578345},
pmid = {41137556},
issn = {1744-411X},
abstract = {INTRODUCTION: Many studies have established the relationship between greater burden of beta-amyloid (aβ), a marker of Alzheimer's disease (AD), and poorer neuropsychological performance. However, it is poorly understood whether neuropsychological test scores predict aβ deposition. This study aimed to evaluate the predictive utility of neuropsychological test scores on aβ deposition in a sample of older adults across the late-life cognitive spectrum.

METHOD: One hundred and sixty-five older adults classified as cognitively intact (n = 68), single- or multi-domain amnestic mild cognitive impairment (MCI; n = 52) or mild dementia (n = 45) completed amyloid positron emission topography (PET), and neuropsychological measures including Hopkins Verbal Learning Test - Revised (HVLT-R), Brief Visual Memory Test - Revised (BVMT-R), Trail Making Test (TMT) Parts A and B, and Symbol Digit Modalities Test (SDMT). A series of hierarchical regression were evaluated to assess the predictive association of cognitive test scores to aβ deposition.

RESULTS: In a predominantly non-Hispanic White, college-educated sample, HVLT-R Total and Delayed Recall were negatively associated with aβ deposition above and beyond demographic covariates (i.e. age, sex, years of education, estimated premorbid functioning), accounting for 31% and 39% of variance in aβ, respectively (p < .001). Similarly, BVMT-R Total and Delayed Recall scores each accounted for 31% of variance (p < .001). Effect sizes for processing speed and executive functioning scores were smaller, with SDMT explaining 12% of the variance and TMT-A and TMT-B explaining 7% and 9% of the variance, respectively (p < .001).

CONCLUSION: Cognitive test scores significantly predicted aβ deposition, with memory measures in particular accounting for approximately a third of the variance. These results provide a proof of concept for use of neuropsychological test scores as tools for estimating biomarkers in neurodegenerative disease.},
}

@article {pmid41137217,
year = {2025},
author = {Sun, R and Liu, Y},
title = {The causal association between hyperlipidemia and Alzheimer disease: A combined NHANES and Mendelian randomization study.},
journal = {Medicine},
volume = {104},
number = {43},
pages = {e45393},
doi = {10.1097/MD.0000000000045393},
pmid = {41137217},
issn = {1536-5964},
mesh = {Humans ; *Alzheimer Disease/epidemiology/genetics/blood ; Mendelian Randomization Analysis ; *Hyperlipidemias/epidemiology/genetics/complications/blood ; Male ; Female ; Nutrition Surveys ; Cross-Sectional Studies ; Aged ; Middle Aged ; Triglycerides/blood ; Risk Factors ; Cholesterol, HDL/blood ; Cognitive Dysfunction/epidemiology ; Cholesterol, LDL/blood ; Cholesterol/blood ; },
abstract = {This study examines the causal association between hyperlipidemia and Alzheimer disease (AD) by utilizing a mix of data from the National Health and Nutrition Examination Survey (NHANES) and 2 sample Mendelian randomization (MR) analysis. The NHANES cross-sectional data (2011-2012 and 2013-2014) was used to investigate the correlation between hyperlipidemia and cognitive impairment in individuals with AD, as measured by the consortium to establish a registry for AD word learning (CERAD-WL). This was accomplished by employing multivariable logistic regression models to compute odds ratios (ORs). The MR analysis leveraged summary-level genetic data to assess the causal effects of various cholesterol traits, consisting of total cholesterol, triglycerides, low-density lipoprotein (LDL) cholesterol, and high-density lipoprotein (HDL) cholesterol, medium HDL cholesterol, and cholesteryl ester levels in small very LDL, on AD risk. There were several MR approaches that were utilized, including the inverse-variance weighted, weighted median, MR-Egger, and weighted mode. The NHANES data showed that participants with low cognition (lowest quartile of CERAD-Total score) had significantly greater incidences of hyperlipidemia in comparison to individuals who possessed normal cognitive abilities. The multivariable-adjusted OR was 2.159 (95% CI: 1.161-4.451, P <.001) for the lowest versus highest CERAD-Total score quartile. The MR analysis provided evidence for causal links between cholesterol traits and AD risk. Higher levels of total cholesterol (OR: 0.867, 95% CI: 0.776-0.968, P = .011), triglycerides (OR:0.870, 95% CI: 0.767-0.985, P = .028) were connected to increased AD risk. Higher HDL cholesterol was protective (OR: 1.045, 95% CI: 1.000-1.092, P = .049). Not a very strong causative effect was found for LDL cholesterol, medium HDL cholesterol or cholesteryl ester in small very LDL and AD. This combined NHANES and MR analysis provides robust evidence that hyperlipidemia, specifically elevated total cholesterol, and triglycerides, is causally associated with increased risk of AD, while higher HDL cholesterol is protective. These data indicate that addressing irregularities in cholesterol levels could be a potential strategy for controlling and preventing AD.},
}

Humans
*Alzheimer Disease/epidemiology/genetics/blood
Mendelian Randomization Analysis
*Hyperlipidemias/epidemiology/genetics/complications/blood
Male
Female
Nutrition Surveys
Cross-Sectional Studies
Aged
Middle Aged
Triglycerides/blood
Risk Factors
Cholesterol, HDL/blood
Cognitive Dysfunction/epidemiology
Cholesterol, LDL/blood
Cholesterol/blood

@article {pmid41137085,
year = {2025},
author = {Zhang, W and Song, J and Zhong, F and Yu, W and Qin, Z and Yang, Z and Liu, J and Wang, X and Chen, L and Lü, W and Xing, D and Liu, J and Huang, C and Wu, J and Liu, X and Yu, W and Lü, Y},
title = {Computerized cognitive training enhances cognitive function in Alzheimer's disease by downregulating Ruminococcus-TMAO pathway.},
journal = {Journal of translational medicine},
volume = {23},
number = {1},
pages = {1173},
pmid = {41137085},
issn = {1479-5876},
support = {2022YSZX-JSX0002CSTB//grants from Innovation Programs Led by the Academicians in Chongqing under Project/ ; cstc2022ycjh-bgzxm0184//Chongqing Talent Plan/ ; CSTC2021jscx-gksb-N0020//Jiangsu Provincial Agricultural Science and Technology Independent Innovation Fund/ ; 2021ZD0201802//STI2030-Major Projects/ ; 2018YFC2001700//National Key R&D Program of China/ ; 0201[2023]160 202412//Chongqing Medical Key Discipline and Regional Medical Key Discipline Development Project/ ; },
mesh = {Humans ; Male ; *Alzheimer Disease/microbiology/physiopathology/therapy/blood ; Female ; *Cognition/physiology ; Aged ; *Methylamines/blood/metabolism ; *Down-Regulation ; Gastrointestinal Microbiome ; Cognitive Dysfunction/physiopathology ; Cognitive Training ; },
abstract = {BACKGROUND: The microbiota-gut-brain (MGB) axis is implicated in Alzheimer's disease (AD), but evidence for interventional strategies targeting this axis remains limited.

METHODS: In a 24-week, single-blind, randomized controlled trial, 84 individuals with mild cognitive impairment (MCI) or mild AD received either computerized cognitive training (CCT) or treatment as usual (TAU). Alzheimer's Disease Assessment Scale-cognitive subscale (ADAS-cog) was the primary outcome. We also assessed functional connectivity (fNIRS), plasma trimethylamine N-oxide (TMAO) levels, and gut microbiota at baseline and 24 weeks.

RESULTS: Seventy-four participants completed the study. The CCT group showed significant improvement in ADAS-cog scores compared to controls (Cohen's d = 1.57 by week 24). Notably, CCT also induced a distinct reorganization of prefrontal functional connectivity and significantly reduced plasma TMAO levels. Microbiome analysis revealed that CCT mitigated the expansion of Ruminococcus torques group (R.torques), which was observed in the control group. Crucially, R.torques was the only genus significantly correlated with improvements in cognition (ADAS-cog, r = 0.407), neuropsychiatric symptoms (NPI, r = 0.395), TMAO reduction (r = 0.443), and functional connectivity changes (r = 0.449).

