@article {pmid41248283,
year = {2025},
author = {Akhter, F and Akhter, A and Zhu, X and Schiff, H and Maffei, A and Douglas, JT and Zhou, Q and Zhao, Z and Zhu, D},
title = {Amyloid-beta glycation induces neuronal mitochondrial dysfunction and Alzheimer's pathogenesis via VDAC1-dependent mtDNA efflux.},
journal = {Proceedings of the National Academy of Sciences of the United States of America},
volume = {122},
number = {47},
pages = {e2505046122},
doi = {10.1073/pnas.2505046122},
pmid = {41248283},
issn = {1091-6490},
mesh = {Animals ; *Voltage-Dependent Anion Channel 1/metabolism/genetics ; *Alzheimer Disease/metabolism/pathology/genetics ; Mice ; Humans ; *Mitochondria/metabolism/pathology ; *Neurons/metabolism/pathology ; *Amyloid beta-Peptides/metabolism ; *DNA, Mitochondrial/metabolism/genetics ; Nucleotidyltransferases/metabolism/genetics ; Membrane Proteins/metabolism/genetics ; Receptor for Advanced Glycation End Products/metabolism/genetics ; Glycation End Products, Advanced/metabolism ; Mice, Transgenic ; Glycosylation ; Male ; },
abstract = {Glycation, the nonenzymatic attachment of reactive dicarbonyls to proteins, lipids, or nucleic acids, contributes to the formation of advanced glycation end-products (AGEs). In Alzheimer's disease (AD), amyloid-beta (Aβ) undergoes posttranslational glycation to produce glycated Aβ (gAβ), yet its pathological role remains poorly understood. Here, we demonstrate that gAβ promotes neuronal mitochondrial DNA (mtDNA) efflux via a VDAC1-dependent mechanism, activating the innate immune cGAS-STING pathway. Using aged AD mice and human AD brain samples, we observed cGAS-mtDNA binding and cGAS-STING activation in the neuronal cytoplasm. Knockdown of RAGE, cGAS, or STING, as well as pharmacological inhibition of VDAC1, protected APP mice from mitochondrial dysfunction and Alzheimer's-like pathology. Neuron-specific cGAS knockdown confirmed its pivotal role in driving neuroinflammation and cognitive deficits. Treatment with ALT-711, an AGE cross-link breaker, alleviated gAβ-associated pathology. Furthermore, RAGE inhibition in APP knock-in mice suppressed innate immune activation and disease-associated gene expression, as revealed by spatially resolved transcriptomics. Collectively, our findings establish a mechanistic link between gAβ and innate immune activation, identifying VDAC1, the AGE-RAGE axis, and the cGAS-STING pathway as promising therapeutic targets in AD.},
}

Animals
*Voltage-Dependent Anion Channel 1/metabolism/genetics
*Alzheimer Disease/metabolism/pathology/genetics
Mice
Humans
*Mitochondria/metabolism/pathology
*Neurons/metabolism/pathology
*Amyloid beta-Peptides/metabolism
*DNA, Mitochondrial/metabolism/genetics
Nucleotidyltransferases/metabolism/genetics
Membrane Proteins/metabolism/genetics
Receptor for Advanced Glycation End Products/metabolism/genetics
Glycation End Products, Advanced/metabolism
Mice, Transgenic
Glycosylation
Male

@article {pmid41248192,
year = {2025},
author = {Gehrman, P and McDonald, T and Barilla, H and Lee, R and Harrell, M and Kayser, MS},
title = {Insomnia disorder and cerebrospinal fluid markers of dementia.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877251395091},
doi = {10.1177/13872877251395091},
pmid = {41248192},
issn = {1875-8908},
abstract = {Sleep disturbance may increase risk of Alzheimer's disease and related dementias (ADRD). Acute sleep deprivation increases cerebrospinal fluid (CSF) levels of amyloid-β, but the impact of chronic insomnia remains unclear. We compared 13 adults aged 30-60 with Insomnia Disorder to matched good sleepers. After overnight polysomnography a lumbar puncture was performed to collect CSF for assays of ADRD biomarkers. Contrary to our hypotheses, we found no significant differences in objective sleep measures or any CSF biomarkers, except for lower levels of neurofilament light. These findings suggest that mild-to-moderate Insomnia Disorder may not increase ADRD biomarkers, contrasting with effects of acute sleep deprivation.},
}

@article {pmid41248184,
year = {2025},
author = {Wang, Z},
title = {Imaging biomarkers of vascular cognitive impairment: Lessons from structural progression in cerebral small vessel disease.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877251396050},
doi = {10.1177/13872877251396050},
pmid = {41248184},
issn = {1875-8908},
abstract = {The study by Lu et al. highlights progressive structural changes in cerebral small vessel disease, spanning subcortical vascular mild cognitive impairment to vascular dementia. Using voxel-based morphometry, diffusion tensor imaging, and fixel-based analysis, the authors demonstrate converging gray and white matter alterations associated with both cognitive and motor decline. This commentary discusses the significance of their multimodal approach, its clinical implications for early diagnosis and disease monitoring, and the methodological challenges of generalizability and mixed pathology. We situate these findings within the broader literature on vascular cognitive impairment and emphasize directions for biomarker-driven translational research.},
}

@article {pmid41248175,
year = {2025},
author = {Georgescu, MF},
title = {Agitation and neuropsychiatric symptoms in Alzheimer's disease: Potential for reverse causal associations.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877251396056},
doi = {10.1177/13872877251396056},
pmid = {41248175},
issn = {1875-8908},
abstract = {Agitation is a common complex neuropsychiatric symptom in older adults. Agitation is well-interconnected with other neuropsychiatric symptoms (NPS). A recent study by Nagata and colleagues examined correlates between agitation and NPS in each dementia stage, ranging from mild to moderate and severe, using data from the Clinical Antipsychotic Trials of Intervention Effectiveness-Alzheimer's Disease. They found irritability consistently correlates with agitated behaviors in moderate and severe stages of Alzheimer's disease (AD), and sleep disorders influence the agitation in the severe stage of AD. Here, we discuss the strengths and limitations of the study and highlight potential reverse causality of NPS and AD.},
}

@article {pmid41247916,
year = {2025},
author = {Koenig, KA and Huang, X and Bonner-Jackson, A and Leverenz, JB and Lowe, MJ and Pillai, JA},
title = {Patterns of cortical atrophy are associated with specific cognitive domains in patients with logopenic primary progressive aphasia.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877251392928},
doi = {10.1177/13872877251392928},
pmid = {41247916},
issn = {1875-8908},
abstract = {BackgroundLogopenic primary progressive aphasia (LPA) is often associated with Alzheimer's disease (AD) pathology. However, few studies have compared cortical atrophy patterns in LPA and AD and their association with cognitive performance.ObjectiveTo identify atrophy patterns specific to LPA and determine whether those patterns relate to deficits in specific cognitive domains.MethodsElectronic health records from 2014-2024 were retrospectively reviewed to identify patients with LPA who had undergone MRI and neuropsychological (NP) examinations. Patients with LPA (n = 26) were matched in terms of age, sex, education, and symptom duration to patients with amnestic mild cognitive impairment (aMCI; n = 13). Logistic regression was used to assess group differences in MRI measures of cortical volume and thickness. Cluster analysis was used to identify patterns of atrophy that were associated with specific cognitive domains.ResultsThe LPA group performed significantly worse than the aMCI group on NP measures assessing verbal learning, attention/working memory, language, and executive functioning (p < 0.05). Compared to the aMCI group, the LPA group demonstrated both smaller and thinner cortex in the left lateral aspect of the superior temporal gyrus, superior temporal sulcus, and fusiform gyrus (p < 0.05), with the left superior temporal sulcus providing the most accurate measure of discrimination. Severity of language related cognitive deficits was not associated with a specific cluster in the LPA group.ConclusionsPatients with LPA demonstrate specific patterns of cortical atrophy that are distinguishable from atrophy due to aMCI and may be useful for diagnostic purposes.},
}

@article {pmid41247839,
year = {2025},
author = {Čihák, M and Bezdicek, O and Nikolai, T and Georgi, H and Kopeček, M},
title = {The extended Czech uniform data set 2.0 neuropsychological battery: Reliable change indices and logistic regression analysis.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877251392270},
doi = {10.1177/13872877251392270},
pmid = {41247839},
issn = {1875-8908},
abstract = {BackgroundEarly identification of cognitive decline is crucial for diagnosing neurocognitive disorders at a stage when interventions may be most effective. Longitudinal neuropsychological assessment plays a key role in this process. However, distinguishing genuine cognitive decline from normal age-related variability remains a significant clinical challenge.ObjectiveThis study aimed to provide Reliable Change Indices (RCIs) and regression-based models for evaluating cognitive trajectories using the Czech version of the Uniform Data Set 2.0 (UDS 2.0) neuropsychological battery, enhanced with additional tests.MethodsBased on a longitudinal study of 197 cognitively normal older adults, we computed various RCIs, alongside logistic regression models predicting follow-up scores from baseline data and demographic variables.ResultsSignificant practice effects with small effect sizes were found only for a subset of tests, while other measures remained stable over time. Regression-based models allow for a nuanced interpretation of individual change trajectories, with baseline score being the most consistent predictor.ConclusionsThe provided indices and statistical tools support clinicians in making data-driven decisions regarding cognitive changes in individual patients. These findings enhance the clinical utility of neuropsychological assessments and may contribute to the early detection of pathological cognitive decline, including Alzheimer's disease-related decline.},
}

@article {pmid41247815,
year = {2025},
author = {Rathnam, M and Hunter, H and Paul, PS and Schirrmacher, R and Serpe, MJ and Kar, S},
title = {Native PEG-PLGA Attenuates β-Amyloid Aggregation and Toxicity under In Vitro Conditions.},
journal = {ACS chemical neuroscience},
volume = {},
number = {},
pages = {},
doi = {10.1021/acschemneuro.5c00379},
pmid = {41247815},
issn = {1948-7193},
abstract = {Self-aggregation of amyloid-β (Aβ) peptide plays a key role in the pathogenesis of Alzheimer's disease (AD), the most prevalent cause of dementia affecting the elderly population. The development of an effective treatment for AD pathology remains elusive due to the presence of the blood-brain barrier (BBB) and the heterogeneous nature of disease progression. Recently, we reported that FDA-approved native poly(d,l-lactic-co-glycolic acid) (PLGA) nanoparticles without any conjugated/encapsulated agent can attenuate Aβ aggregation/toxicity in cellular and animal models of AD. Given the limitation associated with the fast clearance of the native PLGA by the reticuloendothelial system (RES), in the present study, we synthesized PEGylated native PLGA nanoparticles (PEG-PLGA-1) to reduce their clearance via the RES and evaluated their effects on Aβ aggregation/toxicity after biochemical and structural characterization. Determined with Thioflavin T kinetic assay, dynamic light scattering and fluorescence imaging, it was revealed that the native PEG-PLGA-1, which exhibits increased stability, not only inhibits the aggregation of Aβ peptides, but also triggers the disassembly of Aβ aggregates. Additionally, we showed that PEG-PLGA-1 are nontoxic and can significantly enhance the viability of mouse primary cortical cultured neurons against Aβ-mediated toxicity. Collectively, these results suggest that native PEG-PLGA-1 nanoparticles can inhibit Aβ aggregation and trigger disassembly of Aβ aggregates and can protect neurons against Aβ-mediated toxicity, thus suggesting their unique therapeutic potential in the treatment of AD pathology.},
}

@article {pmid41247623,
year = {2025},
author = {Dosseto, A and Tonge, K and Karl, T},
title = {Cannabidiol Modulates Brain Copper Homeostasis in Wild-Type-Like But Not Alzheimer's Disease Transgenic Female Mice: Implications for Neuroprotective Therapy.},
journal = {Molecular neurobiology},
volume = {63},
number = {1},
pages = {57},
pmid = {41247623},
issn = {1559-1182},
mesh = {Animals ; *Copper/metabolism ; Mice, Transgenic ; *Alzheimer Disease/metabolism/drug therapy/pathology ; Female ; *Cannabidiol/pharmacology/therapeutic use ; *Homeostasis/drug effects ; *Brain/metabolism/drug effects/pathology ; *Neuroprotective Agents/pharmacology/therapeutic use ; Mice ; Iron/metabolism ; Mice, Inbred C57BL ; },
abstract = {Alzheimer's disease (AD) is a progressive neurodegenerative disorder marked by cognitive decline, synaptic dysfunction, and neuroinflammation. Disrupted metal homeostasis-especially copper (Cu), zinc (Zn), and iron (Fe)-is implicated in AD pathogenesis, contributing to amyloid-beta (Aβ) aggregation and oxidative stress. Cannabidiol (CBD), a non-toxic phytocannabinoid with antioxidant and neuroprotective properties, has unclear effects on brain metal regulation. Using high-resolution laser ablation-inductively coupled plasma mass spectrometry (LA‑ICP‑MS), we quantified regional metal distributions in sagittal brain sections from 12‑month‑old female wild‑type (WT) and APP/PS1 transgenic mice treated chronically with CBD or vehicle. CBD significantly elevated whole‑brain Cu in WT mice but not in APP/PS1 mice. Although Zn and Fe concentrations did not differ significantly, effect-size trends revealed regional differences in Cu and Zn patterns across treatment groups, particularly in the hippocampus. Correlation analysis revealed coordinated inter‑regional metal regulation in WT and vehicle‑treated APP/PS1 groups, which was disrupted in CBD‑treated APP/PS1 mice. Additionally, CBD‑treated WT mice exhibited increased variance in cerebellar Cu, suggesting individual differences in response. These findings suggest that CBD influences Cu homeostasis in WT animals, though not significantly altered in transgenic animals under the conditions tested. Our results support integrating spatially resolved metallomics into preclinical AD frameworks and highlight the utility of metrics beyond mean concentration-such as regional ratios, correlation structures, and variability-for detecting subtle treatment effects.},
}

Animals
*Copper/metabolism
Mice, Transgenic
*Alzheimer Disease/metabolism/drug therapy/pathology
Female
*Cannabidiol/pharmacology/therapeutic use
*Homeostasis/drug effects
*Brain/metabolism/drug effects/pathology
*Neuroprotective Agents/pharmacology/therapeutic use
Mice
Iron/metabolism
Mice, Inbred C57BL

@article {pmid41247426,
year = {2025},
author = {Xiong, Y},
title = {Future Directions for Studying the Potential of Mammalian Dscam in Autism Spectrum Disorder and Alzheimer's Disease: Insights from Dose Sensitivity.},
journal = {Molecular neurobiology},
volume = {63},
number = {1},
pages = {61},
pmid = {41247426},
issn = {1559-1182},
support = {202311544//Health Commission of Jiangxi Province/ ; 2022A001//Jiangxi Provincial Administration of Traditional Chinese Medicine/ ; S2023ZDYFN545//Science and Technology Bureau of Jiujiang/ ; },
mesh = {Animals ; Humans ; *Autism Spectrum Disorder/genetics/metabolism ; *Alzheimer Disease/genetics/metabolism ; *Cell Adhesion Molecules/metabolism/genetics ; Mammals/metabolism ; Protein Isoforms/metabolism ; },
abstract = {Down syndrome cell adhesion molecule (Dscam), a macromolecular member of the immunoglobulin (Ig) superfamily, is widely distributed in the nervous system. Over the past few decades, significant progress has been made in studies of the Dscam gene and its protein products across multiple species, advancing our understanding of its alternative splicing mechanisms, isoform-specific homophilic binding properties, and crucial neurological functions during neural development. In Drosophila, the Dscam gene undergoes extensive alternative splicing, generating thousands of isoforms that differ in their extracellular and/or transmembrane domains. These isoforms confer unique cellular identities and mediate cell-cell recognition and downstream signaling cascades primarily via homophilic interactions. In contrast, mammalian Dscam lacks the extreme alternative splicing and vast isoform diversity found in Drosophila, yet it retains crucial neurological functions. Studies indicate that the expression levels serve as an important regulator of Dscam-dependent neural processes, underlying its dosage-sensitive phenotypes. Abnormal Dscam expression has been implicated in the pathology of several neurological diseases. For example, heterozygous loss of Dscam function is convincingly associated with autism spectrum disorder (ASD), while trisomy of the Dscam gene is linked to Down syndrome (DS). Recent studies also suggest a connection between Dscam overexpression and Alzheimer's disease (AD), implicating Dscam in previously unrecognized neurodegenerative mechanisms. However, efforts to clarify Dscam's role in the neuropathology of diseases are severely hampered by the etiological and phenotypic heterogeneity of these diseases, necessitating novel approaches. This review integrates cross-species evidence on Dscam's dose sensitivity to elucidate the molecular mechanisms behind its dosage-dependent phenotypes in mammals, thereby advancing the understanding of how dysregulated Dscam expression contributes to phenotypic heterogeneity in ASD and disease onset in AD. Insights into Dscam's dose sensitivity highlight that alterations in dosage likely perturb genetic regulatory networks, leading to nonlinear phenotypic consequences through multi-level molecular interactions. Therefore, we propose a biphasic framework to address current mechanistic challenges in future research: (1) systematic identification of key regulatory nodes within genetic networks using emerging big-data methodologies, followed by (2) mechanistic validation through targeted experimental studies of prioritized molecular pathways. These efforts may establish Dscam as a promising therapeutic target for modulating pathological cascades in both ASD and AD.},
}

Animals
Humans
*Autism Spectrum Disorder/genetics/metabolism
*Alzheimer Disease/genetics/metabolism
*Cell Adhesion Molecules/metabolism/genetics
Mammals/metabolism
Protein Isoforms/metabolism

@article {pmid41247384,
year = {2025},
author = {Schönberger, A and Schild, AK and Steinmetz, A and Simandi, F and Benson, GS and Hausner, L and Schöttler, M and Hennig, B and Knudsen, A and Maier, F and Frölich, L and Jessen, F},
title = {[Optimization of the work of outpatient memory clinics under aspects of value-based healthcare-An approach from the Center for Memory Disorders of the University Hospital Cologne].},
journal = {Der Nervenarzt},
volume = {},
number = {},
pages = {},
pmid = {41247384},
issn = {1433-0407},
abstract = {BACKGROUND: Memory clinics in Germany are facing major challenges due to increasing numbers of patients and the first available disease-modifying treatments for Alzheimer's disease. Capacities for counselling, biomarker-based diagnostics, drug administration and follow-up examinations must be achieved, which creates the need for modified workflows. Value-based healthcare (VBHC) aims at optimizing the value for patients (outcome in relation to costs) and can serve as a framework for a patient-oriented increase in efficacy.

