@article {pmid41205924,
year = {2025},
author = {Shapley, SM and Shantaraman, A and Gadhavi, J and Kearney, MA and Dammer, EB and Duong, DM and Bowen, CA and Watson, CM and Bagchi, P and Guo, Q and Rangaraju, S and Seyfried, NT},
title = {Proximity labeling of the Tau repeat domain enriches RNA-binding proteins that are altered in Alzheimer's disease and related tauopathies.},
journal = {Molecular & cellular proteomics : MCP},
volume = {},
number = {},
pages = {101458},
doi = {10.1016/j.mcpro.2025.101458},
pmid = {41205924},
issn = {1535-9484},
abstract = {In Alzheimer's disease (AD) and other tauopathies, tau dissociates from microtubules and forms toxic aggregates that contribute to neurodegeneration. Although some of the pathological interactions of tau have been identified from postmortem brain tissue, these studies are limited by their inability to capture transient interactions. To investigate the interactome of aggregate-prone fragments of tau, we applied an in vitro proximity labeling technique using split TurboID biotin ligase (sTurbo) fused with the tau microtubule repeat domain (TauRD), a core region implicated in tau aggregation. We characterized this sTurbo TauRD tagging interactors with the requirement for both ligase fragment co-expression for robust enzyme activity and nuclear and cytoplasmic localization of the recombinant proteins. Following enrichment of biotinylated proteins and mass spectrometry, we identified over 700 TauRD interactors. Gene ontology analysis of enriched TauRD interactors highlighted processes often dysregulated in tauopathies, including spliceosome complexes, RNA-binding proteins (RBPs), and nuclear speckles. The disease relevance of these interactors was supported by integrating recombinant TauRD interactome data with human AD tau interactome datasets and protein co-expression networks from individuals with AD and related tauopathies. This revealed an overlap with the TauRD interactome and several modules enriched with RBPs and increased in AD and progressive supranuclear palsy. These findings emphasize the importance of nuclear pathways in tau pathology, such as mRNA surveillance and RNA splicing, establishing the sTurbo TauRD system as a valuable tool for exploring the tau interactome.},
}

@article {pmid41205906,
year = {2025},
author = {Ma, J and Liu, Y and Lu, D and Sun, Q},
title = {The association of the Wnt/β-catenin signaling pathway with Alzheimer's disease.},
journal = {Neuropharmacology},
volume = {},
number = {},
pages = {110754},
doi = {10.1016/j.neuropharm.2025.110754},
pmid = {41205906},
issn = {1873-7064},
abstract = {With the global rise in population aging, the incidence of Alzheimer's disease (AD) continues to increase, posing a substantial burden on individuals, families, and healthcare systems. However, at present, the drugs approved by FDA for treating AD can only relieve symptoms, but cannot cure or reverse the disease. Therefore, it is urgent to study the signal pathways related to AD and the drugs to improve the pathological changes of AD.The Wnt/β-catenin signaling pathway, known for its functional diversity, evolutionary conservation, and relevance to multiple diseases, holds a pivotal role in both basic research and therapeutic development. This pathway is essential for regulating critical biological processes, including embryonic development, tissue homeostasis, cell proliferation, differentiation, and apoptosis.In AD , downregulation of the Wnt/β-catenin signaling pathway has been implicated in key pathological features, such as tau hyperphosphorylation, amyloid-β (Aβ) accumulation, neuronal degeneration, synaptic loss, cognitive impairment, oxidative stress, mitochondrial dysfunction, blood-brain barrier disruption, and neuroinflammation. This review comprehensively discusses the deregulation of the Wnt/β-catenin pathway in AD and how it contributes to disease progression. Furthermore, we highlighted emerging pharmacological activators of this pathway exhibiting potential as therapeutic agents for AD.},
}

@article {pmid41205899,
year = {2025},
author = {Ali, S and Kosar, S and Sina, RM and Sima, A and Mohammad, A and Mohammad, S and Zahra, Z and Vida, HH and Fatemeh, K and Zohreh, Z and Fatemeh, SE and Farhang, G and Mahan, S and Mahsa, M and , and , },
title = {Serum bile acids and brain hypometabolism in patients across Alzheimer's disease continuum: An [[18]F]FDG-PET study.},
journal = {Neuroscience},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.neuroscience.2025.11.001},
pmid = {41205899},
issn = {1873-7544},
abstract = {The present study compares the predictive performance of serum bile acids with that of traditional Cerebrospinal Fluid (CSF) biomarkers for brain hypometabolism in the Alzheimer's disease (AD) continuum using [[18]F]-Fluorodeoxyglucose Positron Emission Tomography ([[18]F]-FDG-PET). Data were extracted from the Alzheimer's Disease Neuroimaging Initiative (ADNI). Conventional CSF biomarker data, serum bile acid measurements, and [[18]F]-FDG-PET data were used. We studied 556 participants, including 185 cognitively normal (CN) individuals, 289 patients with mild cognitive impairment (MCI), and 82 patients with AD. Glucose Standardized Uptake Value Ratios (SUVRs) were significantly lower in the CN group compared to the MCI and AD groups. Serum levels of lithocholic acid and Glycolithocholic acid were significantly elevated in AD compared to MCI and CN participants. Overall, CSF biomarkers had lower predictive power compared to brain hypometabolism in distinguishing AD from other groups. Stronger correlations with brain glucose hypometabolism were observed for conventional CSF biomarkers compared to bile acids in MCI and AD patients. Regression analyses indicated that while certain bile acids predicted brain hypometabolism in CN subjects better than conventional biomarkers, their predictive performance underperformed CSF biomarkers in MCI and AD. Overall, FDG-PET remains more effective than traditional CSF biomarkers for staging the AD continuum. While bile acids show potential, their ability to predict brain glucose metabolism in the AD spectrum has not yet surpassed that of established CSF biomarkers.},
}

@article {pmid41205896,
year = {2025},
author = {Easton, A and Parui, A},
title = {Driving forward a new perspective on everyday memory in the real world.},
journal = {Neuroscience},
volume = {590},
number = {},
pages = {93-94},
doi = {10.1016/j.neuroscience.2025.10.058},
pmid = {41205896},
issn = {1873-7544},
}

@article {pmid41205777,
year = {2025},
author = {Boreland, AJ and Abbo, Y and Li, X and Stillitano, AC and Zhang, S and Duan, J and Pang, ZP and Hart, RP},
title = {Ethanol induces neuroimmune dysregulation and soluble TREM2 generation in a human iPSC neuron, astrocyte, microglia triculture model.},
journal = {Alcohol (Fayetteville, N.Y.)},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.alcohol.2025.10.006},
pmid = {41205777},
issn = {1873-6823},
abstract = {Alcohol use disorders (AUDs) affect substantial populations worldwide and increase the risk of developing cognitive impairments and alcohol-associated dementia. While chronic inflammatory signaling likely plays an important role in alcohol-associated neurological sequalae, the precise mechanisms underlying alcohol-associated neuropathology remain enigmatic. We hypothesize that alcohol leads to neuroimmune dysregulation among neurons, astrocytes, and microglia; and is perpetuated by innate immune signaling pathways involving cell-cell signaling. To investigate how alcohol dysregulates neuroimmune interactions in a human context, we constructed a triculture model comprising neurons, astrocytes, and microglia derived from human induced pluripotent stem cells. After exposure to ethanol, we observed significant differential gene expression relating to innate immune pathways, inflammation, and microglial activation. Microglial activation was confirmed with morphological analysis and expression of CD68, a lysosomal-associated membrane protein and marker for phagocytic microglial activation. A striking finding in our study was the elevation of TREM2 expression and, specifically, TREM2 alternatively spliced isoforms that are predicted to give rise to soluble TREM2. TREM2 loss-of-function variants have been reported to be a risk factor for Alzheimer's disease. These results suggest that ethanol exposure in the brain may lead to increased microglial activation and production of soluble isoform named TREM2[219] through alternate splicing. Deciphering the molecular and cellular mechanisms underpinning ethanol-related neuroimmune dysregulation within a human context promises to shed light on the etiology of AUD-related disorders, potentially contributing to the development of effective therapeutic strategies.},
}

@article {pmid41205745,
year = {2025},
author = {Maramai, S and Taddei, M and Castagnetti, A and Viciani, E and Koufi, FD and Neri, I and Boschetti, E and Evangelisti, C and Ratti, S and Baldelli, L and Calandra-Buonaura, G and Cani, I and Cortelli, P and Sambati, L and Scorziello, A and Taglialatela, M and Pardini, M and Corsaro, A and Florio, T and Giannini, G},
title = {Drug enteric metabolism in gut microbiota-brain crosstalk.},
journal = {Life sciences},
volume = {},
number = {},
pages = {124075},
doi = {10.1016/j.lfs.2025.124075},
pmid = {41205745},
issn = {1879-0631},
abstract = {Neurodegenerative diseases (NDs), such as Alzheimer's (AD) and Parkinson's disease (PD) represent the leading cause of illness and disability worldwide. In the effort to unveiling the etiopathogenesis of these neurological diseases, increasing attention has recently been paid to the emerging role of the gut microbiota (GMB) in the so-called gut-brain axis, and to the correlation of neurodegenerative processes with intestinal dysbiosis, either of genetic bases or induced by drugs and their metabolites. Over time, there has been a notable surge in the quantity of scientific publications pertaining to the gut-brain axis and GMB metabolism, reaching top levels in 2023-2024. As a result, the body of research on the effects of the gut-brain axis on AD and PD has begun to increase. Nonetheless, the identification of gut-derived metabolites and their effects on the central nervous system (CNS) is frequently missing or only partially reported. It is therefore necessary to raise awareness on the importance of enteric metabolism and its assessment while designing new drugs and investigating their pharmacokinetic properties, since both healthy and dysbiotic gut can hamper or modify drugs activity and efficacy. This review aims at providing a critical overview of gut-derived metabolism of different drugs, focusing on their effects on the GMB and gut-brain axis. The discussion focused on common therapeutic agents against AD and PD, as well as non-prescription drugs and food supplements with known beneficial effects on the CNS, reviewing relevant literature of the last decade.},
}

@article {pmid41205698,
year = {2025},
author = {Dunk, MM and Delac, L and Rapp, SR and Driscoll, I and Latorre-Leal, M and Farland, LV and Haring, B and Harris, HR and Jung, SY and Manson, JE and Ochs-Balcom, HM and Shadyab, AH and Weitlauf, JC and Xu, H and Maioli, S},
title = {Exploring biomarkers of neurodegenerative risk: Associations of oxysterols, sex hormones, and reproductive characteristics in older women.},
journal = {Journal of lipid research},
volume = {},
number = {},
pages = {100938},
doi = {10.1016/j.jlr.2025.100938},
pmid = {41205698},
issn = {1539-7262},
abstract = {Women face a higher lifetime risk of developing neurodegenerative diseases such as Alzheimer's disease (AD) and related dementia (ADRD). The menopausal transition, characterized by a decline in estrogen levels, may affect cholesterol metabolism and neurodegenerative processes. Oxysterols, oxidized cholesterol derivatives, play a role in these pathways, with 24(S)-hydroxycholesterol (24HC) reflecting brain cholesterol turnover and 27-hydroxycholesterol (27HC) linked to systemic cholesterol metabolism. We investigated associations of plasma oxysterols with circulating sex hormones and characteristics of reproductive history in 1,974 postmenopausal women with no history of dementia from the Women's Health Initiative, taking into account APOE4 status and cholesterol-lowering medication. We found that higher levels of bioavailable estradiol were associated with higher 24HC and 27HC levels, and higher estrone was associated with higher 24HC (all p-values < 0.05). Associations of estradiol with 24HC and 27HC were stronger among those not using cholesterol medication and APOE4 carriers, with a significant interaction between 27HC and APOE4 in relation to 27HC (p for interaction = 0.04). Having an older age at menopause was associated with lower 24HC among those taking cholesterol medication (p for interaction = 0.03). Our findings suggest that 24HC and 27HC may be proxy biomarkers of neuronal health and estrogen status in postmenopausal women. The stronger associations between estradiol and oxysterols among APOE4 carriers and those not using cholesterol-lowering medication suggest the need to account for hormonal, genetic, and pharmacological factors when evaluating neurodegenerative risk. Longitudinal studies are warranted to further investigate oxysterols as potential early biomarkers of ADRD risk.},
}

@article {pmid41205642,
year = {2025},
author = {Kishi, T and Matsunaga, S and Saito, Y and Iwata, N},
title = {Lithium for Alzheimer's Disease: Insights from a Meta-analysis.},
journal = {Neuroscience and biobehavioral reviews},
volume = {},
number = {},
pages = {106458},
doi = {10.1016/j.neubiorev.2025.106458},
pmid = {41205642},
issn = {1873-7528},
}

@article {pmid41205639,
year = {2025},
author = {Bhosale, S and Chakor, R and Lohidasan, S and Sivakkumar, S and Arulmozhi, S},
title = {Neuroprotective and Nootropic Effects of a Standardised Siddha Polyherbal Formulation, Bhiramiyadhi Bhavanai Choornam, Against β-Amyloid-Induced Neurodegeneration.},
journal = {Journal of ethnopharmacology},
volume = {},
number = {},
pages = {120850},
doi = {10.1016/j.jep.2025.120850},
pmid = {41205639},
issn = {1872-7573},
abstract = {Bhiramiyadhi bhavanai choornam (BBC) is a traditional Siddha polyherbal formulation composed of 15 medicinal plants. The classical text claims that regular intake of BBC strengthens cognitive function, improves memory, boosts morale, enhances longevity, and promotes overall physical vitality Aim of the study: The present investigation focused on standardising Bhiramiyadhi bhavanai choornam and assessing its neuroprotective effect against β-amyloid-induced neurodegeneration in Wistar rats.

MATERIALS AND METHODS: Standardisation of BBC was carried out following AYUSH guidelines. A validated HPTLC method was developed for the marker compounds ascorbic acid, gallic acid, quercetin, piperine, and asiaticoside. Experimental neurodegeneration was induced by intracerebroventricular administration of Aβ1-42 in male Wistar rats. The effects of BBC were evaluated using behavioural paradigms, such as the Morris water maze, locomotor activity, social recognition, and novel object recognition tests. Biochemical assessments included acetylcholinesterase activity, brain-derived neurotrophic factor (BDNF), oxidative stress and antioxidant indices, and inflammatory cytokines. Brain histopathology was performed to assess neuronal architecture and the deposition of amyloid plaques.

RESULTS: and discussion: The HPTLC method developed provided accurate and reliable chemical profiling of BBC. Treatment with BBC significantly improved cognitive and memory performance in Aβ1-42-treated rats. It enhanced brain BDNF levels, improved antioxidant defence mechanism, reduced acetylcholinesterase activity, and suppressed oxidative stress and inflammatory cytokines. Histological studies further confirmed its protective effect by attenuating neuronal damage and plaque formation.

CONCLUSION: A validated HPTLC method was developed for the standardisation of BBC. Pharmacological findings indicate its strong neuroprotective and nootropic activities, highlighting its potential for Alzheimer's disease and related neuro disorders.},
}

@article {pmid41205623,
year = {2025},
author = {Wisch, JK and Jiao, Z and Kennedy, JT and Cohen, AD and Schlachetzki, Z and Petersen, M and Handen, BL and Christian, BT and Mapstone, M and Rosas, HD and Lai, F and Lee, JH and Krinsky-McHale, SJ and Schmitt, FA and Harp, JP and Hom, C and Lott, IT and Hartley, S and Zaman, S and Ptomey, L and Burns, JM and Tudorascu, D and Ibanez, L and Rafii, MS and Head, E and Ances, BM},
title = {Imaging and plasma biomarkers for pathological accumulation in Down syndrome.},
journal = {Brain : a journal of neurology},
volume = {},
number = {},
pages = {},
doi = {10.1093/brain/awaf418},
pmid = {41205623},
issn = {1460-2156},
abstract = {Down syndrome is characterized by triplication of chromosome 21, leading to early-onset Alzheimer disease pathology, with nearly all individuals with Down syndrome developing amyloid and tau pathology. In the new era of amyloid modifying therapies, it is vital to identify early biomarkers for Alzheimer disease (AD) pathology in Down syndrome. Striatal amyloid may begin to accumulate sooner than cortical amyloid in Down syndrome. Tau phosphorylation at specific sites, including 217, can be quantified in plasma and may represent an important mechanistic step in the development of tau pathology. This study had two aims: 1. To compare the relative age at increase of multiple biomarkers (cortical amyloid, striatal amyloid, plasma pTau217 and summary tau pathology) 2. To test whether plasma pTau217 can identify both the current presence and likely future accumulation of amyloid and tau pathology. To identify optimal biomarkers for early intervention, we examined longitudinal cortical and striatal amyloid PET, plasma pTau217, and tau PET in 328 individuals with Down syndrome enrolled in the Alzheimer Biomarker Consortium - Down Syndrome study. To compare the timing of biomarker changes, we modeled longitudinal biomarkers using generalized additive mixed models relative to age. We used receiver operating characteristic curve analysis to identify thresholds for both current and likely future accumulation of amyloid and tau pathology. For all comparisons, we used age as the null model, performing Delong tests to evaluate the performance of age relative to biomarker-based prediction. Imaging biomarkers increased around 40 years old, with plasma pTau217 increasing somewhat later than the three PET biomarkers. Striatal amyloid increased before cortical amyloid in some participants; however, this was not uniform across individuals. If an individual was classified as a reliable accumulator with one biomarker, he or she was likely to be a reliable accumulator in other biomarkers. Age was as sensitive as plasma pTau217 in its ability to both detect preclinical Alzheimer disease pathology and predict near future accumulation of both amyloid and tau. These results suggest that all adults with Down syndrome should be screened for Alzheimer disease pathology starting shortly before age 40 and considered for clinical trials. Age alone was as effective at detecting both current pathology and likely future accumulation as plasma pTau217. Because this disease is so closely concurrent with age in individuals with Down Syndrome, plasma pTau217 may not provide more diagnostic benefits than age.},
}

@article {pmid41205374,
year = {2025},
author = {Venkatraman, S and P R, JD and Kavitha, MS},
title = {Hierarchical graph-guided contextual representation learning for Neurodegenerative pattern recognition in MRI.},
journal = {Computers in biology and medicine},
volume = {199},
number = {},
pages = {111276},
doi = {10.1016/j.compbiomed.2025.111276},
pmid = {41205374},
issn = {1879-0534},
abstract = {Neurodegenerative (ND) diseases are autoimmune diseases that affect the central nervous system, including the brain and spinal cord. In recent years, deep learning has demonstrated its potential in medical imaging for diagnostic purposes. However, for these techniques to be fully accepted in clinical settings, they must achieve high performance and gain the confidence of medical professionals regarding their interpretability. Therefore, an interpretable model should make decisions based on clinically relevant information like a domain expert. To achieve this, we present an interpretable classifier dedicated to the most common autoimmune ND diseases. The lesions associated with ND diseases exhibit irregular distributions and spatial dependencies in different regions of the brain, challenging traditional models to effectively capture both local and global relationships. To address this issue, we present a Residual Graph Neural Network enhanced Vision Transformer (RG-ViT) that represents MRI data as a graph of interconnected patches. By integrating residual connections into the GNN framework, we preserve critical features while promoting effective message passing. This approach overcomes the problem of spatial disconnection prevalent in standard patch-based methods and provides a cohesive and context-aware analysis of MRI data. Experimental results in detecting multiple sclerosis (MS), Parkinson's (PD), and Alzheimer's disease (AD) demonstrated our approach's consistent accuracy scores of 98.7%, 99.6%, and 99.1%, respectively. On the combined dataset for the global classification of ND diseases, it achieved an F1 score of 99.2%, justifying its generalizability.},
}

@article {pmid41205203,
year = {2025},
author = {Channalli, SR and Pattanashetti, L and Patil, SB and Yaraguppi, DA and Prasanth, DSNBK and Halkavatagi, SG and Naik, R},
title = {Deciphering the Multitarget Neuroprotective Potential of Ficus microcarpa L. f. Leaf Extract: Insights From Phytochemical, Computational, and Experimental Approaches.},
journal = {Chemistry & biodiversity},
volume = {},
number = {},
pages = {e02568},
doi = {10.1002/cbdv.202502568},
pmid = {41205203},
issn = {1612-1880},
abstract = {Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by memory loss, cognitive decline, and cholinergic dysfunction. This study evaluated the neuroprotective potential of Ficus microcarpa leaf extract via a multidisciplinary approach that integrates phytochemical profiling, in silico analysis, and in vivo validation. LC‒MS analysis revealed key bioactive compounds, including fortunellin, thalsimine, and vocalristine, which are flavonoids, alkaloids, and terpenoids, that are known for their neuroprotective effects. Drug-likeness and toxicity evaluations via SwissADME and ProTox-II revealed favorable pharmacokinetic properties. Network pharmacology and KEGG enrichment analyses identified AChE, APP, and GSK3β as central AD-related targets. Molecular docking (AutoDock 4.2) revealed strong binding affinities of fortunellin (-9.2 kcal/mol) and donepezil (-9.0 kcal/mol) with AChE, which was supported by active site interactions. Molecular dynamics (200 ns, GROMACS) confirmed the complex stability via RMSD, RMSF, SASA, and hydrogen bond analyses. The MM-PBSA calculations further validated the binding stability. In vivo studies revealed that F. microcarpa (100 and 200 mg/kg, po) and donepezil (3 mg/kg, po) administered for 21 days significantly reversed scopolamine-induced (2 mg/kg, ip) memory deficits in Wistar rats, as assessed by the Morris water maze, elevated plus maze, and novel object recognition tests. Biochemical analysis revealed reduced oxidative stress, increased antioxidant enzyme levels, and the restoration of cholinergic function. Histopathological studies revealed that the integrity of the hippocampus was preserved. Overall, these findings support F. microcarpa, particularly fortunellin, as a promising multitarget candidate for AD therapy, meriting further pharmacological investigation.},
}

@article {pmid41205178,
year = {2025},
author = {Royo Marco, A and Bruch, KR and Cowan, MN and Dill, JG and Moore, KA and Bolte, AC and Lukens, JR},
title = {Therapeutic VEGFC treatment provides protection against traumatic-brain-injury-driven tauopathy pathogenesis.},
journal = {Cell reports},
volume = {44},
number = {11},
pages = {116521},
doi = {10.1016/j.celrep.2025.116521},
pmid = {41205178},
issn = {2211-1247},
abstract = {Traumatic brain injury (TBI) increases one's risk of developing Alzheimer's disease and tauopathy. Yet, the mechanisms linking TBI to neurodegenerative disease remain poorly defined. Mounting recent evidence indicates that defects in brain lymphatic drainage contribute to multiple neurodegenerative diseases. Here, we investigated whether promoting brain lymphatic drainage recuperation following TBI via treatment with the lymphangiogenic factor vessel endothelial growth factor C (VEGFC) mitigates the ability of TBI to exacerbate tauopathy. In this study, we show that a single mild TBI leads to worsened neuropathology, brain macrophage activation, and neurodegeneration in the PS19 mouse model of tauopathy. Moreover, we find that viral-vector-based delivery of VEGFC into the meningeal compartment 24 h post-TBI ameliorates tau-mediated neurodegenerative disease pathogenesis. Findings from these studies offer new insights into how TBI leads to the development of tauopathy later in life and suggest that VEGFC-based treatments might offer a therapeutic strategy to limit tauopathy after sustaining a head injury.},
}

@article {pmid41205094,
year = {2025},
author = {Manzano, S and Maurino, J and Balasa, M and Piñol-Ripoll, G and Boada, M and Landete, L and Abellán, I and Berbel, Á and Espejo, B and Almagro, M and Rodrigo, J and Sánchez-Juan, P and García-Arcelay, E and Ballesteros, J},
title = {Psychometric Properties of the 7-Item Sense of Competence Questionnaire: Assessing Informal Caregivers' Self-Perceived Competence in Mild Cognitive Impairment.},
journal = {Neurology and therapy},
volume = {},
number = {},
pages = {},
pmid = {41205094},
issn = {2193-8253},
support = {ML44177//Roche/ ; },
abstract = {INTRODUCTION: Caregivers provide essential support to patients with mild cognitive impairment (MCI). However, limited research has been conducted to validate instruments that assess their self-perceived competence in caregiving. This study aimed to assess the psychometric properties of the 7-item Sense of Competence Questionnaire (S-SCQ) in informal caregivers of patients with MCI.

METHODS: A non-interventional, cross-sectional study was conducted in collaboration with the Spanish Confederation of Alzheimer's Disease, enrolling informal caregivers of patients with MCI. A non-parametric item response theory procedure (Mokken analysis) was performed to evaluate the S-SCQ's dimensional structure using scalability coefficients. Internal reliability was assessed using Cronbach's α. Concurrent validity was examined through Spearman's correlations between S-SCQ scores and measures of caregiver burden, psychological distress, resilience, and the caregiver-patient relationship.

RESULTS: A total of 196 caregivers were studied. Caregivers had a mean age of 63.5 (SD 13.1) years, and most (63%) were female. The care recipients had a mean age of 72.9 (7.0) years, with a mean disease duration of 2.9 (2.2) years. The mean S-SCQ score was 26.1 (6.1). The S-SCQ demonstrated strong unidimensionality (H = 0.52) and good internal reliability (Cronbach's α = 0.86). Higher S-SCQ scores (greater sense of competence) correlated with lower caregiver burden (ρ = - 0.63, p < 0.001), reduced anxiety and depressive symptoms (ρ = - 0.32, p < 0.001), stronger caregiver-patient relationship (ρ = 0.72, p < 0.001), and greater resilience (ρ = 0.34, p < 0.001).