CONCLUSION: A 24-week CCT program improves cognitive function in MCI and mild AD, potentially through downregulating the R.torques-TMAO pathway within the MGB axis. This pathway represents a promising novel target for multi-domain intervention in AD.},
}

Humans
Male
*Alzheimer Disease/microbiology/physiopathology/therapy/blood
Female
*Cognition/physiology
Aged
*Methylamines/blood/metabolism
*Down-Regulation
Gastrointestinal Microbiome
Cognitive Dysfunction/physiopathology
Cognitive Training

@article {pmid41136919,
year = {2025},
author = {Katagiri, R and Yamada, Y and Shinkawa, K and Kobayashi, M and Nemoto, M and Ota, M and Nemoto, K and Arai, T and Takiyama, K},
title = {Dual-task walking for early detection of Alzheimer's disease: comparative analysis of tasks using whole-body gait variables.},
journal = {BMC geriatrics},
volume = {25},
number = {1},
pages = {807},
pmid = {41136919},
issn = {1471-2318},
support = {19H01084//Japan Society for the Promotion of Science/ ; 21K12153//Japan Society for the Promotion of Science/ ; 19H01084//Japan Society for the Promotion of Science/ ; 24K02840//Japan Society for the Promotion of Science/ ; },
mesh = {Humans ; Male ; Female ; *Alzheimer Disease/diagnosis/physiopathology/psychology ; Aged ; *Walking/physiology ; *Gait/physiology ; *Cognitive Dysfunction/diagnosis/physiopathology/psychology ; Early Diagnosis ; Aged, 80 and over ; *Task Performance and Analysis ; Middle Aged ; },
abstract = {BACKGROUND: The worldwide rise in dementia creates an urgent need for screening methods that are both sensitive and easy to administer. Dual-task walking-requiring people to walk while performing a second cognitive or motor task-meets these criteria because it stresses gait and cognition simultaneously, revealing deficits that emerge early in Alzheimer's disease and Mild Cognitive Impairment (MCI). Although recent studies have explored integrating various gait variables from dual-task assessment with classification models, there remains uncertainty regarding the effective gait variables for inclusion in these models and the selection of the most effective tasks. This study aims to investigate whether incorporating gait variables derived from whole-body movement characteristics improves the performance of classification models and to identify the most effective tasks for inclusion in these models.

METHODS: We analyzed data from 36 participants, including 18 cognitively normal individuals and 18 with MCI. Using motion capture technology, gait variables encompassing whole-body movements, including upper body dynamics, were recorded under both normal walking conditions and during dual-task performance. The dual tasks included: (1) Subtracting threes from a given number, (2) Carrying a cup on a tray without moving it, (3) Holding a cup filled with water without spilling it, and (4) Answering verbal questions. Classification models utilized were k-nearest neighbors, random forest, and support vector machines, with performance evaluated by the area under the curve (AUC).

RESULTS: First, we observed that variables related to upper-body motion (i.e., Anterior-Posterior and Medial-Lateral sway) while walking played an important role in the classification models for detecting MCI, particularly during cognitively demanding tasks (subtracting numbers and answering verbal questions) while walking. Second, the tasks carrying a cup on a tray and holding a cup filled with water while walking yielded superior classification model performance to other tasks especially in considering multiple features (AUC = 0.79).

CONCLUSIONS: This study underscores the benefits of incorporating gait variables of the upper body to enhance the performance of classification models for MCI detection. These insights could contribute to the development of more precise and practical screening tools for MCI.},
}

Humans
Male
Female
*Alzheimer Disease/diagnosis/physiopathology/psychology
Aged
*Walking/physiology
*Gait/physiology
*Cognitive Dysfunction/diagnosis/physiopathology/psychology
Early Diagnosis
Aged, 80 and over
*Task Performance and Analysis
Middle Aged

@article {pmid41136905,
year = {2025},
author = {Wang, X and Liu, J and Hu, SS and Liu, Z and Lu, H and Liu, L and , },
title = {HILAMA: High-dimensional multi-omics mediation analysis with latent confounding.},
journal = {BMC medical research methodology},
volume = {25},
number = {1},
pages = {239},
pmid = {41136905},
issn = {1471-2288},
support = {No. 12471274//National Science Foundations of China Grants/ ; No.12090024//National Science Foundations of China Grants/ ; No.23JS1400700//Science and Technology Commission of Shanghai Municipality/ ; },
}

@article {pmid41136851,
year = {2025},
author = {Li, Z and Xu, L and Sun, F and Wei, W and Liu, S and Wang, H and Ma, Q and Zhang, W and Zhang, Y and Li, W and Wu, J},
title = {Development of Animal Models for Preclinical Testing of hPSCs Products.},
journal = {Advances in experimental medicine and biology},
volume = {1486},
number = {},
pages = {329-338},
pmid = {41136851},
issn = {0065-2598},
mesh = {Animals ; Humans ; *Disease Models, Animal ; *Pluripotent Stem Cells/transplantation/cytology ; *Stem Cell Transplantation/methods ; },
abstract = {The preclinical evaluation of human pluripotent stem cells (hPSCs) products is a complex and crucial process, in which the use of animal models plays a pivotal position. Animal models are diverse, possess unique research value and applicability, and can provide abundant data to support the preclinical evaluation of stem cell products. When selecting animal models, various factors need to be considered comprehensively. The models should exhibit similarities to human diseases in terms of anatomical structure, physiological and biochemical characteristics, and pathological features to better simulate stem cell behavior in the human body. The choice of models also needs to consider experimental objectives, the characteristics of stem cell products, and animal welfare and ethical principles. Finally, this review introduces some examples of preclinical evaluation of hPSCs products in animal disease models, including acute lung injury, acute liver failure, Parkinson's disease, Alzheimer's disease, osteoarthritis, membranous nephropathy, corneal alkali damage, and intrauterine adhesions.},
}

Animals
Humans
*Disease Models, Animal
*Pluripotent Stem Cells/transplantation/cytology
*Stem Cell Transplantation/methods

@article {pmid41136693,
year = {2025},
author = {Khandayataray, P and Murthy, MK},
title = {Investigating the ameliorative effect of Kalanchoe pinnata on neuroinflammation-associated Alzheimer's disease using network pharmacology, molecular docking, and in vitro studies.},
journal = {Journal of computer-aided molecular design},
volume = {39},
number = {2},
pages = {105},
pmid = {41136693},
issn = {1573-4951},
mesh = {*Alzheimer Disease/drug therapy/metabolism/pathology ; Molecular Docking Simulation ; Network Pharmacology ; *Neuroprotective Agents/pharmacology/chemistry ; Amyloid beta-Peptides/metabolism ; *Plant Extracts/pharmacology/chemistry ; *Kalanchoe/chemistry ; Humans ; Animals ; Signal Transduction/drug effects ; Mice ; Microglia/drug effects/metabolism ; Cell Line ; Antioxidants/pharmacology/chemistry ; Phosphatidylinositol 3-Kinases/metabolism ; Cytokines/metabolism ; Proto-Oncogene Proteins c-akt/metabolism ; },
abstract = {Alzheimer's disease (AD) is a neurodegenerative disease with no cure, with aggregates of amyloid-beta (Aβ) plaques, neurofibrillary tangles, and permanent neurodegeneration. Current therapies have been found to provide complementary effects; therefore, there is a need to establish new therapeutic strategies. The neuroprotective activity of Kalanchoe pinnata (KP) was explored in this study using network pharmacology, molecular docking, and in vitro studies. Bioactive compounds with good pharmacokinetic properties have been identified as the 10 bioactive compounds of KP, such as bryotoxin B, kaempferol, and quercetin. A total of 449 common targets of KP and AD that participate in the PI3K-Akt, MAP, and cAMP signaling pathways were identified (AKT1, TNF, and STAT3). Molecular docking results indicated good binding affinities of these KP compounds with AD-related targets. KP aqueous extract (KPAE) inhibited protrophic cytokines and PI3K/Akt signaling in BV-2 microglial cells in a dose-dependent manner by inhibiting Aβ aggregation, antioxidant activity, and neuroinflammation. The above observations indicate that KP has a multi-target effect against AD, which should be proven by preclinical and clinical trials.},
}

*Alzheimer Disease/drug therapy/metabolism/pathology
Molecular Docking Simulation
Network Pharmacology
*Neuroprotective Agents/pharmacology/chemistry
Amyloid beta-Peptides/metabolism
*Plant Extracts/pharmacology/chemistry
*Kalanchoe/chemistry
Humans
Animals
Signal Transduction/drug effects
Mice
Microglia/drug effects/metabolism
Cell Line
Antioxidants/pharmacology/chemistry
Phosphatidylinositol 3-Kinases/metabolism
Cytokines/metabolism
Proto-Oncogene Proteins c-akt/metabolism

@article {pmid41136671,
year = {2025},
author = {Zhong, M and Song, Q and Zhang, S and Liu, Z and Yuan, C and Li, P and Wang, N and Yu, D and Wang, K and Dong, C and Zhao, J and Liu, J and Yang, C},
title = {Correction: Morphological and metabolic alterations in different stages of Alzheimer's diseases: a study using surface-based morphometry (SBM) and amide proton transfer (APT) imaging.},
journal = {Scientific reports},
volume = {15},
number = {1},
pages = {37338},
doi = {10.1038/s41598-025-25188-w},
pmid = {41136671},
issn = {2045-2322},
}