OBJECTIVE: This project applied approaches of VBHC to analyze and improve the diagnostic processes in our memory clinic in order to achieve a better value for patients and care partners with a more efficient use of existing resources.

METHODS: In a first survey among memory clinic patients and relatives the essential aspects in relation to VBHC were collated and based on the results the existing workflow processes were modified. These modifications were evaluated by a second survey and analysis particularly of process-oriented aspects.

RESULTS: The first survey revealed a general satisfaction with the presentation in the memory clinic. The main point of criticism was the duration of the diagnostic process. After the modification the duration and extent of the diagnostics could be reduced. The second evaluation showed improved patient and care partner satisfaction. The respondents considered the modified trajectories to be better and resources were conserved.

CONCLUSION: In our memory clinic an improvement in the sense of VBHC could be achieved through an increased satisfaction with the treatment (outcome) and reduced personnel binding times (costs). This approach can serve as a model for other memory clinics for the development of a more efficient and patient-centered care.},
}

@article {pmid41247156,
year = {2025},
author = {Gu, Y and Hao, M and Wang, L and Alimujiang, A and Gao, J and Ji, W and Xu, W and Xiong, R and Zhang, J and Yin, Y},
title = {Mesenchymal stem cell-derived nanovesicles coated PLGA nanoparticle (MSC-PLGA-NPs) remodel lysosomal function to clear pathological proteins in Alzheimer's disease models.},
journal = {Nanomedicine (London, England)},
volume = {},
number = {},
pages = {1-15},
doi = {10.1080/17435889.2025.2588421},
pmid = {41247156},
issn = {1748-6963},
abstract = {AIMS: To develop a novel multifunctional nanoparticle platform by combining mesenchymal stem cell-derived nanovesicles (MSC-NVs) with poly(lactic-coglycolic acid) (PLGA) nanoparticles for Alzheimer's disease (AD) therapy.

MATERIALS & METHODS: Mesenchymal stem cell-derived nanovesicle-poly(lactic-coglycolic acid) nanoparticles (MSC-PLGA-NPs) were prepared via sonication-loading. Blood-brain barrier (BBB) penetration was evaluated using in vitro transwell models and in vivo mouse models. Lysosomal function, autophagy, pathological protein clearance, and anti-inflammatory effects were assessed using various cellular and molecular biology techniques.

RESULTS: MSC-PLGA-NPs demonstrated 2.3-fold higher BBB penetration efficiency compared to PLGA alone. In a chloroquine(CQ)-induced lysosomal injury model and mice model, they effectively restored lysosomal pH, enhanced autophagy (reducing LC3-II/I ratio by 0.4-fold and p62 expression by 52%), cleared amyloid precursor protein (APP) and phosphorylated tau (p-tau) proteins, and inhibited IL-6 and TNF-α without hepatorenal toxicity.

CONCLUSIONS: These results demonstrate that MSC-PLGA-NPs, a novel multifunctional nanoparticle platform, synergistically integrates the BBB penetration capability of MSC-NVs and the lysosomal acidification function of PLGA. The synergistic combination represents a pioneering "delivery-repair-clearance" integrated strategy for AD therapy. Offering significant advantages over single-component approaches, MSC-PLGA-NPs provide a promising preclinical candidate and new insight into lysosome-targeted nanomedicines for neurodegenerative diseases.},
}

@article {pmid41247064,
year = {2025},
author = {Basha, S and Ks, P and Chattopadhyay, A and Ramakrishna Pai, A and Kishore Mahato, K},
title = {Emerging insights into dairy products and Alzheimer's disease: exploring the potential neuroprotective effects.},
journal = {Critical reviews in food science and nutrition},
volume = {},
number = {},
pages = {1-28},
doi = {10.1080/10408398.2025.2578711},
pmid = {41247064},
issn = {1549-7852},
abstract = {Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by cognitive decline, synaptic dysfunction, and chronic neuroinflammation. While genetic and environmental factors are well-established contributors, emerging evidence suggests that diet, particularly dairy intake, may modulate AD risk. This review critically evaluates epidemiological and clinical findings on the neuroprotective potential of dairy products. Bioactive components, including milk-derived peptides, milk fat globule membrane (MFGM), and fermentation-derived metabolites, exhibit antioxidant and neurotrophic properties that support mitochondrial function and synaptic plasticity. Fermented dairy products may further influence cognition through modulation of the gut-brain axis and production of neuroactive microbial metabolites. Observational studies often indicate a positive association between dairy consumption and cognitive health, yet findings remain inconsistent, with neutral or contradictory outcomes reported. Clinical investigations are limited by small cohorts, heterogeneous methodologies, and population variability. Literature for this review was systematically retrieved from PubMed and Google Scholar. To clarify the role of dairy in AD prevention, future research should integrate precision nutrition approaches that account for genetic susceptibility, microbiota composition, and metabolic profiles. Overall, dairy represents an accessible source of bioactive compounds with potential to promote cognitive resilience, though robust longitudinal and interventional studies are required to establish causality and inform dietary guidelines.},
}

@article {pmid41246936,
year = {2025},
author = {Pan, Y and Zhu, L and Wang, ZL},
title = {EEG Spectral Power Differences in Alzheimer's Disease and Frontotemporal Dementia.},
journal = {The International journal of neuroscience},
volume = {},
number = {},
pages = {1-14},
doi = {10.1080/00207454.2025.2591129},
pmid = {41246936},
issn = {1563-5279},
abstract = {BACKGROUND: Differentiating between Alzheimer's disease (AD) and frontotemporal dementia (FTD) based on clinical symptoms alone can be challenging. This study investigates the utility of resting-state EEG spectral power as a tool to distinguish between these two neurodegenerative conditions.

METHODS: We analyzed a publicly available dataset containing EEG recordings from 36 AD patients, 23 FTD patients, and 29 age-matched healthy controls (HC). Spectral power across delta, theta, alpha, and beta frequency bands was computed for both eyes-closed and eyes-open conditions. Rigorous statistical analysis with FDR correction was employed to identify group differences. To further investigate the relationship between EEG spectral alterations and clinical cognitive status, a correlation analysis was conducted.

RESULTS: Both patient groups showed significant deviations from HC, but with distinct patterns. AD was characterized by a classic pattern of posterior alpha power decrease and frontal theta power increase. In contrast, FTD showed a more focused reduction of alpha power at frontal and central sites. These patterns were robust across both eyes-closed and eyes-open states, suggesting their potential as stable biomarkers. The spectral features showed limited correlation with MMSE scores, indicating they may capture unique aspects of neuropathology not reflected in standard cognitive screening.

CONCLUSION: Resting-state EEG reveals distinct spectral signatures for AD and FTD, supporting its potential as a low-cost, non-invasive adjunctive tool for differential diagnosis. The replication of these findings in an independent, open-access dataset underscores their reliability and provides a foundation for developing automated diagnostic algorithms.},
}

@article {pmid41246827,
year = {2025},
author = {Lee, EH and Huang, YN and Park, T and Liu, S and Adzibolosu, N and Chaudhuri, S and Chang, C and Bice, PJ and Dage, JL and Brosch, JR and Gao, S and Apostolova, LG and Wilcock, DM and Risacher, SL and Saykin, AJ and Jo, T and Nho, K},
title = {Longitudinal plasma proteomics: relation to incident Alzheimer's disease dementia and biomarkers.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21},
number = {11},
pages = {e70900},
doi = {10.1002/alz.70900},
pmid = {41246827},
issn = {1552-5279},
mesh = {Humans ; *Alzheimer Disease/blood/diagnosis ; *Biomarkers/blood ; *Proteomics ; Male ; Female ; Longitudinal Studies ; Aged ; Disease Progression ; *Blood Proteins/metabolism ; Aged, 80 and over ; },
abstract = {INTRODUCTION: We investigated whether longitudinal changes in plasma proteins were associated with baseline cognitive stages related to Alzheimer's disease (AD), their progression, and AD biomarkers.

METHODS: We analyzed longitudinal proteomics (SomaScan 7K) data (N = 347) from the Indiana AD Research Center using linear mixed-effects models for associations with baseline cognitive stages, AD dementia (ADD) conversion, and AD imaging/plasma biomarkers, followed by machine learning analysis to evaluate predictive performance for incident ADD.

RESULTS: Our analysis identified two proteins (ACES and IGFALS) associated with baseline diagnosis stages and six proteins (ACES, C7, ZCD1, IL-17C, CC055, and SO5A1) associated with incident ADD. Longitudinal changes of the identified proteins were also associated with AD imaging/plasma biomarkers. The inclusion of longitudinal protein changes yielded an AUC of 84.8% for predicting incident ADD.

CONCLUSION: Our findings showed molecular signatures for AD progression and the potential of dynamic changes in plasma proteins as biomarkers for predicting incident ADD.

HIGHLIGHTS: Changes in plasma ACES and IGFALS linked to baseline AD cognitive stages Changes in ACES, C7, ZCD1, IL-17C, CC055, and SO5A1 associated with incident ADD Changes in those proteins correlated with baseline AD imaging and plasma biomarkers Proteomics model achieved 84.8% AUC-ROC in predicting incident ADD.},
}

Humans
*Alzheimer Disease/blood/diagnosis
*Biomarkers/blood
*Proteomics
Male
Female
Longitudinal Studies
Aged
Disease Progression
*Blood Proteins/metabolism
Aged, 80 and over

@article {pmid41246746,
year = {2025},
author = {Bethea, JP and Sharma, H and Doberstein, N and Shenker, T and Gregory, B and Hoffman, R and Aizenman, D and Guirguis, G and Hoffmann, J and Tazani, S and Harris, Z and Costin, J},
title = {Application of Osteopathic Manipulative Treatment (OMT) in Neurodegenerative Disorders: A Scoping Review.},
journal = {Cureus},
volume = {17},
number = {10},
pages = {e94748},
doi = {10.7759/cureus.94748},
pmid = {41246746},
issn = {2168-8184},
abstract = {Neurodegenerative diseases are comprised of a host of chronic conditions that impair the central nervous system. Osteopathic manipulative treatment (OMT) consists of many non-invasive modalities that can be used to treat a wide variety of ailments and conditions. OMT is reported to increase the range of motion and lymphatic flow, as well as decrease pain in a wide array of disorders. However, the efficacy of using OMT in neurodegenerative disorders has not been well established. The objective of this scoping review is to map the evidence that pertains to the application of OMT in treating neurodegenerative disorders and identify the gaps in the literature on this subject. This study was designed according to the Joanna Briggs Institute (JBI) guidelines for scoping reviews to gather information on OMT's potential efficacy in managing Parkinson's disease (PD), Alzheimer's disease (AD) dementia, amyotrophic lateral sclerosis (ALS), and Huntington's disease (HD). Peer-reviewed literature was collected through the Excerpta Medica database (EMBASE), Ovid Medical Literature Analysis and Retrieval System Online (MEDLINE), and Web of Science. The criteria were limited to papers in English published between 1999 and 2023. The following search string was utilized: "osteopathic manipulative treatment" OR "osteopathic manipulation" AND "neurodegenerative disorders" OR "Alzheimer's disease" OR "dementia" OR "amyotrophic lateral sclerosis" OR "Parkinson's disease" OR "Huntington's chorea". One hundred and forty-three articles were identified following final screening and critical appraisal, with eleven articles selected for analysis in this study. Data from the selected articles demonstrated that OMT can possibly attenuate symptoms in patients diagnosed with neurodegenerative diseases. Studies in rats showed that OMT techniques were found to alter cholinergic neuronal genes, improve spatial learning and memory, reduce amyloid β protein levels, modulate synaptic transmission, and increase levels of the cytokines IL-1, IL-10, IL-13, RANTES, IL-17A, and EOTAXIN effects in AD dementia. ALS patients demonstrated a high level of satisfaction with OMT and did not report any adverse effects, though there was no decrease in pain or increased quality of life reported. PD patients reported improved postural stability, balance, and gait after OMT. No results were returned regarding OMT's effects on HD. Preliminary results in human PD and ALS patients who received OMT as an adjunct to traditional treatment regimens showed promising results, though few studies were found that address the topic, and the sample sizes of the studies that were found were small. There were no studies of the effects of OMT on human patients with AD or HD found, though preclinical studies in rats supported their trial in subsequent human studies. While current research on the impact of OMT on these neurodegenerative diseases is promising, there remain large gaps in the literature. Further research is necessary to support the use of and long-term efficacy of OMT in neurodegenerative diseases.},
}

@article {pmid41246694,
year = {2025},
author = {Pergolizzi, JV and Tenenbaum, JT and Pergolizzi, C and LeQuang, JAK},
title = {Neurocognitive and Neurological Effects of Coffee and Caffeine: A Narrative Review.},
journal = {Cureus},
volume = {17},
number = {10},
pages = {e94742},
doi = {10.7759/cureus.94742},
pmid = {41246694},
issn = {2168-8184},
abstract = {Coffee, a popular beverage, is surprisingly complex and increasingly studied for its potential health benefits. In particular, coffee contains caffeine, which may play a role in alertness, cognition, and memory. Coffee also contains an abundance of polyphenols and other compounds, which may confer specific health benefits. It is well known that coffee drinking can ward off drowsiness and fatigue, but the mechanisms behind this are not clearly understood. The caffeine in coffee can inhibit adenosine, but this mechanism is not well understood. Whether or not coffee has protective effects against neurodegenerative conditions is being actively studied. Coffee may confer significant neuroprotective, anti-inflammatory, and cognitive benefits, which are of particular interest in aging populations and warrant greater study. A challenge in studying coffee's neurocognitive aspects is that there are multiple types of coffee, and "dosing," or how much coffee is consumed over time, can vary widely among studies.},
}

@article {pmid41246477,
year = {2025},
author = {Manckoundia, P and Mourey, F and Larosa, F and Renoncourt, T},
title = {Balance and Gait Disorders in the Aged Population. Causes, Assessment and Management: A Literature Review.},
journal = {Clinical interventions in aging},
volume = {20},
number = {},
pages = {1945-1962},
doi = {10.2147/CIA.S531235},
pmid = {41246477},
issn = {1178-1998},
mesh = {Humans ; *Accidental Falls/prevention & control ; *Postural Balance/physiology ; Aged ; *Gait/physiology ; Geriatric Assessment/methods ; Activities of Daily Living ; *Aging/physiology ; *Gait Disorders, Neurologic/etiology/diagnosis/therapy ; },
abstract = {With aging, compensatory mechanisms and physiological reserve may become insufficient to maintain balance and gait (BG), particularly when associated with stroke, Alzheimer's disease, diabetes, osteoarticular diease, vestibular disorders, orthostatic hypotension (OH), heart rhythm disorders, or drug side effects. This leads to poorer postural-motor function and increased risk of falling (RoF). This review aims to highlight recent scientific advancements relative to BG disorders (BGDs) for gerontology professionals. When assessing older adults (OAs) with BGDs, a thorough assessment of patient history is needed to identify the origins. This should include the history of falls, an inventory of medications, and an analysis of the home environment. A comprehensive clinical examination is also required to guide etiological diagnoses. A clinical suspicion of cardiac arrhythmia/conduction disorders, for example, will be confirmed by electrocardiogram (ECG)/Holter ECG, whereas suspected OH (on questioning) will be confirmed by an OH test, and, in the presence of confusion, epilepsy will be confirmed by the electroencephalogram. Several tools, ranging from simple and quick to more complex and thorough, have been validated to evaluate BGDs in OAs. These tests involve activities of daily living tasks required to preserve independence. Emerging technologies for RoF assessment (ie, surface electromyography, force platforms, three-dimensional motion capture systems) while not yet used in routine geriatric practice, can improve early detection, monitoring, and rehabilitation. Optimal BGD management requires the implication of several health professionals. Rehabilitation programs such as the "Otago exercise programme" and "falls management exercise" have been validated. Assistive technologies (canes, walkers, grab bars, and orthopedic footwear or automated alert systems), and new technologies (virtual reality) can also be used. Additional steps include medication review and deprescribing, occupational therapy and home environment adaptations. Understanding and managing BGDs in OAs remains a major public health issue, and is vital for preserving independence in later life.},
}

Humans
*Accidental Falls/prevention & control
*Postural Balance/physiology
Aged
*Gait/physiology
Geriatric Assessment/methods
Activities of Daily Living
*Aging/physiology
*Gait Disorders, Neurologic/etiology/diagnosis/therapy

@article {pmid41246359,
year = {2025},
author = {Young, SR and Shono, Y and Hauner, K and Dworak, EM and Mansolf, M and Curtis, L and Benavente, JY and Batio, S and Gershon, RC and Wolf, MS and Nowinski, CJ},
title = {Clinical validation and machine learning optimization of MyCog: A self-administered cognitive screener for primary care settings.},
journal = {Alzheimer's & dementia (Amsterdam, Netherlands)},
volume = {17},
number = {4},
pages = {e70219},
doi = {10.1002/dad2.70219},
pmid = {41246359},
issn = {2352-8729},
abstract = {BACKGROUND: Primary care offers ideal opportunities for early detection of cognitive impairment, yet clinics face significant barriers to routine screening. MyCog is an electronic health record-integrated tablet application self-administered during a primary care visit designed to overcome barriers to screening.

METHODS: We compared MyCog performance between 65 adults age 65+ with diagnosed cognitive impairment and 80 cognitively normal adults. Five modeling approaches achieved consensus to select consistently discriminative variables for the final detection algorithm. Performance was primarily assessed via receiver operating characteristic area under the curve (AUC), sensitivity, specificity, and accuracy.

RESULTS: All models demonstrated strong diagnostic performance (AUC 0.817 to 0.873). Memory accuracy and executive function efficiency scores were consistently selected as predictors of impairment across models. The final logistic regression achieved AUC 0.890, with sensitivity 0.723 to 0.831, specificity 0.788 to 0.912, and accuracy 0.807 to 0.828 depending on threshold.