CONCLUSIONS: The S-SCQ is a reliable tool for assessing self-perceived competence in informal caregivers of patients with MCI. Its integration into clinical and research settings may offer an opportunity to enhance the early detection of caregiver burden and facilitate timely, targeted interventions.},
}

@article {pmid41205072,
year = {2025},
author = {Sun, Y and Meng, D and Yu, H and Yin, G and Zhang, X and Yu, W and Liu, H and Jiang, W and Zhang, F},
title = {Genetic evidence for a causal relationship between 179 lipid species and cognitive function and alzheimer's disease: a bidirectional Mendelian randomization study.},
journal = {European archives of psychiatry and clinical neuroscience},
volume = {},
number = {},
pages = {},
pmid = {41205072},
issn = {1433-8491},
support = {No.81573945//National Natural Science Foundation of China/ ; No.ZR2021MH054//Natural Science Foundation of Shandong Province/ ; },
abstract = {The public health burden of cognitive decline escalates with population aging. While lipid species alterations are associated with cognitive function and Alzheimer's disease (AD), causal evidence remains limited. We applied two-sample Mendelian randomization (TSMR) and Bayesian-weighted MR (BWMR) to investigate the causal effects of lipid species on cognitive function and to assess the bidirectional causal relationships between lipid species and AD. We analyzed genome-wide association study (GWAS) data from large-scale cohorts: AD (East African Development Bank [EADB], N = 487,511); cognitive function (UK Biobank, N = 20,346); and lipid species (THL Biobank, N = 7,174). Analyses were conducted using multiple MR methods, including inverse variance weighting (IVW), BWMR, MR-Egger regression, and false discovery rate (FDR) correction. Sensitivity analyses-MR-Egger intercept test, MR-Pleiotropy Residual Sum and Outlier (MR-PRESSO), Cochran's Q test, and leave-one-out analysis-were conducted to evaluate horizontal pleiotropy and heterogeneity. TSMR results identified 51 lipid species with causal associations for cognitive function and AD, among which 27 showed protective effects. Conversely, AD was found to influence 17 lipid species, with 14 exhibiting negative effects. These genetically supported findings highlight potential lipid-related targets for preventive and therapeutic interventions aimed at combating cognitive decline.},
}

@article {pmid41205008,
year = {2025},
author = {Jana, K and Ghosh, S and Parua, P and Debnath, B and Halder, J and Sahoo, RK and Rai, VK and Pradhan, D and Dash, P and Das, C and Kar, B and Ghosh, G and Rath, G},
title = {Insights into the Versatile Role of Extracellular Vesicles in the Treatment of CNS Disorders.},
journal = {Molecular neurobiology},
volume = {63},
number = {1},
pages = {14},
pmid = {41205008},
issn = {1559-1182},
mesh = {Humans ; *Extracellular Vesicles/metabolism ; Animals ; *Central Nervous System Diseases/therapy/metabolism ; Drug Delivery Systems/methods ; Blood-Brain Barrier/metabolism ; },
abstract = {E xtracellular vesicles (EVs) are lipid bilayer-enclosed nanocarriers composed primarily of phospholipids and membrane proteins. They are released by cells into the surrounding extracellular environment and vary in size, composition, and biogenesis pathways. Beyond their natural role in intercellular communication, mediating the transfer of proteins, lipids, and nucleic acids (like mRNA and miRNA) between cells, EVs have emerged as a highly versatile and promising therapeutic platform for a range of challenging disorders, particularly those affecting the central nervous system (CNS) and various cancers. The CNS presents unique therapeutic challenges, notably the formidable blood-brain barrier (BBB), which restricts the entry of most conventional drugs. EVs, however, possess an inherent capacity to traverse this barrier, either naturally or through engineered modifications. This characteristic positions them as ideal nanocarriers for delivering therapeutic payloads such as neurotrophic factors, gene therapy constructs, or anti-inflammatory agents directly to target neural cells for conditions like Alzheimer's disease, Parkinson's disease, stroke recovery, multiple sclerosis, and even glioblastoma. Their biocompatibility and low immunogenicity further reduce systemic side effects, making them a safer alternative to synthetic delivery systems. This review outlines recent progress in extraction techniques using EVs for treating neurological disorders. It covers clinical applications in neurodegenerative, infectious diseases, inflammatory, genetic, and oncological diseases and highlights current limitations and considerations for advancing future research in this evolving field.},
}

Humans
*Extracellular Vesicles/metabolism
Animals
*Central Nervous System Diseases/therapy/metabolism
Drug Delivery Systems/methods
Blood-Brain Barrier/metabolism

@article {pmid41204969,
year = {2025},
author = {Phuong, HT and Tomas, RF and Akmese, C and Mijares, A and Gerstin, IM and Guo, S and Bell, LR and Ellwood, R and Yegorova, S and Ng, SK and Massey, G and Phillips, J and Melloni, A and Pletnikova, O and Lou, X and Clark, HB and Troncoso, JC and Hyman, BT and Prokop, S and Ranum, LPW and Nguyen, L},
title = {PolyGR-containing aggregates link with pathology and clinical features of Alzheimer's disease.},
journal = {Acta neuropathologica},
volume = {150},
number = {1},
pages = {49},
pmid = {41204969},
issn = {1432-0533},
mesh = {Humans ; *Alzheimer Disease/pathology/metabolism ; Male ; Female ; Aged ; Aged, 80 and over ; *Brain/pathology/metabolism ; tau Proteins/metabolism ; Plaque, Amyloid/pathology/metabolism ; Middle Aged ; Amyloid beta-Peptides/metabolism ; Protein Aggregates ; *Protein Aggregation, Pathological/pathology/metabolism ; Neurofibrillary Tangles/pathology/metabolism ; },
abstract = {Alzheimer's disease is the most common form of dementia; however, its molecular mechanisms are not fully understood. We recently identified polymeric glycine-arginine-containing (polyGR+) aggregates as a novel type of proteinopathy in AD autopsy brains. Here, we performed a comprehensive analysis to study if polyGR+ aggregates are associated with AD neuropathological changes (ADNC) and clinical features of AD cases. We show polyGR+ aggregates are detected in ~ 60% of AD postmortem brains from three AD cohorts but not age-similar controls or disease controls with primary age-related tauopathy (PART). A subtype of polyGR+ aggregates with a clustered-punctate morphology that is positive for the markers of dystrophic neurites is associated with earlier onset and shortened survival in AD cases. Increased levels of Aβ plaques and phosphorylated tau (pTau) tangles are detected in the hippocampus of AD autopsy brains with high levels of polyGR+ aggregates compared to AD autopsy brains with minimal polyGR+ staining. In addition to ADNC, a subset of polyGR+ aggregates coexists with limbic-predominant age-related TDP-43 encephalopathy neuropathological changes (LATE-NC) or Lewy body pathology (LBP). Hippocampal polyGR+ aggregate levels are ~ 3.8- and ~ 3.71-fold higher in late-onset AD cases who experienced stroke or high blood pressure, respectively. In SH-SY5Y cells, hydrogen peroxide treatment which mimics oxidative stress leads to increased levels of polyGR+ proteins produced by the CASP8 GGGAGA repeat expansion, which was recently shown to associate with increased AD risk. In addition, we show the accumulation of pTau induced by CASP8 polyGR+ protein aggregates is elevated upon hydrogen peroxide treatment. In summary, our results demonstrate polyGR+ aggregates are a frequent and understudied type of proteinopathy in AD autopsy brains and that polyGR proteinopathy is associated with ADNC.},
}

Humans
*Alzheimer Disease/pathology/metabolism
Male
Female
Aged
Aged, 80 and over
*Brain/pathology/metabolism
tau Proteins/metabolism
Plaque, Amyloid/pathology/metabolism
Middle Aged
Amyloid beta-Peptides/metabolism
Protein Aggregates
*Protein Aggregation, Pathological/pathology/metabolism
Neurofibrillary Tangles/pathology/metabolism

@article {pmid41204877,
year = {2025},
author = {Pini, L and Tuzzato, C and Griffa, A and Brusini, L and Cruciani, F and Allali, G and Corbetta, M and Menegaz, G and Boscolo Galazzo, I and , },
title = {Brain Connectivity Gradients Alterations in Discordant Cerebrospinal Fluid Profile for Alzheimer's Disease Biomarkers.},
journal = {Human brain mapping},
volume = {46},
number = {16},
pages = {e70406},
doi = {10.1002/hbm.70406},
pmid = {41204877},
issn = {1097-0193},
support = {IZSEZ0_229208//Swiss National Science Foundation (SNSF)/ ; 68076//Fondazione Cariparo/ ; //The Ministero della Salute Italiano/ ; RF-2018-1236689//NEUROCONN/ ; 101071900//HORIZON-ERC-SyG/ ; 101147319//HORIZON-INFRA-2022/ ; //MIUR D.M. 737/2021/ ; 202292PHR2//MUR PRIN 2022/ ; //Alzheimer's Disease Neuroimaging Initiative/ ; U01 AG024904/NH/NIH HHS/United States ; W81XWH-12-2-0012//DOD ADNI/ ; /AG/NIA NIH HHS/United States ; /EB/NIBIB NIH HHS/United States ; //AbbVie/ ; /ALZ/Alzheimer's Association/United States ; //Alzheimer's Drug Discovery Foundation/ ; //Araclon Biotech/ ; //BioClinica Inc./ ; //Biogen/ ; //Bristol-Myers Squibb Company/ ; //CereSpir Inc./ ; //Cogstate/ ; //Eisai Inc./ ; //Elan Pharmaceuticals Inc./ ; //Eli Lilly and Company/ ; //EuroImmun/ ; //F. Hoffmann-La Roche Ltd./ ; //Genentech Inc./ ; //Fujirebio/ ; //GE Healthcare/ ; //IXICO Ltd./ ; //Janssen Alzheimer Immunotherapy Research & Development LLC./ ; //Johnson & Johnson Pharmaceutical Research & Development LLC./ ; //Lumosity/ ; //Lundbeck/ ; //Merck & Co. Inc./ ; //Meso Scale Diagnostics LLC./ ; //NeuroRx Research/ ; //Neurotrack Technologies/ ; //Novartis Pharmaceuticals Corporation/ ; //Pfizer Inc./ ; //Piramal Imaging/ ; //Servier/ ; //Takeda Pharmaceutical Company/ ; //Transition Therapeutics/ ; /CAPMC/CIHR/Canada ; //Foundation for the National Institutes of Health/ ; //Northern California Institute for Research and Education/ ; },
mesh = {Humans ; *Alzheimer Disease/cerebrospinal fluid/diagnostic imaging/physiopathology/pathology ; Male ; Female ; *tau Proteins/cerebrospinal fluid ; *Amyloid beta-Peptides/cerebrospinal fluid ; Aged ; Biomarkers/cerebrospinal fluid ; Magnetic Resonance Imaging ; *Peptide Fragments/cerebrospinal fluid ; *Brain/diagnostic imaging/physiopathology ; *Connectome ; Aged, 80 and over ; Middle Aged ; *Nerve Net/diagnostic imaging/physiopathology ; *Cognitive Dysfunction/cerebrospinal fluid/physiopathology/diagnostic imaging ; Diffusion Magnetic Resonance Imaging ; },
abstract = {Alzheimer's disease (AD) is a heterogeneous disorder characterized by brain accumulation of amyloid-beta (Aß, simplified as A for the AD biological model) and tau (T) proteins, with Aß emerging first. However, a significant proportion of individuals exhibit discordant biomarkers' profiles, such as elevated phosphorylated tau181 (p-tau181) with normal Aß42 from cerebrospinal fluid (CSF), posing diagnostic and mechanistic challenges. This study investigated whether functional and structural brain connectivity can distinguish individuals with discordant CSF profiles (A-T+) from those with concordant patterns (A+T+), hypothesizing that distinct connectivity patterns may reflect early divergent pathophysiological processes. Data from cognitively unimpaired or mildly impaired individuals in the ADNI3 repository were analyzed, selecting those with resting-state functional MRI (rsfMRI) and/or diffusion MRI (dMRI) within 18 months of CSF testing for Aß and p-tau181. Participants were grouped into A-T+ or A+T+ groups. Structural and functional connectivity gradients were generated for each participant and summarized using a Euclidean distance measure from reference gradient templates derived from cognitively unimpaired individuals without pathology (A-T-). We applied linear mixed models and analysis of variance to assess connectivity-based gradient differences between A-T+ and A+T+ groups, adjusting for relevant variables. Classification analyzes using logistic regression and support vector machine, along with feature importance via the Boruta algorithm, evaluated the discriminative power of gradient connectivity profiles. Multimodal integration was performed using partial least square canonical analysis (PLSC), and relationships between gradients and cognition were assessed via UMAP-based dimensionality reduction and bootstrapped linear regressions. Results were compared with a classical network analysis examining within- and between-network connectivity differences. Among 424 participants, n = 67 were classified as A-T+, n = 106 as A+T+, and n = 56 as cognitively healthy A-T-. The remaining 195 participants (n = 86 A+T+ and n = 109 cognitively impaired A-T-) were not included. A-T+ individuals (age = 75 ± 8.2) exhibited less cognitive impairment but greater functional connectivity gradients' distance to the reference templates (false discovery rate-corrected p < 0.05) in the temporo-occipital axis compared to A+T+ (age = 76.1 ± 7.7). Structural connectivity differences were not significant. FC-based models classified A-T+ and A+T+ with good accuracy (AUC = 0.77), loading on the same temporo-occipital regions, unlike SC (AUC = 0.52). The posterior brain involvement in A-T+ was confirmed by PLSC analyzes. A+T+ individuals showed a significant relation between cognitive scores and functional connectivity, primarily mapping the default mode network (DMN). A shift was observed in relation to executive functions and functional connectivity in A-T+. Discordant CSF profiles (A-T+) exhibit distinct functional connectivity patterns, particularly in posterior brain regions, compared to concordant CSF patterns (A+T+), which are characterized by a significant cognitive-DMN connectivity association. These results suggest that CSF p-tau181 accumulation in the absence of Aß42 may be associated with specific functional trajectories, suggesting specific pathophysiological patterns.},
}

Humans
*Alzheimer Disease/cerebrospinal fluid/diagnostic imaging/physiopathology/pathology
Male
Female
*tau Proteins/cerebrospinal fluid
*Amyloid beta-Peptides/cerebrospinal fluid
Aged
Biomarkers/cerebrospinal fluid
Magnetic Resonance Imaging
*Peptide Fragments/cerebrospinal fluid
*Brain/diagnostic imaging/physiopathology
*Connectome
Aged, 80 and over
Middle Aged
*Nerve Net/diagnostic imaging/physiopathology
*Cognitive Dysfunction/cerebrospinal fluid/physiopathology/diagnostic imaging
Diffusion Magnetic Resonance Imaging

@article {pmid41204697,
year = {2025},
author = {Fu, J and Huang, T and Li, G and Zhang, X and Tan, L and Zhu, C and Zhang, W and Zhang, W},
title = {Toxicological Perspectives on RNA m1A Methylation: Biological Processes and Pathological Consequences.},
journal = {Journal of applied toxicology : JAT},
volume = {},
number = {},
pages = {},
doi = {10.1002/jat.4981},
pmid = {41204697},
issn = {1099-1263},
support = {2023A1515010353//Natural Science Foundation of Guangdong Province of China/ ; 2025A1515012372//Natural Science Foundation of Guangdong Province of China/ ; （R2022PY-QY004）//Special Fund for Scientific Innovation Strategy-Construction of High-level Academy of Agriculture Science/ ; 2023B1212060038//Science and Technology Plan Project of Guangdong Province/ ; },
abstract = {RNA N1-methyladenosine (m1A) methylation is dynamically regulated by methyltransferases (TRMT6/61/61B/10C), demethylases (ALKBH1/3), and binding proteins (YTHDF1/2/3), which collectively fine-tune gene expression through site-specific modifications. Exogenous environmental factors such as persistent organic pollutants, heavy metals, and radiation can trigger cellular oxidative stress and stimulate the secretion of reactive oxygen species and senescence-associated secretory phenotypes. The concurrent accumulation of these damaging agents, along with dysregulation of intracellular conditions including temperature, pH, and divalent metal ion concentrations under pathological states, disrupts m1A methylation and alters the expression of associated genes, ultimately leading to adverse cellular outcomes. In addition, we searched a large number of literature and found that m1A methylation exhibits elevated levels in neurodegeneration, ischemia-reperfusion injury, and hepatocellular and bladder cancer, whereas decreased levels are observed in Alzheimer's disease and myocardial infarction. Correspondingly, methyltransferases and binding proteins involved in m1A modification are generally upregulated across multiple disease contexts. We propose that m1A methylation serves as a molecular sensor for environmental-cell interactions, dynamically regulating gene expression through regulators and exerting bidirectional control in disease processes. Given its regulatory versatility, m1A modification holds promise for applications in toxicological risk assessment, precision medicine, and the development of targeted therapies against exogenous factor-induced pathologies.},
}

@article {pmid41204665,
year = {2025},
author = {Pallbo, J and Linse, S and Olsson, U},
title = {Does amyloid fibril nucleation occur at surfaces only?.},
journal = {Biophysical journal},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.bpj.2025.11.002},
pmid = {41204665},
issn = {1542-0086},
abstract = {The Aβ42 peptide (APP(672-713)), associated with Alzheimer's disease, is highly prone to form amyloid fibrils and has been extensively studied through in vitro experiments. Such experiments represent a basis for understanding the biophysical chemistry of amyloid-related diseases. In this communication we show that homogeneous primary nucleation in vitro of Aβ42 fibrils is a very rare event, implying that primary nucleation occurs almost exclusively at interfaces, by heterogeneous nucleation. Recognizing that the protein molecules in amyloid fibrils possess a two-dimensional fold, we discuss the nucleation in relation to protein folding and Levinthal's paradox. In the much more rapid heterogeneous nucleation, we suggest that one catalyzing effect is the significant reduction of the effective conformational space when a monomer polypeptide chain (strongly) adsorbs to a surface, facilitating its search for the target fold.},
}

@article {pmid41204331,
year = {2025},
author = {Choe, K and Ahmad, R and Kang, MH and Lee, HJ and Ahmad, S and Park, TJ and Kim, MO},
title = {The novel sphingolipids cP1P and P1P attenuate neuroinflammation and enhance S1PR1/Akt/mTOR signaling to mitigate cognitive decline in an Alzheimer's disease mouse model.},
journal = {Cell communication and signaling : CCS},
volume = {23},
number = {1},
pages = {482},
pmid = {41204331},
issn = {1478-811X},
support = {RS-2024-00441331//National Research Foundation of Korea/ ; },
mesh = {Animals ; *Alzheimer Disease/drug therapy/metabolism/pathology/complications ; Male ; *Sphingosine-1-Phosphate Receptors/metabolism ; Mice ; Disease Models, Animal ; *Cognitive Dysfunction/drug therapy/metabolism/pathology ; *Proto-Oncogene Proteins c-akt/metabolism ; *Signal Transduction/drug effects ; *TOR Serine-Threonine Kinases/metabolism ; *Sphingolipids/pharmacology/therapeutic use ; Mice, Inbred C57BL ; Amyloid beta-Peptides ; *Neuroinflammatory Diseases/drug therapy/pathology/metabolism ; Sphingosine/analogs & derivatives/pharmacology ; },
abstract = {BACKGROUND: Alzheimer's disease (AD) is the leading cause of dementia, characterized by the accumulation of amyloid-βeta (Aβ) peptides and hyperphosphorylated tau protein. Altered sphingosine 1-phosphate (S1P) metabolism is associated with abnormal Aβ peptide accumulation in the brain. S1P receptors are increasingly being targeted for modulating the neuroinflammatory process in AD.

METHODS: Wild-type male C57BL/6J mice were administered Aβ to induce the pathological state. The study included four experimental groups: (1) Control group (saline-treated), (2) Aβ group (Aβ + saline-treated), (3) Aβ + cP1P group (Aβ + cP1P at doses of 0.1 mg/kg and 1 mg/kg), and (4) Aβ+ P1P group (Aβ + P1P at doses of 0.1 mg/kg and 1 mg/kg). Behavioral experiments were conducted to assess cognitive and memory functions. Additionally, western blotting and confocal microscopy were performed to investigate molecular and cellular changes.

RESULTS: The findings demonstrate that administration of S1P analogs cP1P and P1P at 0.1 mg/kg and 1 mg/kg significantly reduced Aβ burden by inhibiting the amyloidogenic pathway and decreasing hyperphosphorylated tau protein levels in the mouse brain. Additionally, cP1P and P1P inhibited glial cell activation, as indicated by reduced GFAP and Iba-1 expression, and modulated neuroinflammatory markers, including p-NF-κB, TNF-α, and IL-1β. Furthermore, they regulated S1PR1-mediated Akt/mTOR signaling while preserving mitochondrial function by decreasing the expression levels of p-JNK, Caspase-3, and PARP-1. Moreover, the cP1P and P1P effectively restored synaptic markers such as PSD-95, SNAP-25, and Syntaxin, and significantly improved behavioral outcomes in the Aβ-treated mice. In vitro, results also demonstrated that the novel cP1P and P1P enhanced cell viability against Aβ toxicity.},
}

Animals
*Alzheimer Disease/drug therapy/metabolism/pathology/complications
Male
*Sphingosine-1-Phosphate Receptors/metabolism
Mice
Disease Models, Animal
*Cognitive Dysfunction/drug therapy/metabolism/pathology
*Proto-Oncogene Proteins c-akt/metabolism
*Signal Transduction/drug effects
*TOR Serine-Threonine Kinases/metabolism
*Sphingolipids/pharmacology/therapeutic use
Mice, Inbred C57BL
Amyloid beta-Peptides
*Neuroinflammatory Diseases/drug therapy/pathology/metabolism
Sphingosine/analogs & derivatives/pharmacology

@article {pmid41204243,
year = {2025},
author = {Schechter, M and Fishkin, A and Mosenzon, O and Sehtman-Shachar, DR and Cukierman-Yaffe, T and Leibowitz, G and Aharon-Hananel, G},
title = {Neurodegeneration onset with glucagon-like peptide-1 receptor agonists in people with type 2 diabetes: a real-world multinational cohort study.},
journal = {Cardiovascular diabetology},
volume = {24},
number = {1},
pages = {426},
pmid = {41204243},
issn = {1475-2840},
mesh = {Humans ; Female ; Male ; *Diabetes Mellitus, Type 2/drug therapy/diagnosis/epidemiology/blood ; *Glucagon-Like Peptide-1 Receptor Agonists ; Retrospective Studies ; Middle Aged ; Aged ; *Neurodegenerative Diseases/epidemiology/diagnosis/prevention & control ; Risk Factors ; *Dipeptidyl-Peptidase IV Inhibitors/therapeutic use/adverse effects ; *Incretins/therapeutic use/adverse effects ; Time Factors ; Treatment Outcome ; Risk Assessment ; Biomarkers/blood ; *Blood Glucose/drug effects/metabolism ; *Hypoglycemic Agents/therapeutic use/adverse effects ; Electronic Health Records ; Glucagon-Like Peptide-1 Receptor ; },
abstract = {BACKGROUND: Type 2 diabetes (T2D), affecting approximately 12% of the global population and over 30% of older adults, is among the most prevalent and fast-growing risk factors for neurodegenerative disorders. Evidence is lacking on whether specific glucose-lowering agents may reduce the risk of neurodegeneration onset in people living with T2D.

METHODS: In this retrospective cohort study, we utilized the TriNetX platform, which contains electronic health records of over 170 million people worldwide. We propensity-score matched (1:1) people with T2D lacking evidence of neurodegeneration who initiated glucagon-like peptide-1 receptor agonists (GLP-1 RAs) or dipeptidyl peptidase-4 inhibitors (DPP4i) (2010-2021). In a separate analytical cohort, we compared individuals initiating GLP-1 RA with those initiating basal insulin. Follow-up continued for ≤ 5 years. We used Cox proportional-hazard regression models to assess the risk of the composite outcome of developing new neurodegenerative conditions, including Alzheimer's disease, Parkinson's disease, dementia subtypes, and other synucleinopathies. We also assessed each component individually. Analyses were repeated among subgroups defined by sex, age, and the specific GLP-1 RA initiated.

RESULTS: Overall, 214,442 matched individuals initiated GLP-1 RAs or DPP4i (109,731 women, mean age 58.6 years [SD 12], and mean HbA1c 7.7% [1.4]). During a 4.0-year mean follow-up, neurodegenerative disorder onset occurred in 2,393 (2.2%) and 3,062 (2.9%) people initiating GLP-1 RAs and DPP4i, respectively (hazard ratio of 0.81 [95% CI 0.77 to 0.86]; absolute risk difference - 0.6% [- 0.8 to - 0.5]). The associations were separately observed among women (0.78 [0.72 to 0.84]) and men (0.90 [0.83 to 0.98]), individuals aged ≥ 65 years old (0.82 [0.78 to 0.87]) or < 65 years old (0.84 [0.70 to 1.00]), and in those initiating semaglutide (0.75 [0.67 to 0.84]), liraglutide (0.77 [0.70 to 0.84]), or dulaglutide (0.82 [0.77 to 0.88]). The hazard ratios for dementia, Alzheimer's disease, vascular dementia, and Parkinson's disease onset were 0.76 [0.72 to 0.81], 0.77 [0.68 to 0.87], 0.75 [0.67 to 0.85], and 1.04 [0.93 to 1.17] with GLP-1 RAs versus DPP4i, respectively. The results were in the same direction when comparing individuals initiating GLP-1 RAs with those initiating basal insulin.

CONCLUSIONS: In a real-world cohort of people living with T2D with a multinational representation, the initiation of GLP-1 RAs, compared to DPP4i or basal insulin, was associated with a lower risk of new-onset neurodegeneration. These data support the rationale for dedicated clinical trials to assess the potential neuroprotective properties of GLP-1 RAs in this population.},
}

Humans
Female
Male
*Diabetes Mellitus, Type 2/drug therapy/diagnosis/epidemiology/blood
*Glucagon-Like Peptide-1 Receptor Agonists
Retrospective Studies
Middle Aged
Aged
*Neurodegenerative Diseases/epidemiology/diagnosis/prevention & control
Risk Factors
*Dipeptidyl-Peptidase IV Inhibitors/therapeutic use/adverse effects
*Incretins/therapeutic use/adverse effects
Time Factors
Treatment Outcome
Risk Assessment
Biomarkers/blood
*Blood Glucose/drug effects/metabolism
*Hypoglycemic Agents/therapeutic use/adverse effects
Electronic Health Records
Glucagon-Like Peptide-1 Receptor

@article {pmid41204236,
year = {2025},
author = {Li, L and Yang, H and Yu, L and Zhou, Y and Xiao, S and Bian, G and Zhu, F},
title = {The independent association of social isolation and loneliness with cognitive frailty in Chinese older adults: a cross-sectional study.},
journal = {BMC public health},
volume = {25},
number = {1},
pages = {3860},
pmid = {41204236},
issn = {1471-2458},
support = {2024J367//General Program of Ningbo Municipal Natural Science Foundation/ ; PPXK2024-07//Ningbo Medical and Health Brand Discipline/ ; 2022-F28//Ningbo Medical & Health Leading Academic Discipline Project/ ; 2022030410//Ningbo Top Medical and Health Research Program/ ; 2022030410//Ningbo Top Medical and Health Research Program/ ; },
mesh = {Humans ; *Loneliness/psychology ; *Social Isolation/psychology ; Aged ; Female ; Male ; Cross-Sectional Studies ; China/epidemiology ; *Frail Elderly/statistics & numerical data/psychology ; Aged, 80 and over ; *Frailty/epidemiology ; *Cognitive Dysfunction/epidemiology ; Surveys and Questionnaires ; Risk Factors ; East Asian People ; },
abstract = {BACKGROUND: Cognitive frailty (CF) is a distinct clinical phenotype characterized by the co-occurrence of physical frailty and cognitive impairment (excluding Alzheimer's disease and other forms of dementia). Both of social isolation and loneliness are risk factors for cognitive frailty in older adults. However, limited research has explored their independent and combined associations with CF.

METHODS: A multi-stage cluster sampling approach was employed to recruit adults aged ≥ 65 years from communities in Ningbo. Basic demographic and health-related information was collected through face-to-face interviews using self-reported questionnaires. CF was defined as the co-occurrence of physical frailty, assessed using the FRAIL scale, and cognitive impairment, evaluated with the Brief Screening Scale for Dementia. Social isolation and loneliness were assessed using standardized questions. Logistic regression was employed to examine their associations with CF, and multiplicative and additive interactions were analyzed to assess potential interaction effects.

RESULTS: Overall, 10,151 older adults with a mean age of 72.83 years were included in our study. The prevalence of social isolation, loneliness and CF were 32.3%, 11.8% and 7.22%. After adjusting for covariates, social isolation (odds ratio [OR] = 1.325, 95% confidence interval [CI]: 1.106-1.586) and loneliness (OR = 1.492, 95% CI: 1.196-1.862) were independently associated with CF. However, social isolation and loneliness showed no multiplicative or additive interaction effects on CF (Both P > 0.05).