@article {pmid41136637,
year = {2025},
author = {Danysz, W and Hansen, N and Wiltfang, J and Kornhuber, J and Scheschonka, A and Gravius, A},
title = {Memantine: updates from the past decade and implications for future novel therapeutic applications.},
journal = {Journal of neural transmission (Vienna, Austria : 1996)},
volume = {},
number = {},
pages = {},
pmid = {41136637},
issn = {1435-1463},
abstract = {This review provides an update on advances during the past decade in our knowledge of the pharmacology and clinical use of memantine. It covers aspects related to preclinical research, such as new findings about the mechanism of action, and the efficacy of memantine in animal models of various diseases beyond dementia. In particular, new emerging indications since the publication of our latest review almost a decade ago were investigated. Where possible, preclinical findings were reinforced by data obtained in clinical studies in patients with Alzheimer's disease, as well as in other indications reported by researchers who initiated off-label studies. This comprehensive narrative review demonstrates that memantine continues to show robust efficacy in its primary indication of Alzheimer's disease. However, while numerous potential new indications have emerged from preclinical studies, only a limited number show sufficient evidence to warrant further clinical investigation.},
}

@article {pmid41136538,
year = {2025},
author = {Zhang, R and Yi, F and Mao, H and Huang, Z and Wang, K and Zhang, J},
title = {Brain age gap as a predictive biomarker that links aging, lifestyle, and neuropsychiatric health.},
journal = {Communications medicine},
volume = {5},
number = {1},
pages = {441},
pmid = {41136538},
issn = {2730-664X},
support = {2024C04024//Science and Technology Department of Zhejiang Province/ ; 2024C03023//Science and Technology Department of Zhejiang Province/ ; LHZSZ25H090002//Natural Science Foundation of Zhejiang Province (Zhejiang Provincial Natural Science Foundation)/ ; 82272129//National Natural Science Foundation of China (National Science Foundation of China)/ ; },
abstract = {BACKGROUND: The brain age gap (BAG) is a neuroimaging-derived marker of accelerated brain aging. However, its clinical application faces challenges due to model inaccuracies and unclear links to disease mechanisms. This study investigates the clinical relevance of BAG across neuropsychiatric disorders, cognitive decline, mortality, and lifestyle interventions.

METHODS: We use data from multiple cohorts, including 38,967 participants from the UK Biobank (ages 45-82, 52.5% female), 1,402 individuals from the ADNI study (ages 55-96, 56.0% female), and 1,182 from the PPMI study (ages 45-83, 58.0% female). We develop a 3D Vision Transformer for whole-brain age estimation. Survival analysis, restricted cubic splines, and regression models assess BAG's associations with cognitive, neuropsychiatric disorders, mortality and impact of lifestyle factors.

RESULTS: Here we show that the model achieves a mean error of 2.68 years in the UK Biobank and 2.99-3.20 years in ADNI/PPMI. Each one-year increase in BAG raises Alzheimer's risk by 16.5%, mild cognitive impairment by 4.0%, and all-cause mortality by 12%. The highest-risk group (Q4) shows a 2.8-fold increased risk of Alzheimer's disease, a 6.4-fold risk of multiple sclerosis, and a 2.4-fold higher mortality risk. Cognitive decline is most evident in Q4, particularly in reaction time and processing speed. Lifestyle interventions, especially smoking cessation, moderate alcohol consumption, and physical activity, significantly slow BAG progression in individuals with advanced neurodegeneration.

CONCLUSIONS: BAG predicts accelerated brain aging, neuropsychiatric disorders, and mortality. Its ability to detect nonlinear cognitive thresholds and modifiability through lifestyle changes makes it useful for risk stratification and prevention.},
}

@article {pmid41136359,
year = {2025},
author = {Pan, X and Su, Z and Huang, Z and Chen, Y and Li, X and Zheng, X},
title = {N-acetylcysteine (NAC) ameliorates ethanol-induced oxidative stress, neuroinflammation, and cognitive dysfunction in APP/PS1 mouse model.},
journal = {Translational psychiatry},
volume = {15},
number = {1},
pages = {435},
pmid = {41136359},
issn = {2158-3188},
mesh = {Animals ; *Acetylcysteine/pharmacology ; *Ethanol/toxicity/adverse effects ; Mice ; *Oxidative Stress/drug effects ; Disease Models, Animal ; *Cognitive Dysfunction/chemically induced/drug therapy/metabolism ; *Alzheimer Disease/drug therapy/metabolism ; *Neuroinflammatory Diseases/chemically induced/drug therapy ; Mice, Transgenic ; Male ; Microglia/drug effects ; *Antioxidants/pharmacology ; Brain-Derived Neurotrophic Factor/metabolism/drug effects ; Amyloid beta-Peptides/metabolism ; NLR Family, Pyrin Domain-Containing 3 Protein/metabolism/drug effects ; Disks Large Homolog 4 Protein/metabolism/drug effects ; Amyloid beta-Protein Precursor/genetics ; },
abstract = {Alzheimer's disease (AD) is the most prevalent neurodegenerative disorder that predominantly affects the elderly, leading to a progressive decline in cognitive function. Accumulating evidence suggests that many environmental and dietary factors, especially chronic ethanol exposure, aggravate the risk of this disease. However, its precise influence on AD has not yet been clarified. Here, we show that ethanol exposure caused earlier and severer cognitive behavioral impairments, more beta amyloid (Aβ) depositions, microglia activation, decreased total antioxidant capacity (T-AOC). Moreover, inflammatory mediators, such as Nucleotide-binding oligomerization domain-like receptor protein 3 (NLRP3) and Tumor necrosis factor-alpha (TNF-α) increased, while pivotal proteins involved in dendritic and synaptic development, such as Synaptophysin (SYP), postsynaptic density protein 95 (PSD95) and brain-derived neurotrophic factor (BDNF) decreased in APP/PS1 mice. N-acetylcysteine (NAC), a well-known antioxidant, could attenuate cognitive behavioral impairments and neuroinflammatory damage by restoring inflammatory and neurodevelopmental mediators. In general, our study uncovered that chronic ethanol exposure may exacerbate AD progress at the pathological and molecular levels and NAC may act as a potential drug for the treatment of AD patients with chronic ethanol exposure.},
}

Animals
*Acetylcysteine/pharmacology
*Ethanol/toxicity/adverse effects
Mice
*Oxidative Stress/drug effects
Disease Models, Animal
*Cognitive Dysfunction/chemically induced/drug therapy/metabolism
*Alzheimer Disease/drug therapy/metabolism
*Neuroinflammatory Diseases/chemically induced/drug therapy
Mice, Transgenic
Male
Microglia/drug effects
*Antioxidants/pharmacology
Brain-Derived Neurotrophic Factor/metabolism/drug effects
Amyloid beta-Peptides/metabolism
NLR Family, Pyrin Domain-Containing 3 Protein/metabolism/drug effects
Disks Large Homolog 4 Protein/metabolism/drug effects
Amyloid beta-Protein Precursor/genetics

@article {pmid41136345,
year = {2025},
author = {Aguila, E and Mejia-Arango, S},
title = {Job sector and occupational complexity influence on late-life cognitive function among men.},
journal = {The Gerontologist},
volume = {65},
number = {11},
pages = {},
doi = {10.1093/geront/gnaf195},
pmid = {41136345},
issn = {1758-5341},
support = {5P30AG066589/AG/NIA NIH HHS/United States ; AG043073//University of Southern California (USC) AD/ADRD Center on Minority Aging Research/ ; //Texas Resource Center on Minority Aging Research/ ; //P30AG059301/ ; },
mesh = {Humans ; Male ; Aged ; Middle Aged ; *Occupations/statistics & numerical data ; Mexico ; *Cognition ; Educational Status ; Aged, 80 and over ; *Cognitive Aging ; },
abstract = {BACKGROUND AND OBJECTIVES: The rapid aging of population in low- and middle-income countries, their economic disadvantages, and the increase in Alzheimer's disease related dementia point to a need to understand cognitive aging of disadvantaged individuals. This research considers the effects of education, occupational complexity, and cognitive engagement on late-life cognitive performance, and how these may vary by economic sector.

RESEARCH DESIGN AND METHODS: We analyze data from the 2012 Mexican Health and Aging Study (MHAS) linked to O*NET (Occupational Information Network) and social security administrative data. We constructed a lifetime occupational complexity index using information on workers' cognitive abilities for males 60 or older with normal cognitive function.

RESULTS: We found a higher level of education, degree of occupational complexity, and cognitive engagement for formal-sector workers than for informal-sector ones. For both groups of workers, education, occupational complexity, and cognitive engagement are associated with late-life cognitive health. Yet, occupational complexity was associated with higher late-life cognitive health for informal-sector workers than for formal-sector ones.