DISCUSSION: Findings suggest MyCog accurately detects cognitive impairment via a streamlined self-administered app that efficiently fits into primary care workflows.},
}

@article {pmid41246229,
year = {2025},
author = {Şahin, TÖ and Cemali, Ö and Özdemir, M and Ayten, Ş and Ağagündüz, D},
title = {Flavonoids and phenolic compounds: a promising avenue for neurodegenerative disease therapy.},
journal = {Turkish journal of biology = Turk biyoloji dergisi},
volume = {49},
number = {5},
pages = {635-659},
doi = {10.55730/1300-0152.2767},
pmid = {41246229},
issn = {1303-6092},
abstract = {BACKGROUND/AIM: Neurodegenerative diseases such as Alzheimer's, Parkinson's, Huntington's, and ALS are characterized by a progressive loss of nerve cells, for which no definitive cure currently exists. These conditions share common pathological mechanisms, including chronic neuroinflammation, oxidative stress, protein aggregation, and mitochondrial dysfunction. Flavonoids and other plant-derived phenolic compounds have recently attracted attention for the treatment of such conditions due to their antiinflammatory and antioxidant properties. This review explores the neuroprotective mechanisms of flavonoids and evaluates their potential for the prevention and treatment of neurodegenerative diseases.

MATERIALS AND METHODS: A literature search of the Web of Science, PubMed, and ScienceDirect databases was conducted to evaluate the therapeutic potential of flavonoids and phenolic compounds against neurodegenerative diseases. The search terms included "polyphenols", "flavonoids", and related compounds, along with "Alzheimer's", "Parkinson's", "Huntington's", and "Amyotrophic lateral sclerosis". Eligible studies included clinical trials, randomized controlled trials, and in vitro and in vivo research published in English. Priority was given to studies from the last decade, although older but significant publications were also included.

RESULTS: The findings of multiple studies report the ability of flavonoid compounds such as quercetin, myricetin, apigenin, and epigallocatechin gallate (EGCG) to modulate critical signaling pathways, reduce oxidative stress, prevent the accumulation of neurotoxic proteins, and support mitochondrial function. These bioactive molecules have exhibited significant potential in slowing disease progression and preserving neuronal integrity. Their therapeutic application, however, has been limited by their poor bioavailability, low stability, and rapid metabolism.

CONCLUSION: Flavonoids have shown promise as naturally derived agents with multi-targeted activity against neurodegenerative processes. Enhancing their absorption and stability through novel delivery systems and structural modifications could significantly improve their clinical efficacy. When administered early or as a complementary therapy, flavonoids can be considered a safe and effective approach to the management of neurodegenerative diseases.},
}

@article {pmid41246081,
year = {2025},
author = {Shubair, SA},
title = {Caregiving-related strain among informal caregivers of older adults with dementia: findings from a nationally representative study.},
journal = {Frontiers in public health},
volume = {13},
number = {},
pages = {1618379},
doi = {10.3389/fpubh.2025.1618379},
pmid = {41246081},
issn = {2296-2565},
mesh = {Humans ; *Caregivers/psychology/statistics & numerical data ; *Dementia/nursing ; Cross-Sectional Studies ; Male ; Female ; Aged ; Middle Aged ; Aged, 80 and over ; *Stress, Psychological/epidemiology ; United States ; },
abstract = {BACKGROUND AND OBJECTIVES: Informal caregivers (ICs) of older adults with dementia experience caregiving-related physical, emotional, and financial strain. Little is known about their characteristics and caregiving-related strain differences by dementia status.

RESEARCH DESIGN AND METHODS: A cross-sectional study was implemented among probable, possible, and non-dementia ICs of older adults from the 2017 National Health and Ageing Trend Study and linked to the National Study of Caregiving data for a nationally representative sample of 2,652. Analysis of variance was used to investigate differences in characteristics and caregiving-related strain by dementia status.

RESULTS: ICs of older adults with possible dementia were more likely to report an income ≤$99,999 (97.2%, p < 0.001) than ICs of older adults with probable dementia (94.8%) or non-dementia (86.9%), with no other group characteristic observed. Caregiving-related strain varied significantly by dementia status (p < 0.001), with ICs of older adults with probable dementia reporting the highest physical, emotional, and financial strain compared to ICs caring for possible or non-dementia older adults.

DISCUSSION AND IMPLICATIONS: Dementia ICs face disproportionately higher strain and greater financial vulnerability, underscoring the need for targeted interventions such as respite care, financial support, and caregiver training to sustain caregiver well-being as dementia prevalence rises.},
}

Humans
*Caregivers/psychology/statistics & numerical data
*Dementia/nursing
Cross-Sectional Studies
Male
Female
Aged
Middle Aged
Aged, 80 and over
*Stress, Psychological/epidemiology
United States

@article {pmid41245907,
year = {2025},
author = {Katz, MJ and Johns, TS and Martin, MM and Burgess, A and Claris, V and Volda, GS and Roque, N and Shaw, PA and Hyun, N and Hakun, JG and Pavlovic, JM and Wylie-Rosett, J and Sliwinski, MJ and Mossavar-Rahmani, Y},
title = {Recruitment of mid-life adults to a randomized clinical trial: The multicultural healthy diet study to reduce cognitive decline and Alzheimer's disease risk.},
journal = {Alzheimer's & dementia (New York, N. Y.)},
volume = {11},
number = {4},
pages = {e70174},
doi = {10.1002/trc2.70174},
pmid = {41245907},
issn = {2352-8737},
abstract = {INTRODUCTION: Poor representation of racial/ethnic minority groups limits the validity and generalizability of clinical trials and contributes to inequities in medicine and science.

OBJECTIVES: To recruit a multicultural sample of mid-life individuals using multiple recruitment modalities for a randomized controlled trial of diet and cognition comparing an anti-inflammatory dietary intervention versus usual diet and the effect on cognition.

METHODS: This study describes the utility of various modalities to recruit a multi-cultural cohort. Recruitment techniques, the success rate of each, and characteristics of participants are compared to representative Bronx U.S. Census statistics. Participants were identified in target communities using voter registration rolls paired with marketing lists and enriched patient lists extracted from electronic health records of mid-life (40-65 years) adults in Bronx, New York. Outreach activities, including print and social media, supplemented these lists to promote the study.

RESULTS: Over 4 years of recruitment, invitation letters, followed by telephone calls, yielded the highest number of randomized recruits, with 80.5% of participants recruited prior to the pandemic and 90.1% during the pandemic. A total of 290 participants enrolled in proportion to the racial/ethnic breakdown of targeted Bronx communities. However, women were overrepresented compared to the overall Bronx population. Each recruitment modality had strengths and weaknesses. The combination resulted in reaching an important sector of the population that could benefit from interventions. Voter registration lists reached a broad spectrum of targeted communities and resulted in enrollment and randomization of the majority of participants. Online registries (e.g., ResearchMatch) and outreach activities yielded efficient enrollment.

DISCUSSION: Our multi-pronged strategy led to successful enrollment of a multi-cultural sample. Although the systematic list approach was the most productive, the importance of reaching out to community was crucial. Refining techniques of online registries, working with trusted community organizations, continuous assessment, and experimentation with other modalities may be helpful.

HIGHLIGHTS: ADRD affects US minority populations disproportionately.Multiple recruitment methods help engage the underrepresented in clinical trials.Use of voter registration and EHR lists allow recruiters to reach a wide and heterogenous audience.Letters followed by personal phone calls are effective in recruitment.Outreach to the community provides a person-to-person connection to the study.},
}

@article {pmid41245880,
year = {2025},
author = {Mahdavi, SA and Maghooli, K and Farokhi, F},
title = {A Fuzzy Cognitive Map-based Framework for Alzheimer's Disease Diagnosis Using Multimodal Magnetic Resonance Imaging-Positron Emission Tomography Registration.},
journal = {Journal of medical signals and sensors},
volume = {15},
number = {},
pages = {31},
doi = {10.4103/jmss.jmss_3_25},
pmid = {41245880},
issn = {2228-7477},
abstract = {BACKGROUND: Alzheimer's disease (AD) is a progressive and irreversible brain disorder, characterized by a gradual decline in cognitive and memory function, with memory loss being one of the most prominent symptoms. Accurate and early diagnosis of AD is essential for effective management and treatment. Structural magnetic resonance imaging (sMRI) and positron emission tomography (PET) are widely utilized neuroimaging modalities for diagnosing AD due to their ability to provide complementary structural and functional insights into brain abnormalities.

METHODS: This study introduces a novel computer-aided diagnosis system that integrates sMRI and PET data using Fuzzy Cognitive Maps (FCM) to improve diagnostic accuracy. The research is conducted using the ADNI dataset, where preprocessing of sMRI and PET images is performed using FSL and statistical parametric mapping tools, respectively. In a key innovation, features extracted from both modalities are fused and dimensionality reduction is achieved through an Autoencoder model. The reduced feature set is then classified using FCM, Support Vector Machine, k-Nearest Neighbors, and Multilayer Perceptron.

RESULTS: The FCM-based approach demonstrates superior performance, achieving the highest accuracy of 93.71%, surpassing other classifiers tested.

CONCLUSIONS: This study underscores the effectiveness of integrating FCM with multimodal neuroimaging data and highlights its potential for enhancing the early and reliable diagnosis of AD.},
}

@article {pmid41245492,
year = {2025},
author = {Hines, D and Tobey, H and Dugan, P and Boehringer, S and Helm, R and Anandakrishnan, R and Werre, S and VandeVord, P and Costa, BM},
title = {A preliminary study on the effect of quantified cranial osteopathic manipulation on wild-type and transgenic rat models of Alzheimer's disease.},
journal = {Journal of Alzheimer's disease reports},
volume = {9},
number = {},
pages = {25424823251393742},
doi = {10.1177/25424823251393742},
pmid = {41245492},
issn = {2542-4823},
abstract = {Alzheimer's disease is a chronic progressive neurodegenerative disorder that impairs the meningeal lymphatics, glymphatic system, and compartmental fluid exchange, leading to a decline in cognitive function. Due to the lack of non-pharmacological and physiological treatments, cranial osteopathic manipulation (COM) poses a potential minimally invasive therapeutic choice. To understand the treatment and related effects objectively, we have established a technique to quantify the force applied during COM on an animal model of AD for the first time. Our results indicate that quantified COM can be applied to rodents to study behavioral and biochemical phenotype changes.},
}

@article {pmid41245437,
year = {2025},
author = {Kozlovski, T and Maidan, I and Gazit, E and Droby, A and Thaler, A and Hausdorff, JM and Giladi, N and Benjamini, Y and Mirelman, A},
title = {Quantifying motor-cognitive reserve using a novel multi-modal stress test.},
journal = {Brain communications},
volume = {7},
number = {6},
pages = {fcaf412},
doi = {10.1093/braincomms/fcaf412},
pmid = {41245437},
issn = {2632-1297},
abstract = {Reserve is a physiological capacity used under demanding situations. The concept was developed to account for the discrepancy between pathology and clinical manifestation. In neuroscience, motor, brain and cognitive reserves are abstract measures, conceptually defined yet elusive to quantify. Reserve is indirectly assessed using proxies such as years of education and brain volume, limiting its utility. Moreover, the dichotomy in definitions of cognitive and motor reserves is artificial, as daily function requires an intricate network of connections between these domains. Here, we assessed the validity of a newly developed graded motor cognitive 'stress test' to quantify the combined motor and cognitive reserve (MCR). The study included 144 participants (ages between 18 and 85, 50% women) with a range of reserve capacities (i.e. healthy young and older adults and individuals with Parkinson's disease, Alzheimer's disease, dementia with Lewy bodies and mild cognitive impairment). The assessment included walking on a treadmill while negotiating motor and cognitive challenges delivered using virtual reality. To establish an MCR index score, we used a semi-supervised machine learning algorithm. The model includes performance measures from completing the stress test and measures obtained from wearable sensors used during the test. Validation of the proposed MCR index was examined through: (i) model face validity-reflecting decline of performance as challenge increased; (ii) known-groups validity-classification of scores according to neurological status; (iii) construct validity (convergent)-association with common MCRs proxies as well as MRI-derived regional brain volumes. The model's face validity revealed decreased performance with increased motor and cognitive challenges (both domains P < 0.001). The index accurately discriminated between healthy controls and those diagnosed with neurological conditions with an area under the curve of 0.89 [95% CI: 0.79-0.99] which was significantly higher than all other commonly used proxies. Statistically significant Spearman's ρ correlations were observed with all commonly used motor and cognitive proxies (0.56 ≤ r ≤ 0.79, after multiplicity correction all P < 0.05), reflecting construct validity. In addition, statistically significant correlations were observed between the MCR index and whole-brain grey matter and white matter volumes (r = 0.63 and 0.55), as well as the pre-defined left and right caudate nucleus (r = 0.56 and 0.68) and inferior-frontal gyrus (r = 0.47 and 0.58). This proof-of-concept study shows that the novel MCR index is valid, with high sensitivity to neurological deficits and is able to quantify reserve on an individual level. This new innovative tool can assist in screening for motor cognitive deficits and potentially, for predicting motor and cognitive decline associated with neurodegenerative disease.},
}

@article {pmid41245435,
year = {2025},
author = {Soskic, S and Tregidgo, HFJ and Todd, EG and Bouzigues, A and Cash, DM and Russell, LL and Thomas, DL and Malone, IB and Foster, PH and Ferry-Bolder, E and van Swieten, JC and Jiskoot, LC and Seelaar, H and Sanchez-Valle, R and Laforce, R and Graff, C and Galimberti, D and Vandenberghe, R and de Mendonça, A and Tiraboschi, P and Santana, I and Gerhard, A and Levin, J and Nacmias, B and Otto, M and Bertoux, M and Lebouvier, T and Ducharme, S and Butler, CR and Le Ber, I and Finger, EC and Tartaglia, MC and Masellis, M and Rowe, JB and Synofzik, M and Moreno, F and Borroni, B and Alexander, DC and Iglesias, JE and Rohrer, JD and Bocchetta, M and , },
title = {Thalamus involvement in genetic frontotemporal dementia assessed using structural and diffusion MRI: a GENFI study.},
journal = {Brain communications},
volume = {7},
number = {6},
pages = {fcaf420},
doi = {10.1093/braincomms/fcaf420},
pmid = {41245435},
issn = {2632-1297},
abstract = {Thalamic subregions are commonly, but variably, affected by different forms of frontotemporal dementia. We aimed to better characterize thalamic subregional involvement in genetic frontotemporal dementia with a recently published thalamus segmentation tool that utilizes structural and diffusion MRI, offering additional assessment of mean diffusivity and a more fine-grained analysis of the pulvinar specifically compared to previous studies. Using this tool, we performed thalamus segmentations in MRI scans from C9orf72, GRN and MAPT mutation carriers and mutation non-carriers with suitable 3-Tesla MRI cross-sectional data from the GENetic Frontotemporal dementia Initiative. Mutation carriers were divided according to their genetic group and Clinical Dementia Rating® Dementia Staging Instrument plus National Alzheimer's Coordinating Center Behaviour and Language Domains global score (0 or 0.5: presymptomatic/prodromal stage, 1 or higher: symptomatic stage). Following stringent quality control and harmonization across sites and scanners, we compared volumes and mean diffusivity values of thalamic subregions in C9orf72 (47 presymptomatic, 10 symptomatic), GRN (57 presymptomatic, 11 symptomatic) and MAPT (31 presymptomatic, 12 symptomatic) mutation carriers to those in 109 mutation non-carriers with analyses of covariance including age and sex (and total intracranial volume for volumetric comparisons) as covariates. Presymptomatic C9orf72 expansion carriers showed smaller volumes (3-8% difference from non-carriers) and higher mean diffusivity (2-5% difference from non-carriers) for several thalamic subregions, including all pulvinar subdivisions. We found subtly larger volumes of the ventral anterior subregion and the non-medial pulvinar (3% difference from non-carriers for both) in presymptomatic GRN mutation carriers, and of the anteroventral subregion (5% difference from non-carriers) in presymptomatic MAPT mutation carriers. Symptomatic mutation carriers in all three genetic groups showed significantly smaller volumes and widespread higher mean diffusivity of thalamic subregions compared with non-carriers, which were overall most prominent in subregions involved in associative and limbic functions (the midline, medial pulvinar, anteroventral, mediodorsal, laterodorsal and lateral posterior subregions). Notably smaller volume (12-23% difference from non-carriers) and higher mean diffusivity (16-23% difference from non-carriers) of the most medial part of the medial pulvinar was a shared feature across the three genetic groups at the symptomatic stage. Overall, our study confirms that thalamic subregions are affected in genetic frontotemporal dementia and identifies prominent involvement of the most medial part of the medial pulvinar as a potential unifying feature in the variable pattern of thalamic subregional involvement across the main genetic groups.},
}

@article {pmid41245356,
year = {2025},
author = {Racette, SB and Gunning, JA and Eagan, DE and Zaniletti, I and Smith, TL and DeCuna, CJ and Hettiwatte, YS and Demeke, MT and Khan, NA and Aliskevich, EL and Krell-Roesch, J and Geda, YE},
title = {Time-restricted eating in Alzheimer's disease: TREAD pilot trial design.},
journal = {Contemporary clinical trials communications},
volume = {48},
number = {},
pages = {101564},
doi = {10.1016/j.conctc.2025.101564},
pmid = {41245356},
issn = {2451-8654},
abstract = {BACKGROUND AND OBJECTIVE: Time-restricted eating (TRE) may slow neurodegeneration and cognitive decline by stimulating metabolic processes that are neuroprotective. The primary aim of the TRE in Alzheimer's Disease (TREAD) pilot trial is to evaluate the feasibility of implementing a TRE intervention among individuals with mild cognitive impairment (MCI) and to obtain preliminary data on cognitive domains and blood biomarkers that are responsive to TRE.

METHODS: TREAD is an intervention trial for 30 adults aged 55-89 years with MCI. A pre/post design is used, with neuropsychological assessments, surveys, and blood biomarkers of cardiometabolic health and AD obtained before and after the intervention. The TRE intervention involves 16 h of continuous fasting and an 8 h eating window on 5 or more days per week for 12 weeks. Feasibility measures include participant enrollment, retention, adherence, acceptability of the intervention, and safety. Cognitive measures include executive function, working memory, processing speed, auditory attention, auditory verbal learning, visuospatial memory, category fluency, and phonemic fluency.