CONCLUSION: Social isolation and loneliness are independently associated with CF in Chinese older adults, highlighting the necessity of implementing effective and feasible interventions to concurrently address both factors in the prevention of CF among the elderly population.},
}

Humans
*Loneliness/psychology
*Social Isolation/psychology
Aged
Female
Male
Cross-Sectional Studies
China/epidemiology
*Frail Elderly/statistics & numerical data/psychology
Aged, 80 and over
*Frailty/epidemiology
*Cognitive Dysfunction/epidemiology
Surveys and Questionnaires
Risk Factors
East Asian People

@article {pmid41204210,
year = {2025},
author = {Afxenti, S and Zachariou, M and Athieniti, E and Lambrianides, A and Pantzaris, M and Spyrou, GM},
title = {Integrating imaging and omics for enhanced subtyping of mild cognitive impairment associated with Alzheimer's disease.},
journal = {Journal of translational medicine},
volume = {23},
number = {1},
pages = {1240},
pmid = {41204210},
issn = {1479-5876},
support = {This research was supported by the Muscular Dystrophy Association Cyprus/Telethon Cyprus.//This research was supported by the Muscular Dystrophy Association Cyprus/Telethon Cyprus./ ; },
mesh = {Humans ; *Cognitive Dysfunction/diagnostic imaging/complications/classification ; *Alzheimer Disease/diagnostic imaging/complications/cerebrospinal fluid ; Male ; *Neuroimaging ; Female ; Aged ; Magnetic Resonance Imaging ; *Proteomics ; Biomarkers/metabolism ; Cluster Analysis ; },
abstract = {BACKGROUND: Mild Cognitive Impairment (MCI), considered the prodromal stage of Alzheimer's disease (AD), is a heterogeneous condition characterised by mild but measurable cognitive decline. However, not all individuals with MCI follow the same trajectory-some remain stable, while others progress rapidly to AD. Understanding variation in clinical, molecular, and imaging features is crucial for reducing disease heterogeneity, improving prognosis, and developing targeted interventions. This study aims to increase MCI subtyping resolution by generating enriched individual-level profiles through the integration of imaging and omics data, facilitating precision medicine approaches for AD prevention and treatment.

METHODS: We used data from the Alzheimer's Disease Neuroimaging Initiative (ADNI), including structural MRI, CSF peptidomics/proteomics, and clinical indices. Using a multi-modal integration and clustering framework, we identified distinct MCI subgroups, characterised by clinical and neuropsychological scores, AD biomarkers, biological pathway enrichments, and imaging patterns. We further employed supervised multi-modal integration and correlation analyses to explore the links between imaging, peptidomic/proteomic and clinical features within each subgroup. Additionally, we labelled individuals by future conversion to AD and analysed longitudinal cognitive function (CDRSB and MMSE scores). Finally, we performed in silico drug repurposing to identify candidate drugs targeting each subgroup's molecular profile.

RESULTS: (1) Multi-modal integration revealed two distinct MCI subgroups. (2) The Resilient Neuronal Hyperplasticity subgroup was characterised by elevated markers of neuronal plasticity, minimal brain atrophy and cortical thinning, better clinical scores, and upregulated peptide/protein markers associated with less severe structural changes. In contrast, the Vulnerable Neurodegenerative subgroup exhibited AD-like disturbances, pronounced atrophy and cortical thinning, primarily affecting executive functions, and downregulation of peptide/protein markers linked to significant structural changes. (3) Future conversion analysis revealed the second subgroup predominantly comprised fast converters, while the first predominantly consisted of stable individuals. (4) Longitudinal cognitive analysis showed a more pronounced decline in the second subgroup compared to the first. (5) Drug repurposing identified both shared and subgroup-specific candidate compounds aligned with the underlying pathologies.

CONCLUSIONS: This study delineates two MCI subgroups, using multi-modal integration, offering insights into disease heterogeneity and laying the foundation for precision medicine and AI-driven strategies in MCI and AD research and clinical care.},
}

Humans
*Cognitive Dysfunction/diagnostic imaging/complications/classification
*Alzheimer Disease/diagnostic imaging/complications/cerebrospinal fluid
Male
*Neuroimaging
Female
Aged
Magnetic Resonance Imaging
*Proteomics
Biomarkers/metabolism
Cluster Analysis

@article {pmid41203949,
year = {2025},
author = {Feng, X and Zhao, X and Zhang, L},
title = {Innovative D-peptide strategy for targeting tau fibrils in Alzheimer's disease.},
journal = {Science China. Life sciences},
volume = {},
number = {},
pages = {},
pmid = {41203949},
issn = {1869-1889},
}

@article {pmid41203876,
year = {2025},
author = {Chirmade, S and Wang, Z and Mastromatteo, S and Sanders, E and Thiruvahindrapuram, B and Nalpathamkalam, T and Pellecchia, G and Lin, F and Keenan, K and Patel, RV and Sung, WW and Roshandel, D and Whitney, J and Allana, S and Avolio, J and Eckford, PD and Ratjen, F and Strug, LJ},
title = {GWAS SVatalog: a visualization tool to aid fine-mapping of GWAS loci with structural variations.},
journal = {Heredity},
volume = {},
number = {},
pages = {},
pmid = {41203876},
issn = {1365-2540},
abstract = {Genome-wide association studies (GWAS) have been successful in identifying single nucleotide polymorphisms (SNPs) associated with phenotypic traits. However, SNPs form an incomplete set of variation across the genome and since a large percentage of GWAS-significant SNPs lie in non-coding regions, their impact on a given trait is difficult to decipher. Recognizing whether these SNPs are tagging other polymorphisms, like structural variations (SV), is an important step towards understanding the putative causal variation at GWAS loci. Here, we develop GWAS SVatalog (https://svatalog.research.sickkids.ca/), a novel open-source web tool that computes and visualizes linkage disequilibrium (LD) between SVs and GWAS-associated SNPs throughout the human genome. The tool combines GWAS Catalog's SNP-trait association data across 14,479 phenotypes with LD statistics calculated between 35,732 SVs and 116,870 SNPs identified in 101 whole-genome long-read sequences. We show that different SV types are more likely to overlap regulatory features, and that SVs less directly tagged by GWAS-associated SNPs more frequently overlap CpG islands and promoters. We use GWAS SVatalog to identify SVs that may explain GWAS loci for iron levels, refractive error, and Alzheimer's disease, where previously SNPs were unable to provide a causal explanation. GWAS SVatalog advances the fine-mapping of GWAS loci with structural variations, enabling researchers to associate 35,732 common SVs with 14,479 phenotypes, accelerating the understanding of disease etiology.},
}

@article {pmid41203507,
year = {2025},
author = {Zhang, YP and Kedia, S and Klenerman, D},
title = {Rethinking neurodegeneration through a co-proteinopathy lens.},
journal = {Trends in neurosciences},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.tins.2025.10.006},
pmid = {41203507},
issn = {1878-108X},
abstract = {Neurodegenerative diseases have long been considered distinct proteinopathies: amyloid-β and tau in Alzheimer's disease, α-synuclein in Parkinson's disease, and TDP-43 in amyotrophic lateral sclerosis. This single-protein paradigm has guided therapeutic development for decades; yet clinical outcomes remain modest. Mounting evidence, however, reveals that protein aggregates rarely occur in isolation; instead, they coexist, colocalise, and modulate each other's pathogenicity. Here, we propose a co-proteinopathy framework that views neurodegeneration as an interactive network of misfolded proteins rather than as isolated disorders. Adopting this framework demands multiplexed quantification of protein aggregates and disease models that better reflect the biological complexity of human neurodegeneration. The co-proteinopathy perspective offers a more realistic foundation for next-generation approaches to neurodegeneration research and treatment.},
}

@article {pmid41202963,
year = {2025},
author = {Padhy, DS and Dhanve, P and Chaturvedi, K and Banerjee, S},
title = {Ambroxol rescues cognitive impairment by ameliorating oxidative stress and autophagic dysfunction in the streptozotocin-induced Alzheimer's disease model.},
journal = {European journal of pharmacology},
volume = {},
number = {},
pages = {178334},
doi = {10.1016/j.ejphar.2025.178334},
pmid = {41202963},
issn = {1879-0712},
abstract = {Alzheimer's disease (AD) is the most prevalent neurodegenerative disease, contributing to the majority of dementia cases worldwide. Due to its multifaceted and complex pathogenesis, drugs that completely halt the disease progression are still elusive. Several reports suggest that repurposing a clinically approved drug could be an excellent strategy to tackle this devastating disease. Ambroxol, a US-FDA and EMA-approved generic mucolytic drug, possess ameliorative action on various neurological ailments. However, its role as a disease-modifying drug targeting AD is yet to be studied. In this study, we elucidate the therapeutic potential of ambroxol in the streptozotocin (STZ)-induced AD model by assessing the behavioural, biochemical, and histological parameters. Intracerebroventricular (ICV) administration of STZ (3 mg/kg) was performed to mimic the AD pathology in rats. Ambroxol was administered (p.o.) at doses of 500 and 1000 mg/kg for three weeks. On day 21, behavioural tests, including the Y-maze test, novel object recognition test, and passive avoidance test, were performed to assess memory function. Subsequently, the animals were euthanised and the hippocampus was collected for biochemical, molecular and histological analysis. Three weeks of ambroxol treatment improved the cognitive performance in ICV-STZ-treated rats. Ambroxol treatment reduces oxidative stress by upregulating heme oxygenase-1 (HO-1) and lowering inducible nitric oxide synthase (iNOS) levels in the hippocampus of diseased rats. It also attenuates inflammatory and autophagic dysfunction, facilitating the clearance of amyloid beta (Aβ) aggregates in the hippocampus of ICV-STZ rats. The findings of this study suggest that ambroxol could be a viable repurposed drug candidate for AD treatment.},
}

@article {pmid41202949,
year = {2025},
author = {Prešern, U and Goličnik, M and Bavec, A},
title = {Genetic and functional dynamics of Butyrylcholinesterase in Alzheimer's disease: From mechanisms to clinical relevance.},
journal = {Chemico-biological interactions},
volume = {423},
number = {},
pages = {111809},
doi = {10.1016/j.cbi.2025.111809},
pmid = {41202949},
issn = {1872-7786},
abstract = {Butyrylcholinesterase (BChE), once regarded as a redundant cholinesterase, has emerged as an important modulator of Alzheimer's disease (AD). Unlike acetylcholinesterase (AChE), which declines during disease progression, BChE activity is preserved or elevated in the AD brain and becomes the predominant cholinesterase in advanced stages. Beyond its enzymatic role in acetylcholine hydrolysis, BChE is directly associated with amyloid plaques and tau pathology and has been implicated in neuroinflammatory processes. Genetic variants of the BCHE gene, most notably the K-variant, further contribute to inter-individual differences in AD susceptibility, disease onset, and therapeutic response, particularly in the context of APOE4. Evidence from biochemical, histological, and clinical studies indicates that BChE influences both the pathophysiology of AD and the effectiveness of cholinesterase inhibitor therapy, with rivastigmine providing unique benefits through dual AChE and BChE inhibition. Recent efforts to develop selective or multitarget BChE inhibitors underscore the enzyme's potential as a therapeutic target, while BChE-specific positron emission tomography tracers highlight its diagnostic promise by distinguishing AD-related amyloid plaques from those of normal aging. Despite these advances, uncertainties remain regarding the precise dynamics of BChE activity across disease stages, its contribution to plaque maturation and inflammation, and its influence on responses to novel anti-amyloid antibody therapies. Overall, BChE represents a multifaceted factor in AD pathogenesis, therapy, and biomarker development, warranting further genotype-stratified and mechanistic investigations to clarify its clinical utility.},
}

@article {pmid41202930,
year = {2025},
author = {Dong, W and Bai, J and Wu, B and Zhou, K and Jiang, H},
title = {Incidence and synergistic Association of Type 2 diabetes and apolipoprotein E epsilon 4 with dementia risk in the Kunshan aging research with E-health cohort study.},
journal = {Preventive medicine},
volume = {},
number = {},
pages = {108439},
doi = {10.1016/j.ypmed.2025.108439},
pmid = {41202930},
issn = {1096-0260},
abstract = {OBJECTIVE: To investigate the independent and combined associations of type 2 diabetes (T2D) and APOE genotype on dementia risk.

METHODS: We analyzed 104,911 participants aged ≥50 years from the Kunshan Aging Research with E-Health cohort (2018-2024). Incident dementia was identified using electronic medical records. Cox proportional hazards models and additive interaction analyses assessed associations and interactions.

RESULTS: Over a median follow-up of 6.19 years, 8115 participants developed dementia. T2D was associated with higher risks of all-cause dementia (HR:2.06), Alzheimer's disease (HR:2.16), and vascular dementia (HR:1.62). APOE ε4 carriers had higher Alzheimer's risk (HR:1.35), while ε2 carriers had lower risk (HR:0.87). The combination of T2D and ε4 was associated with the highest Alzheimer's risk (HR:2.87) with a significant positive additive interaction. In men, T2D interacted with ε2 on a multiplicative scale, whereas in women, a positive additive interaction was observed between T2D and ε2 for Alzheimer's disease.

CONCLUSIONS: T2D was associated with higher dementia risk. APOE ε4 was associated with higher and ε2 with lower Alzheimer's risk. A positive additive T2D-ε4 interaction and sex-specific ε2 associations underscore integrating diabetes management with genetic profiling to optimize dementia risk reduction strategies.},
}

@article {pmid41202895,
year = {2025},
author = {Gupta, G and Ali, H and Singh, SK and Dua, K and Jha, SK},
title = {Exploring the Causal Relationship between Telomere Regulation, Aging and Neurological Disorders.},
journal = {Ageing research reviews},
volume = {},
number = {},
pages = {102930},
doi = {10.1016/j.arr.2025.102930},
pmid = {41202895},
issn = {1872-9649},
abstract = {Telomere biology is important for aging and is the cause of the pathogenesis of many neurological disorders, including Alzheimer's disease (AD), Parkinson's disease (PD), multiple sclerosis (MS), stroke, and brain tumors. Telomere shortening is considered to play a role in neurodegeneration, immune senescence, and cerebrovascular dysfunction. Shorter leukocyte telomere length (LTL) is associated with increased risk and severity of stroke, poorer cognitive outcomes in AD, and increased neuroinflammation in MS, highlighting a possible biomarker for disease progression. Glioblastoma and medulloblastoma are characterized as adult and childhoodd neoplasms,respectively; however they aree similarinn terms of telomere regulatio,nwhicht allows malignant growth. However, disease pathophysiology has been associated with telomere dynamics, oxidative stress, and neuroinflammation, but the causal association between telomere attrition and neurological disorders is still unclear. In studies of Mendelian randomization, neurodegenerative diseases have been associated with telomere length regulation in addition to telomere attrition. Approaches to target telomeres include telomerase activators for neuroprotection, telomerase inhibitors, and ALT-directed therapies for brain tumors. These telomere-derived biomarkers should be further refined, and their mechanistic links to the acceleration of neurodegeneration should be determined. Telomere-modifying therapies should be balanced to optimize benefits with minimal oncogenic risks. This review explores the causal relationship between telomere biology, aging, and neurological disorders, indicating novel therapeutic strategies and future directions in telomere research.},
}

@article {pmid41202775,
year = {2025},
author = {Long, X and Zhang, Z and Wen, S and Mo, L and Lin, J and Xu, M and , },
title = {Longitudinal trajectories of neuropsychological functions of MCI subtypes in population-based cohort of older adults.},
journal = {Asian journal of psychiatry},
volume = {114},
number = {},
pages = {104757},
doi = {10.1016/j.ajp.2025.104757},
pmid = {41202775},
issn = {1876-2026},
abstract = {OBJECTIVES: To identify different mild cognitive impairment (MCI) subtypes depending on overall cognitive function and daily function, and then describe the complex changes of neuropsychological functions in MCI subtypes over time.

METHODS: 815 MCI participants were recruited from the Alzheimer's Disease Neuroimaging Initiative (ADNI) at baseline. Data-driven MCI subtypes were obtained on the basis of group-based multi-trajectory modeling (GBMTM) to analyze longitudinal trajectory changes in overall cognitive function and daily function. Neuropsychological functions were characterized in terms of longitudinal trajectory changes by linear mixed models.

RESULTS: This study included MCI subjects with an average age of 73.71 ± 6.85 years (range: 60-91 years), of whom 77.7 % were married. Three data-driven subtypes of MCI were obtained through the GBMTM modeling, defined as the "Rapid cognitive decline group" (RCD, 15.5 %), the "Slow cognitive decline group" (SCD, 34.4 %), and the "No cognitive decline group" (NCD, 50.1 %). The RCD individuals had the greatest mean age (75.22 years) at baseline, the most APOE ε4 carriage (66.4 %), the highest dementia conversion rates (89.6 %) and the shortest time to dementia progression (10.41 months). Importantly, the fastest changes in neuropsychological function trajectories were observed in the RCD subtype during the first 36 months, with attention declining the fastest, followed by visuospatial function, whereas the slowest changes were detected in the NCD subtype.

CONCLUSION: MCI subjects may produce finer-grained cognitive subtypes with unique longitudinal neuropsychological function declines. Identifying the above may improve prediction of clinical course, which has important implications for providing more accurate risk assessment for MCI individuals.},
}

@article {pmid41202483,
year = {2025},
author = {Yuan, C and Li, L and Lin, HY and Aubry, AV and Parise, LF and Morel, C and Chen, F and Wong, J and Russo, SJ and Wang, J},
title = {Targeting neuronal activity and neuroinflammation for the treatment of Alzheimer's disease in a mouse model.},
journal = {Neurobiology of aging},
volume = {157},
number = {},
pages = {111-118},
doi = {10.1016/j.neurobiolaging.2025.10.006},
pmid = {41202483},
issn = {1558-1497},
abstract = {Alzheimer's disease (AD) is characterized by progressive cognitive decline driven by complex pathological processes, including tau hyperphosphorylation (p-Tau), amyloid-beta (Aβ) accumulation, and neuroinflammation. In this study, we investigated the effects of two bioactive compounds, dihydrocaffeic acid (DHCA) and malvidin-glucoside (Mal-gluc), targeting inflammation and neuronal activity, respectively, on cognitive function and AD pathology in a mouse model of AD. Our results demonstrate that chronic DHCA/Mal-gluc treatment significantly improves recognition memory in 3xTg-AD mice without reducing p-Tau or Aβ burden. Employing a newly developed whole-brain cFOS and IBA-1 mapping technique, we found that this combination treatment enhances neuronal activity and promotes microglial homeostasis across multiple brain regions in 3xTg-AD mice. These findings underscore the potential of restoring neuronal function and immune homeostasis as a therapeutic approach for AD. Future study will explore the underlying mechanisms and evaluate whether DHCA/Mal-gluc, combined with currently approved Aβ monoclonal therapy, can synergistically prevent or delay AD onset and progression.},
}

@article {pmid41202479,
year = {2025},
author = {Samsami, S and Parvar, MD and Mehralitabar, H and Dehghanbanadaki, N and Naderi-Manesh, H},
title = {In silico investigation of CNS-11 as a potential inhibitor of Aβ42 aggregation and its protofibril disassembly.},
journal = {Biochemical and biophysical research communications},
volume = {790},
number = {},
pages = {152899},
doi = {10.1016/j.bbrc.2025.152899},
pmid = {41202479},
issn = {1090-2104},
abstract = {Amyloidogenic peptide aggregation and fibril formation are key components in neurodegenerative diseases such as Alzheimer's disease (AD). One effective strategy for treating these conditions involves preventing amyloid peptide aggregation by using interfering agents, such as small molecules, at the onset of amyloid peptide assembly. Another approach could involve destabilizing the formed fibrils using small molecules as well. In this study, we utilized both all-atom and coarse-grained molecular dynamics (MD) simulation methods to investigate the aggregation mechanistic details of amyloid-β42 (Aβ42) peptides, the impact of CNS-11 (a small molecule inhibitor with proven Tau fibrils decomposing agent) on this Aβ42 aggregation, and the destabilization effect of CNS-11 on an Aβ42 fiber section, alongside the Aβ42 fiber section itself. Our results demonstrated that Aβ42 monomers in the free state strongly tend to dimerize and form beta-sheets by integrating the hydrophobic sections of the Aβ42 peptides. Still, as CNS-11 was added to the system, the ligand formed a hydrophobic core composed of CNS-11 and Aβ42 peptides surrounding this core, resulting in an amorphous and significantly disordered structure. Additionally, CNS-11 could interact with the Aβ42 pre-formed fiber section, partially destabilizing it through interactions with the buried hydrophobic core. Moreover, simulating the Aβ42 fiber section revealed that the N-terminal region of these peptide aggregates is naturally flexible and capable of becoming disorganized even without the addition of external disrupting agents. This study provides comprehensive insights into the molecular-level mechanisms underlying the dual effects of CNS-11 on amyloid beta aggregation and fibril degradation. This study can provide a computational framework with the potential to be applied to various small molecules, exploring their potential in the prevention and treatment of Alzheimer's disease.},
}

@article {pmid41202432,
year = {2025},
author = {Belviranlı, M and Okudan, N and Sezer, T},
title = {Exercise upregulates Mitsugumin 53 and ameliorates behavioral deficits and mitochondrial biogenesis in a sporadic Alzheimer's disease model in rats.},
journal = {Archives of gerontology and geriatrics},
volume = {141},
number = {},
pages = {106078},
doi = {10.1016/j.archger.2025.106078},
pmid = {41202432},
issn = {1872-6976},
abstract = {Chronic physical exercise is a promising non-pharmacological strategy to mitigate the progression of Alzheimer's disease (AD), yet the underlying molecular mechanisms remain incompletely understood. This study investigated the effects of chronic treadmill exercise on behavioral deficits and key molecular pathways in a d-galactose and AlCl3-induced rat model of sporadic AD. Animals were assigned to control, AD, exercise and AD + exercise (AE) groups for a ten-week intervention. Behavioral assessments included the elevated plus maze and Morris Water Maze, followed by molecular and biochemical analyses (RT-qPCR, ELISA) of the hippocampus, skeletal muscle, and plasma. Our results demonstrate that the AD model induced profound cognitive impairments, diminished locomotor activity, heightened anxiety-like behavior, and elevated plasma tau levels. These pathological changes were accompanied by a significant downregulation of the AMPK/SIRT1/PGC-1α mitochondrial biogenesis pathway and, notably, a marked suppression of the membrane repair protein Mitsugumin 53 (MG53) in both the hippocampus and skeletal muscle. The physical exercise regimen successfully ameliorated these behavioral deficits and normalized plasma tau. Mechanistically, physical exercise potently upregulated the AMPK/PGC-1α/FNDC5/BDNF axis in both central and peripheral tissues. Crucially, this study reveals for the first time that physical exercise also triggers a robust upregulation of MG53 at both the gene and protein levels in the brain, muscle, and circulation. These findings identify the physical exercise-induced mobilization of MG53 as a novel and powerful neuroprotective mechanism, linking systemic cellular repair capacity to the enhancement of cognitive resilience against AD.},
}

@article {pmid41202209,
year = {2025},
author = {Amirpour, A and Saarijärvi, M and Eckerblad, J and Markovic, G and Thorell, A and Nilsson, U and Bergman, L},
title = {Evaluation of a Digital, Self-Administered, Cognitive Test Battery in Older Adult Patients Undergoing Abdominal Surgery: Nonrandomized Feasibility Trial.},
journal = {JMIR formative research},
volume = {9},
number = {},
pages = {e71911},
doi = {10.2196/71911},
pmid = {41202209},
issn = {2561-326X},
mesh = {Humans ; Feasibility Studies ; Female ; Aged ; Male ; *Neuropsychological Tests/standards ; *Abdomen/surgery ; Aged, 80 and over ; Middle Aged ; Cognition ; Geriatric Assessment/methods ; },
abstract = {BACKGROUND: Older adults undergoing surgeries face increased risks of postoperative neurocognitive disorders, which impair cognitive functions. Analog neurocognitive tests are commonly used, but digital tests offer faster, more accessible assessments.

OBJECTIVE: The primary aim of this study was to evaluate the feasibility of a digital cognitive test battery in older adults undergoing abdominal surgery. Feasibility included estimation of recruitment and retention rates, acceptability, perceived value, and usability of the test. The secondary aim was to explore outcome trajectories of cognition, depression, functional status, and quality of recovery.

METHODS: This nonrandomized feasibility study measured recruitment and retention rates using patient logs and expanded on these findings in semistructured interviews with nurses. Acceptability, perceived value, and usability were explored through interviews with patients and nurses, and the System Usability Scale (SUS). Cognitive functions were assessed with a digital cognitive test battery (Consortium to Establish a Registry for Alzheimer Disease [CERAD] word list learning test, Trail Making Test Parts A and B, Victoria Stroop Test, and Symbol Digit Pairing Test) and the Nursing Delirium Screening scale (NU-DESC), and depression with the Geriatric Depression Scale (GDS-15). Functional status was measured using the World Health Organization Disability Assessment Schedule (WHODAS), and postoperative recovery with the Swedish Quality of Recovery questionnaire (SwQoR-24). Quantitative data were analyzed using descriptive statistics and nonparametric tests and qualitative data with content analysis.

RESULTS: The test battery was feasible, acceptable, and demonstrated excellent usability. The mean SUS score was 87 (SD 17.9; 95% CI 78.9-95.2), and all predefined progression criteria were met. Recruitment spanned over 1.5 years, during which 24 patients were included (mean age of 77, SD 6.5 years; range: 63-90 years; n=13, 54% women). Most patients underwent laparoscopic colorectal cancer surgery. Three patients developed postoperative delirium for 1 day only. No patient developed delayed neurocognitive recovery or mild/major neurocognitive disorder at the postoperative follow-up. Qualitative data showed that both nurses and patients regarded the digital cognitive test battery as important for assessing cognitive function and found it easy to use and understand. Nurses reported that recruitment was challenging, partly because not all patients attended a preoperative in-person consultation before surgery.