DISCUSSION AND IMPLICATIONS: This study, the first to analyze the role of informal-sector work in shaping late-life cognitive health, highlights the relevance of occupation for cognitive health. Our findings are relevant for both developing countries with large shares of workers in the informal sector and developed ones with ethnic minorities and growing proportions of workers in the "gig economy."},
}

Humans
Male
Aged
Middle Aged
*Occupations/statistics & numerical data
Mexico
*Cognition
Educational Status
Aged, 80 and over
*Cognitive Aging

@article {pmid41136336,
year = {2025},
author = {Fu, CH and Park, J and Tosi, U and Blanco, FA and Silva-Pérez, M and Muralidharan, K and You, JC and Lee, M and Stephens, GS and Zhang, X and Zheng, Y and Scharfman, H and Tolias, KF and Chin, J},
title = {Restoration of sFRP3 preserves the neural stem cell pool and spatial discrimination ability in a mouse model of Alzheimer's disease.},
journal = {The Journal of neuroscience : the official journal of the Society for Neuroscience},
volume = {},
number = {},
pages = {},
doi = {10.1523/JNEUROSCI.0049-25.2025},
pmid = {41136336},
issn = {1529-2401},
abstract = {Individuals with Alzheimer's disease (AD) have an increased incidence of seizures, which worsen cognitive decline. Using a transgenic mouse model of AD neuropathology that exhibits spontaneous seizures, we previously found that seizure activity stimulates and accelerates depletion of the hippocampal neural stem cell (NSC) pool, which was associated with deficits in neurogenesis-dependent spatial discrimination. However, the precise molecular mechanisms that drive seizure-induced activation and depletion of NSCs are unclear. Here, using mice of both sexes, we performed RNA-sequencing on the hippocampal dentate gyrus and identified differentially-expressed regulators of neurogenesis in the Wnt signaling pathway that regulates many aspects of cell proliferation. We found that the expression of sFRP3, a Wnt signaling inhibitor, is altered in a seizure-dependent manner and might be regulated by ΔFosB, a seizure-induced transcription factor. Increasing sFRP3 expression prevented NSC depletion and improved spatial discrimination, suggesting that the loss of sFRP3 might mediate seizure-driven impairment in cognition in AD model mice, and perhaps also in AD.Significance statement There is increased incidence of seizures in individuals with Alzheimer's disease (AD), but it is unclear how seizures contribute to cognitive decline. Here, we uncover a molecular mechanism by which seizures in AD induce expression of a long-lasting transcription factor in the hippocampal dentate gyrus that suppresses expression of sFRP3, an inhibitor of neural stem cell division, accelerating the depletion of a finite pool of neural stem cells and dysregulating adult hippocampal neurogenesis. We found that restoring sFRP3 expression prevents accelerated use and depletion of neural stem cells and improves performance in an adult neurogenesis-dependent cognitive task. Our findings have implications for AD, epilepsy, and other neurological disorders that are accompanied by seizures.},
}

@article {pmid41136300,
year = {2025},
author = {Jenkins, LM and Heywood, AA and Gurvich, C},
title = {Beyond Alzheimer's Pathology: Contributions to Cognitive Decline in Late Life Depression.},
journal = {The American journal of geriatric psychiatry : official journal of the American Association for Geriatric Psychiatry},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.jagp.2025.09.021},
pmid = {41136300},
issn = {1545-7214},
}

@article {pmid41135829,
year = {2025},
author = {Yang, Y and He, S and Lin, Y and Chen, J and Yang, R and Li, X and Sun, J and Wang, G and Tian, W and Chen, H},
title = {Euphorbia diterpenoids from Euphorbia peplus possessing anti-Alzheimer's activity via targeting PPARγ and upregulating the level of ABCA1.},
journal = {Phytochemistry},
volume = {},
number = {},
pages = {114712},
doi = {10.1016/j.phytochem.2025.114712},
pmid = {41135829},
issn = {1873-3700},
abstract = {Four previously undescribed Euphorbia diterpenoids (1-3, 13), along with 19 known derivatives (4-12, 14-23), were isolated from the whole plant of Euphorbia peplus. Their structures were characterized by a combination of spectroscopic studies, single-crystal X-ray diffraction and ECD calculations. In this study, all isolates were investigated for their effects on the expression of ABCA1 protein in BV-2 cells. Compound 4 increased ABCA1 levels in a dose-dependent manner. Network pharmacology analysis predicted that PPARγ might be the potential target for the anti-AD effect of compound 4. Binding of 4 to the PPARγ was further confirmed by the fluorescence quenching assay, surface plasmon resonance, fluorescein-labeled differential scanning fluorimetry method, and molecular docking technology. Thus, compound 4 may exert anti-AD effect by targeting PPARγ and upregulating the level of ABCA1.},
}

@article {pmid41135777,
year = {2025},
author = {Zhang, S and Fan, Z and Ji, D},
title = {Advances in eye-brain axis: anatomy, immunity, and association with visual dysfunction.},
journal = {Ageing research reviews},
volume = {},
number = {},
pages = {102925},
doi = {10.1016/j.arr.2025.102925},
pmid = {41135777},
issn = {1872-9649},
abstract = {The "eye-brain axis" refers to the dynamic system of interactions between the eyes and the brain, collectively encompassing the visual signal transmission and integration pathways. The eyes and the brain exhibit structural and functional synergy, and visual dysfunction not only impairs information processing within the eye but also induces structural and functional remodeling of the central nervous system (CNS) via the eye-brain axis. For instance, the effects of glaucoma on the visual cortex are manifested as reduced blood perfusion and decreased efficiency of mitochondrial adenosine triphosphate (ATP) synthesis. Moreover, the eye can serve as an important window and biomarker for the early diagnosis and intervention of neurodegenerative diseases of the CNS. Relevant research findings include the parallelism of beta amyloid (Aβ) and phosphorylated Tau (p-Tau) between the retina and Alzheimer's disease (AD), glaucomatous neurodegeneration with AD-like features, and the role of vascular endothelial growth factor C (VEGF-C) expression along the eye-brain lymphatic pathway in regulating intraocular pressure (IOP) and correcting macular edema. Therefore, eye-brain axis research provides novel perspectives for understanding the pathophysiological mechanisms underlying visual dysfunction and related disorders, while simultaneously supporting the development of cross-organ neuroprotective strategies. This review explores the anatomical foundations, immune regulation, and bidirectional interactions of the eye-brain axis, and evaluates its relevance to the diagnosis and treatment of visual dysfunction and degenerative diseases of the CNS.},
}

@article {pmid41135743,
year = {2025},
author = {Wang, Y and Chen, HJ and Cheng, Y and Xie, Y and Cheng, Y and Zhao, S and Jiang, Y and Bai, T and Huo, Y and Wang, K and Zhang, M and Huang, W and Feng, G and Han, Y and Shu, N},
title = {Multimodal Integration of Plasma Biomarkers, MRI, and Genetic Risk to Predict Cerebral Amyloid Burden in Alzheimer's Disease.},
journal = {NeuroImage},
volume = {},
number = {},
pages = {121550},
doi = {10.1016/j.neuroimage.2025.121550},
pmid = {41135743},
issn = {1095-9572},
abstract = {Alzheimer's disease (AD), the most prevalent neurodegenerative disorder, is marked by the accumulation of amyloid-β (Aβ) plaques. Although cerebral Aβ positron emission tomography (Aβ-PET) remains the gold standard for assessing cerebral Aβ burden, its clinical utility is hindered by cost, radiation exposure, and limited availability. Plasma biomarkers have emerged as promising, non‑invasive indicators of Aβ pathology, yet they do not incorporate individual genetic risk or neuroanatomical context. To address this gap, we developed a multimodal machine‑learning framework that integrates plasma biomarkers, MRI‑derived brain structural features (regional volumes, cortical thickness, cortical area and structural connectivity), and genetic risk profiles to predict cerebral Aβ burden. This approach was evaluated in 150 participants from the Alzheimer's Disease Neuroimaging Initiative (ADNI) and 101 participants from a domestic Chinese Sino Longitudinal Study of Cognitive Decline (SILCODE). Incorporating multimodal features substantially improved predictive performance: the baseline model using plasma and clinical variables alone achieved an R[2] of 0.56, whereas integrating neuroimaging and genetic information increased accuracy (R[2] = 0.63 with apolipoprotein E genotypes and R[2] = 0.64 with polygenic risk scores). Furthermore, a multiclass classifier trained on the same multimodal features achieved robust discrimination of cognitive status, with area‑under‑the‑curve values of 0.87 for normal controls, 0.76 for mild cognitive impairment, and 0.95 for AD dementia. These findings highlight the value of combining plasma, imaging, and genetic data to non-invasively estimate cerebral Aβ burden, offering a potential alternative to PET imaging for early AD risk assessment.},
}