SUMMARY: TREAD is exploring an innovative approach to address cognitive decline and will provide critical preliminary data to inform and power a larger, longer-term, randomized controlled trial of TRE on cognitive trajectory among adults with cognitive impairment.},
}

@article {pmid41245147,
year = {2025},
author = {Pluta, R},
title = {Direct and indirect role of non-coding RNAs in company with amyloid and tau protein in promoting neuroinflammation in post-ischemic brain neurodegeneration.},
journal = {Frontiers in cellular neuroscience},
volume = {19},
number = {},
pages = {1670462},
doi = {10.3389/fncel.2025.1670462},
pmid = {41245147},
issn = {1662-5102},
abstract = {Post-ischemic brain neurodegeneration with subsequent neuroinflammation is a major cause of mortality, permanent disability, and the development of Alzheimer's disease type dementia in the absence of appropriate treatment. The inflammatory response begins immediately after ischemia and can persist for many years. Post-ischemic neuroinflammation plays a dual role: initially, it is essential for brain repair and maintenance of homeostasis, but when it becomes uncontrolled, it causes secondary damage and worsens neurological outcome. Neuroinflammation is a complex phenomenon involving interactions between infiltrating immune cells from the peripheral circulation and resident immune cells in ischemic brain areas. This review focuses on the complex relationship between non-coding RNAs, amyloid accumulation, tau protein modifications, and the development of neuroinflammation in the post-ischemic brain. In particular, it clarifies whether the cooperation of non-coding RNAs with amyloid and tau protein enhances neuroinflammation and whether the vicious cycle of neuroinflammatory responses affects the production, behavior, and aggregation of these molecules. Ultimately, elucidating these interactions is critical, as they may contribute to resolving the phenomenon of post-ischemic brain neurodegenerative mechanisms. Furthermore, this review highlights the role of neuroinflammation as a functionally complex immune response regulated/mediated by transcription factors and cytokines. Additionally, it examines how the presence of non-coding RNAs, amyloid aggregation, and modified tau protein may shape the inflammatory landscape. This review aims to advance our understanding of post-ischemic neuroinflammation and its implications for long-term brain health.},
}

@article {pmid41245137,
year = {2025},
author = {Croteau, DL and Navarro, JF and Comptdaer, T and Andrusivova, Z and Jurek, A and Bonnefoy, E and Buée, L and Bohr, VA and Lundeberg, J and Galas, MC},
title = {Spatial transcriptomics reveals an unexpected impact of tau and tau pathology on the expression of transthyretin.},
journal = {Frontiers in aging neuroscience},
volume = {17},
number = {},
pages = {1656850},
doi = {10.3389/fnagi.2025.1656850},
pmid = {41245137},
issn = {1663-4365},
abstract = {INTRODUCTION: RNA expression is modulated by tau. We used two mouse models, THY-Tau22 mice, which express pro-aggregation tau, and TauKO mice, which are null for tau, to improve our understanding of tau-altered mRNA expression in brain.

METHODS: Spatial transcriptomics on Tau22 and TauKO mice were used to interrogate regional mRNA expression changes. We focused on mRNA expression changes in the hippocampus and ventricles; two regions altered early in Alzheimer's disease.

RESULTS: We identified the transthyretin mRNA, Ttr, as being dysregulated in a tau-dependent manner. Immunofluorescence (IF) revealed increased TTR protein expression in THY-Tau22 mice and lowered expression in TauKO mice in the choroid plexus epithelial cells.

CONCLUSION: As TTR is involved in the clearance of Aβ and the prevention of Aβ aggregation, we evaluated endogenous mouse Aβ in TauKO mice and observed increased Aβ deposits. Our study reveals a hitherto unknown regulatory role of tau on Ttr mRNA and protein expression, which may participate in a feedback loop contributing to Aβ disease progression.},
}

@article {pmid41244840,
year = {2025},
author = {Yu, H and Feng, T and Zhang, C and Jiao, Z and Fan, W and Jiang, R and Kong, D and Li, F},
title = {Epigenetic pharmacology in aging: from mechanisms to therapies for age-related disorders.},
journal = {Frontiers in pharmacology},
volume = {16},
number = {},
pages = {1699296},
doi = {10.3389/fphar.2025.1699296},
pmid = {41244840},
issn = {1663-9812},
abstract = {Aging is a multidimensional process regulated by the interplay of genetic and environmental factors, with epigenetic alterations serving as a central regulatory hub. Aberrant DNA methylation patterns, dysregulation of histone-modifying enzymes (e.g., SIRT1, EZH2), and non-coding RNA-mediated mechanisms collectively remodel gene expression networks, impacting critical pathways such as cellular senescence and mitochondrial homeostasis. This establishes an "environment-epigenome-disease" causal axis, closely associated with pathologies including β-amyloid deposition in Alzheimer's disease, atherosclerosis, immunosenescence, osteoporosis, sarcopenia, and tumorigenesis. Capitalizing on the reversible nature of epigenetic modifications, pharmacological epigenetics has emerged as a cutting-edge field for intervening in aging and age-related diseases. Targeting key epigenetic modifiers such as DNA methyltransferases and histone deacetylases enables the modulation of disease-associated epigenetic states, providing a promising avenue for therapeutic intervention in aging and age-related diseases. This review synthesizes the molecular mechanisms of epigenetic regulation in aging, their role in age-related diseases, and advances in pharmacological epigenetics-from basic research to clinical translation. It further situates key challenges such as target specificity, long-term safety, and tissue-specific delivery within a translational framework, aiming to inform strategies for the diagnosis and intervention of age-related conditions.},
}

@article {pmid41244831,
year = {2025},
author = {Ye, S and Zhang, S and Zhang, L and Peng, G and Xie, M and Huang, X and Hu, Y},
title = {Screening and experimental validation of modified Gandou Decoction-targeted inhibitors for alleviating AD components via network pharmacology, machine learning, and molecular dynamics simulation.},
journal = {Frontiers in pharmacology},
volume = {16},
number = {},
pages = {1685866},
doi = {10.3389/fphar.2025.1685866},
pmid = {41244831},
issn = {1663-9812},
abstract = {BACKGROUND: Alzheimer's disease (AD) is a neurodegenerative disease characterized by abnormal accumulation of β-amyloid (Aβ) and hyperphosphorylation of the Tau protein. Currently, there is a lack of effective and safe therapeutic approaches. In Traditional Chinese medicine (TCM), Gandou Decoction has shown significant efficacy in improving cognitive decline and dementia-related symptoms, but its specific mechanism remains unclear.

METHODS: This study systematically analyzed the active components and anti-AD mechanism of Modified Gandou Decoction (MGD) by integrating network pharmacology, machine learning, molecular docking, molecular dynamics (MD) simulation, and in vitro experimental validation. Obtain the components of Chinese medicines in MGD from TCMSP and screen them via ADMET; obtain AD targets by combining databases and select core targets through machine learning; verify their effects through various analyses and experiments.

RESULTS: A total of 21 potential active molecules of MGD and 68 intersection targets were screened out. Among them, 8 core targets (EIF2AK2, PPARG, BACE1, ESR1, GSK3B, ACE, CASP3, MAPK14) were confirmed to be significantly associated with AD pathology by gene expression difference analysis (P ≤ 0.05). KEGG enrichment analysis showed that MGD mainly intervenes in the amyloid production pathway, the MAPK pathway, and the IL-17 pathway. Molecular docking demonstrated that the majority of the 21 potential active compounds exhibited strong binding affinities to the 8 core targets. Moreover, some potential active molecules exhibited better binding energy and similar binding modes compared with known inhibitors when binding to the corresponding target proteins. Molecular dynamics simulation showed that Alisol B, a potential active component of MGD, could stably bind to BACE1, EIF2AK2, and CASP3. In vitro cell experiments confirmed that Alisol B could significantly reverse okadaic acid-induced damage in SH-SY5Y cells (p < 0.001).

CONCLUSION: MGD exerts its anti-AD effect through its potential active component Alisol B, which binds to target proteins BACE1, EIF2AK2, and CASP3, and synergistically inhibits Aβ production, Tau phosphorylation, and neuroinflammatory processes through multiple pathways. This study provides a foundation for developing MGD-derived natural products for AD treatment, although the precise mechanisms require further experimental validation.},
}

@article {pmid41244800,
year = {2025},
author = {Yang, Y and Jung, KJ and Kwak, YT},
title = {A prospective pilot study on plasma amyloid beta oligomers and postoperative delirium.},
journal = {Frontiers in medicine},
volume = {12},
number = {},
pages = {1673496},
doi = {10.3389/fmed.2025.1673496},
pmid = {41244800},
issn = {2296-858X},
abstract = {INTRODUCTION: Postoperative delirium (POD) is common in older adults and has been linked to Alzheimer's disease (AD). Plasma amyloid-β oligomers (AβOs) may clarify this relationship. We evaluated whether preoperative AβO burden is associated with POD severity.

METHODS: In this single-center prospective pilot study, we enrolled 22 patients aged ≥65 years undergoing hip or knee arthroplasty under general anesthesia. Blood was drawn preoperatively and postoperatively to quantify oligomerized amyloid-β using the multimer detection system (MDS-Oaβ). POD was assessed with the Korean version of the Delirium Rating Scale-98 (K-DRS-98). Group comparisons and correlations examined associations between MDS-Oaβ and POD.

RESULTS: Eleven of 22 patients developed POD. Those with POD were older and had higher preoperative MDS-Oaβ than those without POD (0.81 vs 0.56 ng/mL). There was no significant perioperative change in MDS-Oaβ, suggesting surgery or anesthesia did not alter the plasma Aβ oligomerization tendency. Within the POD group, preoperative MDS-Oaβ correlated with both K-DRS-98 severity and total scores.

DISCUSSION: In this pilot cohort, higher preoperative AβO burden was associated with the occurrence and severity of POD, while perioperative factors did not measurably affect AβO levels. These findings support a potential mechanistic link between AD-related pathology and POD. Given the small sample (N=22), estimates are imprecise and hypothesis-generating; validation in larger, multicenter studies is required before clinical application.},
}

@article {pmid41244754,
year = {2025},
author = {Qayed, WS and Hassan, MA and Şenol, H and Taslimi, P and Aboul-Fadl, T},
title = {2-Oxoindolin-thiazoline hybrids as scaffold-based therapeutics for T2DM-associated cognitive impairment: design, synthesis, in vitro and in silico studies.},
journal = {RSC medicinal chemistry},
volume = {},
number = {},
pages = {},
doi = {10.1039/d5md00628g},
pmid = {41244754},
issn = {2632-8682},
abstract = {Alzheimer's disease (AD) and type 2 diabetes mellitus (T2DM) are closely linked neurodegenerative and metabolic disorders, sharing overlapping pathological mechanisms. In this study, structure-based drug design combined with molecular hybridization strategies was employed to develop dual-acting compounds targeting both conditions. A series of twenty hybrid molecules, comprising 2-oxoindolin-3-thiosemicarbazones (3a-i) and thiazolines (4a-k) were successfully synthesized and characterized using spectroscopic techniques and elemental analysis. Biological evaluations demonstrated that compounds 3d and 3h exhibit potent inhibitory activity against α-glucosidase (α-Glu) and α-amylase (α-Amy), surpassing the efficacy of acarbose. These findings highlight their promising antidiabetic potential and support further investigation into their therapeutic relevance for AD and T2DM comorbidity (3d (α-glucosidase K i = 41.41 ± 2.53 nM; α-amylase IC50 = 1.25 ± 0.02 nM), 3h (α-glucosidase K i = 44.19 ± 2.41 nM; α-amylase IC50 = 2.87 ± 0.16 nM and acrabose (α-glucosidase K i = 101.20 ± 7.53, α-amylase IC50 9.73 ± 0.20). Furthermore, compounds 3i and 4i exhibited significantly higher inhibitory activity against acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) compared to the reference drug tacrine. Notably, compound 4i demonstrated exceptional multi-enzyme inhibition, with kinetic parameters indicating strong binding affinity: 3i (AChE K i = 59.71 ± 2.24 nM; BChE K i = 8.43 ± 0.97 nM), 4i (AChE K i = 53.31 ± 1.74 nM; BChE K i = 10.72 ± 2.19 nM), and tacrine (AChE K i = 132.35 ± 5.90 nM; BChE K i = 137.42 ± 4.01 nM). Molecular docking and dynamics simulations corroborated these findings by revealing stable and favorable interactions within the active sites of both enzymes. Additionally, in silico ADME profiling indicated desirable pharmacokinetic properties, further supporting the therapeutic potential of these compounds as dual-action agents for the management of Alzheimer's disease and type 2 diabetes mellitus.},
}

@article {pmid41244710,
year = {2025},
author = {Singh, TR and Vannier, B and Singh, RR and Yadav, HO and Fröhlich, H},
title = {Editorial: Bioinformatics and systems biology strategies in disease management with a special emphasis on cancer, Alzheimer's disease and aging.},
journal = {Frontiers in molecular biosciences},
volume = {12},
number = {},
pages = {1725000},
doi = {10.3389/fmolb.2025.1725000},
pmid = {41244710},
issn = {2296-889X},
abstract = {Bioinformatics and systems biology strategies for managing cancer and Alzheimer's disease. Key concepts include multi-omics data, computational modeling, network analysis, and nanotechnology. Translational applications cover diagnostics, prognostics, and therapeutics. Arrows suggest a circular process between concepts and applications.},
}

@article {pmid41244707,
year = {2025},
author = {Baeken, MW and Bekbulat, F and Körschgen, H and Clement, AM and Behl, C},
title = {The sigma-1 receptor as a neurohomeostatic decision hub for GABARAP-mediated receptor trafficking and macroautophagy.},
journal = {Frontiers in molecular biosciences},
volume = {12},
number = {},
pages = {1673249},
doi = {10.3389/fmolb.2025.1673249},
pmid = {41244707},
issn = {2296-889X},
abstract = {Gamma-aminobutyric acid receptor-associated protein (GABARAP) is a multifunctional member of the autophagy-related (ATG8) protein family, playing key roles in two distinct cellular pathways: macroautophagy and plasma membrane protein trafficking. In the context of autophagy, GABARAP modulates cargo recognition and supports the maturation and fusion of autophagosomes with lysosomes, a critical step in intracellular clearance and proteostasis. Separately, GABARAP also regulates vesicular receptor protein transport from the Golgi apparatus to the plasma membrane, contributing to proper surface localization and receptor recycling. Both tasks are especially vital for neurons, where protein turnover and receptor localization are tightly linked to synaptic plasticity and neuroprotection. We recently identified a direct interaction between GABARAP and the sigma-1 receptor (σ1R), an ER-resident receptor involved in diverse cellular stress responses, mitochondrial function, and protein homeostasis. Our findings suggest that σ1R acts as an upstream regulatory hub, influencing GABARAP's functional commitment to either membrane trafficking or autophagy. Specifically, we hypothesize that ligand-dependent σ1R activation promotes GABARAP's involvement in macroautophagy at the expense of its role in membrane transport. This regulatory switch may underline part of the neuroprotective effects observed with σ1R agonists in neurodegenerative disease models, where enhanced autophagy is often beneficial. Overall, we discuss the emerging molecular crosstalk between σ1R and GABARAP, its potential impact on neuronal homeostasis, and how σ1R's pharmacological modulation might be leveraged to bias GABARAP function toward autophagy in diseases such as amyotrophic lateral sclerosis, Huntington's, Parkinson's, and Alzheimer's disease.},
}

@article {pmid41244473,
year = {2025},
author = {Florio, D and Gallo, E and Saviano, A and Schettino, A and Marigliano, N and Leone, I and Maione, F and Marasco, D},
title = {Mangiferin as a Novel In Vitro Polyphenolic Inhibitor of Amyloid Aggregation.},
journal = {ACS omega},
volume = {10},
number = {44},
pages = {52773-52782},
doi = {10.1021/acsomega.5c06703},
pmid = {41244473},
issn = {2470-1343},
abstract = {Amyloid aggregation is a pathological hallmark of several neurodegenerative disorders, including Alzheimer's disease. Polyphenolic compounds are emerging as promising candidates for therapeutic intervention due to their capacity to interfere with multiple stages of amyloidogenesis. In this study, we investigated, in vitro, the antiamyloidogenic potential of mangiferin (MGF), a xanthonoid polyphenol with established pharmacological activity but previously unexplored in the context of amyloid modulation. Using a combination of biophysical, spectroscopic, and microscopic techniques, we assessed the effects of MGF on the aggregation behavior of two distinct amyloidogenic peptides: Aβ1-42 and Cterm_mutA. Thioflavin T (ThT) assays revealed that MGF significantly inhibited aggregation in a concentration-dependent manner, with maximal inhibition at a 1:5 peptide:MGF ratio. Nanoparticle tracking analysis (NTA) and microscopy studies demonstrated peptide-specific differences in the mechanism of action of MGF: MGF promoted the formation of larger, nonfibrillar oligomers in Aβ1-42, while it reduced oligomer size in Cterm_mutA. This effect was most likely attributable to the disruption of π-π interactions. Importantly, MGF exhibited no cytotoxicity in SH-SY5Y cells and significantly attenuated the amyloid-induced toxicity of both peptides. These findings highlight MGF as a promising, multitargeted modulator of amyloid aggregation with potential applications in neuroprotection and the development of novel antiamyloid therapies.},
}

@article {pmid41244451,
year = {2025},
author = {Zhou, L and Luo, X},
title = {Boron, Titanium, and Calcium Doped Graphene Monolayers for Alzheimer's Disease Biomarker Detection: A Density Functional Theory Study.},
journal = {ACS omega},
volume = {10},
number = {44},
pages = {53074-53083},
doi = {10.1021/acsomega.5c07690},
pmid = {41244451},
issn = {2470-1343},
abstract = {Alzheimer's disease remains a critical public health concern, with early detection hindered by the limited sensitivity and invasiveness of conventional diagnostic techniques. Two-dimensional monolayer materials offer a promising alternative by enabling label-free, real-time, and noninvasive detection of disease-specific biomarkers. In this study, we analyzed the effectiveness of doped graphene monolayers as biosensing platforms for two emerging biomarkers of Alzheimer's disease: glycine and d-serine. Using density functional theory, we investigated the adsorption behavior of these biomarkers on pristine graphene as well as boron-, titanium-, and calcium-doped graphene monolayers. Our results showed that calcium-doped graphene exhibits the most favorable sensing characteristics across multiple criteria. Glycine adsorption on calcium-doped graphene resulted in a recovery time of 0.170 s, indicating a rapid sensor response and high reversibility. Both biomarkers induced a semiconductor-to-metal transition, significantly enhancing electrical conductivity. Charge density and band structure analyses further revealed strong orbital interactions and substantial electronic modulation upon adsorption. These findings demonstrate that calcium-doped graphene is a promising candidate for the development of highly sensitive, reversible, and real-time biosensors for the early stage detection of Alzheimer's disease.},
}