CONCLUSIONS: The digital, self-administered cognitive test battery was found to be feasible, acceptable, and usable in older adults undergoing abdominal surgery. However, recruitment challenges and a small, homogeneous sample limit generalizability and warrant careful consideration in a larger-scale study.},
}

Humans
Feasibility Studies
Female
Aged
Male
*Neuropsychological Tests/standards
*Abdomen/surgery
Aged, 80 and over
Middle Aged
Cognition
Geriatric Assessment/methods

@article {pmid41202177,
year = {2025},
author = {Arslan, B and Gobom, J and Andreasson, U and Gonzalez-Ortiz, F and Ashton, NJ and Zetterberg, H and Kvartsberg, H},
title = {Comparative analysis of plasma p-tau217 immunoassays: challenges for standardization and harmonization.},
journal = {Clinical chemistry and laboratory medicine},
volume = {},
number = {},
pages = {},
pmid = {41202177},
issn = {1437-4331},
}

@article {pmid41202143,
year = {2025},
author = {Ai, R and Mao, L and Jin, X and Campos-Marques, C and Zhang, SQ and Pan, J and Lagartos-Donate, MJ and Cao, SQ and Barros-Santos, B and Nóbrega-Martins, R and Katsaitis, F and Yang, G and Xie, C and Kang, X and Wang, P and Novello, M and Hu, Y and Bergersen, LH and Storm-Mathisen, J and Kuroyanagi, H and Escobar-Doncel, B and González, NV and Chaudhry, FA and Wang, Z and Zhang, Q and Lu, G and Sotiropoulos, I and Niu, Z and Chen, G and Nair, RR and Silva, JM and Luo, OJ and Fang, EF},
title = {NAD[+] reverses Alzheimer's neurological deficits via regulating differential alternative RNA splicing of EVA1C.},
journal = {Science advances},
volume = {11},
number = {45},
pages = {eady9811},
pmid = {41202143},
issn = {2375-2548},
mesh = {*Alzheimer Disease/genetics/metabolism/drug therapy/pathology ; Animals ; Humans ; *NAD/pharmacology/metabolism ; Mice ; *Alternative Splicing/drug effects ; Male ; Disease Models, Animal ; Female ; Hippocampus/metabolism ; Aged ; },
abstract = {Dysfunctional alternative splicing events (ASEs) in RNA are markers of aging and Alzheimer's disease (AD). As a key neuronal resilience metabolite, the oxidized nicotinamide adenine dinucleotide (NAD[+]) slows down AD progression in preclinical studies with several clinical trials ongoing. However, the underlying molecular mechanisms around how NAD[+] enhances neuronal resilience, especially whether it has any effect on ASEs, have remained elusive. This study shows that NAD[+] augmentation corrects the ASEs of many genes via a key protein, EVA1C (epithelial V-like antigen 1 homolog C), which is involved in neuronal development and activities. EVA1C is reduced in the hippocampus in patients with AD compared to cognitively normal ones. NAD[+]-induced memory retention is partially dependent on EVA1C, as adeno-associated virus-based Eva1c knockdown in the hippocampal CA1 region annuls NAD[+]-induced memory improvement in pathological Tau-bearing mice. We propose that NAD[+] reduces AD pathologies, at least partially, via amplification of the NAD[+]-EVA1C splicing axis, pointing to a potential splice-switching therapy for AD.},
}

*Alzheimer Disease/genetics/metabolism/drug therapy/pathology
Animals
Humans
*NAD/pharmacology/metabolism
Mice
*Alternative Splicing/drug effects
Male
Disease Models, Animal
Female
Hippocampus/metabolism
Aged

@article {pmid41202125,
year = {2025},
author = {Yang, R and Wang, L and Li, Y and Zhu, J and Wang, J and Schlessinger, D and Sima, J},
title = {DKK3-LRP1 complex and a chemical inhibitor regulate Aβ clearance in models of Alzheimer's disease.},
journal = {Science advances},
volume = {11},
number = {45},
pages = {eadz2099},
pmid = {41202125},
issn = {2375-2548},
mesh = {*Alzheimer Disease/metabolism/pathology/drug therapy/genetics ; Animals ; *Amyloid beta-Peptides/metabolism ; Humans ; Mice ; *Low Density Lipoprotein Receptor-Related Protein-1/metabolism/genetics ; Disease Models, Animal ; *Adaptor Proteins, Signal Transducing/metabolism ; *Intercellular Signaling Peptides and Proteins/metabolism/genetics ; *Chemokines/metabolism ; Mice, Transgenic ; Protein Binding ; Neurons/metabolism ; Astrocytes/metabolism ; },
abstract = {Impaired clearance of amyloid-β (Aβ) contributes to Alzheimer's disease (AD) pathogenesis, but its upstream modulators remain poorly defined. We report secreted Dickkopf (DKK) proteins-DKK1 through DKK4-as previously unrecognized ligands of low-density lipoprotein receptor-related protein 1 (LRP1), a principal Aβ clearance receptor. Analyses of cells derived from a patient with AD, postmortem tissue, and 5×FAD mice reveal that DKK1 and DKK3 are elevated in AD and reduce Aβ uptake and degradation in neurons and astrocytes. Mechanistically, DKKs inhibit Aβ clearance by competitively binding LRP1 and promoting its internalization. In 5×FAD mice, DKK3 overexpression worsens, while knockout improves, Aβ pathology and cognitive outcomes. A targeted high-throughput screen of ~3000 compounds identified SJ-300 as a potent and selective inhibitor of the DKK3-LRP1 interaction. SJ-300 restores Aβ clearance and rescues cognitive function and neuropathology in 5×FAD mice. These findings uncover DKK3-LRP1 axis as a contributor for Aβ metabolism and nominate SJ-300 as a promising therapeutic candidate for AD intervention.},
}

*Alzheimer Disease/metabolism/pathology/drug therapy/genetics
Animals
*Amyloid beta-Peptides/metabolism
Humans
Mice
*Low Density Lipoprotein Receptor-Related Protein-1/metabolism/genetics
Disease Models, Animal
*Adaptor Proteins, Signal Transducing/metabolism
*Intercellular Signaling Peptides and Proteins/metabolism/genetics
*Chemokines/metabolism
Mice, Transgenic
Protein Binding
Neurons/metabolism
Astrocytes/metabolism

@article {pmid41202124,
year = {2025},
author = {Di Lucente, J and Tena, J and Bai, Y and Shafer, CC and Mendiola, UR and Neumann, EK and Chen, X and Lebrilla, CB and Maezawa, I and Jin, LW},
title = {l-Fucose is a candidate monosaccharide neuromodulator and mitigates Alzheimer's synaptic deficits.},
journal = {Science advances},
volume = {11},
number = {45},
pages = {eadt4123},
pmid = {41202124},
issn = {2375-2548},
mesh = {*Alzheimer Disease/metabolism/pathology/drug therapy/physiopathology ; Animals ; *Fucose/metabolism/pharmacology ; Mice ; Humans ; Hippocampus/metabolism/drug effects ; Long-Term Potentiation/drug effects ; *Synapses/metabolism/drug effects/pathology ; *Neurotransmitter Agents/metabolism/pharmacology ; Synaptic Transmission/drug effects ; Disease Models, Animal ; Mice, Transgenic ; },
abstract = {Fucosylation, a major glycan modification, has been shown to influence neuronal and microglial mechanisms, but whether unconjugated free l-fucose can affect brain function is unknown. l-Fucose can be transported into cells and metabolized by fucokinase (FCSK) via the poorly understood salvage pathway. Using mouse hippocampal slices, we showed that l-fucose enhanced excitatory neurotransmission and long-term potentiation (LTP) through regulation of presynaptic release. Such effects required l-fucose be metabolized through the FCSK-driven salvage pathway, suggesting a metabolic-signaling mechanism. Human Alzheimer's disease (AD) and 5xFAD mouse brains showed signs of fucose hypometabolism with impaired l-fucose signaling. Such abnormalities were corrected by exogenous l-fucose, exemplified by rectification of LTP deficits in 5xFAD hippocampus. A dietary l-fucose supplement, which increased cerebral free l-fucose levels and up-regulated FCSK to drive the salvage pathway, mitigated synaptic and behavioral deficits of 5xFAD mice. Our data suggest an unrecognized neuromodulatory function of free l-fucose and reveals its therapeutic potential for AD.},
}

*Alzheimer Disease/metabolism/pathology/drug therapy/physiopathology
Animals
*Fucose/metabolism/pharmacology
Mice
Humans
Hippocampus/metabolism/drug effects
Long-Term Potentiation/drug effects
*Synapses/metabolism/drug effects/pathology
*Neurotransmitter Agents/metabolism/pharmacology
Synaptic Transmission/drug effects
Disease Models, Animal
Mice, Transgenic

@article {pmid41201943,
year = {2025},
author = {Yan, J and Ying, S and Du, S and Gao, Y},
title = {Graph Quality Matters on Revealing the Semantics behind the Data in Physical World.},
journal = {IEEE transactions on pattern analysis and machine intelligence},
volume = {PP},
number = {},
pages = {},
doi = {10.1109/TPAMI.2025.3630605},
pmid = {41201943},
issn = {1939-3539},
abstract = {The physical world is composed of graphs, such as the protein structures in life science, the patient relations in medical diagnosis, the user connections in social media, etc. Graphs help both build the world itself and understand the semantics behind the data for humans. However, how such graph structures work toward semantic representation is still unclear, where existing attempts focus on employing the graphs for special tasks. In this work, we first introduce two measures to evaluate graph quality, namely structural complexity and homophily. Structural complexity describes the quantity of graph structural information representing the graph structure's symmetry, and homophily describes the percentage of intra-class edges to quantify edge consistency. Using these two measures, we then discover the relationship between the graph quality and the corresponding performance for general tasks, that is the performance positively correlates with the structural complexity, and "J"-shaped correlates with homophily, which are proved mathematically. Based on these, we design a graph augmentation tool Graph+. Graph+ can enhance the natural graph structure and accordingly improve the general tasks. Empirical validation on tasks including Alzheimer's diagnosis and breast cancer subtype identification shows Graph+'s ability to improve both graph structure and task performance, revealing the underlying data semantics.},
}

@article {pmid41201919,
year = {2025},
author = {Serna Orozco, MF and Reinosa Rivera, H and Jaramillo-Losada, J and Payan-Salcedo, HA and Escudero, MM},
title = {Association of the Timed Up and Go Test With Alzheimer's Disease: Systematic Review and Meta-Analysis.},
journal = {Journal of applied gerontology : the official journal of the Southern Gerontological Society},
volume = {},
number = {},
pages = {7334648251394486},
doi = {10.1177/07334648251394486},
pmid = {41201919},
issn = {1552-4523},
abstract = {PurposeTo evaluate and estimate the association between Time and Go (TUG) test performance and mild cognitive impairment (MCI) or Alzheimer's disease (AD) in older adults.MethodsA systematic review and meta-analysis were conducted to synthesize data from studies examining the relationship between TUG test score and AD or MCI in adult subjects. The search strategy was applied to MEDLINE (OVID), Web of Science, Scopus, LILACS, and the Cochrane Central Register of Controlled Trials (CENTRAL). Studies were selected based on predefined inclusion criteria. For meta-analysis, effect sizes were pooled using a random-effects model to account for heterogeneity across studies. Heterogeneity was assessed using the I[2] statistic, and publication bias was evaluated through funnel plot analysis. Sensitivity analyses were performed to test the robustness of the findings.ResultsA total of 25 studies were included in this review, of which 15 were incorporated into the meta-analysis. Participants with AD (4.22 [95% CI 2.76-5.69 s], p < 0.00001) and those with MCI (1.83 [95% CI 1.03-2.57 s], p < 0.00001) exhibited significantly longer times in the simple TUG test compared to healthy controls. The Dual-Task TUG test showed a stronger association with AD in the studies included in the analysis. AD participants demonstrated significantly longer test times (12.28 [95% CI 6.56-18.0 s], p < 0.0001) compared to cognitively normal controls.ConclusionsThis review highlights a potential association between TUG completion time and cognitive impairment in individuals with AD and MCI. The TUG test shows promise as a tool for the early identification and screening of cognitive decline and AD.},
}

@article {pmid41201693,
year = {2025},
author = {Parithathvi, A and Harshitha, P and Mumbrekar, KD and Dsouza, HS},
title = {Systematic Review on Neurotoxic Implications of Lead-Induced Gene Expression Alterations in the Etiology of Alzheimer's Disease.},
journal = {Cellular and molecular neurobiology},
volume = {45},
number = {1},
pages = {98},
pmid = {41201693},
issn = {1573-6830},
mesh = {*Alzheimer Disease/genetics/chemically induced/pathology/etiology ; Humans ; *Lead/toxicity ; Animals ; *Gene Expression Regulation/drug effects ; Amyloid beta-Peptides/metabolism ; },
abstract = {Lead (Pb) is a hazardous heavy metal frequently used because it is readily available and inexpensive. Due to contaminated soil, dust, and items like paints and batteries, lead exposure is still an issue of concern in many nations. There is no known safe threshold of exposure, and it can have serious adverse effects on human health. Exposure to lead has been linked to detrimental effects on the developing nervous system of both children and adults. Alzheimer's disease (AD) is the most prevalent type of dementia affecting adults over the age of 65, resulting in a decrease in memory and thinking skills. In this review, we describe the role of lead in exacerbating the build-up of hyperphosphorylated tau proteins and formation of amyloid-β (Aβ) plaques, major neurotoxicants which can impair neuronal function leading to AD. We highlight the effect of developmental and lifelong lead exposure on various gene expression changes resulting in the formation of the neurotoxicants responsible to AD. Understanding the mechanisms related to Aβ plaques and neurofibrillary tangles (NFTs) formation serves as a novel approach to identify biomarkers for lead-induced AD and developing therapeutic interventions. Lead exposure has been related to adverse effects on the developing neurological systems of both adults and children.},
}

*Alzheimer Disease/genetics/chemically induced/pathology/etiology
Humans
*Lead/toxicity
Animals
*Gene Expression Regulation/drug effects
Amyloid beta-Peptides/metabolism

@article {pmid41201687,
year = {2025},
author = {Hazra, A and Hoda, M and Jethwa, M and Saha, A and Das, S},
title = {Metabolomic Based Insight Reveals a few Metabolites at Various Germination Stages of Black Rice, Demonstrating Potential Efficacy Against Dementia and Other Neurodegenerative Conditions.},
journal = {Applied biochemistry and biotechnology},
volume = {},
number = {},
pages = {},
pmid = {41201687},
issn = {1559-0291},
support = {Jagadish Chandra Bose Research Fellowship Award under Research Fellowship Award (RFA) (Sanction No. & Date: 230/STBT-12014/22/2021WBSCST SEC Dept. of STBT; 26.04.2022)//Department of Science and Technology, Government of West Bengal/ ; },
abstract = {Dementia is a brain disorder that impairs the cognitive abilities like memory, thinking, reasoning, and judgement, thereby restricts an individual's capacity to carry out daily activities. Alzheimer's disease (AD) is a prominent example of one such condition, representing approximately 60-70% of dementia cases and is characterized as an irreversible multifaceted neurodegenerative disorder. The enzyme Acetylcholinesterase (AChE) is a significant contributor to dementia and other neurodegenerative disorder, where this enzyme hydrolyses acetylcholine, a crucial neurotransmitter, thereby disrupting neurotransmission. AChE inhibitors (AChEi) can help delay or mitigate this degradation process. Black rice (purple rice, forbidden rice), a glutinous pigmented rice variety rich in bioavailable phytonutrients like phenols, has shown the potential in alleviating several biological disorders. It has also been reported to possess anti-Alzheimer's properties. This study aims to investigate the metabolomic changes in an indigenous variety of black rice throughout its different germination stages, as well as the impact of metabolite dynamics on the inhibition of acetylcholinesterase. The germination stages exhibited significant variation in terms of their metabolomic constituents. The G2 stage showed the highest AChE inhibition potential among the germination stages, with an IC50 value of 0.217 ± 0.009 mg mL[- 1]. Among the compounds identified in the black rice extract, benzene-1,2,4-triol, pyrogallol, hydroquinone, and phloroglucinol* (reported for the first time) exhibited superior activity than the standard drug galantamine. Furthermore, the combination of these authentic compounds with the standard drug (galantamine) showed promising results in reducing the complications associated with the synthetic drug in both in vitro and in silico studies.},
}

@article {pmid41201670,
year = {2025},
author = {Qi, S and Wang, S and Tan, Y and Pan, C and Bi, X},
title = {Extracellular Matrix (ECM)-Regulated Molecular Switches: Tissue Inhibitors of Metalloproteinases in Synaptic Formation and Neuropathic Diseases.},
journal = {Cellular and molecular neurobiology},
volume = {45},
number = {1},
pages = {100},
pmid = {41201670},
issn = {1573-6830},
support = {32200636//National Natural Science Foundation of China/ ; KM202310025028//R&D Program of Beijing Municipal Education Commission/ ; },
mesh = {Humans ; *Extracellular Matrix/metabolism ; Animals ; *Synapses/metabolism ; *Tissue Inhibitor of Metalloproteinases/metabolism ; *Matrix Metalloproteinases/metabolism ; *Nervous System Diseases/metabolism ; Neuronal Plasticity/physiology ; },
abstract = {Synaptic formation, the cornerstone of neurological function, underpins complex behaviors and cognitive processes, with structural/functional aberrations implicated in neurodevelopmental disorders and neurodegenerative pathologies. Synaptogenesis involves dynamic interplay between cell adhesion molecules (CAMs) and extracellular matrix (ECM) components, which collectively regulate neuronal connectivity and plasticity. Matrix metalloproteinases (MMPs) and their endogenous inhibitors, tissue inhibitors of metalloproteinases (TIMPs), emerge as critical regulators of these processes through ECM remodeling and modulation of cell surface receptor signaling. This review synthesizes current understanding of ECM-TIMP-MMP axes in synaptic development, highlighting their dual roles in physiological plasticity and pathological disruption across neurodegenerative diseases (e.g., Alzheimer's disease, Parkinson's disease), neuro-oncological disorders, and neuroinflammatory conditions. By dissecting the context-dependent functions and therapeutic implications of TIMP family members in synaptic maintenance and disease progression, this work provides a conceptual framework for advancing TIMP-based neurotherapeutic strategies and a theoretical basis for future exploration of TIMP as a potential therapeutic target for neurological disorders.},
}

Humans
*Extracellular Matrix/metabolism
Animals
*Synapses/metabolism
*Tissue Inhibitor of Metalloproteinases/metabolism
*Matrix Metalloproteinases/metabolism
*Nervous System Diseases/metabolism
Neuronal Plasticity/physiology

@article {pmid41201576,
year = {2025},
author = {Zhao, B and Zhou, S and Wei, T and Xu, J and Geng, C and Wang, Z and Tang, Y},
title = {Lost in Space and Thought: Navigating the Cognitive Map in Alzheimer's Disease.},
journal = {Neuroscience bulletin},
volume = {},
number = {},
pages = {},
pmid = {41201576},
issn = {1995-8218},
abstract = {Spatial navigation is one of the brain's most fundamental abilities, enabling us to move through the world with ease. The seemingly effortless act of navigation depends on complex cognitive functions, with the cognitive map playing a central role. In individuals with Alzheimer's disease (AD) and mild cognitive impairment (MCI), however, this once intuitive ability becomes disoriented and impaired before the emergence of noticeable memory symptoms. AD pathology disrupts structural and functional disabilities in the brain's navigation system, resulting in cognitive map-based navigational difficulties. These deficits affect not only physical navigation but also extend into abstract, knowledge-based domains. In this review, we explore the role of cognitive map dysfunction in the navigation impairments seen in AD, synthesizing current evidence from studies of both spatial and non-spatial deficits. These insights may deepen our knowledge of how the brain navigates and also offer promising avenues for predictive biomarkers and targeted interventions.},
}

@article {pmid41201547,
year = {2025},
author = {Akkaya, EC and Ilgin, R and Adil, H and Çelik, A},
title = {Magnesium L-Threonate Reduces Hippocampal Amyloid-β Load without Cognitive Improvement in a PTU-induced Hypothyroidism Model in Young Rats.},
journal = {Molecular neurobiology},
volume = {63},
number = {1},
pages = {8},
pmid = {41201547},
issn = {1559-1182},
support = {TSA-2024-565//Usak University Research Foundation/ ; },
mesh = {Animals ; *Hippocampus/metabolism/drug effects/pathology ; *Amyloid beta-Peptides/metabolism ; *Hypothyroidism/chemically induced/drug therapy/metabolism ; *Cognition/drug effects ; Disease Models, Animal ; Male ; Rats ; Rats, Wistar ; Brain-Derived Neurotrophic Factor/metabolism ; Maze Learning/drug effects ; },
abstract = {The brain is among the most critical target organs for thyroid hormones. Therefore, both congenital and acquired hypothyroidism can have significant neuropsychiatric consequences. Learning and memory problems, concentration disorders, and some psychiatric disorders such as depression can be observed in diseases causing acquired hypothyroidism. Although thyroid hormone therapy is the standard treatment, it does not always fully reverse these neuropsychiatric complications. Several studies have demonstrated the positive effects of magnesium L-threonate (MgT) supplementation on cognitive functions. Research suggests that MgT may help alleviate cognitive deficits, particularly in neurodegenerative conditions like Alzheimer's disease, where it has been associated with improvements in memory and reductions in hippocampal amyloid-β accumulation. However, there is limited data on the effect of MgT supplementation on hypothyroid conditions in the brain. The purpose of this study was to evaluate the effects of MgT supplementation on cognitive functions in hypothyroid rats. We report that while MgT supplementation did not significantly improve cognitive performance in behavioral tasks or inflammatory markers in hypothyroid rats, it did increase hippocampal BDNF levels in euthyroid animals and reduced hippocampal amyloid-β load under both euthyroid and hypothyroid conditions. The reduction in amyloid beta load under hypothyroid conditions suggests that MgT may exert partial therapeutic effects even in the absence of thyroid hormone replacement. These findings highlight the need for further studies to evaluate the therapeutic potential of MgT, particularly in combination with thyroid hormone replacement.},
}

Animals
*Hippocampus/metabolism/drug effects/pathology
*Amyloid beta-Peptides/metabolism
*Hypothyroidism/chemically induced/drug therapy/metabolism
*Cognition/drug effects
Disease Models, Animal
Male
Rats
Rats, Wistar
Brain-Derived Neurotrophic Factor/metabolism
Maze Learning/drug effects

@article {pmid41201520,
year = {2025},
author = {Lv, H and Mao, N and Liu, A and Zhao, X and Zhu, B},
title = {Puerarin Alleviates High-fat High-sugar Diet-induced Alzheimer's Disease-like Pathology and Insulin Resistance in Mice by Inhibiting p35/CDK5-mediated Mitochondrial Fission.},
journal = {Molecular neurobiology},
volume = {63},
number = {1},
pages = {9},
pmid = {41201520},
issn = {1559-1182},
mesh = {Animals ; *Isoflavones/pharmacology/therapeutic use ; *Cyclin-Dependent Kinase 5/metabolism ; *Insulin Resistance/physiology ; *Alzheimer Disease/drug therapy/pathology/metabolism ; *Diet, High-Fat/adverse effects ; Humans ; Male ; *Mitochondrial Dynamics/drug effects ; Cell Line, Tumor ; Mice ; Mice, Inbred C57BL ; Amyloid beta-Peptides/metabolism ; Signal Transduction/drug effects ; Mitochondria/drug effects/metabolism ; Glucose ; },
abstract = {Puerarin has demonstrated protective effects against Alzheimer's disease (AD) and diabetes. This study aimed to explore the therapeutic potential and mechanistic basis of puerarin against high-fat high-sugar (HFHS) diet-induced AD-like pathology and insulin resistance, with a specific focus on p35/cyclin-dependent kinase 5 (CDK5) signaling. SH-SY5Y cells were cultured under high glucose (HG) conditions to induce AD-like pathology, and mice were fed with an HFHS diet to establish an AD model. Both models were treated with various concentrations of puerarin. The expression and activity of p35/CDK5 were examined by Western blot and kinase assays. Rescue experiments were conducted by transfecting SH-SY5Y cells with p35 overexpression plasmids. The protein levels of amyloid-beta (Aβ)42, amyloid precursor protein (APP), and phosphorylated-Tau were assessed by immunofluorescence. The protein levels in the insulin signal-related signaling pathway were examined. Mitochondrial dysfunction mediated by CDK5/dynamin-related protein 1 (DRP1) was determined. Additionally, cognitive function in mice was evaluated using behavioral tests, including the open field test, novel object recognition test, and Morris water maze. Insulin resistance in mice was assessed using biochemical assays. Puerarin inhibited HG-induced p35/CDK5 activation in SH-SY5Y cells. It also decreased the HG-induced upregulation of Aβ42, APP, and p-Tau in SH-SY5Y cells. Moreover, puerarin ameliorated HG-induced insulin resistance and mitochondrial dysfunction in SH-SY5Y cells, as evidenced by improved insulin signaling and restored mitochondrial ultrastructure. However, p35 overexpression abrogated these protective effects. In vivo, puerarin alleviated HFHS diet-induced cognitive impairment, Aβ deposition, and Tau phosphorylation in mice. Furthermore, puerarin ameliorated HFHS diet-induced insulin resistance and mitochondrial dysfunction in mice. Puerarin ameliorated HFHS diet-induced cognitive impairment, insulin resistance, and mitochondrial dysfunction by inhibiting p35/CDK5 activity. Our findings highlight the therapeutic potential of puerarin in the management of diet-induced AD.},
}

Animals
*Isoflavones/pharmacology/therapeutic use
*Cyclin-Dependent Kinase 5/metabolism
*Insulin Resistance/physiology
*Alzheimer Disease/drug therapy/pathology/metabolism
*Diet, High-Fat/adverse effects
Humans
Male
*Mitochondrial Dynamics/drug effects
Cell Line, Tumor
Mice
Mice, Inbred C57BL
Amyloid beta-Peptides/metabolism
Signal Transduction/drug effects
Mitochondria/drug effects/metabolism
Glucose

@article {pmid41201456,
year = {2025},
author = {Francia, M and Ramesh, N and Boltz, T and Bot, M and van der Flier, WM and Visser, PJ and van der Lee, S and Teunissen, CE and Pijnenburg, YA and den Braber, A and Olde Loohuis, L and Reus, LM and Tijms, BM and Ophoff, RA},
title = {Integrative analysis of cerebrospinal fluid biomarkers, metabolomics, and polygenic risk reveals novel metabolite associations with Alzheimer's disease.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877251389924},
doi = {10.1177/13872877251389924},
pmid = {41201456},
issn = {1875-8908},
abstract = {BackgroundCerebrospinal fluid (CSF) metabolomics offers an opportunity to investigate in vivo biological pathways impacted in the human brain by Alzheimer's disease (AD). While impairments in brain glucose metabolism and lipid homeostasis are implicated in AD, the underlying metabolic pathways remain unclear. Genotype information can also be leveraged to study associations between CSF metabolites and AD genetic risk.ObjectiveTo evaluate how CSF metabolomic profiles and genetic risk are associated with AD pathology as reflected by established CSF biomarkers (Aβ, P-Tau, and T-Tau).MethodsWe collected CSF mass spectrometry measurements of 678 metabolites and 4865 unnamed compounds, as well as genome-wide genotype data from 487 individuals in the Amsterdam Dementia cohort. Polygenic risk scores (PRS) for AD were calculated. Elastic net regression models were used to predict AD biomarker levels with CSF metabolites, and pathway enrichment analysis was performed to assess the metabolic pathways involved.Results98 CSF metabolites were found to be significantly correlated with P-Tau or T-Tau, but none with Aβ CSF levels. Elastic net regression models identified 42 and 34 metabolites predicting P-Tau and T-Tau, respectively, including novel associations with Anserine and Fucose. Pathway enrichment analysis implicated Pentose and Glucuronate Interconversions, Glycerophospholipid Metabolism, and ABC Transporters in AD pathology. PRS analysis highlighted four CSF phosphatidylcholines significantly associated with AD genetic risk.ConclusionsCSF metabolites demonstrate a lack of Aβ levels associations, contrasting with multiple significant findings for P-Tau and T-Tau. Novel associations with Anserine and Fucose may provide new insights into metabolic pathways impacted by AD pathology.},
}

@article {pmid41201240,
year = {2025},
author = {Lee, CY and Shi, H and Ma, D and Beg, MF and Cao, J},
title = {Identification of Regions of Interest in Neuroimaging Data With Irregular Boundary Based on Semiparametric Transformation Models and Interval-Censored Outcomes.},
journal = {Statistics in medicine},
volume = {44},
number = {25-27},
pages = {e70309},
doi = {10.1002/sim.70309},
pmid = {41201240},
issn = {1097-0258},
support = {RGPIN-2023-04057//Natural Sciences and Engineering Research Council of Canada/ ; RGPIN-2021-02963//Natural Sciences and Engineering Research Council of Canada/ ; },
mesh = {Humans ; Alzheimer Disease/diagnostic imaging ; *Neuroimaging/methods/statistics & numerical data ; Computer Simulation ; *Models, Statistical ; Algorithms ; Disease Progression ; Likelihood Functions ; Brain/diagnostic imaging/pathology ; Magnetic Resonance Imaging ; Prognosis ; },
abstract = {Alzheimer's disease (AD) is a progressive neurodegenerative disorder that leads to memory loss, cognitive decline, and behavioral changes, without a known cure. Neuroimages are often collected alongside the covariates at baseline to forecast the prognosis of the patients. Identifying regions of interest within the neuroimages associated with disease progression is thus of significant clinical importance. One major complication in such analysis is that the domain of the brain area in neuroimages is irregular. Another complication is that the time to AD is interval-censored, as the event can only be observed between two revisit time points. To address these complications, we propose to model the imaging predictors via bivariate splines over triangulation and incorporate the imaging predictors in a flexible class of semiparametric transformation models. The regions of interest can then be identified by maximizing a penalized likelihood. A computationally efficient expectation-maximization algorithm is devised for parameter estimation. An extensive simulation study is conducted to evaluate the finite-sample performance of the proposed method. An illustration with the AD Neuroimaging Initiative dataset is provided.},
}

Humans
Alzheimer Disease/diagnostic imaging
*Neuroimaging/methods/statistics & numerical data
Computer Simulation
*Models, Statistical
Algorithms
Disease Progression
Likelihood Functions
Brain/diagnostic imaging/pathology
Magnetic Resonance Imaging
Prognosis

@article {pmid41201155,
year = {2025},
author = {Afxenti, S and Bourdakou, MM and Loizidou, EM and Zachariou, M and Lambrianides, A and Pantzaris, M and Spyrou, GM},
title = {Integrative analysis of proteomic and mri data reveals protein associations with brain imaging features in Alzheimer's disease.},
journal = {Expert review of proteomics},
volume = {},
number = {},
pages = {},
doi = {10.1080/14789450.2025.2584129},
pmid = {41201155},
issn = {1744-8387},
abstract = {BACKGROUND: Alzheimer's disease (AD) is a progressive neurodegenerative disorder and the leading cause of dementia worldwide. Despite extensive research, the complex molecular mechanisms underlying AD remain incompletely understood, limiting diagnostic and therapeutic advancements.