@article {pmid41135742,
year = {2025},
author = {Hu, T and Xi, J and Xie, N and Zhang, X and Huang, N and Cheng, Y},
title = {Multi-Omics Analysis Reveals the Protective Role of Transcriptional Enhancer Factor and the Pathogenic Mechanism of Monocytes in Parkinson's Disease.},
journal = {Brain research bulletin},
volume = {},
number = {},
pages = {111594},
doi = {10.1016/j.brainresbull.2025.111594},
pmid = {41135742},
issn = {1873-2747},
abstract = {Parkinson's disease (PD) is a multifactorial neurodegenerative disorder whose pathogenic mechanisms remain incompletely elucidated. This study aimed to systematically identify key regulatory factors involved in PD at the genetic, cellular, and molecular levels. Using univariate Mendelian randomization (UVMR), we identified plasma proteins and genes associated with Alzheimer's disease (AD), PD, and amyotrophic lateral sclerosis (ALS), and validated their causal relationships through colocalization analysis. Cross-validation across multi-omics datasets revealed transcriptional enhancer factor (TEF) as a protective factor for PD, whereas increased counts of CD14[+]CD16[+] monocytes were identified as a risk factor. Single-cell analysis and multivariate Mendelian randomization (MVMR) further suggested potential mediating roles of these factors in PD pathogenesis. In vitro experiments demonstrated that TEF overexpression significantly enhanced the resistance of neuroblastoma cells to rotenone-induced damage, inhibited apoptosis, and preserved tyrosine hydroxylase (TH) expression. In vivo, TEF notably improved motor coordination and exploratory behavior in PD mouse models. Collectively, these findings suggest that TEF may exert neuroprotective effects by modulating immune and neuronal pathways, offering a novel therapeutic target for the prevention and treatment of Parkinson's disease.},
}

@article {pmid41135687,
year = {2025},
author = {Yousefi, A and Karimani, F and Delphi, L and Ghahfarokhi, MR and Dehagani, MA and Rezayof, A},
title = {Modulation of the mediodorsal thalamus nitric oxide system ameliorated amnesia and medial prefrontal abnormal network activity in a streptozotocin-induced rat model of Alzheimer's disease.},
journal = {Experimental neurology},
volume = {},
number = {},
pages = {115524},
doi = {10.1016/j.expneurol.2025.115524},
pmid = {41135687},
issn = {1090-2430},
abstract = {Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by amnesia and neuronal network dysfunction. Given that the mediodorsal thalamus (MD) is connected to the medial prefrontal cortex (mPFC), and nitric oxide (NO) signaling is crucial for synaptic plasticity in memory formation, the present study aimed to investigate the role of the MD nitric oxide system in a streptozotocin (STZ)-induced Alzheimer's rat model. Also, the mPFC electrophysiological activity with the local field potential (LFP) was assessed following memory formation under STZ and/or NO agents to evaluate the mPFC interictal epileptiform discharges (IEDs) rate. The results showed that the microinjection of STZ (3 mg/kg/10 μl, 2 times) into the lateral ventricle (LV-STZ) impaired memory formation. Acute intra-MD microinjection of a precursor of nitric oxide, L-Arginine (1.5-6 μg/rat), improved the LV-STZ-induced amnesia. Sub-chronic intra-MD microinjection of an NO system inhibitor, L-NAME (0.5 and 1 μg/rat, 5 times) from the 5th to 13th days after the LV-STZ microinjection, a critical period for producing the neurotoxic effects of STZ on the brain, improved STZ-induced amnesia. Interestingly, the LV-STZ microinjection increased the IEDs in the mPFC, reflecting heightened neuronal hyperexcitability. The manipulation of the MD-NO system was associated with a decrease in the mPFC-IEDs rate, suggesting a negative correlation between the IEDs rate and memory formation. Taken together, these findings highlight the critical role of the MD-NO system in STZ-induced amnesia. Moreover, the dual effects of the MD-NO system manipulation, depending on the context and timing, may counteract STZ-induced amnesia by modulating the mPFC neural activity.},
}

@article {pmid41135680,
year = {2025},
author = {Wu, JW and Titterton, K and Sebastian, R and Romanul, N and Yanamandra, K and Mastis, B and Chang, R and Khasnavis, S and Kwon, T and Chai, Y and Manos, JD and Preiss, CN and Hu, M and Welker, AM and Liao, F and Dellovade, T and Karran, E and Langlois, X},
title = {Development of a robust, physiologically relevant neuronal tau aggregation assay for tau-related drug discovery.},
journal = {The Journal of biological chemistry},
volume = {},
number = {},
pages = {110853},
doi = {10.1016/j.jbc.2025.110853},
pmid = {41135680},
issn = {1083-351X},
abstract = {Therapeutic interventions to block extracellular tau seeding to prevent endogenous tau aggregation and progression of Alzheimer's disease pathology are currently being investigated in clinical trials. However, the translation of promising preclinical findings to benefit clinical outcomes remains problematic due to the lack of pathophysiological models that recapitulate key features of sporadic Alzheimer's disease-related tauopathies. We developed a primary neuronal tau (hTau) seeding and propagation model. Neurons expressing wild-type human tau protein at a physiological level, seeded with a sub-nanomolar tau derived from Alzheimer's disease brain tissues, rapidly and robustly form tau aggregates and develop impaired mitochondria function. Resulting aggregates are quantitatively measured using automated high content algorithms. The considerable pathophysiological relevance coupled with a highly sensitive dynamic range makes this assay a valuable model system for studying tau pathobiology and an efficient screening tool for modulators of tau aggregation. Using this model, we demonstrate that by targeting a phosphorylation specific epitope of tau, an antibody effectively stops tau aggregation.},
}

@article {pmid41135662,
year = {2025},
author = {Yang, ZL and Huang, LY and Luo, XY and Zhang, XH and Tan, CC and Tan, L and Sun, FR and Xu, W},
title = {Multiplicative and additive interaction effects of vascular risk factor burden with APOE genotypes on dementia: Associations and peripheral biological mechanisms based on a large cohort study.},
journal = {Journal of affective disorders},
volume = {394},
number = {Pt A},
pages = {120451},
doi = {10.1016/j.jad.2025.120451},
pmid = {41135662},
issn = {1573-2517},
abstract = {BACKGROUND: Gene-environment interaction is important for understanding precise etiology of dementia. We aimed to assess the associations of vascular risk factor (VRF) and its interaction by APOE genotypes with all-cause dementia (ACD) and Alzheimer's disease (AD), and to delineate peripheral biological mechanisms.

METHODS: A total of 264,382 participants (median age: 57 years) from the UK Biobank were followed for an average of 13 years. A VRF burden score (VRFS) was constructed incorporating hypertension, diabetes, hyperlipidemia, and current smoking. Cox proportional hazards regression was performed to explore the additive and multiplicative interactions of APOE by VRFS. Blood proteomics, bioinformatics, and mediation analyses were applied to investigate the mechanisms.

RESULTS: An elevated VRFS was significantly linked to a 33 % higher risk of ACD and AD (P < 0.001). Significant multiplicative and additive interaction effects were detected (P < 0.001). The co-existence of higher VRFS and APOE ε4 produced significantly larger effects on dementia risk than their presence alone (attributable proportion due to interaction = 0.12). The effect magnitudes of VRFS on dementia were enlarged in the presence of APOE ε2 (risk elevation ∼70 %, P < 0.001) than APOE ε4 (∼24 %). Biological mediating mechanisms specifically for APOE ε2 were annotated with disulfide bond, TNFR, bone metabolism, and hemopoiesis.

CONCLUSIONS: APOE genotypes significantly interacts with VRFS in the development of dementia and AD. These findings highlight the importance of considering interaction of genetic predispositions with vascular risk factors when assessing an individual's overall risk for dementia and developing personalized prevention strategies.},
}

@article {pmid41135612,
year = {2025},
author = {Herbet, M and Wicha-Komsta, K and Pawłowski, K and Bąk, E and Sterczewski, P and Hryć, B and Walczak, Ł and Skalicka-Woźniak, K and Siedlaczek, W and Gawrońska-Grzywacz, M and Kocki, T and Piątkowska-Chmiel, I},
title = {Behavioral, Neurochemical, and Biochemical Investigations of Coumarin Derivatives in Modulating Neuroinflammation, Cholinergic Dysfunction, and Cytokine Responses: In Vivo Studies for Potential Alzheimer's Disease Therapy.},
journal = {Behavioural brain research},
volume = {},
number = {},
pages = {115891},
doi = {10.1016/j.bbr.2025.115891},
pmid = {41135612},
issn = {1872-7549},
abstract = {AIMS: Neurodegenerative diseases (NDDs), including Alzheimer's disease (AD), are characterized by progressive cognitive decline driven by pathological mechanisms such as neuroinflammation, oxidative stress, and cholinergic dysfunction. The kynurenine pathway (KP) plays a critical role in these processes, making it a potential therapeutic target. Natural compounds like coumarins, including umbelliferone (UMB) and imperatorin (IMP), are gaining attention for their neuroprotective properties.