@article {pmid41244379,
year = {2025},
author = {Mizgalska, K and Al-Aani, U and Aljaidah, Y and Panek, D and Chaari, A and Bajda, M},
title = {Inhibition of Human Amylin Aggregation: In Silico and In Vitro Studies.},
journal = {ACS omega},
volume = {10},
number = {44},
pages = {52269-52288},
doi = {10.1021/acsomega.5c02443},
pmid = {41244379},
issn = {2470-1343},
abstract = {Human islet amyloid polypeptide (hIAPP), also termed amylin, is an endocrine hormone that plays a key role in regulating blood glucose levels. Pathological conformational changes in amylin can lead to its aggregation into amyloid deposits, which are significant markers in the development of type 2 diabetes (T2D) and Alzheimer's disease (AD). In this study, we explored 1-benzylamino-2-hydroxyalkyl derivatives as potential amylin aggregation inhibitors. These compounds have previously demonstrated activity against amyloid-β aggregation in AD. We conducted ThT and DLS assays to identify compounds 18 and 22 as the most active derivatives, inhibiting amylin aggregation with IC50 values of 3.04 and 2.71 μM, respectively. These compounds preserved small-sized oligomers, which exhibited reduced cytotoxicity compared to controls. The fluorescence quenching assay revealed that compounds 18 and 22 significantly quenched the intrinsic fluorescence of amylin without altering the emission spectra, indicating conformational changes without major modifications in the Tyr37 region. Binding and thermodynamic analyses indicated strong, spontaneous interactions dominated by hydrophobic forces. An in silico study compared the behavior of compound 18 (the most potent) and compound 9 (the least potent) in the ThT assay. Overall, compound 18 formed more interactions with amylin than compound 9 and remained attached to the peptide for a longer time during the simulation, more frequently stabilizing the α-helical fragments. This stabilization may help delay the transition into intermediate structures associated with amyloidogenic β-sheet formation. Our findings offer new insights into the aggregation process and may inform the design of more effective aggregation inhibitors.},
}

@article {pmid41243988,
year = {2025},
author = {Tang, J and Zhang, Y and Wang, Y and Fu, Y and Qi, J and Xiang, A and Zhao, R and Tan, G and Deng, H and Zhou, X and Wu, L},
title = {Histone Lactylation as an Epigenetic Regulator in Alzheimer's Disease Pathophysiology: A Narrative Review.},
journal = {Journal of inflammation research},
volume = {18},
number = {},
pages = {15701-15716},
doi = {10.2147/JIR.S557031},
pmid = {41243988},
issn = {1178-7031},
abstract = {Alzheimer's disease (AD) represents a progressive neurodegenerative disorder clinically defined by insidious multidomain cognitive deterioration and neuropathologically characterized by extracellular amyloid-β plaques and intraneuronal neurofibrillary tangles. Its pathological core includes β-amyloid protein (Aβ) deposition, neurofibrillary tangles (NFT) and neuroinflammation, seriously threatening the health of the elderly population worldwide. With the intensification of population aging, the socio-economic burden brought by AD is increasingly heavy. However, its complex pathogenesis has not been fully clarified, and there is an urgent need to explore new molecular markers and therapeutic targets. Lactylation, a novel metabolite-derived post-translational modification (PTM) where lactate groups are covalently conjugated to lysine residues, has recently been implicated in the pathological process of AD. For example, lactylation at histone H4 lysine 12 (H4K12la) has been reported to promote neuroinflammation via a "glycolysis/H4K12la/PKM2" positive feedback loop and activate the NLRP3 inflammasome-mediated pyroptosis. Similarly, lactylation at histone H3 lysine 18 (H3K18la) may enhance microglial activation through the NF-κB pathway. However, the role of lactylation in AD appears to be complex and context-dependent, as evidenced by seemingly contradictory findings regarding its impact on Aβ pathology. Therefore, this article reviews the relevant literature on lactylation and AD, summarizes the possible mechanisms by which lactylation regulates AD, and provides theoretical basis and reference for the related research on molecular markers and therapeutic targets of AD.},
}

@article {pmid41243936,
year = {2025},
author = {Ahmad, E and Mehmood, A and Inam, V},
title = {Feeding the mind: Nutritional strategies across different stages of Alzheimer's disease and their significance.},
journal = {JPMA. The Journal of the Pakistan Medical Association},
volume = {75},
number = {10},
pages = {1681},
doi = {10.47391/JPMA.30195},
pmid = {41243936},
issn = {0030-9982},
}

@article {pmid41243816,
year = {2025},
author = {Lech, S and Kohl, R and O'Sullivan, JL and Thevathasan, T and Schuster, J and Kuhlmey, A and Gellert, P and Yasar, S},
title = {Statin Use Is Not Associated With Reduced Cardio- and Cerebrovascular Hospitalizations in Older Adults With Dementia.},
journal = {Stroke},
volume = {},
number = {},
pages = {},
doi = {10.1161/STROKEAHA.125.051157},
pmid = {41243816},
issn = {1524-4628},
abstract = {BACKGROUND: Cardiovascular and cerebrovascular diseases are significant global health challenges and leading causes of death worldwide. Although there is substantial evidence supporting the positive effects of statins for both primary and secondary prevention of these diseases, evidence is lacking regarding the benefits in people with dementia. This study investigated the associations between statin use and cardiovascular and cerebrovascular hospitalizations in nursing home residents with and without dementia.

METHODS: This retrospective cohort study of nursing home residents with and without dementia using insurance claims data was conducted in Germany between January 2015 and December 2019. Propensity score-based models were used to evaluate the association of statin use with hospitalizations due to cerebrovascular and cardiovascular events among nursing home residents with and without dementia. Subgroup analyses were performed based on the presence or absence of atherosclerotic cardiovascular disease, dementia type, presence of hyperlipidemia, and newly prescribed statin use, as well as age groups, care dependency level, and sex.

RESULTS: The final sample included data from 96 162 individuals, 37 262 without dementia, and 58 900 with dementia. Statin use was associated with an increased risk of hospitalization due to cardiovascular or cerebrovascular events among people with dementia (hazard ratio [HR], 1.06 [95% CI, 1.01-1.12]; P=0.023). Moderate and high statin intensity was associated with an increased risk of hospitalization (moderate: HR, 1.15 [95% CI, 1.07-1.23]; P<0.001; high: HR, 1.55 [95% CI, 1.15-2.10]; P=0.005) In subgroup analyses, we found an association between statin use and increased risk of hospitalization among individuals without atherosclerotic cardiovascular disease (HR, 1.30 [95% CI, 1.12-1.52]; P<0.001), with vascular dementia and Alzheimer disease (HR, 1.18 [95% CI, 1.06-1.32]; P=0.003; HR, 1.14 [95% CI, 1.00-1.31]; P=0.047, respectively) as well as among newly prescribed statin users (HR, 2.71 [95% CI, 2.33-3.15]; P<0.001). Among individuals without dementia, we found no differences (HR, 1.03 [95% CI, 0.96-1.11]; P=0.397) in the primary analysis and subanalyses except for the high statin intensity group (HR, 1.51 [95% CI, 1.04-2.19]; P=0.029) and among participants with newly prescribed statins (HR, 1.99 [95% CI, 1.56-2.52]).

CONCLUSIONS: In our study, statin use was associated with an increased risk of hospitalization due to cardiovascular or cerebrovascular events among people with dementia. These findings highlight the need for further research and cautious consideration of statin use in people with dementia.},
}

@article {pmid41243598,
year = {2025},
author = {Jiang, M and Zhang, C and Chen, J and Qi, Y and Zhu, L and Liu, Z and Li, J and Zhou, T and Wang, X and Guo, X},
title = {Unveiling Aging and Alzheimer's Disease-Associated Dynamics of LINE1 DNA Content and Protein Expression in Mouse Brains.},
journal = {Aging cell},
volume = {},
number = {},
pages = {e70296},
doi = {10.1111/acel.70296},
pmid = {41243598},
issn = {1474-9726},
support = {32260148//National Natural Science Foundation of China/ ; 31900410//National Natural Science Foundation of China/ ; 202001AU070055//Yunnan Fundamental Research Projects/ ; //Xing Dian Plan "Youth Talent Program" of Yunnan Province/ ; },
abstract = {Despite the long interspersed nuclear element-1 (LINE1, L1) retrotransposons having been implicated in Alzheimer's disease (AD), a fundamental understanding of the AD-specific lifespan-long trajectory of L1 has been limited. Here, we characterize the content and expression of L1 covering four brain regions (hippocampus, prefrontal cortex, cerebellum, and the rest of brain tissue) of APP/PS1 mice, a murine model of AD, and their wild-type C57BL/6 littermates from 3 to 24 months of age. We report that both L1 content (indicated by DNA copy number) and expression (indicated by protein levels of L1-encoded ORF1 and ORF2) across brain regions had nonlinear, U-shaped associations with age in wild-type and APP/PS1 mice. Compared to age-matched wild-types, APP/PS1 mice constantly have significantly decreased L1 content but increased L1 expression, suggesting L1 differences between wild-type and APP/PS1 mice establish early and remain stable throughout the life course. Strikingly, L1 content and expression in wild-type and APP/PS1 mice are sexually different, depending on age and brain region. The appearance of L1 alteration precedes the onset of β-amyloidosis by 3 months in APP/PS1 mice, and β-amyloidosis is positively correlated with L1 content and expression in males but anti-correlated with L1 content in females of both wild-type and APP/PS1 mice. Overall, this study (i) reveals an unanticipated U-shaped trajectory of L1 content and expression in both normal and pathological aging of mouse brains and (ii) discerns specific changes in L1 content and expression tied to AD neuropathology in a sex-different manner.},
}

@article {pmid41243261,
year = {2025},
author = {Bramen, JE and Siddarth, P and Popa, ES and Kress, GT and Rapozo, MK and Hodes, JF and Ganapathi, AS and Sparks, WM and Tongson, YM and Torres, AM and Meysami, S and Slyapich, CB and Glatt, RM and Pierce, K and Miller, KJ and Elhelou, SH and Porter, VR and Wong, C and Kim, M and Panos, S and Hirsch, DA and Raji, CA and Bookheimer, SY and Hood, L and Roach, JC and Merrill, DA},
title = {A multi-modal medical management and lifestyle intervention increase cerebral blood flow and lowers diabetic risk in persons with early Alzheimer's disease: Mid-trial results from the PREVENTION trial.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877251388933},
doi = {10.1177/13872877251388933},
pmid = {41243261},
issn = {1875-8908},
abstract = {BackgroundMedical and lifestyle management are crucial for Alzheimer's disease (AD). Cerebral blood flow (CBF), vital for brain health, and influenced by modifiable risk factors, is reduced in AD and may become uncoupled from metabolism due to neurovascular dysfunction in later stages.ObjectiveThis mid-trial analysis tested the hypothesis that a coached, multi-modal intervention (PREVENTION) improved ASL-MRI-measured CBF and diabetic risk (QUICKI) in patients with early AD.MethodsThe control arm received recommendations and medical management for one year; the active arm additionally received coaching, exercise training, and supplementation. We hypothesized that those in (1) the active arm and (2) with higher intervention adherence would have improved post-trial QUICKI and CBF, particularly in regions relevant to exercise, cardiovascular, diabetic, and AD risk. Post-trial CBF was analyzed using a linear model including arm, baseline CBF, adherence, age, education, and depressive symptoms. Change in QUICKI was analyzed using mixed effects general linear models, including arm, adherence, time, and interactions between time and treatment group and time and adherence, controlling for age.ResultsThe active arm (n = 18) showed greater post-trial CBF in regions related to exercise, cardiovascular, diabetic, and AD risk, compared to control (n = 20), but did not differ in global CBF, QUICKI, or adherence. Higher adherence scores were associated with greater regional post-trial CBF and improvement in QUICKI, but not global CBF.ConclusionsIn this small sample, we found evidence that a multi-modal intervention focused on medical management, exercise, and a carbohydrate-restricted diet improved diabetic risk and CBF in patients with AD.},
}

@article {pmid41243143,
year = {2025},
author = {Palpatzis, E and Locascio, JJ and Palmer, P and Diez, I and Gatchel, J and Marshall, GA and Arenaza-Urquijo, EM and Vannini, P},
title = {Adaptive stress coping is associated with cognitive resilience in at-risk cognitively unimpaired older adults.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21},
number = {11},
pages = {e70713},
doi = {10.1002/alz.70713},
pmid = {41243143},
issn = {1552-5279},
support = {P01 AG036694/AG/NIA NIH HHS/United States ; R01 AG053184/AG/NIA NIH HHS/United States ; R21AG088163//NIH/NIA/ ; },
mesh = {Humans ; Female ; Male ; Aged ; *Adaptation, Psychological/physiology ; *Resilience, Psychological ; *Cognitive Dysfunction/psychology ; *Stress, Psychological/psychology ; *Cognition/physiology ; *Alzheimer Disease/psychology ; Longitudinal Studies ; Cross-Sectional Studies ; Aged, 80 and over ; Neuropsychological Tests ; Positron-Emission Tomography ; },
abstract = {INTRODUCTION: Coping strategies are potentially modifiable factors that may contribute to cognitive resilience. We examined whether adaptive coping modifies the association between Alzheimer's disease (AD) pathology and cognitive decline.

METHODS: We included 99 cognitively unimpaired older adults (mean age = 75.2, 59% females) from two observational cohorts who completed coping strategy assessments. Participants underwent yearly longitudinal cognitive assessments (extended PACC) over 5.3 years on average and cross-sectional Aβ (PiB-PET) and tau (F[18]-Flortaucipir) neuroimaging. We used linear mixed-effects models.

RESULTS: More frequent use of adaptive coping was associated with better cognitive trajectories, independent of AD pathology. Further, three-way interactions between tau, adaptive coping, and time indicated that individuals with elevated tau and less adaptive coping showed accelerated cognitive decline, while those with more adaptive coping maintained cognitive function.

DISCUSSION: Adaptive coping strategies may confer resilience against cognitive decline. Interventions targeting coping skills could represent promising approaches for maintaining cognition in individuals at risk for AD.

HIGHLIGHTS: Adaptive coping associates with better cognition independent of Alzheimer's disease (AD) pathology. Adaptive coping buffers tau-related effects on cognitive trajectories. Coping strategies may be modifiable targets for cognitive decline.},
}

Humans
Female
Male
Aged
*Adaptation, Psychological/physiology
*Resilience, Psychological
*Cognitive Dysfunction/psychology
*Stress, Psychological/psychology
*Cognition/physiology
*Alzheimer Disease/psychology
Longitudinal Studies
Cross-Sectional Studies
Aged, 80 and over
Neuropsychological Tests
Positron-Emission Tomography

@article {pmid41243142,
year = {2025},
author = {Misiura, M and Bartlett, A and Claar-Pressley, C and Burnette, J and Munkombwe, C and Ikanga, J},
title = {Not just the medial temporal lobe: Precuneus and posterior cingulate volumes relate to plasma biomarkers and cognition in a sub-Saharan African cohort.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21},
number = {11},
pages = {e70768},
doi = {10.1002/alz.70768},
pmid = {41243142},
issn = {1552-5279},
support = {P30AG066511/AG/NIA NIH HHS/United States ; },
mesh = {Humans ; Male ; Female ; Biomarkers/blood ; Amyloid beta-Peptides/blood ; Aged ; *Gyrus Cinguli/pathology/diagnostic imaging ; Neuropsychological Tests/statistics & numerical data ; Cohort Studies ; *Parietal Lobe/pathology/diagnostic imaging ; Neurofilament Proteins/blood ; tau Proteins/blood ; *Cognition/physiology ; Atrophy/pathology ; Magnetic Resonance Imaging ; Peptide Fragments/blood ; *Temporal Lobe/pathology/diagnostic imaging ; Democratic Republic of the Congo ; *Dementia/blood/pathology ; },
abstract = {INTRODUCTION: The precuneus and posterior cingulate-key regions in early Alzheimer's disease (AD)-undergo atrophy before clinical symptoms emerge. Limited research in sub-Saharan Africa (SSA) has explored how blood-based biomarkers relate to brain changes and cognition. This study examined these associations in older adults with dementia in Kinshasa, Democratic Republic of Congo (DRC).

METHODS: A total of 117 adults (≥ 65 years; five dementia, and 58 controls) completed neuropsychological testing and blood draws, with 75 completing neuroimaging. Plasma amyloid-beta (Aβ) 40, Aβ42, pTau181, pTau217, and neurofilament light chain (NfL) were analyzed using single molecule array (Simoa). Regional volumes were obtained via Freesurfer. Linear models assessed biomarker, volume, and cognitive associations.

RESULTS: Lower Aβ42/40 and higher NfL levels were associated with reduced posterior cingulate and right precuneus volumes. Posterior cingulate atrophy correlated with poorer semantic fluency, memory, and executive function. Male sex and higher education were linked to larger volumes.

CONCLUSIONS: Plasma Aβ42/40 and NfL are promising biomarkers of AD-related brain atrophy in SSA. Results support region-specific screening approaches in global dementia research.

HIGHLIGHTS: First biomarker-neuroimaging study of dementia in sub-Saharan Africa (SSA). Lower amyloid-beta (Aβ) 42/40 linked to reduced posterior cingulate volumes. Higher plasma NfL associated with right precuneus and PCC atrophy. Posterior cingulate atrophy predicted memory and executive dysfunction. Study supports plasma biomarkers for AD screening in SSA settings.},
}

Humans
Male
Female
Biomarkers/blood
Amyloid beta-Peptides/blood
Aged
*Gyrus Cinguli/pathology/diagnostic imaging
Neuropsychological Tests/statistics & numerical data
Cohort Studies
*Parietal Lobe/pathology/diagnostic imaging
Neurofilament Proteins/blood
tau Proteins/blood
*Cognition/physiology
Atrophy/pathology
Magnetic Resonance Imaging
Peptide Fragments/blood
*Temporal Lobe/pathology/diagnostic imaging
Democratic Republic of the Congo
*Dementia/blood/pathology

@article {pmid41243131,
year = {2025},
author = {Renli, A and Sun, B and Gu, M and Martin, T and Kavcic, V and Li, T and Giordani, B},
title = {EEG-based information transfer paths during motion discrimination: Detectable differences between normal cognition and MCI.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21},
number = {11},
pages = {e70868},
doi = {10.1002/alz.70868},
pmid = {41243131},
issn = {1552-5279},
support = {2032709//National Science Foundation/ ; R21-AG046637//National Institutes of Health (NIH)/ ; R01-AG054484//National Institutes of Health (NIH)/ ; P30AG024824//National Institutes of Health (NIH)/ ; P30AG053760//National Institutes of Health (NIH)/ ; P30AG072931//National Institutes of Health (NIH)/ ; HAT-07-60437/ALZ/Alzheimer's Association/United States ; },
mesh = {Humans ; *Cognitive Dysfunction/physiopathology ; Aged ; Male ; *Electroencephalography ; Female ; Aged, 80 and over ; Middle Aged ; *Brain/physiopathology ; *Cognition/physiology ; Neuropsychological Tests ; *Motion Perception/physiology ; Brain Mapping ; },
abstract = {BACKGROUND: This study explores how cognitive impairment can affect the effective connectivity of the brain network under task stimuli.