RESEARCH DESIGN AND METHODS: We presented an integrative, multi-layer computational framework to highlight proteins associated with AD-related brain changes using imaging, proteomic, genetic and network-based analyses. Utilizing data from the Alzheimer's Disease Neuroimaging Initiative (ADNI), we combined cerebrospinal fluid (CSF) proteomics with structural brain MRI features through a supervised multi-omics integration method.

RESULTS: This approach enabled the identification of key proteins linked to imaging traits. To contextualize these findings, proteins were mapped to their corresponding genes, investigated AD brain-imaging genetic associations through genome-wide association studies (GWAS) and applied network-based analyses. Proteins highlighted from both analyses were further verified in brain-specific databases to assess their functional roles, recurrence across studies, and spatial expression. Five proteins -APP, VGF, APOE, SCG3, and NCAN- were consistently associated with imaging-derived traits and are implicated in neurodegenerative mechanisms.

CONCLUSIONS: This study highlights the critical role of integrating imaging and proteomic data as part of the genotype-to-phenotype roadmap for AD, revealing molecular underpinnings of brain changes and offering a blueprint for the development of targeted therapeutic strategies.},
}

@article {pmid41201135,
year = {2025},
author = {Gai, K and Song, Y and Gao, D and Nie, Q and Luo, X and Xu, C and Cai, C and Smith, A and Li, X and Shi, W and Zhang, L and Sun, W and Lin, F},
title = {Advanced Stem Cell Therapy: 3D-Bioprinted Brain-Like Transplants for Alzheimer's Disease-Like Dementia.},
journal = {Advanced science (Weinheim, Baden-Wurttemberg, Germany)},
volume = {},
number = {},
pages = {e10062},
doi = {10.1002/advs.202510062},
pmid = {41201135},
issn = {2198-3844},
support = {SQ2024YFB4600188//National Key Research and Development Program of China/ ; 52375295//National Natural Science Foundation of China/ ; },
abstract = {Alzheimer's disease (AD) is a neurodegenerative disorder that lacks effective treatments and urgently requires innovative therapeutic strategies. Although stem cell therapy has demonstrated efficacy in preclinical and clinical studies, it faces challenges such as low cell survival (<5%) and uncontrolled glial differentiation. This study aims to develop a 3D-bioprinted neural patch to enhance stem cell therapy for AD. The hypothesis is that a supportive bioengineered microenvironment would improve cell integration and neuronal differentiation, leading to functional recovery. A tri-component bioink (gelatin/alginate/fibrinogen) is created with tunable printability, biocompatibility, and biodegradation, establishing functional transplantation microenvironments for a 3D-printed human induced pluripotent stem cell (hiPSC)-derived neural progenitor cell (NPC) construct as a hippocampal patch. The system (TTBT) maintains NPC survival and promotes neuronal differentiation, neurite development, and calcium signaling in vitro. In AD-like rats, these constructs improved cell retention (3.41-fold over suspensions), enhanced neuron (79.21 ± 6.67% vs 65.08 ± 7.14%) and GABAergic neuron (29.85 ± 7.69% vs 15.93 ± 10.33%) differentiation, and restored long-term potentiation (LTP) to 97.89% ± 19.84% of healthy control levels. Behavioral tests also show memory improvement, particularly in the Morris water maze. This 3D-printed therapy not only holds potential for enhancing stem cell treatments but also addresses other 3D brain defects.},
}

@article {pmid41201009,
year = {2025},
author = {Chong Chie, JAK and Persohn, SA and Pandey, RS and Carter, GW and Simcox, OR and Salama, P and Territo, PR and , },
title = {Neurometabolic and vascular dysfunction as an early diagnostic for Alzheimer's disease and related dementias.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21},
number = {11},
pages = {e70790},
doi = {10.1002/alz.70790},
pmid = {41201009},
issn = {1552-5279},
support = {//Initiative ADNI/ ; U01 AG024904/NH/NIH HHS/United States ; W81XWH-12-2-0012/NH/NIH HHS/United States ; T32AG071444/AG/NIA NIH HHS/United States ; },
mesh = {Humans ; *Alzheimer Disease/diagnosis/metabolism/diagnostic imaging ; Male ; Female ; Aged ; Retrospective Studies ; Early Diagnosis ; Disease Progression ; *Brain/metabolism/diagnostic imaging ; Biomarkers/metabolism ; Aged, 80 and over ; Neuroimaging ; },
abstract = {INTRODUCTION: Recent studies suggest that the brain undergoes anatomical and functional restructuring, resulting in neurometabolic and vascular dysregulation (MVD) prior to amyloid beta accumulation, which begins at an early age and leads to the onset of Alzheimer's disease (AD).

METHODS: Using a retrospective clinical population (n = 403) from the Alzheimer's Disease Neuroimaging Initiative, cerebral perfusion and metabolism changes across 59 brain regions were evaluated from clinical studies. Results were verified by transcriptomic signatures and clinical cognitive assessments.

RESULTS: Our findings suggest that disease progression follows a stage-dependent MVD pattern that can identify at-risk regions. Although each region progresses at a different pace, regions related to memory, cognition, and motor function showed significant early dysregulation. Importantly, these changes aligned with transcriptomic and cognitive signatures.

DISCUSSION: This study underscores that MVD in brain regions varies by sex and disease stage, making it a sensitive tool for early AD diagnosis. This approach could improve patient monitoring, stratification, and therapeutic testing.

HIGHLIGHTS: The potential of metabolic and vascular dysfunction as an early biomarker was assessed. An analytical method to assess dysregulation via imaging was developed. An analytical and graphical method to visualize the changes across disease spectrum was developed. Brain regions progress at different rates across Alzheimer's disease progression. Results were aligned with transcriptomics and cognitive signatures.},
}

Humans
*Alzheimer Disease/diagnosis/metabolism/diagnostic imaging
Male
Female
Aged
Retrospective Studies
Early Diagnosis
Disease Progression
*Brain/metabolism/diagnostic imaging
Biomarkers/metabolism
Aged, 80 and over
Neuroimaging

@article {pmid41200978,
year = {2025},
author = {Zhang, Y and Fan, J and Nan, S and Pan, J and Guo, W and Zhang, Y},
title = {Rubiadin Alleviates Alzheimer's Disease Pathology via NF-κB Pathway Regulation.},
journal = {Journal of integrative neuroscience},
volume = {24},
number = {10},
pages = {33497},
doi = {10.31083/JIN33497},
pmid = {41200978},
issn = {0219-6352},
support = {20210101293JC//Natural Science Foundation of Jilin Province/ ; },
mesh = {Animals ; *Alzheimer Disease/drug therapy/metabolism/pathology ; Mice ; *NF-kappa B/metabolism/drug effects ; Disease Models, Animal ; *Neuroprotective Agents/pharmacology/administration & dosage ; *Signal Transduction/drug effects ; Mice, Transgenic ; Male ; Amyloid beta-Peptides/metabolism ; Plaque, Amyloid/metabolism/drug therapy ; },
abstract = {BACKGROUND: Alzheimer's disease (AD) is a severe neurodegenerative disorder that impacts the global impact on the population. Nevertheless, the intricate nature of its pathogenesis has posed significant challenges to drug discovery in this field. This study aimed to verify the therapeutic potential of rubiadin (RB) on AD through both in vivo and in vitro experiments, thereby facilitating translational research for the advancement of AD treatment.

METHODS: We investigated the neuroprotective effects of RB on AD using both in vivo and in vitro models. Immunohistochemistry and western blot analysis were employed to evaluate inflammatory factors and the Nuclear Factor kappa-light-chain-enhancer of activated B cells (NF-κB) pathway in Mo/HuAPP695swe (APP)/PS1-dE9 (PS1) mice and N2a cells.

RESULTS: RB enhanced the memory performance of APP/PS1 mice in various tests, including the Morris water maze, step-down and step-through passive avoidance tasks, and novel object recognition. RB reduced the accumulation of Amyloid-beta (Aβ) plaques, as shown by immunohistochemical analysis. It also decreased the expression levels of pro-inflammatory cytokines interleukin (IL)-1β, IL-6, and tumor necrosis factor-alpha (TNF-α), while increasing the release of IL-4. Additionally, RB inhibited the NF-κB pathway, as demonstrated by western blot. Moreover, a cell viability test showed that RB protected N2a cells against toxicity caused by Aβ1-42 through a cell viability test. Western blot analysis revealed that neuroinflammation and the NF-κB pathway were inhibited by RB treatment in Aβ1-42-induced N2a cells. Accordingly, RB suppressed the nuclear translocation of NF-κB in Aβ1-42-induced N2a cells.

CONCLUSIONS: Our results provide experimental evidence supporting the preclinical research and future clinical applications of RB, thereby facilitating the development of new drugs for AD clinical therapy.},
}

Animals
*Alzheimer Disease/drug therapy/metabolism/pathology
Mice
*NF-kappa B/metabolism/drug effects
Disease Models, Animal
*Neuroprotective Agents/pharmacology/administration & dosage
*Signal Transduction/drug effects
Mice, Transgenic
Male
Amyloid beta-Peptides/metabolism
Plaque, Amyloid/metabolism/drug therapy

@article {pmid41200903,
year = {2025},
author = {Chockchowwat, W and Hannongbua, S and Saparpakorn, P},
title = {Role of triterpenoid derivatives from Centella asiatica as quantum chemical calculations.},
journal = {Journal of biomolecular structure & dynamics},
volume = {},
number = {},
pages = {1-17},
doi = {10.1080/07391102.2025.2578225},
pmid = {41200903},
issn = {1538-0254},
abstract = {To date, the treatment for Alzheimer's disease (AD) has focused on the cholinergic hypothesis, particularly through the inhibition of acetylcholinesterase (AChE). Asiatic acid, madecassic acid, asiaticoside, and madecassoside, which are triterpenoid derivatives from Centella asiatica, have previously been reported to exhibit the AChE inhibitory activity. This study aimed to investigate their binding modes and to determine efficient computational methods for analyzing their interactions with AChE. Molecular dynamics simulations demonstrated that most of their equilibrated structures remained within the AChE binding site. Principal component analysis and free energy landscape (FEL) confirmed their stability of the binding. Among the evaluated methods, the MM-(ALPB)SA binding energies, when combined with ligand surface binding efficiency index, showed the best correlation with experimental binding free energy. Density functional theory (DFT) calculations revealed the common key interaction between triterpenoids and AChE, including hydrogen bonds (Tyr124, Arg296, Tyr337, and Tyr341), H-π (Tyr341) and van der Waals (Trp86) interactions. Additionally, pharmacokinetics and drug-likeness predictions indicated that madecassic acid and asiatic acid are promising candidates for drug development. This study highlights the potential of triterpenoid derivatives in AChE inhibition and provides valuable insights into their binding efficiency, which could contribute to future drug discovery targeting Alzheimer's disease.},
}

@article {pmid41200863,
year = {2025},
author = {Wang, C and Shao, X and Cao, X and Fan, T and Li, Z and Wang, K and Li, M and Wang, X and Guan, P and Hu, X},
title = {Silver-functionalized carbon dots regulate amyloid aggregation and microbial infection.},
journal = {Nanoscale},
volume = {},
number = {},
pages = {},
doi = {10.1039/d5nr03379a},
pmid = {41200863},
issn = {2040-3372},
abstract = {Amyloid accumulation and microbial infections are major risk factors for Alzheimer's disease (AD). However, most of the current drugs are limited to single-target therapeutic strategies against amyloid or microbial infections, resulting in poor clinical treatment effects. Herein, we propose a novel multi-targeted strategy that can achieve multiple effects of inhibition of amyloid aggregation, depolymerization of mature amyloid fibrils, and anti-microbial infection. Experiments conducted in vitro have shown that silver-functionalized carbon dots (Ag@TACDs), at concentrations as low as 10 μg mL[-1], significantly impact the misfolding of Aβ42 and the depolymerization of Aβ42 fibrils. Moreover, Ag@TACDs exhibit outstanding ability to resist bacterial infections. At the same time, Ag@TACDs have good biocompatibility, enhance cell activity, and alleviate the cytotoxicity caused by Aβ42 oligomers. Our approach provides an effective strategy for the design of multi-target inhibitors for Alzheimer's disease.},
}

@article {pmid41200854,
year = {2025},
author = {Haque, SR and Ghosh, S and Banerjee, R and Maity, D},
title = {An Excited-State Intramolecular Proton Transfer Mechanism-Based Reactive Probe for Ratiometric Fluorescence Detection of Epinephrine in Live Cells.},
journal = {Chembiochem : a European journal of chemical biology},
volume = {},
number = {},
pages = {e202500631},
doi = {10.1002/cbic.202500631},
pmid = {41200854},
issn = {1439-7633},
support = {MLP0108//Council of Scientific and Industrial Research-Indian Institute of Chemical Technology/ ; SRG/2023/001243//Science and Engineering Research Board/ ; },
abstract = {Epinephrine (EPI), also known as adrenaline, is involved in various physiological processes of the sympathetic nervous system and may be linked to the progression of different serious diseases, including cancers, Alzheimer's, and Parkinson's diseases etc. There is an urgency in developing a fluorescence probe for the detection of EPI. An excited-state intramolecular proton transfer mechanism (ESIPT)-based reactive probe HBT-EPI has been successfully developed for ratiometric fluorescent detection of EPI in physiological conditions. EPI undergoes a cascade of nucleophilic attack at the carbonothioate site of the probe using the secondary amine and β-hydroxyl group to release the ESIPT-active 2-(2'-hydroxyphenyl) benzothiazole (HBT) fluorophore. Thus, a ratiometric fluorescence response is obtained. The probe is highly selective for EPI detection compared to other catecholamine-based neurotransmitters. A minimum of 1 µM of EPI can be easily detected using this probe. HBT-EPI has been successfully demonstrated for ratiometric fluorescence detection of EPI in live cells via confocal imaging.},
}

@article {pmid41200797,
year = {2025},
author = {},
title = {Correction to "Age and sex are associated with Alzheimer's disease neuropathology in Down syndrome".},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21},
number = {11},
pages = {e70914},
doi = {10.1002/alz.70914},
pmid = {41200797},
issn = {1552-5279},
}

@article {pmid41200794,
year = {2025},
author = {Udeh-Momoh, CT and Aliwa, B and Atwoli, L and Blackmon, K and Bosire, E and Gitau, S and Kaleli, H and Kamanda, C and Khakali, L and Maina, R and Mativo, P and Mbugua, S and Merali, Z and Muchungi, K and Njogu, N and Nyankira, D and Okech, V and Ondieki, A and Onyancha, C and Onyango, SO and Shah, J and Shah, S and Smith, C and Sokhi, D and Waa, S and Gregory, S and Hill-Jarrett, TG and Kafetsouli, D and Mielke, MM and Muniz-Terrera, G and Solomon, A and Thesen, T and Tsoy, E and Yasoda-Mohan, A and Yokoyama, JS and Watermeyer, TJ},
title = {Identifying sex- and gender-specific endocrinological, lifestyle, psychosocial, and socio-cultural targets for Alzheimer's disease prevention in Africans: The Female Brain Health and Endocrine Research in Africa (FemBER-Africa) project.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21},
number = {11},
pages = {e70887},
doi = {10.1002/alz.70887},
pmid = {41200794},
issn = {1552-5279},
support = {SAGA23/ALZ/Alzheimer's Association/United States ; SAGA23-1141999/ALZ/Alzheimer's Association/United States ; },
mesh = {Humans ; *Alzheimer Disease/prevention & control ; Female ; *Life Style ; Male ; Brain/diagnostic imaging ; Biomarkers ; Risk Factors ; Africa ; Sex Factors ; Aged ; African People ; },
abstract = {Dementia rates are rising globally, with the burden increasing most rapidly in low- to middle-income countries. Despite this, research into Alzheimer's disease and related dementias (ADRD) among African populations remains limited, with existing models based on Western cohorts that overlook sex-, gender-, and ancestry-specific factors. The Female Brain Health and Endocrine Research in Africa (FemBER-Africa) project, hosted at the Brain and Mind Institute, Aga Khan University, Kenya, will establish a deeply phenotyped cohort of 250 African individuals across the ADRD spectrum. It will assess sex-specific risk factors linked to ethnicity, lifestyle, and endocrinological variables using fluid-based biomarkers (blood and saliva), neuroimaging (magnetic resonance imaging and positron emission tomography), and culturally adapted cognitive tests. By comparing data with Western and diasporic cohorts, the study aims to identify ancestry-specific and shared mechanisms driving ADRD risk and progression. The findings will support targeted, culturally relevant prevention and intervention strategies, addressing the underrepresentation of African populations in global dementia research. HIGHLIGHTS: By 2030, > 78 million individuals are expected to have dementia, with the highest burden among women in low- to middle-income countries. Despite this, African populations remain underrepresented in Alzheimer's disease and related dementias (ADRD) research. Existing ADRD risk models fail to account for the unique influence of sex, gender, and ancestry on dementia risk. Female-specific reproductive and hormonal factors, including menopause transition and hormone therapy use, are poorly integrated into current models. The Female Brain Health and Endocrine Research in Africa (FemBER-Africa) project is the first large-scale study to examine sex- or gender-specific and endocrine contributors to ADRD in an African population, using advanced diagnostic, biomarker, and culturally adapted cognitive assessments. The study will assess how biological (hormonal, metabolic), lifestyle (physical activity, diet), and socio-cultural (education, health-care access) factors interact to influence ADRD risk in African women. Insights from FemBER-Africa will inform the development of sex- and gender-specific, culturally adapted ADRD prevention strategies, enhancing the precision and equity of dementia mitigation efforts globally.},
}

Humans
*Alzheimer Disease/prevention & control
Female
*Life Style
Male
Brain/diagnostic imaging
Biomarkers
Risk Factors
Africa
Sex Factors
Aged
African People

@article {pmid41200792,
year = {2025},
author = {Rosado, AM and Vizcarra, JC and Sharma, SRR and Keene, CD and White, CL and Kim, A and Forrest, SL and Kovacs, GG and Chuah, CN and Flanagan, ME and Pearce, TM and Dugger, BN and Gutman, DA},
title = {Digital neuropathology of neurodegenerative disorders: Foundations, research advances, and future directions.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21},
number = {11},
pages = {e70775},
doi = {10.1002/alz.70775},
pmid = {41200792},
issn = {1552-5279},
support = {T32AG087922/NH/NIH HHS/United States ; K08AG065463/NH/NIH HHS/United States ; R21AG066012/NH/NIH HHS/United States ; R01AG062517/NH/NIH HHS/United States ; R01AG072080/NH/NIH HHS/United States ; R01AG059689/NH/NIH HHS/United States ; RF1AG072080/NH/NIH HHS/United States ; U24NS133949/NH/NIH HHS/United States ; U24NS133945/NH/NIH HHS/United States ; P30AG072972/NH/NIH HHS/United States ; P30AG066546/NH/NIH HHS/United States ; //Chan Zuckerberg Initiative DAF, an advise fund of Silicon Valley Community Foundation/ ; },
mesh = {Humans ; *Neurodegenerative Diseases/pathology ; *Neuropathology/methods/trends ; Machine Learning ; Alzheimer Disease/pathology ; *Image Processing, Computer-Assisted/methods ; },
abstract = {A neuropathology examination after death remains the gold standard for differentiating between Alzheimer disease (AD) and AD and related dementias (ADRD). Increasing interest and familiarity with digital imaging highlights recent shifts to modernize pathology workflows by leveraging technology that automates imaging and analysis. This review provides an overview of digital pathology technologies and their associated infrastructure, available open-source and proprietary digital pathology software, relevant background on neurodegenerative histopathological features, and computational research. It further examines recent developments in digital pathology in neurodegenerative disease research with an emphasis on machine learning. We discuss evidence supporting how recently developed technologies and methodologies can enhance our understanding of histopathologic features of neurodegeneration and correlations of histopathologic features with cognitive performance and age at death. Finally, we review potential directions for neurodegenerative disease digital pathology research given trends in technological infrastructure development and other digital pathology research. HIGHLIGHTS: Provides a historical summary of digital pathology with respect to neuropathology. Examines key digital pathology technologies. Explores digital pathology applications in neurodegenerative disease and their contribution to research. Discusses the future of digital neuropathology.},
}

Humans
*Neurodegenerative Diseases/pathology
*Neuropathology/methods/trends
Machine Learning
Alzheimer Disease/pathology
*Image Processing, Computer-Assisted/methods

@article {pmid41200791,
year = {2025},
author = {Sarwar, MR and Cross, AJ and Godbee, K and Geethadevi, GM and Magin, P and Tullipan, M and Baker, AL and Bonevski, B and Ward, SA and Mahal, A and Versace, V and Bell, JS and Mc Namara, K and O'Reilly, SL and Thomas, D and Manias, E and Anstey, KJ and Varnfield, M and Jayasena, R and Elliott, RA and Lee, CY and Hernan, A and van den Bosch, D and Ferreira, C and George, J},
title = {Identifying dementia risk profiles for targeted interventions: A latent class analysis of at-risk middle-aged Australians.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21},
number = {11},
pages = {e70888},
doi = {10.1002/alz.70888},
pmid = {41200791},
issn = {1552-5279},
support = {GNT1171851//National Health and Medical Research Council/ ; },
mesh = {Humans ; Female ; Male ; Middle Aged ; Latent Class Analysis ; *Dementia/epidemiology/prevention & control ; Cross-Sectional Studies ; Australia/epidemiology ; Risk Factors ; Australasian People ; },
abstract = {INTRODUCTION: This study aimed to identify distinct dementia risk profiles in middle-aged adults with two or more potential dementia risk factors, to inform targeted prevention strategies.

METHODS: Cross-sectional analysis of baseline sociodemographic, clinical, and dementia-risk data from the HAPPI MIND trial. Dementia risk was assessed using the Australian National University Alzheimer's Disease Risk Index. Risk profiles were identified using latent class analysis (LCA).

RESULTS: Among 403 participants (mean age 56.4 ± 5.7 years, 62.5% female), the median number of dementia risk factors was 5.0; hyperlipidaemia (92.5%), low cognitive activity (72.5%), obesity (57.6%), and hypertension (52.7%) were the most prevalent. Several risk factors showed significant positive correlations. LCA identified three distinct classes: 1-High Cardiometabolic Burden; 2-High Behavioural and Psychosocial Risk; and 3-Low Risk with Healthy Behaviours.

DISCUSSION: The identified latent classes highlight heterogeneity of dementia risk profile in midlife. Tailored, multidomain interventions addressing each group's specific needs may improve dementia risk profiles and support broader health outcomes.

HIGHLIGHTS: Middle-aged Australians who participated in the HAPPI MIND dementia risk reduction trial had a median of five modifiable risk factors. Significant positive correlations were observed between behavioral and clinical risk factors, such as depression, along with poor diet, social isolation, and smoking. Latent class analysis revealed three distinct profiles: High Cardiometabolic Burden; High Behavioral and Psychosocial Risk; and Low Risk with Healthy Behaviors. The findings suggest there is a need for personalized, multidomain prevention strategies tailored to individual risk profiles in primary care.},
}

Humans
Female
Male
Middle Aged
Latent Class Analysis
*Dementia/epidemiology/prevention & control
Cross-Sectional Studies
Australia/epidemiology
Risk Factors
Australasian People

@article {pmid41200514,
year = {2025},
author = {Iyer, AK and Moutinho, M and Ayata, P and Karahan, H},
title = {Editorial: Myeloid cells as active players in human neurodegenerative diseases.},
journal = {Frontiers in neuroscience},
volume = {19},
number = {},
pages = {1712394},
pmid = {41200514},
issn = {1662-4548},
}

@article {pmid41200502,
year = {2025},
author = {Chiyanika, C and Chan, NY and Liu, W and Au, LWC and Chen, W and Liu, C and Chen, S and Leung, EYL and Ho, CL and Cai, Y and Ko, H and Chen, Q and Chu, W and Mok, VCT and Abrigo, J},
title = {Comparative analysis of PET and multiparametric MRI biomarkers in Alzheimer's disease continuum cohort.},
journal = {Journal of Alzheimer's disease reports},
volume = {9},
number = {},
pages = {25424823251394399},
pmid = {41200502},
issn = {2542-4823},
abstract = {BACKGROUND: Non-invasive biomarkers are key to early Alzheimer's disease (AD) detection. Multiparametric MRI and advanced imaging offer promising, accessible tools for identifying AD-related changes, supporting timely diagnosis and intervention.

OBJECTIVE: To assess how accurately multiparametric MRI biomarkers identify AD using Aβ-PET imaging as the reference, and to evaluate whether MRI metrics in AD-related brain regions can distinguish between Aβ-positive and Aβ-negative subjects across the AD continuum.

METHODS: In this exploratory retrospective study, 44 subjects aged 50-80 years were classified based on their PET and MRI biomarkers following the NIA-AA 2024 framework. MRI metrics included selected regional brain volumes (T1-weighted), mean diffusivity and fractional anisotropy (DTI-MD, DTI-FA), quantitative susceptibility mapping (QSM), and T1rho imaging. These were compared with amyloid load, and diagnostic performance was assessed using area-under-the-curve (AUC) analysis.

RESULTS: 25 subjects were Aβ+ (AD continuum), while 19 were Aβ- (controls). Volumes of the hippocampus, thalamus, amygdala, cingulate, putamen, and corpus callosum and DTI-MD in the hippocampus, corpus callosum, cuneus, and cingulate showed optimal diagnostic performance (AUC ≥ 0.80), with hippocampal volume and hippocampal DTI-MD showing AUCs > 0.90, (both p < 0.05). Combining hippocampal volumetry and hippocampal DTI-MD (AUC = 0.95, p < 0.001) improved diagnostic accuracy by 2.1% compared to using either biomarker alone. LASSO logistic regression analysis showed that amyloid positivity was significantly associated with hippocampal volume (p < 0.001).