BACKGROUND: Current treatments for AD predominantly address symptoms rather than underlying mechanisms, necessitating the exploration of novel therapeutic approaches. Coumarins, known for their anti-inflammatory and antioxidative effects, may offer multifaceted benefits in combating AD pathophysiology.

OBJECTIVE: This study aims to investigate the neuroprotective effects of UMB and IMP on scopolamine (SCOP)-induced cognitive impairment in a rat model, focusing on their impact on KP metabolites, neuroinflammation, oxidative stress, and cholinergic dysfunction.

METHOD: Cognitive functions were assessed using the Y-maze (Y-M), novel object recognition (NOR), and passive avoidance (PA) tests. Neurochemical analyses measured levels of tryptophan (TRP), kynurenine (LKYN), kynurenic acid (KYNA), the TRP/LKYN ratio, pro- and anti-inflammatory cytokines (IL-10, TGF-β1, IFN-γ), and activities of acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) in the prefrontal cortex (PFC).

RESULTS: Both UMB and IMP improved cognitive performance in behavioral tests. UMB reduced oxidative stress, inhibited AChE activity, and preserved mitochondrial integrity, while IMP attenuated neuronal apoptosis, enhanced synaptic activity, and modulated cytokine levels to favor an anti-inflammatory profile. Both compounds restored KP balance, mitigating neuroinflammation and oxidative damage.

CONCLUSION: UMB and IMP ameliorated SCOP-induced cognitive deficits by addressing key pathological mechanisms, including oxidative stress, neuroinflammation, and cholinergic imbalance. These findings underscore the therapeutic potential of coumarins as multi-targeted agents for AD, meriting further investigation for clinical application.},
}

@article {pmid41135594,
year = {2025},
author = {Kistler, CE and Lynch, ME and Lin, FC and Yang, Y and Frazier, W and Hanson, LC},
title = {An Electronic Health Record Algorithm's Performance to Identify Cognitive Impairment in Primary Care.},
journal = {Journal of the American Medical Directors Association},
volume = {},
number = {},
pages = {105949},
doi = {10.1016/j.jamda.2025.105949},
pmid = {41135594},
issn = {1538-9375},
abstract = {OBJECTIVES: Most people with dementia are diagnosed and cared for in primary care. We examined the performance of an electronic health record (EHR) algorithm to identify older adults with dementia or mild cognitive impairment in primary care.

DESIGN: Retrospective cohort study.

SETTING AND PARTICIPANTS: We identified all adults aged 65+ seen for a routine visit from December 2021 to December 2022 in 59 primary care clinics. We used representative sampling to create a cohort of 525 older adults.

METHODS: We used trained research staff to confirm the presence of dementia or mild cognitive impairment via gold standard chart review. We then applied a list of 114 cognitive impairment-related Internaitonal Classification of Diseases, 10[th] Revision (ICD-10) codes and prescribed dementia medications to the cohort and evaluated the algorithm's performance characteristics.

RESULTS: Of the representative cohort (n = 525), 59% were women and 81% were White, with an average age of 74.5 ± 6.9 years. Dementia or mild cognitive impairment was present on EHR review in 8.6% (n = 45) of the cohort. The algorithm had a specificity of 98.1%, a sensitivity of 60.0%, a positive predictive value of 0.75, and a negative predictive value of 0.96. The overall predictive performance (F-1 score) was 0.667. Nonspecific ICD-10 was the most common, with "unspecified dementia" representing 17 of 34 ICD-10 codes found by the algorithm.

CONCLUSIONS AND IMPLICATIONS: Optimization of an EHR algorithm to detect cognitive impairment by combining cognitive impairment-related ICD-10 codes and dementia medications identified people with dementia or mild cognitive impairment in primary care with high specificity and acceptable sensitivity, although ICD-10 codes remained nonspecific.},
}

@article {pmid41135100,
year = {2025},
author = {Rey-Picazo, J and Pita, J and Peña, L and Ferraz-Torres, M and Martínez-García, O and Ávila-Villanueva, M and Santos-Pérez, G and López-Sanz, D and Moreno-Arribas, MV and Perrino, CG and Muedra, V and Miñano-Molina, AJ and Hernández-Rabaza, V and Gómez-Pinedo, U and León-Espinosa, G},
title = {Potential Risk to Brain Health after Surgical Interventions: Biomarkers to Predict the Occurrence of Cognitive Decline.},
journal = {Aging and disease},
volume = {},
number = {},
pages = {},
doi = {10.14336/AD.2025.1105},
pmid = {41135100},
issn = {2152-5250},
abstract = {As the global population ages, the number of people living with dementia is projected to increase significantly. Estimations indicate that over 150 million people worldwide will be living with dementia by 2050, with Alzheimer's disease being the most common cause. Elderly people are also at greater risk of undergoing surgery, either elective or emergency, escalating the associated likelihood leading to cognitive decline, especially if accumulative. However, the relationship between surgery and dementia development remains controversial. The cause seems to lie in the heterogeneous preoperative state of subjects participating in research studies. Interpreting and comparing the results of these studies could be an arduous task due to variables such as medication, follow-up time, type of surgery and anesthesia, duration and invasiveness of the surgical intervention, differential neuroinflammatory response, the patient metabolic/biochemical status or if there are comorbidities. Considering the complexity of this type of studies, the present review summarizes the most important factors/biomarkers that could provide useful information for pre- and post-operative medical decision making in relation to the development of dementia. Emphasis will be placed on the relationship between temperature, Tau phosphorylation, whose plasma detection as an early diagnostic factor is gaining great relevance, and other neurodegenerative biomarker interplay. The prolonged maintenance of key biomarkers in blood could be detrimental and, therefore, a more comprehensive individualized hospital study may improve the prevention of postoperative complications.},
}

@article {pmid41135031,
year = {2025},
author = {Zhang, Y and Dong, X and Yang, Y and Wang, X and Zhao, T},
title = {Caregiving burden, disease-related knowledge, and quality of life among primary caregivers in Alzheimer's disease: A cross-sectional study.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877251390494},
doi = {10.1177/13872877251390494},
pmid = {41135031},
issn = {1875-8908},
abstract = {BackgroundAlzheimer's disease (AD) is an incurable condition that places primary caregivers in the challenging position of providing long-term care.ObjectiveTo characterize quality of life (QOL) and caregiving burden among primary caregivers of patients with AD, identify the correlates of these outcomes, and evaluate the relationship between disease-specific knowledge levels and their QOL and burden profiles.MethodsA cross-sectional survey was conducted with 120 pairs of patients with AD who were hospitalized between April and September 2023 and their primary caregivers. Sociodemographic and clinical information of patients and caregivers was obtained. Caregivers were assessed using the Chinese versions of the Zarit Burden Interview, Dementia Knowledge Assessment Scale, and 12-Item Short Form Health Survey. Correlates of caregivers' QOL and caregiving burden were analyzed using stepwise multiple linear regression.ResultsPrimary caregivers had high caregiving burden, relatively low disease-related knowledge, and impaired QOL. Patients' age, disease duration, and the frequency of wandering episodes resulting in missing incidents were identified as key potential risk factors for caregivers' QOL. However, caregivers' educational level, the absence of disease, and higher levels of disease knowledge were major protective factors. Core predictors of caregiver burden included compromised Physical and Mental Component Summary scores.ConclusionsEnhancing caregiver education and improving the availability of community-based care resources for families facing AD in remote regions of Southwest China are urgently needed. Creating culturally sensitive and clinically applicable assessment frameworks is also critical to effectively address the impact of traditional cultural values that turn caregiving duties into a moral obligation.},
}