METHOD: Our research focuses on task-based electroencephalography (64-channel), in which participants were asked to perform a motion direction discrimination task. The current dataset includes 56 consensus-diagnosed, community-dwelling American seniors (ages 60-90 years, 28 normal cognition [NC]; 28 mild cognitive impairment [MCI]) recruited through Wayne State University and Michigan Alzheimer's Disease Research Center. We evaluate the effective connectivity across all the possible region of interest (ROI) pairs using causalized convergent cross mapping and identify possible discrepancies between seniors with NC and MCI.

RESULTS: Individuals with MCI exhibit weaker links than those with NC in some region pairs but concurrently activate more information transfer paths in other region pairs, especially in the frontal and temporal areas.

CONCLUSION: Our results demonstrate the compensatory mechanism of the brain communication network for weakened links in critical regions under cognitive impairment.

HIGHLIGHTS: Existing work on brain connectivity analysis was mainly focused on functional connectivity rather than effective connectivity, making it a challenge to fully understand the dynamic interactions and causal relationships within the brain network. As an effort to address this problem, in this study, we applied the new causality model, causalized convergent cross mapping (cCCM), to electroencephalography data under motion discrimination tasks and aimed to capture the differences in brain effective connectivity between mild cognitive impairment (MCI) patients and those with normal cognition (NC). It was shown that cCCM can capture the inter-region information transfer which may not be captured by Pearson correlation. That is, region pairs with low functional connectivity may still exhibit strong effective connectivity. Our results indicated that those with NC exhibit stronger effective connectivity than MCI individuals across certain region pairs, and the number of such region pairs (where those with NC shows more active information transfer) increases as the load imposed upon the brain increases. Concurrently, those with MCI activate many more information transfer paths than NC individuals during the motion detection task. This may reflect the compensatory mechanism of the brain communication network for weakened links under cognitive impairment.},
}

Humans
*Cognitive Dysfunction/physiopathology
Aged
Male
*Electroencephalography
Female
Aged, 80 and over
Middle Aged
*Brain/physiopathology
*Cognition/physiology
Neuropsychological Tests
*Motion Perception/physiology
Brain Mapping

@article {pmid41243062,
year = {2025},
author = {Yitbarek, GY and Alty, J and Roccati, E and Lawler, K and Goldberg, LR},
title = {Association of tongue, handgrip, and pinch strength with blood-based phosphorylated-tau 181 in cognitively healthy older adults.},
journal = {GeroScience},
volume = {},
number = {},
pages = {},
pmid = {41243062},
issn = {2509-2723},
abstract = {The development of blood-based phosphorylated tau (p-tau) biomarkers to identify Alzheimer's disease risk before cognitive decline offers a valuable opportunity for early intervention. Handgrip strength appears as a complementary non-invasive biomarker of dementia risk. Measurement of tongue strength may contribute further insight into the risk of cognitive decline and dementia. We examined associations between tongue strength, handgrip strength, three-finger pinch strength, and plasma p-tau181 in cognitively healthy older adults. A total of 158 cognitively healthy participants aged 50+ years (75.31% female; mean 69.32 years) were recruited. Participants' p-tau181 levels were sourced from a longitudinal study in which they were involved. Pearson correlation coefficients, independent t-tests, and multivariable linear regression analyses were performed to examine the association between strength measures and p-tau181 levels. Tongue strength was positively associated with handgrip (β = 0.53, 95% CI (0.25,0.81), p < 0.001) and pinch strength (β = 2.30, 95% CI (0.92,3.68), p = 0.001), with models adjusted for age, sex, body mass index, and educational level. Based on p-tau181 tertiles, the associations between tongue, handgrip, and pinch strength measures were evident only in the middle and highest tertiles. Handgrip (in adults 69 years and older) and pinch, but not tongue strength, were negatively associated with log-transformed p-tau181 levels. Although preliminary, findings support strength-based non-invasive biomarkers for risk stratification. Future studies are needed to investigate the relation between changes in strength measures with established measures of AD risk as well as frailty.},
}

@article {pmid41243056,
year = {2025},
author = {Rabie, SHM and Ghofrani, S and Barghamadi, H and Eslami, M},
title = {EFD in Comparison with EWT for Synthetic and EEG Signal Decomposition and Classification of Alzheimer's Disease and Mild Cognitive Impairment.},
journal = {Annals of biomedical engineering},
volume = {},
number = {},
pages = {},
pmid = {41243056},
issn = {1573-9686},
abstract = {PURPOSE: This paper investigates the well-known Empirical Wavelet Transform (EWT) and the recently introduced Empirical Fourier Decomposition (EFD) for the early diagnosis of Alzheimer's disease (AD). Both synthetic signals and real EEG data are decomposed and reconstructed, particularly under noisy conditions.

METHODS: EWT and EFD were applied to decompose non-stationary EEG signals into five sub-bands (Delta, Theta, Alpha, Beta, and Gamma). From each sub-band, eight features were extracted and used to classify subjects into AD and Mild Cognitive Impairment (MCI) groups. Among the five classifiers tested, Random Forest (RF) yielded the best performance for both EWT and EFD. In addition to conventional evaluation metrics, Dynamic Time Warping (DTW) and the Kolmogorov-Smirnov (KS) statistic were used for algorithm assessment.

RESULTS: The results show that EFD outperforms EWT and achieves competitive performance compared to state-of-the-art approaches.

CONCLUSION: EFD is a novel decomposition method that demonstrates robust performance on both synthetic and real EEG signals, supporting its potential use in the early diagnosis of Alzheimer's disease.},
}

@article {pmid41242996,
year = {2025},
author = {Zhang, B and Sun, Z and Song, W and Huang, H and Wu, Y},
title = {Engineered butyrate-producing yeasts mitigate Alzheimer-associated phenotypes.},
journal = {Signal transduction and targeted therapy},
volume = {10},
number = {1},
pages = {369},
pmid = {41242996},
issn = {2059-3635},
}

@article {pmid41242668,
year = {2025},
author = {Chethana, HP and Rathan Kumar, U and Chakraborty, G and Sidhu, A},
title = {L-Arginine Interferes with Functional Studies of Amyloid Proteins.},
journal = {Protein expression and purification},
volume = {},
number = {},
pages = {106854},
doi = {10.1016/j.pep.2025.106854},
pmid = {41242668},
issn = {1096-0279},
abstract = {Intrinsically disordered proteins/regions are abundant in cancer signalling pathways and neurodegenerative diseases like Parkinson's disease, amyotrophic lateral sclerosis, Alzheimer's disease, etc. Purification of intrinsically disordered proteins can be challenging due to their sticky nature. For intrinsically disordered amyloid proteins, in-vitro aggregation studies are ideal experiments to study their liquid to solid transition. However, over-expression of these proteins in E. coli often results in insoluble protein fraction that ends up in cell-pellet as inclusion bodies, on lysis and centrifugation. Supplementing purification buffers with l-arginine is known to increase the solubility of proteins. For most of the structured proteins increasing solubility translates into a higher yield of functional proteins. However, for aggregation prone proteins associated with neurodegenerative diseases, like α-synuclein (Parkinson's disease), Aβ (Alzheimer's disease), fused in sarcoma (amyotrophic lateral sclerosis), etc. inclusion of l-arginine might interfere with aggregation studies. To test our hypothesis, we purified aggregation prone α-synuclein and fused in sarcoma protein in the presence and absence of l-arginine and studied their fibrillization. While recombinant FUS is difficult to prepare, purification of α-synuclein is well established but in all the protocols a significant amount of protein remains as insoluble fraction in the pellet. Inclusion of l-arginine increases the yield of protein purification by about 3 folds for both the proteins, but the resulting protein does not aggregate into fibrils thus showing that increased solubility of amyloid proteins (α-synuclein and fused in sarcoma) in the presence of l-arginine is not suitable for aggregation studies.},
}

@article {pmid41242663,
year = {2025},
author = {Ebrahimi, R and Khozani, AASA and Masouri, MM and Seifi, M and Hashempour, A and Soltani, SM and Noori, S},
title = {Neurodegeneration and glial activation related blood biomarkers in Alzheimer's disease: A systematic review and an updated meta- analysis.},
journal = {Experimental gerontology},
volume = {},
number = {},
pages = {112960},
doi = {10.1016/j.exger.2025.112960},
pmid = {41242663},
issn = {1873-6815},
abstract = {BACKGROUND AND OBJECTIVES: This systematic review and meta-analysis aims to evaluate blood biomarkers associated with neurodegeneration and glial activation, specifically GFAP, NfL, YKL-40, MCP-1, neurogranin, GAP-43, S100B, and NSE, in individuals diagnosed with Alzheimer's Disease (AD).

METHODS: PubMed and Web of Science were searched until February 20, 2025, without restrictions on language, time, or study design, to identify studies reporting blood levels of the biomarkers in individuals along the AD continuum (including those with MCI and AD dementia) and cognitively unimpaired (CU) controls. Pooled effect sizes were calculated using the Hedges' g method with a random-effects model.

RESULTS: A total of 3684 studies were identified, with 144 meeting inclusion criteria (AD continuum n = 42,587, CU n = 30,000). Compared with CU individuals, patients on the AD continuum showed higher levels of NfL (SMD = 0.82, 95 % CI 0.67-0.96, p < 0.05), GFAP (SMD = 1.57, 95 % CI 1.26-1.88, p < 0.05), and YKL-40 (SMD = 1.39, 95 % CI 0.56-2.21, p < 0.05). Both biomarkers were significantly elevated in more advanced stages of the disease, particularly in AD dementia compared with mild cognitive impairment (MCI) (GFAP SMD = 0.79, 95 % CI 0.55-1.03, p < 0.05; YKL-40 SMD = 0.98, 95 % CI 0.17-1.79, p = 0.02). No significant differences were found for MCP-1, neurogranin, S100B, or NSE.

DISCUSSION: Our findings suggest that these biomarkers reflect AD-related pathology. Limitations include the lack of cultural and linguistic diversity in the study populations. Future research should focus on biomarker-defined AD populations for further validation.},
}

@article {pmid41242500,
year = {2025},
author = {Gungor, D and Muratoglu, S and Aytekin, E and Reçber, T and Telli, G and Akdag, Y and Sahin, S and Gulsun, T},
title = {Assessment of intranasal permeability and pharmacological activity of glyburide-loaded nanosuspension formulation for Alzheimer's disease.},
journal = {Journal of pharmaceutical sciences},
volume = {},
number = {},
pages = {104064},
doi = {10.1016/j.xphs.2025.104064},
pmid = {41242500},
issn = {1520-6017},
abstract = {Glyburide is an anti-diabetic drug with promising potential implications for Alzheimer's disease. This study evaluated the permeability and activity of glyburide via intranasal administration in Alzheimer's disease using both in vivo and ex vivo studies. A glyburide nanosuspension, was used as the drug delivery system. Stability studies demonstrated that the nanosuspension formulation presented suitable stability during in vitro and in vivo studies. The chosen in vivo glyburide dose demonstrated a non-toxic profile via MTT. Additionally, the in vitro permeability of the nanosuspension was assessed. Pharmacological activity was further evaluated through in vivo behavioural tests, including the Morris water maze and novel object recognition tests, and amyloid-beta levels were measured in mice brain tissues with ELISA. Ex vivo quantification of glyburide concentration in various tissues was also conducted. In vitro permeability studies showed that the nanosuspension formulation significantly enhanced permeability of glyburide. In vivo behavioural tests demonstrated that the nanosuspension formulation yielded favourable and promising outcomes even it was administered intranasally. This study suggests that, through the solubility enhancement provided by nanocrystal technology increased the bioavailability of glyburide comparing the intranasal administration of glyburide, leading to improve in vivo activity compared to the raw glyburide suspension in the treatment of Alzheimer's disease.},
}

@article {pmid41242458,
year = {2025},
author = {Li, N and Peng, X and Xiong, W and Chen, C and Wang, W},
title = {The gut microbiota-brain axis in Alzheimer's disease model mice.},
journal = {Physiology & behavior},
volume = {},
number = {},
pages = {115178},
doi = {10.1016/j.physbeh.2025.115178},
pmid = {41242458},
issn = {1873-507X},
abstract = {The gut microbiota plays a pivotal role in the pathogeneses of Alzheimer's disease (AD), influencing neuroinflammation and disease progression. Understanding the role of the gut microbiota in this process is critical for uncovering novel therapeutic avenues and deepening insights into AD pathogenesis. Nevertheless, the specific gut microbiota alterations under pathogenetic stress in AD remain unclear. In this study, immunofluorescence was performed to detect β-amyloid (Aβ) deposition, hyperphosphorylated tau proteins (P-tau), and the activation of microglia in the brains of APPswe/PSEN1dE9 transgenic (APP/PS1) mice and C57BL/6J wild-type (WT) mice. Congo red staining and thioflavin-S staining were used to detect Aβ plaques accumulation in the hippocampus and cortex. 16S rRNA sequencing was used to elucidated the bacteria changes between the APP/PS1 and WT mice. The results of immunofluorescence and pathological stainings exhibited that the APP/PS1 mice showed significant increase of Aβ deposition and P-tau, and greater activation of microglia in the hippocampus and cortex, compared with WT mice. 16S rRNA sequencing identified increased abundance of Muribaculaceae, Ligilactobacillus, Dubosiella, Limosilactobacillus, Alistipes, Lactobacillus, and Enterorhabdus, and decreased abundance of Lachnospiraceae_NK4A136_group, Clostridia_UCG-014, and Lachnospiraceae _UCG-006 in APP/PS1 mice, revealing distinct hub bacteria with AD under pathogenetic pressure.},
}

@article {pmid41242442,
year = {2025},
author = {Shao, J and Fan, X and Tian, S and Zhang, F and Li, J and Zhao, Z and Li, Y and Zhou, X},
title = {ATP6V1E1 and NDUFB5 identified as potential biomarkers for Alzheimer's disease through integrative analysis.},
journal = {International journal of biological macromolecules},
volume = {},
number = {},
pages = {148733},
doi = {10.1016/j.ijbiomac.2025.148733},
pmid = {41242442},
issn = {1879-0003},
abstract = {Alzheimer's disease (AD), a leading cause of dementia, is characterized by mitochondrial dysfunction, including impaired oxidative phosphorylation (OXPHOS), which drives neurodegeneration. This study aimed to identify OXPHOS-related AD biomarkers for early intervention. Integrated analysis of differentially expressed genes from AD temporal lobe and peripheral blood samples, using multivariate logistic regression and LASSO, identified ATP6V1E1 and NDUFB5 as key genes and potential AD risk factors. These genes exhibited strong diagnostic performance (AUC >0.7) and were validated in two independent cohorts. Further western blotting validation using an AD mouse model revealed that both genes were significantly downregulated in the hippocampus. Notably, their expression levels showed significant negative correlations with both Aβ and Tau pathology in AD mouse models. Single-cell RNA-seq analysis indicated their predominant expression in microglia, linking their expression to dysregulated immune cell infiltration. Furthermore, we observed a widespread downregulation of multiple mitochondrial complex I and V-ATPase subunits, indicating a systemic impairment in OXPHOS and lysosomal acidification in AD. This coordinated dysregulation underscores the synergistic dysfunction of mitochondrial and lysosomal systems in AD pathogenesis. This research highlights ATP6V1E1 and NDUFB5 as potential early AD indicators, and provides new insights into both the molecular mechanisms underlying AD pathogenesis and novel therapeutic strategies.},
}

@article {pmid41242410,
year = {2025},
author = {Mastnak-Sokolov, P and Knez, D and Meden, A and Strašek Benedik, N and Ferjančič Benetik, S and Hrast Rambaher, M and Zorman, M and Nachon, F and Brazzolotto, X and Jardemark, K and Jungholm, O and Bruton, J and Strandback, E and Nyman, T and Shahid, M and Gobec, S},
title = {Dual Cholinergic Modulation in Dementia: Quinuclidine Carbamates Targeting Butyrylcholinesterase and α7 Nicotinic Receptor.},
journal = {Chemico-biological interactions},
volume = {},
number = {},
pages = {111830},
doi = {10.1016/j.cbi.2025.111830},
pmid = {41242410},
issn = {1872-7786},
abstract = {Alzheimer's disease (AD) is the leading cause of dementia worldwide, but current therapies provide only symptomatic relief. Multi-target directed ligands (MTDLs) represent a promising approach to address AD pathology by modulating multiple targets with a single molecule. Here we describe quinuclidine carbamates that act simultaneously on butyrylcholinesterase (BChE) and the cholinergic α7 nicotinic receptor (α7 nAChR), thereby approaching cholinergic dysfunction at two levels: by modulating acetylcholine degradation and by direct agonism at this receptor. Starting with the α7 nAChR agonist bradanicline, its amide group was replaced by a carbamate moiety to enhance BChE inhibition while retaining receptor agonism. These quinuclidine carbamates inhibited BChE in the submicromolar range with the desired selectivity over acetylcholinesterase (AChE). In a calcium-flux assay on recombinant HEK293T cells expressing the α7 nAChR, all compounds were agonists of the α7 nAChR in the nanomolar range. Importantly, compound 6b displayed balanced, submicromolar activity against both targets. The crystal structures confirmed non-covalent binding to the active site of human BChE, and the 6b-hBChE complex also revealed an unprecedented flip of Tyr440, representing the first described example of backdoor opening for hBChE. Taken together, these results demonstrate that quinuclidine carbamates are promising dual modulators of hBChE and α7 nAChR, supporting their potential as MTDLs for AD therapy and highlighting this underexplored dual-target strategy as a promising approach in cholinergic drug discovery.},
}

@article {pmid41242346,
year = {2025},
author = {Mo, Y and Peng, Y and , },
title = {Bile acid profile and white matter microstructural changes in early Alzheimer's disease.},
journal = {Brain research bulletin},
volume = {},
number = {},
pages = {111642},
doi = {10.1016/j.brainresbull.2025.111642},
pmid = {41242346},
issn = {1873-2747},
abstract = {BACKGROUND: Although recent disease-modifying treatments such as Lecanemab have shown promise in reducing amyloid burden and modestly slowing cognitive decline in early Alzheimer's disease (AD), effective long-term interventions remain limited. Emerging evidence links dysregulated gut-liver bile-acid (BA) metabolism to AD pathology. We examined whether peripheral BA signatures correspond to early white-matter microstructure changes in prodromal AD.