CONCLUSIONS: Hippocampal volumetry and hippocampal DTI-MD may be superior and more sensitive imaging biomarkers for AD. Their combined use could improve diagnostic accuracy and enhance early AD detection.},
}

@article {pmid41200274,
year = {2025},
author = {Chowdhury, SR and Katari, V and Sen, D and Mondal, P},
title = {Editorial: Current chemical approaches in combating neuroinflammation in Alzheimer's disease (AD).},
journal = {Frontiers in aging neuroscience},
volume = {17},
number = {},
pages = {1712601},
pmid = {41200274},
issn = {1663-4365},
}

@article {pmid41200152,
year = {2025},
author = {Wang, W and Feng, Z and Shu, L and Hu, Y and Chen, Y and Zhang, B and Huang, H},
title = {Bridging prion biology and Alzheimer's disease: from pathogenic seeds to precision therapeutics.},
journal = {Frontiers in molecular neuroscience},
volume = {18},
number = {},
pages = {1660151},
pmid = {41200152},
issn = {1662-5099},
abstract = {Alzheimer's disease (AD) is characterized by the pathological aggregation of amyloid-beta (Aβ) and tau proteins, which display self-templating propagation reminiscent of the prion protein (PrP [Sc]). Despite these similarities, distinct structural heterogeneities and host interaction mechanisms offer unique avenues for disease-modifying therapies. This review comprehensively synthesizes recent advancements addressing: (1) the conformational commonalities and strain-specificities shared between Aβ/tau and PrP [Sc] ; (2) the spatiotemporal dissemination patterns of pathogenic seeds within neural networks; and (3) the development of biomarkers and therapeutic strategies rooted in prion theory. By integrating insights from prion biology with AD pathogenesis, we propose a comprehensive "conformation-propagation-microenvironment" framework for precision intervention, thereby offering a novel paradigm to surmount current therapeutic limitations.},
}

@article {pmid41200107,
year = {2025},
author = {Ghadami, S and Dellinger, K},
title = {Developing and optimizing a biocompatible tauopathy model using extracellular vesicle-mediated gene delivery.},
journal = {Frontiers in medicine},
volume = {12},
number = {},
pages = {1672046},
pmid = {41200107},
issn = {2296-858X},
abstract = {INTRODUCTION: Tauopathy models are essential in vitro systems for investigating tau-targeted therapies and advancing Alzheimer's disease research. Extracellular vesicles (EVs), owing to their high biocompatibility, low toxicity, and reduced immunogenicity, represent promising carriers for gene delivery and disease modeling.

METHODS: We investigated the potential of EVs as a delivery system for the human four-repeat tau isoform lacking N-terminal sequences (4R0N) and enhanced green fluorescent protein (EGFP) into Neuro-2a cells. EV-mediated transfection efficiency was compared with conventional methods, including lentiviral and chemical (lipofectamine and polyethyleneimine, PEI) approaches. Response surface methodology (RSM) was used to optimize EV-mediated delivery parameters.

RESULTS: EVs successfully delivered large plasmid DNA into Neuro-2a cells, resulting in detectable tau and EGFP expression. Optimization via RSM further improved gene delivery efficiency and reproducibility compared to unoptimized EV preparations and conventional transfection methods.

DISCUSSION: These findings demonstrate that EVs can serve as a robust and biocompatible platform for tau gene delivery, providing a promising alternative to traditional transfection strategies for generating physiologically relevant tauopathy models.},
}

@article {pmid41199994,
year = {2025},
author = {Rajamani, G and Naqvi, S and Sharma, A},
title = {Structure-activity relationship of GSK-3β inhibitors: insight into drug design for Alzheimer's disease.},
journal = {RSC medicinal chemistry},
volume = {},
number = {},
pages = {},
pmid = {41199994},
issn = {2632-8682},
abstract = {Alzheimer's disease (AD) is a neurodegenerative disorder characterised by cognitive impairment, memory loss, and decline in thinking and learning skills. The exact pathophysiology of the disease is still unknown; however, theories such as tau hyperphosphorylation, amyloid-β (Aβ) aggregation, and cholinergic dysfunction explain its pathogenesis. A few available drugs provide only symptomatic relief, while recently approved monoclonal antibody-based drugs target aggregated amyloid beta clearance. Extensive research is ongoing for drug development targeting various pathways, where one of the targets is glycogen synthase kinase (GSK-3β). GSK-3β plays diverse roles in physiological functions, and its dysregulation may lead to pathological conditions such as Alzheimer's disease (AD). GSK-3β comprises serine and threonine residues, is responsible for phosphorylation of the tau protein, and activates the amyloid precursor protein (APP) to synthesise Aβ. Consequently, the abnormal functioning of GSK-3β leads to hyperphosphorylation of the tau protein, and the formation of Aβ plaques eventually leads to neurofibrillary tangles. To develop GSK-3β inhibitors, one must know the requirements of crucial structural features in drug candidates to act at the active site for interaction. This review focuses on the latest pool of GSK-3β inhibitors and their design strategy, structure-activity relationship (SAR), molecular docking, and permeability across the brain layers. This broad review collection may benefit readers by providing the structural requirements to develop new GSK-3β inhibitors for treating AD.},
}

@article {pmid41199875,
year = {2025},
author = {Chande, K and Nirmal, R and Varpe, N and Doke, R and Vinchurkar, K and Singh, S},
title = {Alkaloid's undiscovered neuroprotective potential: a multi-target strategy to fight against neurodegenerative illnesses.},
journal = {3 Biotech},
volume = {15},
number = {12},
pages = {409},
pmid = {41199875},
issn = {2190-572X},
abstract = {Neurodegeneration (ND) refers to the progressive decline of neurons, leading to Alzheimer's disease, Parkinson's disease, multiple sclerosis, and Huntington's disease. These conditions are marked by gradual neuronal loss and cognitive impairment, with limited treatment options currently available. The available strategies only provide symptomatic relief and having more side effects, however none of them able to halt the disease progression, so there is strong need to develop alternative therapeutic strategies with no or less toxicity. Alkaloids, a class of naturally occurring compounds, exhibit diverse biological activities, including antioxidant and neuroprotection. Emerging research suggests that these molecules can influence key signaling pathways associated with neurodegeneration, potentially offering therapeutic benefits. By targeting multiple aspects of disease progression and modulating neuroinflammatory responses, alkaloids interact with critical molecular components such as transcription factors, receptors, and enzymes essential for neuronal survival and homeostasis. This review underscores the therapeutic potential of alkaloids in ND treatment and emphasizes the need for further research to explore their clinical applications. Future studies should aim to identify neuroprotective alkaloids, elucidate their mechanisms of action, and assess their effectiveness in treating neurodegenerative diseases. A deeper understanding of their interactions with key disease pathways is crucial for the development of effective therapeutic strategies.},
}

@article {pmid41199715,
year = {2025},
author = {Ko, H and Mok, VCT and Shi, L and Abrigo, J and Lam, BYK and Lee, ATC},
title = {Magnetic resonance imaging-based machine learning to detect mild cognitive impairment associated with Alzheimer's disease: abridged secondary publication.},
journal = {Hong Kong medical journal = Xianggang yi xue za zhi},
volume = {31 Suppl 7},
number = {5},
pages = {22-24},
pmid = {41199715},
issn = {1024-2708},
}

@article {pmid41199607,
year = {2025},
author = {Bae, JS},
title = {Vaccine trends: a narrative review.},
journal = {Journal of Yeungnam medical science},
volume = {42},
number = {},
pages = {71},
doi = {10.12701/jyms.2025.42.71},
pmid = {41199607},
issn = {2799-8010},
abstract = {Vaccination has played a central role in the historical and modern fight against infectious diseases. This review explores the evolution of infectious disease perception from ancient humoral theories to the modern "One Health" framework, reflecting the integration of environmental, animal, and human health. Vaccines have not only reduced morbidity and mortality but have also provided profound economic and developmental benefits across societies. Climate change, antimicrobial resistance, and the rapid emergence of new infectious threats have prompted innovations in vaccine technologies, including messenger RNA, DNA, viral vector, and nanoparticle-based platforms. These advances support personalized vaccine strategies, such as vaccinomics, and extend their application to noncommunicable diseases, including cancer and Alzheimer disease. Despite their success, vaccines face challenges including global access disparities, waning immunity, pathogen evolution, and vaccine hesitancy. Nonetheless, vaccination remains a cornerstone of global health security, with strong returns on investment and crucial roles in socioeconomic stabilization during pandemics. Future vaccine strategies must integrate technological innovation with equitable access and public trust, for instance, through global initiatives like the Coalition for Epidemic Preparedness Innovations and the World Health Organization COVID-19 Vaccines Global Access, and the establishment of regional manufacturing hubs to effectively respond to unpredictable threats like "Disease X."},
}

@article {pmid41199470,
year = {2025},
author = {Shao, Y and Liu, L and Zhu, S and Zhu, Z and Wang, P and Biswal, BB and Lin, H},
title = {Fornix Mediates Information Propagation in Brain Networks Following DLPFC-Targeted rTMS in Alzheimer's Disease: A Randomized Controlled Trial.},
journal = {CNS neuroscience & therapeutics},
volume = {31},
number = {11},
pages = {e70630},
doi = {10.1111/cns.70630},
pmid = {41199470},
issn = {1755-5949},
support = {CFH2022-2-2014//Capital's Funds for Health Improvement and Research/ ; 2022YFC2402205//National Key R&D Program of China/ ; 51977205//National Natural Science Foundation of China/ ; NSFC62401106//National Natural Science Foundation of China/ ; NSFC62171101//National Natural Science Foundation of China/ ; NSFC-AF 82211530041//NSFC Projects of International Cooperation and Exchanges/ ; 2024NSFSC1661//Sichuan Science and Technology Program/ ; },
mesh = {Humans ; *Alzheimer Disease/therapy/diagnostic imaging/physiopathology ; Male ; Female ; *Transcranial Magnetic Stimulation/methods ; Aged ; *Fornix, Brain/diagnostic imaging/physiopathology/physiology ; *Dorsolateral Prefrontal Cortex/diagnostic imaging/physiopathology/physiology ; Diffusion Tensor Imaging ; Middle Aged ; *Nerve Net/diagnostic imaging/physiopathology ; White Matter ; Aged, 80 and over ; Neural Pathways ; },
abstract = {AIMS: Repetitive transcranial magnetic stimulation (rTMS) could improve the clinical manifestations in Alzheimer's disease (AD), but its impact on deep brain tissue related to memory remains unclear. This study explored whether rTMS targeting cortical gray matter could regulate the white matter (WM) and exert modulatory effects on the network through WM bundles.

METHODS: Seventy-three AD patients underwent 14-day rTMS over the left dorsolateral prefrontal cortex (44 real, 25 sham). Granger causality analysis assessed changes in effective connectivity (EC) between the fornix and whole-brain voxels. Furthermore, the effects of rTMS treatment on fiber tracking parameters were analyzed.

RESULTS: After rTMS therapy, patients with AD showed increased EC based on fornix in the real-stimulation group. Functional network projections indicated that these clusters belonged to the frontoparietal network, the somatomotor network, as well as three white matter networks. Additionally, increased EC associated with fornix exhibited lateralization on the right side. Diffusion tensor imaging results showed no significant differences after the 14-day rTMS treatment.

CONCLUSION: In conclusion, a 14-day rTMS treatment in AD could regulate fornical function by increasing cortical-fornix EC, indicating neuroplasticity changes in response to therapy.

TRIAL REGISTRATION: Chinese Clinical Trial Registry (https://www.chictr.org.cn/index.html; ChiCTR2200062564).},
}

Humans
*Alzheimer Disease/therapy/diagnostic imaging/physiopathology
Male
Female
*Transcranial Magnetic Stimulation/methods
Aged
*Fornix, Brain/diagnostic imaging/physiopathology/physiology
*Dorsolateral Prefrontal Cortex/diagnostic imaging/physiopathology/physiology
Diffusion Tensor Imaging
Middle Aged
*Nerve Net/diagnostic imaging/physiopathology
White Matter
Aged, 80 and over
Neural Pathways

@article {pmid41199342,
year = {2025},
author = {Liu, Y and Sobue, A and Sahara, N and Isobe, M and Tanaka, R and Zhu, Y and Zhu, W and Matsuzaki, T and Yamanaka, K and Yamada, K and Mizoguchi, H},
title = {Abnormal behaviors and glial responses in an animal model of tau pathology.},
journal = {Molecular brain},
volume = {18},
number = {1},
pages = {83},
pmid = {41199342},
issn = {1756-6606},
support = {JPMJSP2125//JST SPRING/ ; JP24wm0425014//AMED, Japan/ ; 22K19749; 23K27360; 23H02669 (2023)//Japan Society for the Promotion of Science (JSPS) KAKENHI, Japan/ ; },
mesh = {Animals ; *Neuroglia/pathology/metabolism ; Disease Models, Animal ; *Behavior, Animal ; *Tauopathies/pathology/genetics/physiopathology ; Mice, Transgenic ; *tau Proteins/metabolism ; Mice ; Humans ; Male ; Gene Expression Regulation ; },
abstract = {Tau hyperphosphorylation has been considered a major contributor to neurodegeneration in Alzheimer's disease (AD) and frontotemporal dementia, and related tauopathies have gained prominence in the development of therapies for these conditions. Glial responses are key features of AD and frontotemporal dementia, and are associated with neuroinflammation. Numerous transgenic mouse models that recapitulate critical AD-like pathology and cognitive impairment have been developed to examine pathogenic mechanisms and evaluate therapeutic approaches targeting tau and glial reactivity. Glial reactivity and neuroinflammation coincide with tau hyperphosphorylation, which induces behavioral impairment; however, the specific correlation between glial cell activation and abnormal behavior remains unknown. In this study, we investigated changes in glial cell gene expressions related to abnormal behaviors in rTg4510 mice, which phenocopy the tau pathology, neuroinflammation, and neurodegeneration observed in human tauopathies. Both 4- and 6-month-old rTg4510 mice displayed significantly impaired nest-building behavior compared with control mice. Paired association learning was also impaired in 4-month-old rTg4510 mice. Moreover, rTg4510 mice of both age groups exhibited abnormal exploratory behavior, and these mice spent a longer time in the open arms of the plus-maze test than control mice. Using a magnetic-activated cell-sorting technique, we analyzed glial cell gene expressions related to neuroinflammation, phagocytosis, and amyloid synthesis in the prefrontal cortex of rTg4510 mice. Regression analysis of glial gene expressions and behavioral tests revealed that various glial reactivities were associated with behavioral abnormalities. Our findings suggest specific genetic characteristics of glial cells that may lead to abnormal behavior in rTg4510 mice.},
}

Animals
*Neuroglia/pathology/metabolism
Disease Models, Animal
*Behavior, Animal
*Tauopathies/pathology/genetics/physiopathology
Mice, Transgenic
*tau Proteins/metabolism
Mice
Humans
Male
Gene Expression Regulation

@article {pmid41199341,
year = {2025},
author = {Luo, H and Marron Fernandez de Velasco, E and Kim, J and Yang, P and Mermelstein, P and Bonventre, JV and Cooke, PS and Wickman, K},
title = {Membrane-associated estrogen receptor α prevents the amyloid β-induced suppression of GIRK channel activity in hippocampal neurons from female mice.},
journal = {Biology of sex differences},
volume = {16},
number = {1},
pages = {90},
pmid = {41199341},
issn = {2042-6410},
support = {DA048742/NH/NIH HHS/United States ; },
mesh = {Animals ; *G Protein-Coupled Inwardly-Rectifying Potassium Channels/metabolism ; Female ; *Hippocampus/metabolism/cytology ; *Amyloid beta-Peptides/pharmacology/metabolism ; *Neurons/metabolism/drug effects ; Male ; *Estrogen Receptor alpha/metabolism ; Mice ; *Sex Characteristics ; Mice, Inbred C57BL ; Receptor, Metabotropic Glutamate 5/metabolism ; },
abstract = {BACKGROUND: Amyloid β oligomers (oAβ) are a key pathogenic driver in Alzheimer's Disease (AD). Neuronal G protein-gated inwardly rectifying K[+] (GIRK/Kir3) channels are important regulators of neuronal excitability and prominent somatodendritic effectors for inhibitory G protein-coupled receptors, including the γ-aminobutyric acid type B receptor (GABABR). We previously reported a male-specific suppression of GIRK channel activity in hippocampal (HPC) neurons evoked by oAβ in in vitro, ex vivo, and in vivo mouse models of AD, and showed that this adaptation correlated with synaptic and cognitive impairment. Using pharmacological approaches, we showed that this adaptation is mediated by co-activation of cellular prion protein (PrP[C]) and metabotropic glutamate receptor 5 (mGluR5) and requires activation of cytosolic phospholipase A2 α (cPLA2α). However, the mechanisms underlying the sex specificity was unknown. Given the clinical context that females exhibit a 2-fold higher incidence of AD than males, and the loss of neuroprotective estrogen by menopause contributes to the sex differences in AD, we postulated that estrogen-associated resilience underlies this sex dimorphism of oAβ action.

METHODS: To examine the strength of GIRK-dependent signaling in HPC neurons, we performed electrophysiology in primary HPC cultures from neonatal male and female mice and then measured whole-cell currents evoked by the direct-acting GIRK channel agonist ML297 and the GABABR-selective agonist baclofen. We used an array of genetic and pharmacological approaches to investigate the molecular mechanism(s) underlying the vulnerability and resilience of GIRK channel activity to oAβ in male and female HPC neurons, respectively.

RESULTS: We found that resilience to the oAβ-induced and PrP[C]/mGluR5-dependent suppression of GIRK channel activity in female HPC neurons is conferred by membrane-associated estrogen receptor α (mERα) and caveolin 1 (Cav1). When this resilience factor is blocked or absent, oAβ suppresses GIRK channel activity in female HPC neurons via the same PrP[C]-mGluR5-cPLA2α signaling pathway identified previously in male neurons.

CONCLUSION: As estrogen levels decline with aging and menopause, the protective influence of mERα/Cav1 may diminish, unmasking the oAβ-induced suppression of GIRK channel activity and exacerbating disease progression in females. While amyloid β plaques (Aβ) are notable hallmarks of Alzheimer's Disease (AD), cognitive impairment in the early stages of the disease tracks more closely with the level of soluble Aβ oligomers (oAβ) in the brain. oAβ promotes cognitive deficits by disrupting the balance of excitatory and inhibitory influences on neurons in brain regions important for learning and memory such as the hippocampus, but the underlying molecular targets of oAβ and its pathogenic mechanisms are not fully understood. We recently demonstrated that oAβ weakens the activity of a prominent inhibitory influence on neuronal excitability (the GIRK channel) in the hippocampus of male but not female mice. This sexually dimorphic effect of oAβ was interesting and unexpected given that women are twice as likely to develop AD than men, and because disease progression is more aggressive in women. In this study, we investigated the mechanisms underlying the resilience of GIRK channels in female hippocampal neurons to oAβ. We found that resilience is conferred by estrogen and one of its receptors. When the influence of this receptor is diminished using pharmacological or genetic interventions, oAβ weakens GIRK channel activity in female and male neurons to a similar degree, and via the same mechanism. We speculate that with the onset of menopause, the protective influence of estrogen on GIRK channel activity in the hippocampus begins to wane. This, combined with other female-specific effects of oAβ on neuronal activity, contributes to the increased incidence and severity of AD in females.},
}

Animals
*G Protein-Coupled Inwardly-Rectifying Potassium Channels/metabolism
Female
*Hippocampus/metabolism/cytology
*Amyloid beta-Peptides/pharmacology/metabolism
*Neurons/metabolism/drug effects
Male
*Estrogen Receptor alpha/metabolism
Mice
*Sex Characteristics
Mice, Inbred C57BL
Receptor, Metabotropic Glutamate 5/metabolism

@article {pmid41199115,
year = {2025},
author = {},
title = {Correction to "Comparison of plasma p-tau217/Aβ42, p-tau217, and Aβ42/Aβ40 biomarkers by race to detect Alzheimer's disease".},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21},
number = {11},
pages = {e70913},
doi = {10.1002/alz.70913},
pmid = {41199115},
issn = {1552-5279},
}

@article {pmid41199071,
year = {2025},
author = {Zhang, L and Ma, Y and Fang, H and Gong, Y and Li, C and Meng, H and Song, J and Lu, X and Zhang, H and Niu, Q and Wang, L},
title = {Aluminum Exposure Leads to Aβ Deposition via the ciRs-7 Pathway.},
journal = {Biological trace element research},
volume = {},
number = {},
pages = {},
pmid = {41199071},
issn = {1559-0720},
support = {03201250//PhD Start-up Foundation of Shanxi Medical University/ ; 202203021222377//The Natural Science Foundation of Shanxi Province/ ; },
abstract = {Aluminum, a ubiquitous environmental neurotoxin, has been implicated in the pathogenesis of neurodegenerative disorders, including Alzheimer's disease (AD). While Aβ deposition is a hallmark of AD progression, the molecular mechanisms underlying aluminum-induced Aβ aggregation remain incompletely understood. This study examines the role of the ciRs-7-miR-7-UBE2A axis in aluminum-induced Aβ deposition. Healthy male SD rats and PC12 cells were stratified into groups based on aluminum maltolate exposure levels to establish an in vivo and in vitro neurotoxicity model. Hippocampal aluminum content, along with the expression levels of ciRs-7, miR-7, UBE2A, and Aβ1-42, were systematically analyzed. The results demonstrated a dose-dependent decrease in ciRs-7 and UBE2A expression with escalating aluminum exposure, accompanied by concurrent upregulation of miR-7 and Aβ1-42 accumulation. Conversely, ciRs-7 overexpression reversed these pathological trends. Mechanistically, aluminum exposure downregulates ciRs-7 in the hippocampus, thereby derepressing miR-7 activity, which suppresses UBE2A expression and ultimately promotes Aβ deposition. These results identify a novel circRNA-dependent mechanism in aluminum neurotoxicity, suggesting therapeutic targets for AD intervention.},
}

@article {pmid41198987,
year = {2025},
author = {Xu, WL and Chen, L and Fan, HH and Codd, GA and Giesy, JP and Guo, YM and Hilborn, ED and Sedan, D and Andrinolo, D and Chatterjee, S and Wang, HJ and Liu, Y and Wu, QH and He, J and Dai, SM and Xu, LL and Xiao, SM and Liu, YQ and Yang, R and Chen, J and Xie, P},
title = {Novel insights into cyanobacterial (microcystins) neurotoxicity in rats: hepatic encephalopathy.},
journal = {Archives of toxicology},
volume = {},
number = {},
pages = {},
pmid = {41198987},
issn = {1432-0738},
support = {31770555//National Natural Science Foundation of China/ ; 42367038//National Natural Science Foundation of China/ ; 31901186//National Natural Science Foundation of China/ ; },
abstract = {Microcystis, a commonly occurring genus of bloom-forming cyanobacteria, can produce numerous secondary metabolites, including microcystins (MCs), which are hepatotoxic and neurotoxic to humans and animals. However, the mechanisms of cyanobacterial neurotoxicity associated with MCs have not yet been clarified. This study reports the first observations of hepatic encephalopathy (HE) after exposure to Microcystis bloom extracts (MEs), which contained MCs. Mechanisms of toxicity were studied in rats exposed to MEs by use of a single intraperitoneal injection of 80 μg MC-LR equivalents/kg, body mass. Abnormal serum biochemical markers of hepatic functions and histopathological damage of liver and cerebral cortex were observed. Specifically, Alzheimer type II astrocytes, histological markers of HE, were observed. Motor impairment and significantly increased concentrations of ammonia in serum, increased activities of glutamine synthetase, and concentrations of glutamine in the cerebral cortex were detected, which indicated occurrence of HE. Mechanisms of HE, including ammonia poisoning, oxidative stress and inflammation, were confirmed by real-time quantitative PCR and transcriptomics. Also, transcriptomics revealed that zinc ions dyshomeostasis and ferroptosis are involved in the development of HE. This study presents novel insights into neurotoxic symptoms in human poisonings caused by Microcystis, links neurotoxicity in the brain to the liver, i.e., the liver-brain axis, and provides a new perspective on the multi-organ toxicity of Microcystis and a basis for developing treatments.},
}

@article {pmid41198899,
year = {2025},
author = {Ferrari-Souza, JP and Povala, G and Rahmouni, N and Bellaver, B and Ferreira, PCL and De Bastiani, MA and Leffa, DT and Lussier, FZ and Aguzzoli, CS and Brum, WS and Carello-Collar, G and Borelli, WV and Therriault, J and Macedo, AC and Servaes, S and Stevenson, J and Pola, I and Gauthier, S and Souza, DO and Schilling, LP and Lourenco, MV and Triana-Baltzer, G and Kolb, HC and Benedet, AL and Ashton, NJ and Tudorascu, DL and Zetterberg, H and Blennow, K and Johnson, SC and Pascoal, TA and Rosa-Neto, P and Zimmer, ER},
title = {Microglia modulate Aβ-dependent astrocyte reactivity in Alzheimer's disease.},
journal = {Nature neuroscience},
volume = {},
number = {},
pages = {},
pmid = {41198899},
issn = {1546-1726},
support = {AARGD-21-850670, AACSFD-22-928689, AARFD-23-1148735, and BFECAA2024/ALZ/Alzheimer's Association/United States ; 24AARFD-1243899/ALZ/Alzheimer's Association/United States ; AARFD-22-974627/ALZ/Alzheimer's Association/United States ; AARFD-22-923814/ALZ/Alzheimer's Association/United States ; AARFD-23-1148735/ALZ/Alzheimer's Association/United States ; 24AACSF-1200375/ALZ/Alzheimer's Association/United States ; AACSF-D 22-928689/ALZ/Alzheimer's Association/United States ; ADSF-21-831376-C, ADSF-21-831381-C, ADSF-21-831377-C, and ADSF-24-1284328-C/ALZ/Alzheimer's Association/United States ; ZEN-21-848495 and SG-23-1038904 QC/ALZ/Alzheimer's Association/United States ; NIRG-12-92090 and NIRP-12-259245/ALZ/Alzheimer's Association/United States ; 200691/2021-0//Ministry of Science, Technology and Innovation | Conselho Nacional de Desenvolvimento Científico e Tecnológico (National Council for Scientific and Technological Development)/ ; 2023-00356, 2022-01018 and 2019-02397//Vetenskapsrådet (Swedish Research Council)/ ; 2017-00915 and 2022-00732//Vetenskapsrådet (Swedish Research Council)/ ; 201809-2016862//Alzheimer's Drug Discovery Foundation (ADDF)/ ; RDAPB-201809-2016615//Alzheimer's Drug Discovery Foundation (ADDF)/ ; JPND2021-00694//EU Joint Programme - Neurodegenerative Disease Research (Programi i Përbashkët i BE-së për Kërkimet mbi Sëmundjet Neuro-degjeneruese)/ ; JPND2019-466-236//EU Joint Programme - Neurodegenerative Disease Research (Programi i Përbashkët i BE-së për Kërkimet mbi Sëmundjet Neuro-degjeneruese)/ ; R01AG068398//U.S. Department of Health & Human Services | National Institutes of Health (NIH)/ ; AG027161, AG021155, and AG062715//U.S. Department of Health & Human Services | National Institutes of Health (NIH)/ ; R01AG075336 and R01AG073267//U.S. Department of Health & Human Services | National Institutes of Health (NIH)/ ; 2020-VICO-279314 and 2024-VICO-356138//Fonds de Recherche du Québec - Santé (Fonds de la recherche en sante du Quebec)/ ; MOP-11-51-31; RFN 152985, 159815, and 162303//Gouvernement du Canada | Canadian Institutes of Health Research (Instituts de Recherche en Santé du Canada)/ ; },
abstract = {Experimental evidence suggests that activated microglia induce astrocyte reactivity in neurodegenerative disorders, such as Alzheimer's disease (AD). In this study, we investigated the association between microglial activation and amyloid-β (Aβ) with reactive astrogliosis in individuals across the AD spectrum. We examined 101 individuals using positron emission tomography radiotracers to assess Aβ deposition ([[18]F]AZD4694), tau aggregation ([[18]F]MK-6240) and microglial activation ([[11]C]PBR28), along with plasma biomarkers for astrocyte reactivity (GFAP) and tau phosphorylation (p-tau217). We further evaluated 251 individuals with cerebrospinal fluid levels of the microglial marker sTREM2. We found that Aβ pathology was associated with astrocyte reactivity across cortical brain regions only in the presence of microglial activation. The microglia-dependent effects of Aβ on astrocyte reactivity were further related to cognitive impairment through tau phosphorylation and aggregation. Our results suggest that microglial activation plays a key role in Aβ-related astrocyte reactivity, which, in turn, contributes to downstream pathological features of AD.},
}