@article {pmid41135014,
year = {2025},
author = {Jin, H and He, J and Zhang, W and Wang, Y and Wu, Y and Wang, X and Zhao, J and Chu, X and Wang, R},
title = {The association between Alzheimer-associated neuronal thread protein (AD7c-NTP) and plasma inflammatory cytokine levels in individuals with cognitive impairment and demographically-matched controls.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877251389239},
doi = {10.1177/13872877251389239},
pmid = {41135014},
issn = {1875-8908},
abstract = {BackgroundAlzheimer-associated neuronal thread protein (AD7c-NTP) has emerged as a potential diagnostic biomarker for Alzheimer's disease (AD) and mild cognitive impairment (MCI). Growing research indicates neuroinflammatory mechanisms contribute to AD pathogenesis.ObjectiveTo investigate the relationship between AD7c-NTP level and inflammatory biomarkers.MethodsThis cross-sectional study enrolled 112 participants comprising 72 cognitively impaired individuals (CI group) and 40 demographically matched controls with cognitively normal (CN group). Comprehensive physical evaluations and standardized neuropsychological assessments were administered. Urinary AD7c-NTP concentrations were quantified through enzyme-linked immunosorbent assay (ELISA), while plasma levels of twelve inflammatory markers-IL-1β, IL-2, IL-4, IL-5, IL-6, IL-8, IL-10, IL-12p70, IL-17A, TNF-α, IFN-α, and IFN-γ-were analyzed via flow cytometry-based immunofluorescence techniques.ResultsConcentrations of IL-2, IFN-α, and IFN-γ showed marked elevation in CI patients relative to CN controls (p = 0.005, 0.008, and 0.010, respectively). Strong positive associations emerged between AD7c-NTP concentrations and both IL-2 (r = 0.492, p < 0.001) and IFN-α (r = 0.492, p < 0.001). The four-marker panel (AD7c-NTP combined with IL-2, IFN-α, and IFN-γ) achieved optimal diagnostic accuracy for cognitive impairment, yielding an AUC value of 0.9774 with 94% sensitivity and 75% specificity.ConclusionsIntegrating IL-2, IFN-α, and IFN-γ measurements with AD7c-NTP detection could constitute a superior diagnostic framework for early-stage cognitive decline. The observed correlations between AD7c-NTP and these cytokine profiles may indicate previously unrecognized metabolic pathways relevant to AD pathology.},
}

@article {pmid41135006,
year = {2025},
author = {Li, S and Yang, Y and Tian, G and Bai, J and Li, L and An, J and Zhang, Y and Li, X and Zhang, T and Lv, H},
title = {Association between the Geriatric Nutritional Risk Index and mild cognitive impairment in elderly patients with type 2 diabetes mellitus.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877251389914},
doi = {10.1177/13872877251389914},
pmid = {41135006},
issn = {1875-8908},
abstract = {BackgroundDiabetes increases the risk of mild cognitive impairment (MCI). The Geriatric Nutritional Risk Index (GNRI) is an objective indicator for assessing malnutrition risk, and aging and malnutrition are closely associated with MCI. However, the relationship between GNRI and MCI in older type 2 diabetes mellitus (T2DM) remains unclear.ObjectiveTo investigate the correlation between GNRI and MCI in elderly patients with T2DM.MethodsIn this cross-sectional study, 366 T2DM patients aged ≥ 60 years were divided into MCI and normal cognitive function (NCF) group according to the Montreal Cognitive Assessment (MoCA). Nutritional status was evaluated by calculating GNRI levels. GNRI levels and MoCA scores were compared between two groups, and correlation and regression analysis were performed to explore the association between GNRI and MCI.ResultsThe GNRI level in the MCI group was significantly lower than that in the NCF group (p < 0.05) and positively correlated with MoCA scores (r = 0.783, p < 0.001). MCI prevalence increased progressively with decreasing GNRI levels. After adjusting for confounders, the odds of MCI were significantly higher in the 92 ≤ GNRI ≤ 98 and GNR < 92 groups compared to GNRI < 98 (p < 0.05). Binary logistic regression identified that after adjusting for age, education level, body mass index, HbA1c, HOMA-IR, 25(OH)D and DR, GNRI as an independent protective factor for T2DM with MCI (OR = 0.783, 95%CI 0.648-0.874, p < 0.001).ConclusionsLower GNRI levels are associated with increased risk of MCI in elderly T2DM patients; GNRI is a potential predictor of MCI. Assessing nutritional status of elderly with T2DM facilitates the early clinical recognition of MCI.},
}

@article {pmid41134994,
year = {2025},
author = {Mullins, CA and Gannaban, RB and Kramer, A and Shah, H and Haque, ZF and Ramezan, M and Dehghani, F and Palaniyappan, AK and Bowers, F and MohanKumar, SM and MohanKumar, PS and Shin, AC},
title = {Early branched-chain amino acid reduction delays the onset of cognitive decline in a mouse model of Alzheimer's disease.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877251389236},
doi = {10.1177/13872877251389236},
pmid = {41134994},
issn = {1875-8908},
abstract = {BackgroundMany Alzheimer's disease (AD) treatments focus on a single variable of AD that have yet demonstrated clinically meaningful and perceived benefits by the patients. We recently showed that lowering plasma branched-chain amino acids (BCAAs) can deliver multiple pro-neuronal effects in APP/PS1 and 5xFAD mouse models.ObjectiveThe main aim was to determine the optimal point in time for the disease-modifying effects of BCAA reduction during AD development.Methods12-month-old, cognitively impaired male WT and APP/PS1 mice were injected with either vehicle or BCAA-lowering compound BT2 (40 mg/kg/day ip) for 30 days. To test if early BT2 during AD progression would have long-lasting beneficial effects, 2-month-old, cognitively intact male 5xFAD mice were treated with BT2 after which they were left alone for a month.ResultsPlasma BCAAs were reduced in BT2-treated APP/PS1 mice. Despite Aβ42 reduction, BT2 did not modify proteins or genes related to AD-related pathology, dendritic density and neurotransmitters in the cortex and hippocampus, or alleviate cognitive deficit. In another experiment, BT2-treated 5xFAD mice had lower plasma BCAAs. Importantly, early BT2, even after treatment cessation for a month, was able to effectively delay cognitive impairment which was associated with a complete restoration of cortical neurotransmitters. These results were observed without any changes in pathology markers in the brain.ConclusionsOur findings suggest that BT2-induced BCAA reduction is a novel strategy to delay AD progression possibly through enhanced neurotransmission. The efficacy is time-dependent such that treating with BT2 before the onset of AD can successfully rescue cognitive function.},
}

@article {pmid41134992,
year = {2025},
author = {Ketata, I and Ellouz, E},
title = {Artificial intelligence-driven eye tracker models for Alzheimer's disease diagnosis: A systematic review and meta-analysis.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877251389145},
doi = {10.1177/13872877251389145},
pmid = {41134992},
issn = {1875-8908},
abstract = {BackgroundDiagnosis of Alzheimer's disease (AD) is crucial for effective intervention and care planning. Recently, artificial intelligence-driven eye-tracking (AI-driven ET) tools have emerged as promising diagnostic aids.ObjectiveTo evaluate the diagnostic accuracy of AI-driven ET models for AD detection.MethodsA systematic review and meta-analysis were conducted according to PRISMA2020. Different database and grey literature were searched up to March 2025. Data were analyzed with Meta-Disc 1.4 and R software. This meta-analysis has been registered in PROSPERO (CRD420251020284).ResultsTen papers were included in the narrative synthesis and eight in the meta-analysis. Our systematic review found that most studies reported moderate to good accuracy of AI-driven ET tools in AD detection. The meta-analysis revealed that AI-driven ET tools achieved a sensitivity of 0.75 [95% CI: 0.67; 0.79], specificity of 0.75 [95% CI: 0.67; 0.81], positive likelihood ratio of 3.29 [95% CI: 2.36; 4.59], negative likelihood ratio of 0.36 [95% CI: 0.27; 0.48], diagnostic odds ratio of 10.40 [95% CI: 5.58; 19.39], and area under the ROC curve of 0.81. Deep learning seems to have better performance than supervised machine learning (SML). Among classification algorithms, support vector machines appear most robust across studies. The meta-regression identified population size, patient preparation, measurement systems, AI techniques, and SML algorithms as significant sources of heterogeneity.ConclusionsAI-driven ET tools suggest moderate to good diagnostic accuracy for distinguishing AD patients from healthy controls, based on available case-control studies. However, evidence for effective screening in broader populations is lacking. Further research is needed to confirm these results across diverse clinical settings and strengthen model robustness.},
}

@article {pmid41134991,
year = {2025},
author = {Tseng, P},
title = {Does weak gamma entrainment still work? Rethinking the comfort-efficacy trade-off in 40 Hz sensory stimulation.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877251389153},
doi = {10.1177/13872877251389153},
pmid = {41134991},
issn = {1875-8908},
abstract = {As 40 Hz sensory stimulation gains attention as a potential treatment for Alzheimer's disease, comfort-focused designs such as invisible spectral flicker and multi-luminaire are increasingly used to promote long-term compliance. However, these systems often produce significantly weaker electroencephalographic entrainment than traditional stroboscopic lights. It is therefore important to question the common assumption that any level of entrainment is sufficient, and consider the possibility of nonlinear or threshold-based mechanisms that may require a minimum entrainment strength for therapeutic effects. The field needs to empirically test the relationship between entrainment strength and outcome, to ensure efficacy is not compromised for comfort.},
}