METHODS: Baseline data were drawn from the Alzheimer's Disease Neuroimaging Initiative. One-hundred-twenty-seven participants (46 cognitively normal controls, 81 amnestic mild cognitive impairment [MCI]; 55-90y) contributed serum concentrations of 33 BAs plus three predefined BA ratios, cerebrospinal-fluid biomarkers, and diffusion-tensor MRI. Fractional anisotropy (FA), mean (MD), radial (RD) and axial (AxD) diffusivities were derived using tract-based spatial statistics and atlas-based regions of interest.

RESULTS: Higher FA was associated with greater taurochenodeoxycholic acid, L-aspartate and L-asparagine, and with lower apocholic and 12-ketolithocholic acids. Elevated AxD, MD and RD tracked with reduced dehydrolithocholic acid and the glycolithocholic acid to chenodeoxycholic acid (GLCA/CDCA) ratio, and with higher palmitic acid. Participants with high cholic acid to chenodeoxycholic acid (CA/CDCA) ratio exhibited greater AxD in the left hippocampal cingulum; high GLCA/CDCA related to diffusivity increases in the right hippocampal cingulum and uncinate fasciculus. The glycodeoxycholic acid to taurodeoxycholic acid (GDCA/TDCA) ratio showed the strongest pattern, producing widespread AxD, MD and RD elevations in the uncinate fasciculus and cerebral peduncles and reduced FA in the fornix (p ≤ 0.0068).

CONCLUSION: Specific peripheral BA profiles-especially the gut-derived GDCA/TDCA ratio-mirror limbic and motor white-matter degeneration in amnestic MCI, independent of demographic and genetic risk. These findings implicate disrupted hepatic-microbial BA metabolism as a modifiable contributor to prodromal AD and highlight BA-targeted gut interventions as potential disease-modifying strategies.},
}

@article {pmid41242191,
year = {2025},
author = {Kara, F and Joers, JM and Przybelski, SA and Algeciras-Schimnich, A and Gunter, JL and Jack, CR and Petersen, RC and Öz, G and Kantarci, K},
title = {[1]H-MR spectroscopy biomarkers are associated with plasma-derived biomarkers of amyloid-β and tau in the early phase of AD continuum.},
journal = {Neurobiology of aging},
volume = {158},
number = {},
pages = {18-27},
doi = {10.1016/j.neurobiolaging.2025.11.003},
pmid = {41242191},
issn = {1558-1497},
abstract = {The objective of the study was to evaluate the relationship of plasma biomarkers of Alzheimer's disease (AD) with in vivo proton magnetic resonance spectroscopy ([1]H-MRS) markers, and their association with cognitive function across the early stages of the AD continuum. Determining these associations may clarify the AD-related biological pathways and support the development of integrated AD blood and [1]H-MRS biomarkers for early detection of these pathways. Fifty-five older adults (40 cognitively unimpaired; 15 mild cognitive impairment) from the Mayo Clinic Study of Aging underwent single-voxel [1]H-MRS (sLASER) at 3T in the posterior cingulate gyrus (PCG) and left hippocampus (LH), along with plasma assays for Aβ42/40, phosphorylated tau (p-tau181), and the p-tau181/Aβ42 ratio. Associations between plasma biomarkers and [1]H-MRS metabolites (myo-inositol [mIns]/total creatine [tCr], total N-acetylaspartate [tNAA]/tCr, and tNAA/mIns) were examined using partial Spearman correlations (rho, ρ) adjusted for age and sex. Next, associations of the Mini-Mental State Examination with p-tau181/Aβ42 and tNAA/mIns were examined adjusting for the same covariates plus education. In both PCG and LH regions, lower tNAA/mIns was associated with higher p-tau181/Aβ42 (PCG:ρ=-0.59; LH:ρ=-0.54) and p-tau181 (PCG: ρ=-0.38; LH:ρ =-0.39), as well as with lower Aβ42/40 (PCG:ρ=0.40; LH:ρ=0.32). Higher mIns/tCr was associated with higher p-tau181/Aβ42 (PCG: ρ=0.56; LH:ρ=0.46) and p-tau181 (PCG:ρ=0.37; LH:ρ=0.31). Lower PCG and LH tNAA/mIns ratios were associated with lower MMSE (PCG:ρ=0.53; LH:ρ=0.46), while higher p-tau181/Aβ42 was associated with lower MMSE (ρ=-0.49). [1]H-MRS-derived gliosis and neuronal injury biomarkers are associated with early AD pathology, and cognitive performance, supporting their use as noninvasive biomarkers in early AD.},
}

@article {pmid41242190,
year = {2025},
author = {Dintica, CS and Johnson, L and Petersen, M and O'Bryant, S and Yaffe, K},
title = {Depressive symptoms and plasma AT(N) biomarkers among cognitively healthy and mild cognitively impaired in a diverse cohort.},
journal = {Neurobiology of aging},
volume = {158},
number = {},
pages = {11-17},
doi = {10.1016/j.neurobiolaging.2025.11.005},
pmid = {41242190},
issn = {1558-1497},
abstract = {Depression is a known risk factor for dementia and MCI, but its associations with AT(N) biomarkers remain inconsistent and may differ by cognitive status. We cross-sectionally studied 2929 dementia-free participants from the Health & Aging Brain Study-Health Disparities (HABS-HD). Mild cognitive impairment (MCI) was identified as having cognitive complaints, Clinical Dementia Rating scores between 0.5 and 2.0, and at least one cognitive test ≤ 1.5 SD below norms. We defined AT (N) with plasma biomarkers amyloid-β 42/40 (Aβ42/40), phosphorylated tau (p-tau181), neurofilament light (NfL), assessed using SIMOA technology and magnetic resonance imaging (MRI) based Alzheimer disease (AD) signature cortical thickness. Depressive symptoms were measured with the Geriatric Depression Scale (GDS), categorized as high (≥10) or low (<10). We used linear regression to determine association between depressive symptoms and biomarkers, adjusting for age, sex, education, kidney function, and body mass index. High depressive symptoms (19 %) were linked to higher NfL (standardized mean differences [SMD] = 0.10, 95 % confidence interval [CI: 0.02-0.18] and p-tau181 (SMD = 0.15, 95 % CI: 0.07-0.22) levels compared to low symptoms but not with Aβ42/40 or AD cortical thickness. Participants with both MCI and high depressive symptoms had higher NfL (SMD = 0.19, 95 % CI: 0.05-0.33) and p-tau181 (SMD = 0.30, 95 % CI: 0.16-0.45), and lower AD signature cortical thickness (SMD = -0.30, 95 % CI: -0.48 to -0.11). No group differences were found for Aβ42/40. Depressive symptoms, particularly among those with MCI, were linked to greater tau and neurodegeneration; longitudinal studies are needed to clarify this clinical significance.},
}

@article {pmid41242034,
year = {2025},
author = {Bruyère, O and Leroy, L and Olivier, C and Demonceau, C and Buckinx, F and Blavier, M and Lekeu, F},
title = {Exploring the knowledge, attitudes, and practices of physical therapists in care facilities assisting individuals with Alzheimer's disease.},
journal = {Geriatric nursing (New York, N.Y.)},
volume = {67},
number = {},
pages = {103710},
doi = {10.1016/j.gerinurse.2025.103710},
pmid = {41242034},
issn = {1528-3984},
abstract = {INTRODUCTION: Physical therapists (PTs) in nursing homes often treat patients with Alzheimer's disease. This study evaluated their knowledge, attitudes, and practices (KAP) concerning Alzheimer's care.

METHODS: A KAP survey-based questionnaire was administered to PTs in Belgian nursing homes and long-term care facilities, focusing on their understanding of Alzheimer's, care approaches, and practical care aspects.

RESULTS: The survey, completed by 133 PTs, revealed strong knowledge and positive attitudes. PTs adapted communication methods, managed treatment refusals, and prioritized fall prevention and safety. Care practices focused on maintaining patient autonomy through exercises for strength, balance, and coordination. Techniques like massage or aromatherapy were less commonly used, despite potential benefits. Notably, knowledge, experience, or exposure to Alzheimer's patients did not significantly influence attitudes or practices.

CONCLUSION: Targeted practical training in dementia care techniques is needed to enhance caregiving skills, despite a solid foundation in knowledge and attitudes. Future research should examine diverse samples and evaluate training impact on practices.},
}

@article {pmid41241944,
year = {2025},
author = {Jung, HG and Yu, B and Choi, Y and Go, G and Zhang, Q and Tang, Y and Kim, MW and Cai, D},
title = {Control of aging-associated neurodegeneration via hypothalamic extracellular vesicles containing parathymosin.},
journal = {Cell reports},
volume = {44},
number = {11},
pages = {116561},
doi = {10.1016/j.celrep.2025.116561},
pmid = {41241944},
issn = {2211-1247},
abstract = {Aging-associated neurodegeneration underlies various neurological diseases; however, the neurocrine basis remains poorly understood. Here, we investigate the role of parathymosin (PTMS), a secretory protein with nuclear functions that has recently been identified as a circulating factor in the brain. The results show that loss of PTMS is sufficient to cause severe, age-dependent neurodegeneration and reduced lifespan, whereas hypothalamic PTMS gain of function counteracts aging-associated brain disorders and extends lifespan. PTMS is present in hypothalamic extracellular vesicles (EVs), particularly in subpopulations released by hypothalamic neural stem/progenitor cells (htNSCs). These htNSC-derived EVs carry small nuclear and nucleolar RNAs in a PTMS-associated manner to protect recipient neurons from DNA damage. Therapeutically, these htNSC-derived EVs provide a strong effect against neurodegenerative disorders associated with PTMS deficiency in mouse models, including Alzheimer's disease (AD)-like phenotypes in the 5xFAD model. In conclusion, PTMS possesses anti-neurodegenerative properties, and PTMS-containing hypothalamic EVs are significant in combating aging-associated neurodegenerative diseases.},
}

@article {pmid41241725,
year = {2025},
author = {Altona, J and Wiegelmann, H and Mena, E and Schüz, B and Wolf-Ostermann, K},
title = {Neighbourhood-built environment and cognitive or social health in older adults with mild cognitive impairment or dementia: an umbrella review.},
journal = {BMC geriatrics},
volume = {25},
number = {1},
pages = {907},
pmid = {41241725},
issn = {1471-2318},
mesh = {Humans ; *Cognitive Dysfunction/psychology/diagnosis/epidemiology ; *Dementia/psychology/diagnosis/epidemiology ; Aged ; *Built Environment ; *Cognition/physiology ; *Neighborhood Characteristics ; },
abstract = {BACKGROUND: Recent studies underscore the importance of the neighbourhood-built environment (NBE) for the cognitive and social health of older people with mild cognitive impairment (MCI) or people living with dementia (PlwD). While previous overview reviews have provided valuable insights, they often focus narrowly on either objective environmental features or subjective experiences and typically lack an integrated perspective. This umbrella review addresses this gap by systematically examining how specific NBE aspects (a) influence the cognitive and social health of older people with MCI or PlwD, and (b) subjective experiences by PlwD and their caregivers. By combining these perspectives, the review aims to support the development of dementia-friendly neighbourhood design and planning.

METHODS: To answer these questions, an umbrella review was performed. Scopus, MEDLINE (Pubmed), APA PsychINFO (Ebesco), CINAHL Complete (Ebesco), Cochrane Library, and Epistemonikos databases were used for the systematic literature research. We included peer-reviewed reviews or meta-analyses (quantitative, qualitative, or mixed-method studies) in German or English.

RESULTS: Ten reviews with 364 primary studies were identified. Reviews predominantly included quantitative studies, but also qualitative studies. The primary focus of the reviews was on the positive and negative influences of the NBE on MCI and/or dementia. Subjective experiences on social health targets were also addressed, but received less attention.

CONCLUSIONS: The results of the reviews, although heterogeneous, highlight potential relationships between various NBE aspects and the cognitive and social health of older people with MCI or PlwD. Clear associations were identified for certain NBE features-such as green spaces and transportation infrastructure-which demonstrate positive influences on both cognitive functioning and social participation. These findings emphasise the importance of considering both objective environmental characteristics and the subjective perceptions of PlwD and their caregivers when designing dementia-friendly neighbourhoods. By doing so, this umbrella review contributes evidence-based guidance to support autonomy and independent living for people with MCI or dementia. Further research is needed to explore the specific influence of individual NBE aspects on social health and the lived experiences of PlwD and their caregivers.},
}

Humans
*Cognitive Dysfunction/psychology/diagnosis/epidemiology
*Dementia/psychology/diagnosis/epidemiology
Aged
*Built Environment
*Cognition/physiology
*Neighborhood Characteristics

@article {pmid41241612,
year = {2025},
author = {Leffa, DT and Zhang, Y and Wang, Y and Teverovsky, EG and Jacobsen, E and Bellaver, B and Ferreira, PCL and Fan, KH and Kamboh, MI and Karikari, TK and Chang, CH and Snitz, BE and Molina, BSG and Pascoal, TA and Ganguli, M},
title = {Association Between the Genetic Risk for Attention-Deficit/Hyperactivity Disorder and Cognitive Function in Older Age: The MYHAT Population-Based Study.},
journal = {The American journal of geriatric psychiatry : official journal of the American Association for Geriatric Psychiatry},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.jagp.2025.10.005},
pmid = {41241612},
issn = {1545-7214},
abstract = {OBJECTIVES: Attention-deficit/hyperactivity disorder (ADHD) has been associated with increased risk for dementia, including Alzheimer's disease (AD). Polygenic risk scores for ADHD (ADHD-PRS) reflect the genetic liability for the disorder and have been linked to cognitive decline in selected clinical samples. This study examined associations between ADHD-PRS and cognitive function in older adults from a population-based cohort and tested whether these associations were moderated by plasma biomarkers of AD and related disorders (ADRD).

METHODS: We analyzed data from 1,468 dementia-free participants from the Monongahela-Youghiogheny Healthy Aging Team (MYHAT) study, with cognitive assessments across five domains. ADHD-PRS was calculated, and a subset underwent blood draw for the analysis of ADRD biomarkers. We examined cross-sectional and longitudinal associations between ADHD-PRS and cognition using linear regressions and mixed-effects models adjusting for age, sex, and ancestry.

RESULTS: Higher ADHD-PRS was significantly associated with lower visuospatial function in cross-sectional analyses after correction for multiple comparisons. Associations with attention and language were moderated by education, and higher ADHD-PRS was associated with lower performance only among individuals with ≤ high school education. No associations were found between ADHD-PRS and plasma biomarkers, nor did biomarkers modify the relationship between ADHD-PRS and cognition. In longitudinal analyses, no association between ADHD-PRS and cognitive trajectories remained significant after correction for multiple comparisons.

CONCLUSIONS: Overall, ADHD genetic liability appears relevant to cognitive performance in late life, though longitudinal trajectories remain unaffected. In older age, ADHD-PRS seems to negatively impact visuospatial tests, characterized by complex and integrative demands. Educational attainment moderated the associations with attention and language, suggesting a potential buffering effect.},
}

@article {pmid41241298,
year = {2025},
author = {Aung, KZ and Zin, SS and Wu, X and Myint, ZW and Karanth, S and Estus, S and Norris, CM and Nelson, PT and Fardo, DW and Abner, EL and Katsumata, Y},
title = {Disentangling the inverse relationship between cancer and Alzheimer's or Parkinson's disease: A systematic review on Mendelian randomization studies.},
journal = {Neurobiology of disease},
volume = {217},
number = {},
pages = {107190},
doi = {10.1016/j.nbd.2025.107190},
pmid = {41241298},
issn = {1095-953X},
abstract = {INTRODUCTION: Although studies have reported an inverse relationship between cancer and neurodegenerative diseases such as Alzheimer's disease (AD) and Parkinson's disease (PD), findings remain inconsistent. Observational studies are limited by survival bias and reverse causation. To better understand the relationship, we conducted a systematic review of Mendelian randomization (MR) studies examining both directions-assessing cancer as a risk factor for AD or PD, as well as AD or PD as exposures influencing cancer risk.

METHODS: We systematically reviewed MR studies investigating the causal relation between cancer and either AD or PD. Cancer could be specified as either an exposure or an outcome of interest. Articles published until August 2024 were identified, screened, and abstracted by two reviewers following the "Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA)" guidelines.

RESULTS: Twelve studies met the inclusion criteria, comprising data from approximately 10,000 individuals and examining over 20 cancer types in relation to AD and PD risk. Of these, seven studies focused on AD, three on PD, and two examined both. Among nine studies on AD, an inverse association between several cancers and AD was reported, especially with breast cancer (overall and estrogen receptor-positive), with reduced odds (OR < 1) using inverse variance weighting. Studies on PD yielded inconclusive evidence of any causal relationship with cancer.