@article {pmid41198777,
year = {2025},
author = {Koca, S and Kiris, I and Sahin, S and Karsidag, S and Cinar, N and Baykal, AT},
title = {Proteomic signatures and mitochondrial dysfunctions in peripheral T cells reveal novel ınsights into Alzheimer's disease.},
journal = {Scientific reports},
volume = {15},
number = {1},
pages = {38897},
pmid = {41198777},
issn = {2045-2322},
support = {216S605//Türkiye Bilimsel ve Teknolojik Araştırma Kurumu/ ; },
mesh = {Humans ; *Alzheimer Disease/metabolism/pathology/immunology ; *Mitochondria/metabolism/pathology ; *Proteomics/methods ; Male ; Female ; Aged ; *CD4-Positive T-Lymphocytes/metabolism ; *CD8-Positive T-Lymphocytes/metabolism ; *Proteome/metabolism ; Membrane Potential, Mitochondrial ; Aged, 80 and over ; Tandem Mass Spectrometry ; B-Lymphocytes/metabolism ; },
abstract = {Alzheimer's disease (AD) exhibits progressive cognitive decline and recent scientific studies hint to the peripheral immune system as a contributor. In this study, we isolated peripheral immune cells including CD4 + and CD8 + T cells, CD14 + monocytes and CD19 + B cells from AD patients and age-matched controls via fluorescence-activated cell sorting. Label-free LC-MS/MS-based proteomic expression analysis within each cell type, comparing AD and control groups independently, 387 significantly altered proteins were identified in CD4 + and 121 in CD8 + T cells. Bioinformatic analysis uncovered distinct, cell-type-specific signatures: CD4 + cells showed dysregulation in ribosomal and RNA-binding proteins linked to neurodegeneration and oxidative stress while CD8 + cells showed elevated glycolytic enzyme expression and hyperpolarized mitochondrial membrane potential. Furthermore, mitochondrial functional assays, JC-1 and MitoSOX Red, further supported cell-type-dependent differences in mitochondrial activity. These findings may suggest that peripheral T cells have unique proteomic and functional alterations in AD, implicating mitochondrial dysfunction as a potential contributor to disease pathology.},
}

Humans
*Alzheimer Disease/metabolism/pathology/immunology
*Mitochondria/metabolism/pathology
*Proteomics/methods
Male
Female
Aged
*CD4-Positive T-Lymphocytes/metabolism
*CD8-Positive T-Lymphocytes/metabolism
*Proteome/metabolism
Membrane Potential, Mitochondrial
Aged, 80 and over
Tandem Mass Spectrometry
B-Lymphocytes/metabolism

@article {pmid41198665,
year = {2025},
author = {Hill, SA and Bravo-Ferrer, I and Čiulkinytė, A and Pérez Ramos, N and Rossetti, I and Colvin, C and Beltran-Lobo, P and Parra-Pérez, C and Emelianova, K and Dando, O and Geary, B and Nirujogi, RS and Alessi, DR and Lee, DY and Lee, YB and Díaz Castro, B},
title = {Molecular profiling of brain endothelial cell to astrocyte endfoot communication in mouse and human.},
journal = {Nature communications},
volume = {16},
number = {1},
pages = {9750},
pmid = {41198665},
issn = {2041-1723},
support = {RGS\R1\231330//Royal Society/ ; 609/ALZS_/Alzheimer's Society/United Kingdom ; 663/ALZS_/Alzheimer's Society/United Kingdom ; 218493/Z/19/Z//Wellcome Trust (Wellcome)/ ; ARUK-ECRBF2023B-005//Alzheimer's Research UK (ARUK)/ ; MC_UU_00018/1//RCUK | Medical Research Council (MRC)/ ; },
mesh = {Animals ; *Astrocytes/metabolism/cytology ; Humans ; *Endothelial Cells/metabolism ; Mice ; *Blood-Brain Barrier/metabolism/cytology ; *Brain/metabolism/cytology ; *Cell Communication ; Alzheimer Disease/metabolism/pathology ; Male ; Multiple Sclerosis/metabolism/pathology ; Lipopolysaccharides ; Mice, Inbred C57BL ; Female ; Proteome/metabolism ; },
abstract = {Our understanding of how the body communicates with the brain to coordinate their functions is remarkably limited. At the blood-brain barrier (BBB), brain endothelial cells (BECs) are ideally positioned to mediate signaling between blood and brain parenchyma via direct communication with astrocyte perivascular processes (endfeet). We develop a method to define the mouse in vivo astrocyte endfoot proteome, which in combination with BEC-specific RNA-seq, reveal BEC to astrocyte endfoot ligand-receptor pairs that are modulated when mice are exposed to a peripheral inflammatory insult with lipopolysaccharide. We show that over 80% of these mouse BEC-endfoot ligand-receptor pairs are also found in the human BBB, with a subset of them differentially expressed in human multiple sclerosis or Alzheimer's disease compared to healthy individuals. Our findings reveal dynamic BEC-endfoot communication pathways that are relevant to human physiology and provide methodology and datasets for the translational study of BEC-astrocyte crosstalk in health and disease.},
}

Animals
*Astrocytes/metabolism/cytology
Humans
*Endothelial Cells/metabolism
Mice
*Blood-Brain Barrier/metabolism/cytology
*Brain/metabolism/cytology
*Cell Communication
Alzheimer Disease/metabolism/pathology
Male
Multiple Sclerosis/metabolism/pathology
Lipopolysaccharides
Mice, Inbred C57BL
Female
Proteome/metabolism

@article {pmid41198610,
year = {2025},
author = {Pirraglia, E and Osorio, RS and Glodzik, L and Ashebir, Y and Shao, Y},
title = {Subtypes of multiple-etiology dementias and the heterogeneous impact of APOE variants.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21},
number = {11},
pages = {e70872},
doi = {10.1002/alz.70872},
pmid = {41198610},
issn = {1552-5279},
support = {U01OH012486//Centers for Disease Control and Prevention (CDC)/ ; U24 AG072122/NH/NIH HHS/United States ; R01NS104364/NH/NIH HHS/United States ; R01HL111724/NH/NIH HHS/United States ; P01 AG060882/AG/NIA NIH HHS/United States ; P30 AG066512/AG/NIA NIH HHS/United States ; P30AG062429/AG/NIA NIH HHS/United States ; P30AG066468/AG/NIA NIH HHS/United States ; P30AG062421/AG/NIA NIH HHS/United States ; P30AG066509/AG/NIA NIH HHS/United States ; P30AG066514/AG/NIA NIH HHS/United States ; P30AG066530/AG/NIA NIH HHS/United States ; P30AG066507/AG/NIA NIH HHS/United States ; P30AG066444/AG/NIA NIH HHS/United States ; P30AG066518/AG/NIA NIH HHS/United States ; P30AG066462/AG/NIA NIH HHS/United States ; P30AG072979/AG/NIA NIH HHS/United States ; P30AG072972/AG/NIA NIH HHS/United States ; P30AG072976/AG/NIA NIH HHS/United States ; P30AG072975/AG/NIA NIH HHS/United States ; P30AG072978/AG/NIA NIH HHS/United States ; P30AG072977/AG/NIA NIH HHS/United States ; P30AG066519/AG/NIA NIH HHS/United States ; P30AG062677/AG/NIA NIH HHS/United States ; P30AG079280/AG/NIA NIH HHS/United States ; P30AG062422/AG/NIA NIH HHS/United States ; P30AG066511/AG/NIA NIH HHS/United States ; P30AG072946/AG/NIA NIH HHS/United States ; P30AG062715/AG/NIA NIH HHS/United States ; P30AG072973/AG/NIA NIH HHS/United States ; P30AG066506/AG/NIA NIH HHS/United States ; P30AG066508/AG/NIA NIH HHS/United States ; P30AG066515/AG/NIA NIH HHS/United States ; P30AG072947/AG/NIA NIH HHS/United States ; P30AG072931/AG/NIA NIH HHS/United States ; P30AG066546/AG/NIA NIH HHS/United States ; P20AG068024/AG/NIA NIH HHS/United States ; P20AG068053/AG/NIA NIH HHS/United States ; P20AG068077/AG/NIA NIH HHS/United States ; P20AG068082/AG/NIA NIH HHS/United States ; P30AG072958/AG/NIA NIH HHS/United States ; P30AG072959/AG/NIA NIH HHS/United States ; R01AG056031/AG/NIA NIH HHS/United States ; R01AG056531/AG/NIA NIH HHS/United States ; R01AG067523/AG/NIA NIH HHS/United States ; R01AG066870/AG/NIA NIH HHS/United States ; R21AG067549/AG/NIA NIH HHS/United States ; },
mesh = {Humans ; Male ; Female ; *Dementia/genetics/mortality/pathology/classification ; *Apolipoproteins E/genetics ; *Alzheimer Disease/pathology/genetics/mortality ; Aged ; Aged, 80 and over ; Autopsy ; *Apolipoprotein E4/genetics ; Brain/pathology ; Mixed Dementias ; },
abstract = {INTRODUCTION: Multiple-etiology dementias (MEDs) are frequently identified at autopsy but often missed in clinical diagnosis, limiting the efficiency of dementia research and treatment. This study aimed to characterize subtypes of MEDs, evaluate clinical underdiagnosis, and assess the heterogeneous impact of apolipoprotein E (APOE) variants on mortality across MED subtypes.

METHODS: Data from the National Alzheimer's Coordinating Center (NACC) repository, which includes standardized clinical and autopsy assessments, were analyzed using competing risks survival models.

RESULTS: Pure Alzheimer's disease (AD) neuropathology was rare, whereas mixed neuropathologies were common and frequently misdiagnosed as AD alone. APOE ε4 decreased mortality risk in decedents without AD neuropathology and increased mortality in decedents with mixed AD neuropathology, but not in those with AD alone. APOE ε2 increased mortality in decedents having vascular neuropathology with cerebral amyloid angiopathy.

DISCUSSION: Heterogeneity in MEDs remains substantially underrecognized clinically. The effects of APOE variants vary by dementia subtype, emphasizing the need for refined diagnostic tools and personalized dementia treatment and care approaches.

HIGHLIGHTS: Autopsy data revealed that pure Alzheimer's disease (AD) neuropathology is rare, whereas mixed pathologies are highly prevalent and frequently misdiagnosed as AD alone in clinical settings, underscoring the limitations of current diagnostic practices. Comprehensive neuropathological characterization of multiple-etiology dementia (MED) subtypes is crucial for uncovering the true complexity of dementia, which is often masked in clinical assessments. This approach enables a more accurate understanding of disease mechanisms and progression. We found that apolipoprotein E (APOE) ε4 was associated with increased mortality risk in AD with co-pathologies, but not in pure AD without other neuropathologies. Conversely, APOE ε4 was associated with decreased mortality risk in decedents who did not have AD neuropathology. APOE ε2 was protective in some AD-related subtypes but was associated with higher mortality risk in cerebral amyloid angiopathy with other vascular neuropathologies, highlighting the heterogeneous impact of genetic risk factors across subtypes. The differential effects of APOE variants across MED subtypes emphasize the need to evaluate biomarkers and risk factors within the context of underlying neuropathological profiles rather than broad clinical categories. These findings reinforce the need to develop and implement more refined, subtype-specific biomarkers and diagnostic protocols to enable precision prevention and personalized treatment strategies for the diverse forms of MED.},
}

Humans
Male
Female
*Dementia/genetics/mortality/pathology/classification
*Apolipoproteins E/genetics
*Alzheimer Disease/pathology/genetics/mortality
Aged
Aged, 80 and over
Autopsy
*Apolipoprotein E4/genetics
Brain/pathology
Mixed Dementias

@article {pmid41198606,
year = {2025},
author = {Loi, KJ and Radtke, N and Kiriluk, C and Noureldein, MH and Feldman, EL and Bakulski, KM and Chen, KS},
title = {Shared genes and pathways in dementia: Insights from genome-wide association studies.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21},
number = {11},
pages = {e70845},
doi = {10.1002/alz.70845},
pmid = {41198606},
issn = {1552-5279},
support = {K99AG081390/AG/NIA NIH HHS/United States ; U01AG057562/AG/NIA NIH HHS/United States ; P30 AG072931/AG/NIA NIH HHS/United States ; 1K08AG084902/AG/NIA NIH HHS/United States ; AACSF-22-970586/ALZ/Alzheimer's Association/United States ; //Robert E. Nederlander Sr. Program for Alzheimer's Research/ ; //Robert and Katherine Jacobs Environmental Health Initiative/ ; //Andrea and Lawrence A. Wolfe Brain Health Initiative/ ; //Frank L. and Helen Gofrank Foundation Research Program in AD and Brain Health/ ; //Richard and Jane Manoogian Foundation/ ; //Sinai Medical Staff Foundation/ ; //Frances and Kenneth Eisenberg Emerging Scholar Program/ ; //NeuroNetwork for Emerging Therapies/ ; },
mesh = {Humans ; *Genome-Wide Association Study ; *Dementia/genetics ; *Genetic Predisposition to Disease/genetics ; Alzheimer Disease/genetics ; },
abstract = {Dementia, a collective term for neurodegenerative disorders marked by cognitive decline, affects millions worldwide, and is expected to rise significantly in prevalence. Genome-wide association studies (GWASs), as highlighted in this review, have revolutionized our understanding of dementia by identifying contributing genetic loci and pathways, including for Alzheimer's disease, vascular dementia, frontotemporal lobar dementia, and Lewy body dementia. This review critically analyzes published findings to shed insight on shared genes and pathways, encompassing lipid metabolism, immune responses, lysosomal mechanisms, and ionic homeostasis, which underlie neurodegeneration in dementia. We discuss methodological advances, challenges posed by genetic heterogeneity and population diversity, and the utility of polygenic risk scores in disease prediction. Furthermore, the importance of integrating tissue-specific expression data and non-European ancestral study cohorts is emphasized. Finally, this review outlines the next steps for advancing dementia research through GWASs and genetic insights. HIGHLIGHTS: Genome-wide association studies (GWASs) provide insight into the complex genetic architecture underlying dementia. Synthesizing GWASs across dementia subtypes highlights shared mechanisms. Identifying shared pathways may guide therapeutic development. Limitations exist and future GWASs may benefit from use of diverse populations.},
}

Humans
*Genome-Wide Association Study
*Dementia/genetics
*Genetic Predisposition to Disease/genetics
Alzheimer Disease/genetics

@article {pmid41198603,
year = {2025},
author = {Crowley, P and Henry, AL and Flanagan, E and Antonsdottir, I and Bentley, A and Blackman, J and Bliwise, DL and Bubu, OM and Buysse, DJ and Camargos, EF and Cassidy-Eagle, E and Cote, K and Coulthard, E and D'Rozario, AL and Espie, CA and Falck, RS and Gabb, VG and Harvey, AG and Hmwe, NTT and Hoyos, CM and Jobbins, L and Kennelly, S and Kent, BA and Köpke, S and Krystal, A and Leroi, I and Liguori, C and Lim, YY and Lorenz, R and Lucey, BP and Mander, B and Moline, M and Naismith, SL and Ogunniyi, A and Rapaport, P and Reynolds, CF and Richards, K and Siengsukon, CF and Sindi, S and Singer, CM and Wirz-Justice, A and Yaffe, K and O'Caoimh, R},
title = {Development of a core outcome set for clinical trials of interventions to improve sleep in people with cognitive impairment-the Sleep in Cognitive Impairment Core Outcome Set (SCICOS).},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21},
number = {11},
pages = {e70890},
doi = {10.1002/alz.70890},
pmid = {41198603},
issn = {1552-5279},
support = {HRB DTICTN-2021-003//Dementia Trials Ireland, Health Research Board Clinical Trial Network/ ; HRB DTICTN-2021-003/HRBI_/Health Research Board/Ireland ; },
mesh = {Humans ; *Cognitive Dysfunction/complications/therapy ; *Sleep Wake Disorders/therapy/etiology/complications ; *Clinical Trials as Topic ; *Outcome Assessment, Health Care ; Delphi Technique ; *Sleep ; },
abstract = {INTRODUCTION: Sleep disturbances are common in older people with cognitive impairment, potentially contributing to negative outcomes. A core outcome set (COS) is required to reduce heterogeneity in clinical trials and promote the development of high-quality evidence to support clinical management.

METHODS: A multi-stage mixed methods study was conducted in accordance with The Core Outcome Set Standards for Development.

RESULTS: A systematic review identified 287 sleep outcomes from previous clinical trials. Qualitative interviews ensured the COS was informed by what matters most to people with cognitive impairment and their caregivers. A modified Delphi process identified nine outcomes for the COS: total sleep time, sleep onset latency, wakefulness after sleep onset, number of night-time awakenings, sleep efficiency, and measures of sleep quality, daytime sleepiness, cognition, and mood.

DISCUSSION: This COS will support researchers to produce more reliable and coherent trial data to guide the management of sleep disturbances in people with neurodegenerative cognitive impairment.

HIGHLIGHTS: Evidence is lacking regarding the treatment of sleep disturbances in people with cognitive impairment. Heterogeneity of reported outcomes in clinical trials limits data synthesis. A qualitative analysis established what matters most to people with cognitive impairment and their caregivers when determining treatment effectiveness. A Delphi panel of experts agreed upon a core outcome set. This core outcome set will improve the reliability and comparability of data from future trials.},
}

Humans
*Cognitive Dysfunction/complications/therapy
*Sleep Wake Disorders/therapy/etiology/complications
*Clinical Trials as Topic
*Outcome Assessment, Health Care
Delphi Technique
*Sleep

@article {pmid41198597,
year = {2025},
author = {Maioli, S and Nalvarte, I and Ankarcrona, M and Schultzberg, M and Zuloaga, KL and Goikolea, J and Visser, PJ and De Strooper, B and Winblad, B and Pizzo, P and Williams, PA and Rodriguez-Rodriguez, P and Naia, L},
title = {Bioenergetics and lipid metabolism in Alzheimer's disease: From cell biology to systemic health.},
journal = {Journal of internal medicine},
volume = {},
number = {},
pages = {},
doi = {10.1111/joim.70036},
pmid = {41198597},
issn = {1365-2796},
support = {//King Gustaf V:s and Queen Victoria's Foundation, Gun och Bertil Stohnes Stiftelse, Stiftelsen Gamla Tjänarinnor/ ; //Gun och Bertil Stohnes Stiftelse/ ; //Dementia Foundation/ ; NS110749//National Institutes of Health (NIH) research/ ; FO2024-0153-HK-50//the Swedish Brain Foundation/ ; 2024-0287//the Swedish Brain Foundation/ ; //Margaretha af Ugglas Foundation/ ; PRIN2022943TH9//Italian Ministry of University and Scientific Research/ ; PRIN P20225R4Y5//Italian Ministry of University and Scientific Research/ ; //European Union, NextGeneration EU/ ; //Cure Alzheimer's Fund (USA)/ ; //Italian Ministry of Research, NRRP-National Recovery and Resilience Plan grant, National Centre of Research 'Development of gene therapy and drugs with RNA technology', spoke 3 'Neurodegenerative Diseases/ ; //Ulla and Ingemar Dahlberg Foundation/ ; 2024-03440//Swedish Research Council/ ; 2023-02054//Swedish Research Council/ ; 2024-03577//Swedish Research Council/ ; 2022-00799//Swedish Research Council/ ; 2323-02503//Swedish Research Council/ ; //Strategic Research Program in Neuroscience-StratNeuro/ ; AF-1012350//Swedish Alzheimer Foundation/ ; AF-1011030//Swedish Alzheimer Foundation/ ; //Leif Lundblad Family and others/ ; },
abstract = {Alzheimer's disease (AD) is a complex neurodegenerative disorder characterized by progressive cognitive decline. Although amyloid-β and tau pathologies remain central to our understanding of AD, growing evidence suggests that disrupted lipid metabolism and impaired bioenergetics are closely linked to these hallmark features. Genetic, lipidomic and functional studies point to alterations in cholesterol, phospholipids and polyunsaturated fatty acids, which can influence mitochondrial function, organelle communication and glial responses. These processes are further modulated by apolipoprotein E (APOE) genotype, sex differences and systemic metabolic states such as obesity and diabetes, contributing to neuroinflammation and cognitive decline. Although findings are sometimes conflicting, an emerging theme is that lipid and energy metabolisms are central to how genetic and environmental risk factors shape AD pathogenesis. This integrated perspective highlights lipid and bioenergetic pathways as promising therapeutic targets, where metabolic modulators, lipid-directed interventions and lifestyle strategies may complement amyloid-based therapies and offer opportunities for precision approaches, particularly in women and APOE ε4 carriers.},
}

@article {pmid41198595,
year = {2025},
author = {Russ, KA and Lacy, K and Dage, JL and Foroud, T},
title = {The National Centralized Repository for Alzheimer's Disease and Related Dementia's Biomarker Assay Laboratory: A Resource for the Alzheimer's Disease Research Community.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21},
number = {11},
pages = {e70774},
doi = {10.1002/alz.70774},
pmid = {41198595},
issn = {1552-5279},
support = {U24AG021886/AG/NIA NIH HHS/United States ; },
mesh = {Humans ; *Biomarkers/blood/cerebrospinal fluid ; *Alzheimer Disease/diagnosis/blood ; United States ; *Dementia/diagnosis ; Biomedical Research ; *Laboratories ; },
abstract = {Developments in Alzheimer's disease blood-based biomarkers research have provided critical information as to their use in early detection and assessments of progression in patients. The National Centralized Repository for Alzheimer's Disease and Related Dementias (NCRAD) Biomarker Assay Laboratory (BAL) was developed to provide expertise and access to robust and reliable research-use-only biomarkers (not for medical decision making) for the Alzheimer's disease and related dementias (ADRD) research community. The NCRAD BAL is a quality-focused laboratory delivering biomarker data through the use of highly standardized procedures and highly automated instrumentation with the goal of limiting pre-analytical variability while preparing samples for analysis, including limiting lot-to-lot variability of the assays. As biomarkers become United States Food and Drug Administration (FDA) -approved and move into use in CLIA labs, the NCRAD BAL will bring forward new platforms and assays reflecting the most current research-use-only biomarkers to support the research mandate of the ADRD research community. HIGHLIGHTS: The National Centralized Repository for Alzheimer's Disease and Related Dementias (NCRAD) has developed a Biomarker Assay Laboratory to support research of robust and reliable fluid biomarkers for Alzheimer's disease and neurodegeneration. NCRAD supports Alzheimer's Disease Research Centers by providing biomarker analyses on samples with clinical and imaging data through the National Institute on Aging (NIA) -funded Alzheimer's Disease Center Fluid Biomarker Initiative. The NCRAD Biomarker Assay Laboratory focuses on decreasing variability that will affect study results by utilizing highly standardized and automated procedures, strict monitoring of control measures, and controlling for lot-to-lot and instrument-to-instrument variability.},
}

Humans
*Biomarkers/blood/cerebrospinal fluid
*Alzheimer Disease/diagnosis/blood
United States
*Dementia/diagnosis
Biomedical Research
*Laboratories

@article {pmid41198537,
year = {2025},
author = {Zudeh, G and Sossai, S and Angelini, J and Stocco, G and Lucafò, M},
title = {Pharmacological Modulation of NLRP3: From Therapy Personalization to Innovative Drugs.},
journal = {Frontiers in bioscience (Landmark edition)},
volume = {30},
number = {10},
pages = {39537},
doi = {10.31083/FBL39537},
pmid = {41198537},
issn = {2768-6698},
support = {RC 15/23//Italian Ministry of Health/ ; },
mesh = {*NLR Family, Pyrin Domain-Containing 3 Protein/genetics/metabolism/antagonists & inhibitors ; Humans ; Inflammasomes/metabolism/genetics/drug effects ; *Precision Medicine/methods ; Epigenesis, Genetic ; DNA Methylation ; Animals ; Inflammation/drug therapy ; },
abstract = {The nucleotide-binding domain, leucine-rich-containing family, pyrin domain-containing-3 (NLRP3) inflammasome is a multiprotein complex fundamental for the secretion of pro-inflammatory cytokines during the innate immune response. NLRP3 dysregulation is implicated in the pathogenesis of several diseases, such as inflammatory bowel disease, arthritis, cancer, Alzheimer's disease, and type 2 diabetes. The pharmacological modulation of NLRP3 by several compounds, which are fully described in this review, represents an important strategy to regulate inflammatory processes. Moreover, NLRP3 is also involved in drug-related adverse reactions, and its pharmacological modulation represents a rapid strategy to mitigate such adverse effects, as reported in this study. NLRP3 inflammasome activation is tightly regulated by post-transcriptional modifications and epigenetic factors, such as long non-coding RNAs (lncRNAs) and DNA methylation, as well as other interacting regulators. Recently, different studies have revealed the importance of NLRP3 levels in predicting drug response. In particular, the methylation of the NLRP3 promoter, which is associated with the inflammasome expression level, emerged as a new promising pharmacoepigenetic biomarker for the glucocorticoid therapy response in several inflammatory disease conditions.},
}

*NLR Family, Pyrin Domain-Containing 3 Protein/genetics/metabolism/antagonists & inhibitors
Humans
Inflammasomes/metabolism/genetics/drug effects
*Precision Medicine/methods
Epigenesis, Genetic
DNA Methylation
Animals
Inflammation/drug therapy

@article {pmid41198506,
year = {2025},
author = {Lafon, PA and Prézeau, L and Pin, JP and Rondard, P},
title = {Nanobodies: a new paradigm for brain disorder therapies.},
journal = {Trends in pharmacological sciences},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.tips.2025.10.004},
pmid = {41198506},
issn = {1873-3735},
abstract = {Camelid-derived nanobodies offer a promising alternative to conventional antibodies for the treatment of brain disorders. Their current development in models of schizophrenia or Alzheimer's disease highlights their strong therapeutic potential. Optimizing their delivery and ensuring their safety are major challenges, but their modularity and low immunogenicity make them promising candidates for neurotherapy.},
}

@article {pmid41198459,
year = {2025},
author = {Zhao, H and Li, F and Xu, S and Du, Y and Chen, P and Wei, J and Hao, K and Liu, X and Liu, H},
title = {Restoration neurite growth by removing the blockage of endosome trafficking in Alzheimer-like mice.},
journal = {Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics},
volume = {},
number = {},
pages = {e00777},
doi = {10.1016/j.neurot.2025.e00777},
pmid = {41198459},
issn = {1878-7479},
abstract = {Synaptic loss is strongly associated with cognitive decline in Alzheimer's disease (AD). Endosomal trafficking dysfunction, observed in AD brains, impairs neurite growth. Because endosomal trafficking is essential for synaptic development, we selected LMTK1, a negative regulator of Rab11/RE pathway, for this study, given its upregulation in AD models. Clinical genomic data from the ADNI (Alzheimer's Disease Neuroimaging Initiative) database were analyzed to evaluate the relationship between LMTK1 and AD. Two AD mouse models, 3xTg and SAMP8, were examined for neurite outgrowth, synaptic density, LMTK1 expression, and recycling endosomes (RE) transport. LMTK1 knockdown was achieved using AAV. The Morris water maze, Golgi staining, immunofluorescence, and electrophysiology experiments were used to assess cognitive function, neurite outgrowth, synaptic density, RE transport, long-term potentiation (LTP), and synaptic transmission. The mechanism of LMTK1 in regulating RE transport was examined through co-immunoprecipitation, proteomics, and point mutation experiments. This study shows that phosphorylated LMTK1 activates TBC1D9B, which deactivates Rab11a and may suppress Rab11a[+] endosome trafficking and neurite growth. Clinical genomics data from the ADNI database support LMTK1's involvement in cognition in AD and possibly in glucose hypometabolism related to synaptic dysfunction. Knocking down LMTK1 improves neurite atrophy and synaptic density loss, likely by enhancing Rab11[+] endosome transport. Restoration of neurite morphology, hippocampal LTP, and cognitive function in AD mice suggest that inhibiting LMTK1 could represent a novel therapy for promoting neurite growth in AD. Hyperphosphorylation of LMTK1 may induce RE transport dysfunction, leading to neurite atrophy in AD mice. Therefore, targeting LMTK1 may offer a promising therapeutic approach for AD therapy.},
}

@article {pmid41198246,
year = {2025},
author = {Chen, M and Xue, M and Li, Y and Huang, W and Liu, L and Chen, Y and Chen, Y and Huang, F and Tu, S and Tang, J and Liu, J and Hu, J},
title = {Convolutional Neural Network-Self-Attention Mechanism Enhanced Near-Infrared: Non-Invasive Breakthrough for Alzheimer's Disease Versus Vascular Dementia.},
journal = {Journal of biophotonics},
volume = {},
number = {},
pages = {e202500383},
doi = {10.1002/jbio.202500383},
pmid = {41198246},
issn = {1864-0648},
support = {62565003//National Natural Science Foundation of China/ ; 12464028//National Natural Science Foundation of China/ ; 62005056//National Natural Science Foundation of China/ ; 2022GXNSFDA080006//Natural Science Foundation of Guangxi Province/ ; },
abstract = {Alzheimer's disease (AD) and vascular dementia (VaD) are two common forms of dementia. Differentiating between them is challenging due to the lack of clear clinical and auxiliary test differences. In this study, we developed a novel diagnostic method combining near-infrared spectroscopy with a convolutional neural network and self-attention mechanism (CNN-SAM). The CNN-SAM model, which integrates the self-attention mechanism to highlight important spectral features, outperformed other models with 99.3% accuracy. Data pre-processing, feature extraction, and parameter optimization further enhanced the model's performance. Visualization using the self-attention mechanism revealed key spectral bands at 1364 and 1484 nm as crucial for distinguishing AD and VaD. This approach offers a rapid, non-invasive, and accurate method for the diagnosis of AD and VaD, potentially advancing clinical practice.},
}

@article {pmid41198224,
year = {2025},
author = {Yadav, D and Knight-Greenfield, A and Moirano, J and Nordvig, A and Salgado, MW and Hamed, M and Lin, M and RoyChoudhury, A and Blum, S and Keil, SA and Intorcia, B and Ebani, EJ and Osborne, J and Chiang, G and Ivanidze, J},
title = {Amyloid PET Z-score Quantification and correlation with visual semiquantitative grading.},
journal = {AJNR. American journal of neuroradiology},
volume = {},
number = {},
pages = {},
doi = {10.3174/ajnr.A9079},
pmid = {41198224},
issn = {1936-959X},
abstract = {BACKGROUND AND PURPOSE: Amyloid PET imaging plays a crucial role in the diagnosis of Alzheimer's disease (AD) and determines eligibility for anti-amyloid therapies. While visual interpretation using Regional Cortical Tracer Uptake (RCTU) and Brain Amyloid Plaque Load (BAPL) scores remains standard in clinical practice, it is subject to inter-reader variability and may not fully depict the amyloid distribution pattern. RCTU scoring evaluates cortical tracer uptake quantified as 1: no uptake, 2: focal and 3: diffuse uptake, while BAPL provides an overall summary score of amyloid plaque load depending on highest RCTU score. Quantitative techniques such as Centiloid scale or Z-scores may assist in diagnosis, grading and treatment monitoring. This study evaluates the feasibility of a Z-score quantification generated from normative database comparison and its correlation with visual RCTU grading.