@article {pmid41134984,
year = {2025},
author = {Jang, B and Kim, MJ and Choi, H and Ishigami, A and Kim, YS and Choi, EK},
title = {GAPDH citrullination as a molecular signature of neurodegeneration, assessed in prion diseases.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877251389157},
doi = {10.1177/13872877251389157},
pmid = {41134984},
issn = {1875-8908},
abstract = {BackgroundGlyceraldehyde 3-phosphate dehydrogenase (GAPDH) is a well-known glycolytic enzyme that plays multiple roles in energy metabolism, cell growth, and cell death, and functions as a housekeeping protein. GAPDH has been identified as a potential target of citrullination, a calcium-dependent post-translational modification mediated by peptidylarginine deiminase (PAD), in which arginine residues are converted to citrulline. This modification has been implicated in various human pathologies.ObjectiveTo investigate the function and pathological relevance of citrullinated GAPDH.MethodsWe generated mouse monoclonal antibodies (mAbs) specific to citrullinated GAPDH and applied them in both in vitro systems and prion disease models.ResultsCitrullination of GAPDH at residues R200 and R248 was markedly increased in the brains of 22L scrapie-infected mice and sporadic Creutzfeldt-Jakob disease patients. Both full-length GAPDH and its fragments (∼25 kDa) were heavily citrullinated and highly expressed in neurons including Purkinje cells, astrocytes, and in plaque-like formation. In PAD2-expressing neuronal and astrocyte cell lines, citrullinated GAPDH predominantly accumulated in the nucleus and cytoplasm, with cell type-specific distribution patterns. Citrullinated GAPDH existed as both monomers and reversible oligomers, and citrullination did not alter its enzymatic activity. Immunoprecipitation demonstrated that GAPDH containing citrullinated forms interacts with prion protein. Tandem mass spectrometry analysis revealed that all arginine residues in GAPDH can be citrullinated by PAD2 in vitro. Interestingly, several asparagine and glutamine residues underwent deamidation during citrullination.ConclusionsOur findings suggest that post-translationally citrullinated GAPDH serve as a potential molecular signature of neurodegeneration, which could be easily assessed by newly generated mAbs.},
}

@article {pmid41134977,
year = {2025},
author = {Khalsa, DS and Lavretsky, H and Reddy, MY and Fenn, A and Walling, C},
title = {Air pollution and Alzheimer's disease prevention: The science and a prevention plan.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877251386482},
doi = {10.1177/13872877251386482},
pmid = {41134977},
issn = {1875-8908},
abstract = {Today, approximately 7.2 million people have Alzheimer's disease in the United States. That number is expected to double by 2060 if a preventive approach is not undertaken. Globally, those figures are also predicted to increase. As we'll soon discover, air pollution and other aspects of climate change are a predominant cause of this remarkable surge. The purpose of this article is to examine the scientific basis of pollution and suggest that an evolutionary lifestyle medicine program may help mitigate and slow down its negative effects on brain health. This review examines existing literature on pollution, and lifestyle as well as other aspects of a lifestyle medicine program, including diet, exercise, stress reduction especially via yoga and meditation, good sleep and essential and spiritual well-being, thus investigating their potential to enhance awareness of the issue and prevent the increase in Alzheimer's disease predicted to arise from air pollution and other forms of climate stress. Air pollution, and the potential for global warming, presents a critical emergency. Scientific evidence indicates that these factors contribute to an elevated risk of Alzheimer's disease, along with other neurological, mental, and physical health challenges. Our hypothesis is that an evidence-based lifestyle medicine program can potentially prevent, slow, or reverse multiple medical problems that are tied to Alzheimer's disease prevention. It is hypothesized that once practitioners of this program become aware, they can reach out to their family, friends, communities, country and globally to attend to the issue with strength, wisdom and clarity.},
}

@article {pmid41134896,
year = {2025},
author = {Xiang, Q and Lu, Y and Wang, H and Chen, H and Chen, P and Zhao, X and Cortes Morales, L and Yang, Y and Yang, J and Zhang, T and Wang, J},
title = {ITCH regulates Golgi integrity and proteotoxicity in neurodegeneration.},
journal = {Science advances},
volume = {11},
number = {43},
pages = {eado4330},
doi = {10.1126/sciadv.ado4330},
pmid = {41134896},
issn = {2375-2548},
mesh = {*Golgi Apparatus/metabolism/pathology ; *Ubiquitin-Protein Ligases/metabolism/genetics ; Humans ; Animals ; *Neurodegenerative Diseases/metabolism/pathology ; Lysosomes/metabolism ; Amyotrophic Lateral Sclerosis/metabolism/pathology/genetics ; Disease Models, Animal ; Neurons/metabolism ; Alzheimer Disease/metabolism/pathology/genetics ; Mice ; Repressor Proteins ; },
abstract = {Golgi fragmentation is an early and common feature of neurodegenerative diseases such as amyotrophic lateral sclerosis (ALS) and Alzheimer's disease (AD). However, whether a shared mechanism drives Golgi fragmentation across different neurodegenerative conditions remains unclear. Here, we identify the E3 ubiquitin-protein ligase Itchy homolog (ITCH) as a key regulator of proteotoxicity through its role in inducing Golgi fragmentation. Disease-associated accumulation of ITCH promotes fragmentation of both the cis- and trans-Golgi networks, disrupting protein sorting and impairing lysosomal functions. The ITCH-dependent lysosomal dysfunction compromises the clearance of misfolded proteins associated with several neurodegenerative diseases. Inhibition of ITCH protects against proteotoxicity in both mammalian neurons and Drosophila models of neurodegeneration. The accumulation of ITCH in patients with ALS and AD is attributed to up-regulation of the ubiquitin-specific protease USP11, which deubiquitinates and stabilizes ITCH. These results uncover a pathogenic pathway regulating Golgi integrity and contributing to the development of neurodegenerative diseases.},
}

*Golgi Apparatus/metabolism/pathology
*Ubiquitin-Protein Ligases/metabolism/genetics
Humans
Animals
*Neurodegenerative Diseases/metabolism/pathology
Lysosomes/metabolism
Amyotrophic Lateral Sclerosis/metabolism/pathology/genetics
Disease Models, Animal
Neurons/metabolism
Alzheimer Disease/metabolism/pathology/genetics
Mice
Repressor Proteins

@article {pmid41134549,
year = {2025},
author = {Hernandez Arriaza, R and Reil, D and Fatuzzo, N and Fu, M and Dai, Y and Fernandez Martinez, D and Jiang, H and Holtzman, DM and Greicius, MD and Khosla, C},
title = {ApoE is Secreted as a Lipid Nanoparticle by Mammalian Cells: Implications for Alzheimer's Disease Pathogenesis.},
journal = {Biochemistry},
volume = {},
number = {},
pages = {},
doi = {10.1021/acs.biochem.5c00503},
pmid = {41134549},
issn = {1520-4995},
abstract = {The brain is the most cholesterol-rich organ in the body, and ApoE is the main lipid carrier protein in the brain. Although very little, if any, ApoE exists in its apoprotein form in physiological fluids, recombinant ApoE is typically prepared in a lipid-free state to study its physiological functions. We describe a lipid nanoparticle (LNP) form of ApoE as a primary extracellular product of the eukaryotic protein export system. Whereas the apoprotein is the dominant secreted product when the APOE gene is overexpressed in mammalian cells, an LNP form of ApoE is also observed. The LNP form is, however, the major secreted product from unmodified CCF-STTG1 astrocytoma cells. The C-terminal domain of ApoE plays a key role in LNP biosynthesis as the ApoE3 W210* truncation mutant is secreted without lipidation. Secreted ApoE LNPs are markedly better substrates than the apoprotein itself for further growth via the action of ATP-dependent lipid pumps. Compared to ApoE3 or the Alzheimer's disease-protective ApoE2 variant, the recovered yield of the LNP form of the disease-predisposing ApoE4 variant is higher. Intriguingly, the LNP yield of the rare disease-protective R251G variant of ApoE4 is comparable to that of ApoE3 and ApoE2. Analogous to the well-documented intracellular biosynthesis of ApoB-containing LNPs, the biogenesis and pathophysiological relevance of the LNP form of ApoE warrant further investigation.},
}

@article {pmid41134466,
year = {2025},
author = {Strzępa, A and Szczepanik, M},
title = {The role of microbiota modulation in preventing Alzheimer's disease- a review.},
journal = {Pharmacological reports : PR},
volume = {},
number = {},
pages = {},
pmid = {41134466},
issn = {2299-5684},
support = {N43/DBS/000345//Polish Ministry of Science and Higher Education/ ; },
}