MATERIALS AND METHODS: We retrospectively analyzed 100 patients who underwent [F18]-Florbetaben PET imaging between August and October 2024 for cognitive impairment. Visual interpretation was performed using RCTU scoring and overall BAPL score. Quantitative Z-scores were calculated for four cortical regions (frontal, parietal, posterior cingulate/precuneus, and lateral temporal) using a normative database. Correlation between visual and quantitative scores was assessed using Spearman's correlation. Z-score differences among RCTU categories were evaluated with Kruskal Wallis and Mann Whitney tests.

RESULTS: Among 100 patients (median age 78), 31 were amyloid negative (BAPL1), and 69 were amyloid positive (11 BAPL2, and 58 BAPL3). A total of 400 cortical regions were evaluated (143 RCTU1, 46 RCTU2, 211 RCTU3). Strong positive correlations were observed between RCTU and Z-scores in all regions (ρ = 0.78-0.88, p < 0.0001). The regional Z-scores showed significant differences between RCTU1 and RCTU2, RCTU1 and RCTU3, as well as between RCTU2 and RCTU3 across all four regions (p<0.05 for all comparisons. Pooled regional analysis also showed statistically significant differences in Z-scores between all RCTU groups (p < 0.0001).

CONCLUSIONS: Quantitative regional Z-scores derived from amyloid PET imaging demonstrate a strong correlation with visual assessment (RCTU score), validating their feasibility in clinical interpretation. These findings support the integration of quantitative tools into routine practice to enhance diagnostic confidence, reduce reader variability, and monitoring for amyloid-targeted therapies.

ABBREVIATIONS: AD = Alzheimer's Disease; RCTU = Regional Cortical Tracer Uptake; BAPL = Brain Amyloid Plaque Load; PiB = Pittsburgh Compound B; SUVR = Standardized Uptake Value Ratio; SPM = Statistical Parametric Mapping; SSP = Stereotactic Surface Projections.},
}

@article {pmid41197937,
year = {2025},
author = {Yuan, J and Zhang, J and Zhang, H and Tu, Y and Li, M},
title = {Propofol induces mitochondrial dysfunction in hippocampal neurons and postoperative cognitive dysfunction in male 3xTg-AD mice by blocking ESRRG-mediated HSD11B2 transcription.},
journal = {Brain research},
volume = {},
number = {},
pages = {150035},
doi = {10.1016/j.brainres.2025.150035},
pmid = {41197937},
issn = {1872-6240},
abstract = {Cognitive dysfunction is a severe issue of Alzheimer's disease (AD). This study explores the molecular mechanisms underlying propofol-induced postoperative cognitive dysfunction (POCD) in AD mice. Triple transgenic AD (3xTg-AD) male mice or control C57/BL6J mice were subjected to propofol anesthesia and abdominal surgery for modeling. AAV-mediated gene intervention was performed on male 3xTg-AD mice prior to propofol anesthesia. Reduced estrogen-related receptor gamma (ESRRG) and hydroxysteroid 11-beta dehydrogenase 2 (HSD11B2) expression was found in the hippocampus of male 3xTg-AD mice. ESRRG overexpression mitigated POCD and hippocampal mitochondrial dysfunction in male 3xTg-AD mice exposed to propofol. This was evidenced by shorter escape latencies, longer target quadrant times, increased platform crossings, reduced malondialdehyde and mitochondrial reactive oxygen species, decreased cytosolic cytochrome C and phosphorylated dynamin-related protein 1 (p-DRP1), and higher mitochondrial membrane potential, though these effects were reversed by HSD11B2 knockdown. In vitro, propofol lowered HT22 cell mitochondrial membrane potential and elevated cytochrome C and p-DRP1, but ESRRG overexpression countered these changes. Ultimately, propofol disrupts ESRRG-mediated HSD11B2 transcription, driving mitochondrial dysfunction and POCD in male 3xTg-AD mice.},
}

@article {pmid41197936,
year = {2025},
author = {Choi, H and Hwang, SB and Cho, HY and Ahn, S and Yun, HY and Song, JS},
title = {Memantine modulates neuroinflammation and motor coordination in a Parkinson's disease model.},
journal = {Brain research},
volume = {},
number = {},
pages = {150034},
doi = {10.1016/j.brainres.2025.150034},
pmid = {41197936},
issn = {1872-6240},
abstract = {Memantine, an NMDA receptor antagonist clinically approved for Alzheimer's disease, has been implicated in modulating neuroinflammatory responses beyond its anti-excitotoxic actions. To explore its potential relevance in Parkinson's disease, this study evaluated memantine's effects in both LPS-activated microglial cells and a synucleinopathy mouse model. In BV-2 cells, memantine elicited a modest but measurable attenuation of TNF-α and IL-6 secretion, which was accompanied by downregulation of TLR4 and IκB signaling. In vivo, 5-month oral administration of memantine to mThy1-αSyn transgenic mice led to moderate improvements in motor function as assessed by beam-walk performance. Immunohistochemical analyses revealed decreased microglial activation in the cerebral cortex; however, phosphorylated α-synuclein accumulation and tyrosine hydroxylase expression remained unaffected. Furthermore, spatial working memory was not improved by treatment. Taken together, these findings suggest that memantine may exert beneficial effects on neuroinflammatory processes and behavioral deficits in PD-relevant models. However, its impact on the hallmark neuropathology of PD appears limited.},
}

@article {pmid41197929,
year = {2025},
author = {Pattanaik, SK and Sahoo, S and Acharya, SK and Barad, PK and Pattanaik, S and Rath, D},
title = {Crateva magna (Lour.) DC ameliorates rheumatoid arthritis via TNF-signalling pathways: An integration of in-silico, in-vitro and in-vivo approach.},
journal = {Journal of ethnopharmacology},
volume = {},
number = {},
pages = {120854},
doi = {10.1016/j.jep.2025.120854},
pmid = {41197929},
issn = {1872-7573},
abstract = {Crateva magna (Lour.) DC., used in traditional Indian medicine systems such as Ayurveda and Unani, is known for its anti-diabetic, anti-cancer, anti-Alzheimer's, and anti-inflammatory properties. Despite extensive ethnomedicinal applications, its therapeutic role in rheumatoid arthritis (RA) has not yet been scientifically executed.

AIM OF THE STUDY: This study utilized a systematic approach to examine the effects of C. magna on RA.

MATERIALS AND METHODS: Phytoconstituents investigation of C. magna using HR-LCMS-QTOF-MS/MS. Followed by a series of in-silico (network pharmacology, molecular docking), in-vitro (on TNF-α-induced inflammation on SW982), and lastly in-vivo (CFA-induced arthritis model in rats), was adopted to investigate the effects of C. magna.

RESULTS: From C. magna, fifteen compounds were tentatively identified. A network was constructed in which six active phytocompounds and the top ten potential targets were scrutinised. Further, GO and KEGG enrichment analysis were performed. The KEGG mapper was used to execute the pathway where C. magna exhibits anti-arthritis effects by modulating the TNF signalling pathway. Further Molecular docking revealed that all the compounds exhibit good binding affinity towards the target proteins involved in TNF signalling pathways. Lastly, the in-vitro and in-vivo findings suggest that C. magna effectively alleviates the arthritis symptoms and effectively attributes the downstream target genes involved in the TNF signalling pathway.

CONCLUSION: Overall, this study concludes that C. magna potentially alleviates RA via downregulating the TNF signalling pathway. This study supports the traditional use of C. magna against RA and suggests it is a good therapeutic candidate.},
}

@article {pmid41197914,
year = {2025},
author = {Yang, J and Xue, W and Zheng, W and Zhang, H and Tang, C},
title = {Psychiatric symptoms and alzheimer's disease: Depression-anxiety comorbidity effects and their neurobiological mediating mechanisms.},
journal = {Journal of affective disorders},
volume = {},
number = {},
pages = {120594},
doi = {10.1016/j.jad.2025.120594},
pmid = {41197914},
issn = {1573-2517},
abstract = {BACKGROUND: Depression and anxiety are common in Alzheimer's disease (AD), but their mechanisms of impact on disease progression remain unclear. This study investigates the relationships between psychiatric symptoms and AD, exploring potential neurobiological mediating mechanisms.

METHODS: The study analyzed 6209 participants divided into four groups: AD control, AD with depression, AD with anxiety, and AD with comorbid depression and anxiety. Multivariate regression and structural equation modeling assessed the impact of psychiatric symptoms on AD onset, examining 8 potential mediating variables: tau pathology, amyloid pathology (CRREAD score, Thal score), brain weight, cortical atrophy, hippocampal atrophy, Lobar score and APOE genotype, while controlling for age, gender, and education.

RESULTS: Both depressive (β = -1.8 years) and anxiety symptoms (β = -1.5 years) were associated with earlier AD onset, with a more significant effect when coexisting (β = -2.3 years). Depressive symptoms primarily affected executive function through cortical atrophy (32 %) and tau pathology (24 %), while anxiety symptoms mainly influenced memory function through hippocampal atrophy (61 %). The APOE ε4 allele significantly moderated these relationships, with more pronounced effects in ε4 carriers. Subgroup analyses showed more evident impacts in females and late-onset AD.

CONCLUSION: The study provides evidence that depressive and anxiety symptoms are associated with earlier AD onset and affect cognitive function through specific neuropathological pathways. These findings highlight the importance of screening and treating psychiatric symptoms in AD patients and suggest potential intervention strategies.},
}

@article {pmid41197782,
year = {2025},
author = {Ella, FA and Tchamgoue, J and Ambamba, BDA and Mountessou, BYG and Essouman, FM and Essola, NN and Wilhelm, A and Ngondi, JL and Njayou, FN and Kouam, SF},
title = {Anti-Alzheimer potential of Biflavonoids from Allanblackia floribunda: Multi-target inhibition of monoamine oxidase, β-secretase, and glycogen synthase kinase-3β.},
journal = {Fitoterapia},
volume = {},
number = {},
pages = {106967},
doi = {10.1016/j.fitote.2025.106967},
pmid = {41197782},
issn = {1873-6971},
abstract = {The pathogenesis of Alzheimer's disease (AD) is complex, involving multiple interrelated pathways. Consequently, developing multi-target-directed ligands may represent an effective therapeutic strategy. This study investigates the anti-Alzheimer potential of two biflavonoids isolated from Allanblackia floribunda against monoamine oxidase A (MAO-A), β-secretase (BACE-1), and glycogen synthase kinase-3β (GSK-3β), three key enzymes implicated in AD progression. The biflavonoids, (2S,3S)-volkensiflavone-7-O-β-glucopyranoside (1) and (2R,3S)-volkensiflavone-7-O-β-D-acetylglucopyranoside (2), were purified and structurally identified using spectroscopic methods. Enzymatic fluorimetric assays were conducted to assess their inhibition of MAO-A, BACE-1, and GSK-3β. The mode and reversibility of inhibition were characterized for both compounds, confirming them as potent MAO-A inhibitors. In silico simulations were performed on the three enzymes to gain insights into their interactions and modes of action. Compounds 1 and 2 were found to be reversible and moderately selective MAO-A inhibitors with IC50 of 35.85 ± 0.03 μM and 25.54 ± 0.05 μM, respectively. These compounds strongly inhibited BACE1 (IC50 = 2.48 ± 0.11 μM and 2.50 ± 0.17 μM, respectively) and GSK-3β (IC50 = 9.39 ± 0.06 μM and 7.17 ± 0.09 μM, respectively). In conclusion, this study is the first to report these compounds as triple inhibitors of MAO-A, BACE-1, and GSK-3β, offering a promising new therapeutic strategy for AD. Molecular docking simulations supported the observed interactions, reinforcing the selective potential of these inhibitors towards target enzymes. The lack of ethnobotanical precedent regarding the use of A. floribunda for managing neurological conditions highlights the novelty of the current study, which reveals, for the first time, the anti-Alzheimer activity of biflavonoids derived from this plant. This underscores the value of scientific investigation in uncovering previously unknown pharmacological properties of traditionally used plants.},
}

@article {pmid41197760,
year = {2025},
author = {Yao, M and Li, Z and Lin, Y and Cai, H and Sun, C and Liu, L and Long, Y and Ge, Z},
title = {Hyperbaric oxygen therapy ameliorates Alzheimer's disease pathology by restoration of mitophagy and suppressing neuroinflammation in 5xFAD mice.},
journal = {Experimental neurology},
volume = {},
number = {},
pages = {115534},
doi = {10.1016/j.expneurol.2025.115534},
pmid = {41197760},
issn = {1090-2430},
abstract = {Alzheimer's disease (AD) is characterized by amyloid-β (Aβ) accumulation, synaptic dysfunction, and chronic neuroinflammation. Here, we demonstrate that hyperbaric oxygen therapy (HBOT) has multiple therapeutic effects in 5xFAD transgenic mice. HBOT significantly improved cognitive function. Treated mice increasingly moved to the center of the open field in Y-maze tests and preferred a new arm. Longitudinal [18]F-AV-45 PET-MR scans showed progressive reduction in amyloid tracer uptake, which was corroborated by histologically verified reduced plaque burden and upregulation of LRP1, a key Aβ clearance transporter. HBOT preserved neuronal density and enhanced synaptic proteins. Mechanistically, HBOT promoted mitochondrial quality control by upregulating PINK1 and parkin expression, enhancing autophagosome formation, and modulating mitophagy-associated pathways. The transition of microglia to a surveillance phenotype was reflected in decreased soma area and increased branching. The coordinated improvement in amyloid clearance, mitochondrial quality control and synaptic maintenance, and modulation of neuroinflammation suggest that the ability of HBOT to simultaneously act on multiple pathological cascades-in combination with its noninvasive nature and favorable safety profile-makes it a uniquely promising therapeutic strategy. Furthermore, these results suggest that HBOT may be particularly effective at an early stage of the disease. These studies will be critical in establishing the clinical applicability of HBOT in the treatment of Alzheimer's disease.},
}

@article {pmid41197759,
year = {2025},
author = {Zheng, Z and Chen, C and Zhu, S and Zhu, X and Tu, H and Ding, X and Xia, T and Gu, X},
title = {TERT activator compound alleviates cigarette smoke-induced cognitive deficits by modulating hippocampal inflammation and neurogenesis: A comprehensive study integrating Mendelian randomization.},
journal = {Experimental neurology},
volume = {},
number = {},
pages = {115543},
doi = {10.1016/j.expneurol.2025.115543},
pmid = {41197759},
issn = {1090-2430},
abstract = {Cigarette smoking represents a major public health concern, yet its relationship with cognitive function remains controversial. Here, we integrated two-sample Mendelian randomization (MR) with an in vivo model to interrogate this relationship and evaluate a telomerase-based intervention. Two-sample MR provided genetic evidence for a causal effect of smoking behaviors on increased Alzheimer's disease (AD) risk in East Asian and European populations. Guided by these findings, we established a mouse model of cigarette smoke exposure using cigarette smoke extract (CSE) and confirmed significant neurocognitive impairment by fear conditioning and Y-maze behavioral tests. We also found that CSE elicited robust hippocampal inflammation, evidenced by increased IBA1 and elevated pro-inflammatory cytokines (IL-6, IL-1β, TNF-α). This inflammatory milieu was accompanied by reduced hippocampal brain-derived neurotrophic factor (BDNF) and compromised adult hippocampal neurogenesis (AHN), reflected by decreased doublecortin (DCX) expression. Bulk RNA sequencing with gene set enrichment analysis indicated downregulation of telomere maintenance gene set after CSE exposure, and RT-qPCR and Western blotting verified the suppression of telomerase reverse transcriptase (TERT) in the hippocampus. Notably, intraperitoneal administration of a TERT activator compound (TAC) to CSE-treated mice restored hippocampal TERT expression, attenuated neuroinflammation, enhanced BDNF levels and AHN, and ameliorated cognitive deficits. To sum up, our findings integrate population-based genetic evidence with experimental validation to show that cigarette smoke exposure impairs cognition and that pharmacologic activation of TERT confers neuroprotection, highlighting TERT as a promising therapeutic target for smoking-related cognitive disorders.},
}

@article {pmid41197747,
year = {2025},
author = {Ozturk, B and Demir, H and Silindir-Gunay, M and Akdag, Y and Sahin, S and Gulsun, T},
title = {Application of Artificial Neural Network to Determine Optimum Formulation Development and In Vitro Characterization of Methylene Blue and Galantamine Loaded Polymeric Nanoparticles for the Treatment of Alzheimer's Disease.},
journal = {European journal of pharmaceutical sciences : official journal of the European Federation for Pharmaceutical Sciences},
volume = {},
number = {},
pages = {107364},
doi = {10.1016/j.ejps.2025.107364},
pmid = {41197747},
issn = {1879-0720},
abstract = {Alzheimer's disease is a major neurodegenerative disorder characterized by complex pathophysiology and currently lacks a curative treatment. This study aims to develop and characterize methylene blue and galantamine co-loaded PLGA nanoparticles, surface-modified with poloxamer 188 and GSH, to increase blood residence time and improve brain-targeted delivery. The nanoparticles were prepared using the double emulsion solvent evaporation method, and their physicochemical properties were characterized by TEM, FT-IR, DSC, XRD, and [13]C NMR. Artificial neural network modeling was used to optimize the formulation parameters, including PLGA %, PVA %, and sonication time, for predicting particle size and encapsulation efficiencies of methylene blue and galantamine. Results showed that the optimized nanoparticles had particle sizes less than 200 nm, appropriate zeta potential, and high encapsulation efficiencies. DSC, FT-IR, XRD, and NMR analyses confirmed the absence of crystalline peaks for methylene blue and galantamine, indicating successful encapsulation. Artificial neural network models demonstrated high predictive accuracy, serving as a valuable tool for formulation optimization. This dual-drug, surface-modified nanoparticle approach offers promising potential for multi-target therapy in Alzheimer's disease.},
}

@article {pmid41197707,
year = {2025},
author = {Malarvannan, M and Naik, SBT and Soni, N and Mandar, CM and Paul, D},
title = {Exploring lipidomics in biomarker discovery.},
journal = {Clinica chimica acta; international journal of clinical chemistry},
volume = {},
number = {},
pages = {120698},
doi = {10.1016/j.cca.2025.120698},
pmid = {41197707},
issn = {1873-3492},
abstract = {Lipidomics, a fast-growing area of systems biology, provides an in-depth look at lipid species and how they dynamically change in healthy and diseased conditions. Lipids are increasingly understood to be bioactive molecules regulating inflammation, metabolic homeostasis, and cellular signaling, lipidomics has become a potent tool for finding new biomarkers for a wide range of clinical diseases and disorders. To identify disease-specific lipid signatures and biomarkers across various conditions, such as metabolic disorders (e.g., diabetes, obesity), cardiovascular diseases, neurodegenerative diseases (e.g., Alzheimer's, Parkinson's), cancer, and inflammatory disorders. Despite significant advancements, routine integration of lipidomics into clinical practice is hindered by problems such as inter-laboratory variability, data standardization, lack of defined procedures, and insufficient clinical validation. In this study, we examined the significance of lipidomics in various clinical applications, providing a thorough summary of lipidomic markers that have already been investigated and demonstrated their potential. We also discuss the importance of lipidomics methodologies and their comparisons, as well as lipidomics in biomarker discovery. Challenges in the lipidomic biomarker validation process and the translational potential of lipidomics in clinical settings are addressed, along with prospects for lipidomics research, which helps readers understand the future of lipidomic biomarkers. Ultimately, lipidomics-driven biomarker discovery is a revolutionary method that connects fundamental lipid research with clinical application. It has encouraging significance for risk assessment, early diagnosis, and targeted therapy plans for various human diseases and disorders.},
}

@article {pmid41197657,
year = {2025},
author = {Hansen, N and Wiltfang, J},
title = {[News on blood biomarker-based early diagnosis of the preliminary stages of Alzheimer's dementia].},
journal = {Fortschritte der Neurologie-Psychiatrie},
volume = {93},
number = {11},
pages = {446-452},
doi = {10.1055/a-2698-5992},
pmid = {41197657},
issn = {1439-3522},
mesh = {Humans ; *Alzheimer Disease/diagnosis/blood ; *Biomarkers/blood ; Early Diagnosis ; tau Proteins/blood ; Amyloid beta-Peptides/blood ; Cognitive Dysfunction/diagnosis/blood ; },
abstract = {The early diagnosis of Alzheimer's disease (ADD) has gained new significance through the further discovery of blood biomarkers. Blood biomarkers are less expensive, can be measured fully automatically with high throughput, are less invasive and provide faster information on specific dementia biomarkers than current methods used in routine clinical practice such as amyloid positron emission tomography (PET) or CSF examination of underlying pathological changes in Alzheimer's disease (AD) in patients with cognitive impairment. The aim of this review is to provide a presentation of the added value of blood-based biomarkers for the early diagnosis of ADD. Individual blood biomarkers are presented regarding their diagnostic reliability and predictive value for the diagnosis of AD in precursors of ADD ranging from subjective cognitive impairment (SCD) to mild cognitive impairment (MCI). In addition, the revised criteria for the diagnosis and staging of AD are discussed. Markers of tau pathology such as a phosphorylated tau protein 217 (p-tau217), a phosphorylated tau protein 181 (p-tau181), a phosphorylated tau protein 231 (p-tau231), but also amyloid-β (Aβ) markers such as the ratio of Aβ1-42/ 1-40 are described as specific biomarkers for the early diagnosis of AD. In addition, new amyloid peptide ratios such as Aβ-3-42/-3-40 are discussed, which may provide more insights into the pathogenesis of AD, as this N-terminal elongated Aβ peptides are cleaved from the amyloid precursor protein via a biochemical oligodendroglia-dependent pathway (ADAMTS4=disintegrin and metalloproteinase with thrombospondin motifs 4), which is important in AD pathophysiology due to oligodendroglia involvement. In addition, new promising composite hybrid ratios are explained, which could provide advantages in the early diagnosis of AD, such as the AT217-term or the AT181-term, which relates Aβ1-40 to Aβ1-42 and multiplies it by p-tau217 and p-tau181, respectively. Overall, the review provides an overview of the potential of blood biomarkers in the early diagnosis of ADD. However, these biomarkers should not be used alone for early diagnosis, but should always be evaluated in conjunction with other tests such as cerebrospinal fluid analysis.},
}

Humans
*Alzheimer Disease/diagnosis/blood
*Biomarkers/blood
Early Diagnosis
tau Proteins/blood
Amyloid beta-Peptides/blood
Cognitive Dysfunction/diagnosis/blood

@article {pmid41197609,
year = {2025},
author = {Margolis, MP and Tang, M and Gagliardi, M and Wen, C and Wu, Y and Wray, NR and Ziller, MJ and Gandal, MJ},
title = {From variants to mechanisms: Neurogenomics in the post-GWAS era.},
journal = {Neuron},
volume = {113},
number = {21},
pages = {3509-3529},
doi = {10.1016/j.neuron.2025.10.014},
pmid = {41197609},
issn = {1097-4199},
mesh = {Humans ; *Genome-Wide Association Study ; *Genomics/methods ; Autism Spectrum Disorder/genetics ; Genetic Predisposition to Disease/genetics ; Schizophrenia/genetics ; *Mental Disorders/genetics ; Alzheimer Disease/genetics ; Machine Learning ; *Genetic Variation/genetics ; Multifactorial Inheritance ; },
abstract = {Genome-wide association studies (GWASs) have identified thousands of variants associated with neuropsychiatric disorders (NPDs), including autism spectrum disorder (ASD), schizophrenia (SCZ), and Alzheimer's disease (AD). However, deciphering the "causal" biological mechanisms and pathways through which these variants act remains a major obstacle that hinders translational understanding of NPD pathogenesis. NPDs are highly polygenic with contributions from pleiotropic variants across the allelic spectrum, most of which reside within large haplotype blocks in non-coding regions of the genome. Successful mechanistic insight requires identifying disease-relevant cell types and states, mapping variant-to-gene effects, and integrating findings across loci, at scale, to pinpoint pathways of polygenic convergence. Here, we discuss functional genomic, machine learning, and experimental approaches to address each step of this daunting challenge. Ultimately, the convergence of results-across methodologies and within key underlying disease pathways-will be essential to realizing the promise of clinical translation for common, complex brain disorders.},
}

Humans
*Genome-Wide Association Study
*Genomics/methods
Autism Spectrum Disorder/genetics
Genetic Predisposition to Disease/genetics
Schizophrenia/genetics
*Mental Disorders/genetics
Alzheimer Disease/genetics
Machine Learning
*Genetic Variation/genetics
Multifactorial Inheritance