CONCLUSION: These results highlight inverse associations between AD and breast cancers, potentially implicating hormonal signaling pathways. Despite variations in methods and GWAS datasets, consistent protective trends were observed. However, further research is required to confirm causality.},
}

@article {pmid41241284,
year = {2025},
author = {Jiang, ZH and Tian, XX and Sun, MX and Yuan, HZ and Xiang, SR and Zhang, HF and Zhang, JP and Cui, LY and Wang, WF},
title = {Investigation of the effects and mechanisms of endogenous deletion of FGF21 on cognitive functions.},
journal = {Physiology & behavior},
volume = {},
number = {},
pages = {115174},
doi = {10.1016/j.physbeh.2025.115174},
pmid = {41241284},
issn = {1873-507X},
abstract = {Cognitive impairment is characterized by reduced cognitive abilities in one or more areas such as language, memory, and reasoning. It is a common problem in various neurological diseases and the aging process, seriously affecting people's quality of life and overall health. Fibroblast growth factor 21 (FGF21), a hormone regulating glucose/lipid metabolism and energy homeostasis, exhibits neuroprotective properties. To investigate the impact and mechanism of endogenous deletion of FGF21 on cognitive function, FGF21 knockout mice and wild-type mice were used. Different behavioral paradigms were used to study the effects of FGF21 on the cognitive behavior of mice. Morphological changes were observed by Nissl and HE staining, and RNA sequencing was performed to explore potential links between FGF21 and cognitive impairment-related diseases. Behavioral and morphological analyses demonstrated that FGF21 knockout mice exhibited deficits in learning and memory, anxiety-like behaviors, and neuronal degeneration. Transcriptomic profiling revealed that FGF21 deficiency altered multiple neuroprotective processes, including metabolism and synaptic transmission. These deficits may be mediated through downregulation of the PPAR signaling pathway, thereby affecting cognitive function. This research indicates that endogenous FGF21 deletion disrupts basic cognitive and emotional behaviors of mice, which may accelerate the development of cognitive impairment-related diseases (including Alzheimer's disease, vascular cognitive impairment, frontotemporal dementia, dementia with Lewy bodies), and suggests FGF21 as a potential therapeutic target for these diseases.},
}

@article {pmid41241266,
year = {2025},
author = {Sharma, A and Singh, TG},
title = {Next-generation neurotherapeutics: mechanistic insights on monoclonal antibodies in Alzheimer's disease.},
journal = {Brain research},
volume = {},
number = {},
pages = {150047},
doi = {10.1016/j.brainres.2025.150047},
pmid = {41241266},
issn = {1872-6240},
abstract = {Monoclonal antibodies (mAbs) for Alzheimer's disease (AD) present a fundamental translational challenge, as demonstrated by amyloid-beta (Aβ)-targeting mAbs that successfully employed Fragment crystallizable gamma receptor (FcγR)/Immunoreceptor tyrosine-based activation motif (ITAM)-mediated microglial phagocytosis yet achieved only modest cognitive improvements while introducing significant Amyloid-related imaging abnormalities (ARIA) risk, thereby highlighting inherent single-therapy limitations. Building on these findings, tau-directed antibodies show preclinical promise by targeting pathological seeding and propagation, but face translational challenges including limited extracellular accessibility and variable efficacy across disease stages, necessitating expansion beyond single-target approaches. Consequently, the translational field is advancing toward innovative multi-mechanistic strategies, including synaptic restoration through anti-PrP and neurotrophic receptor agonists that provide functional benefits independent of plaque reduction, neuroinflammation modulation via anti-CD33 and complement inhibitors requiring careful patient selection due to variable outcomes, and emerging anti-TREM2 and anti-APOE4 mAbs enabling precision medicine tailored to individual genetic profiles. Importantly, comparative studies also reveal that combination therapies-especially dual Aβ/tau targeting-demonstrate superior synergistic effectiveness, driving next-generation engineering advances including Fc modifications that reduce ARIA risk, nanobodies/single-chain variable fragments (scFvs) with enhanced blood-brain barrier (BBB) penetration, cell-penetrating formats for intracellular tau access, and pH-sensitive glycoengineering for optimized tissue-specific binding. Ultimately, successful clinical translation depends on integrating biomarker-guided patient selection, optimized dosing strategies, and disease-stage-appropriate timing, with future progress anticipated through bispecific/multispecific antibodies targeting complementary pathways alongside personalized biomarker approaches, collectively providing realistic potential for achieving genuine neuroprotection and meaningful disease modification beyond symptomatic treatment in AD patients.},
}

@article {pmid41241264,
year = {2025},
author = {Grandi, R and Gulati, V and Islam, MS and Ekpo, OE and Chitranshi, N},
title = {Investigating the impact of resveratrol and quercetin on glymphatic function, blood-brain barrier, and neuroglial health: a systematic review.},
journal = {Brain research},
volume = {},
number = {},
pages = {150046},
doi = {10.1016/j.brainres.2025.150046},
pmid = {41241264},
issn = {1872-6240},
abstract = {OBJECTIVE: This systematic review evaluates the therapeutic potential of quercetin (QUE) and resveratrol (RSV) in Alzheimer's disease (AD), Parkinson's disease (PD), and multiple sclerosis (MS), focusing on their effects on glymphatic function, cerebrospinal fluid (CSF) dynamics, neuroglial health, and blood-brain barrier (BBB) permeability.

METHODS: A systematic search was conducted across PubMed, ScienceDirect, and ProQuest following PRISMA guidelines for studies published between 2019 and 2024. Thirty-six studies, including experimental models and clinical trials, were identified and assessed for outcomes relating to antioxidant, anti-inflammatory, and neuroprotective effects of QUE and RSV.

RESULTS: Across 56 studies, both QUE and RSV significantly enhanced antioxidant defences (upregulation of SOD, GSH, GPx, CAT) and downregulated pro-inflammatory cytokines (IL-1β, IL-6, TNF-α, NF-κB). Several studies also reported Nrf2/HO-1 and SIRT1/AMPK activation. BBB integrity improved via increased claudin‑5/occludin/ZO‑1 expression and reduced Evans blue/sodium fluorescein extravasation; cerebrovascular reactivity and cerebral blood flow (CBF) were frequently restored. Glymphatic outcomes demonstrated enhanced AQP4 polarization at end feet and accelerated clearance of fluorescent tracers and β-amyloid in vivo, with preserved astrocyte-pericyte coupling. Neuroglial health improved (reduced microglial M1 markers, increased M2/Arg‑1 and astrocytic homeostatic markers), alongside neuronal survival and synaptic proteins. Nanoparticle/liposomal formulations of QUE/RSV increased BBB penetration and brain concentrations relative to free compounds.

CONCLUSION: QUE and RSV demonstrate significant potential as adjunctive therapies for mitigating neuroinflammation, oxidative stress, and neurodegenerative progression through glymphatic and BBB modulation. However, further high-quality, long-term clinical trials are needed to validate these findings, optimise delivery systems, and establish translational relevance to human neurodegenerative conditions.},
}

@article {pmid41241087,
year = {2025},
author = {Miyazaki, S and Mizuno, K and Ikeda, Y},
title = {Effect of ninjin'yoeito on age-related decline in responsiveness of the brain reward system in mice.},
journal = {Experimental gerontology},
volume = {},
number = {},
pages = {112967},
doi = {10.1016/j.exger.2025.112967},
pmid = {41241087},
issn = {1873-6815},
abstract = {The reward system involved in the regulation of appetite and motivated behaviors involves mesolimbic dopamine signaling from the ventral tegmental area (VTA) to the nucleus accumbens (Nac). Age-related loss of dopaminergic neurons and weakening of dopamine signals reportedly cause reward system dysfunction, and similarly, age-related changes in microglia in the VTA have been suggested to be involved in this dysfunction. Ninjin'yoeito (NYT), a traditional Japanese herbal medicine, has been reported to improve anorexia, apathy, and the decline in motivation-related behavior in frail Alzheimer's disease patients and older animal models. Although behavioral and electrophysiological analyses suggest that NYT may affect dopamine signaling, the effects of NYT on the reward system remain unclear. The present study aimed to determine whether NYT modulates dopamine-mediated reward circuits in older mice, and whether its effects are linked to microglial modulation in the VTA. Repeated NYT administration restored the responsiveness of dopaminergic neurons in the VTA and increased dopamine release in the Nac, causing an increase in grooming behavior with sucrose stimulation in older mice. Although NYT did not affect cellular senescence of dopaminergic neurons or glial cells, including astrocytes and microglia, it reduced phosphorylation of TANK-binding kinase 1 and expressions of NLRP3 and IL-1β in the VTA. Furthermore, NLRP3 expression in VTA microglia, but not astrocyte, was attenuated by NYT. Our results suggest that NYT may suppress age-related inflammation in the VTA, thereby ameliorating age-related hypovolition.},
}

@article {pmid41240924,
year = {2025},
author = {Rabinovici, GD},
title = {Progress in Alzheimer's disease: The Lancet Series.},
journal = {The Lancet. Neurology},
volume = {24},
number = {12},
pages = {991-992},
doi = {10.1016/S1474-4422(25)00387-4},
pmid = {41240924},
issn = {1474-4465},
}

@article {pmid41212043,
year = {2025},
author = {Nadubinszky, G and Székács, B},
title = {[Connection between viral infections, vaccines, and dementia].},
journal = {Orvosi hetilap},
volume = {166},
number = {45},
pages = {1763-1768},
doi = {10.1556/650.2025.33423},
pmid = {41212043},
issn = {1788-6120},
mesh = {Humans ; *Dementia/prevention & control/virology/etiology ; *Virus Diseases/complications/prevention & control ; Aged ; Herpes Zoster Vaccine ; COVID-19 Vaccines ; COVID-19/prevention & control ; Female ; Alzheimer Disease ; },
abstract = {Dementia represents a growing public health challenge in the elderly population worldwide, with its development being influenced by multifactorial mechanisms. In recent years, increasing evidence has supported the notion that certain viral infections – particularly herpesviruses, the human immunodeficiency virus (HIV), and SARS-CoV-2 – may contribute to neurodegenerative processes either directly or indirectly. It has been demonstrated that chronic inflammation, immune system dysregulation, and blood–brain barrier damage induced by viral agents potentially promote the pathogenesis of dementia, especially Alzheimer’s disease. Simultaneously, remarkable new research has emerged highlighting the potential protective effects of vaccination. According to a study conducted by Stanford University and published in 2025, elderly adults vaccinated against herpes zoster (shingles) exhibited a significantly lower incidence of dementia over a 7-year follow-up period. Researchers identified a 20% relative risk reduction, particularly among women. Other studies have supported similar effects for vaccines against influenza, tetanus, and diphtheria. The aim of our publication was to summarize the causative role of viral infections in dementia and to present the inhibitory effects of vaccines, which likely extend beyond specific antiviral infection prevention. Furthermore, we sought to emphasize the clinical and public health significance of these findings, particularly for the elderly population with compromised immune systems. Orv Hetil. 2025; 166(45): 1763–1768.},
}

Humans
*Dementia/prevention & control/virology/etiology
*Virus Diseases/complications/prevention & control
Aged
Herpes Zoster Vaccine
COVID-19 Vaccines
COVID-19/prevention & control
Female
Alzheimer Disease

@article {pmid41240919,
year = {2025},
author = {Kaila, LV and Ikeda, M and Sultana, J and Chouliaras, L and O'Brien, JT and Taylor, JP},
title = {The evolving therapeutic landscape of dementia with Lewy bodies.},
journal = {The Lancet. Neurology},
volume = {24},
number = {12},
pages = {1038-1052},
doi = {10.1016/S1474-4422(25)00323-0},
pmid = {41240919},
issn = {1474-4465},
mesh = {Humans ; *Lewy Body Disease/therapy/diagnosis ; },
abstract = {Dementia with Lewy bodies has a complex clinical presentation, with symptoms spanning cognitive, neuropsychiatric, motor, autonomic, and sleep domains. The disorder causes high morbidity, is associated with high caregiver burden, and can result in considerable health-care costs. Although symptomatic treatments remain scarce, emerging evidence supports a multipronged approach that integrates pharmacological and non-pharmacological interventions that target different signs and symptoms. Novel frameworks, such as the DIAMOND Lewy toolkit, provide structured management guidance. Beyond symptom control, research is at a turning point, with increasing focus on disease-modifying therapies. Ongoing clinical trials are exploring many therapeutic targets, including α-synuclein aggregation and neuroinflammation. Other potential targets in the treatment of dementia with Lewy bodies include amyloid β, given that the presence of Alzheimer's disease copathology is common in patients with this disease.},
}

Humans
*Lewy Body Disease/therapy/diagnosis

@article {pmid41240918,
year = {2025},
author = {Scholz, SW and Okubadejo, NU and Prakash, P and Liddelow, SA and Ryten, M and Halliday, GM},
title = {Advances in the genetics and pathology of Lewy body dementia.},
journal = {The Lancet. Neurology},
volume = {24},
number = {12},
pages = {1026-1037},
doi = {10.1016/S1474-4422(25)00363-1},
pmid = {41240918},
issn = {1474-4465},
mesh = {Humans ; *Lewy Body Disease/genetics/pathology ; alpha-Synuclein/genetics/metabolism ; Lewy Bodies/pathology ; Alzheimer Disease/genetics/pathology ; },
abstract = {Lewy body dementia is a heterogeneous disease that is underdiagnosed and poorly understood. Pathologically, Lewy body dementia is characterised by the accumulation of intraneuronal aggregates of misfolded α-synuclein, known as Lewy bodies and Lewy neurites. The genetic architecture of Lewy body dementia is complex, involving both common genetic variants with small risk effects and rare genetic variants with large effects. Alzheimer's disease pathology frequently coexists with Lewy body pathology and influences the clinical presentation. A deeper understanding of the pathophysiological pathways, including mitochondrial dysfunction, lysosomal dysfunction, and neuroinflammation, can enhance disease modelling, and this knowledge will ultimately facilitate the development of therapeutic interventions. The biological relationships that Lewy body dementia shares with other neurodegenerative and psychiatric disorders might also be crucial for the development of therapeutic strategies.},
}

Humans
*Lewy Body Disease/genetics/pathology
alpha-Synuclein/genetics/metabolism
Lewy Bodies/pathology
Alzheimer Disease/genetics/pathology

@article {pmid41240917,
year = {2025},
author = {Jack, CR and Hu, M and Wiste, HJ and Knopman, DS and Vemuri, P and Graff-Radford, J and Lowe, VJ and Vassilaki, M and Cogswell, PM and Schwarz, CG and Algeciras-Schimnich, A and Petersen, RC and Therneau, TM},
title = {Lifetime and 10-year absolute risk of cognitive impairment in relation to amyloid PET severity: a retrospective, longitudinal cohort study.},
journal = {The Lancet. Neurology},
volume = {24},
number = {12},
pages = {1016-1025},
doi = {10.1016/S1474-4422(25)00350-3},
pmid = {41240917},
issn = {1474-4465},
mesh = {Humans ; Male ; *Cognitive Dysfunction/diagnostic imaging/epidemiology/metabolism/genetics ; Female ; Aged ; Longitudinal Studies ; Retrospective Studies ; *Positron-Emission Tomography ; Middle Aged ; Aged, 80 and over ; Apolipoprotein E4/genetics ; Alzheimer Disease/diagnostic imaging/epidemiology ; Severity of Illness Index ; },
abstract = {BACKGROUND: A key knowledge gap concerns the lifetime risk of developing cognitive impairment among individuals who are cognitively unimpaired with abnormal Alzheimer's disease biomarkers. Our aim was to compute lifetime and 10-year absolute risk of cognitive impairment as a function of continuous amyloid PET.

METHODS: In this retrospective, longitudinal cohort study of data from participants of the population-based Mayo Clinic Study of Aging (Olmsted County, MN, USA), we computed lifetime and 10-year absolute risk of cognitive impairment in participants who were cognitively unimpaired and aged 50 years or older at enrolment. The primary predictor of interest was biological Alzheimer's disease severity, based on amyloid PET centiloid value. Starting age, sex, and APOE ε4 carriership status were also predictors. Outcomes were incident mild cognitive impairment (MCI), dementia, and death, which were ascertained or estimated via multistate hidden Markov modelling both in study and out of study.

FINDINGS: Between Nov 29, 2004, and Dec 2, 2024, 5158 participants (2623 [51%] women and 2535 [49%] men) who are cognitively unimpaired and 700 (307 [44%] women and 393 [56%] men) with MCI were included for analysis. Lifetime risk of MCI and dementia increased monotonically with increasing centiloid value (p<0·0001), which was the predictor with the largest effect. Lifetime risk of MCI for male APOE ε4 carriers who are cognitively unimpaired at a starting age of 75 years was 56·2% (95% CI 50·5-61·9) for centiloid 5, 60·2% (54·9-65·6) for centiloid 25, 71·0% (65·2-76·7) for centiloid 50, 75·2% (69·1-81·2) for centiloid 75, and 76·5% (70·5-82·4) for centiloid 100. Lifetime risk of MCI for female APOE ε4 carriers who are cognitively unimpaired at a starting age of 75 years was 68·9% (63·7-74·1) for centiloid 5, 71·3% (66·6-76·0) for centiloid 25, 77·6% (72·5-82·7) for centiloid 50, 81·2% (76·7-85·7) for centiloid 75, and 83·8% (78·5-89·1) for centiloid 100. Within each centiloid group, and for both men and women, lifetime and 10-year absolute risk for MCI and dementia was greater for APOE ε4 carriers than for non-carriers (p<0·0001). Biological severity of Alzheimer's disease was a predictor of 10-year absolute risk of MCI and dementia (p<0·0001); however, starting age (p<0·0001) had a more prominent effect. The rate of incident dementia was two times greater among individuals who had previously left the study than those who remained in the study.

INTERPRETATION: Lifetime and 10-year absolute risk for MCI and dementia among individuals who are currently cognitively unimpaired increase with increasing biological severity of Alzheimer's disease. This information should be important for risk-benefit evaluation of therapeutic interventions in the future. The high lifetime risk in participants with higher centiloid values addresses academic controversies concerning risk of future impairment associated with biomarkers of Alzheimer's disease among individuals who are cognitively unimpaired. Ascertainment and modelling of out-of-study outcomes are necessary for accurate lifetime risk estimates.

FUNDING: US National Institutes of Health, GHR Foundation, and the Alexander Family.},
}

Humans
Male
*Cognitive Dysfunction/diagnostic imaging/epidemiology/metabolism/genetics
Female
Aged
Longitudinal Studies
Retrospective Studies
*Positron-Emission Tomography
Middle Aged
Aged, 80 and over
Apolipoprotein E4/genetics
Alzheimer Disease/diagnostic imaging/epidemiology
Severity of Illness Index

@article {pmid41240899,
year = {2025},
author = {Xu, F and Carro, E},
title = {Early screening for Alzheimer's disease: A scientific, ethical, and value-based framework for targeted screening in at-risk individuals.},
journal = {Med (New York, N.Y.)},
volume = {6},
number = {11},
pages = {100919},
doi = {10.1016/j.medj.2025.100919},
pmid = {41240899},
issn = {2666-6340},
mesh = {*Alzheimer Disease/diagnosis ; Humans ; *Early Diagnosis ; *Mass Screening/ethics/methods ; Biomarkers ; },
abstract = {Although curative therapies for Alzheimer's disease (AD) remain elusive, recent approval of disease-modifying treatments and advances of less- or non-invasive biomarkers have shifted the paradigm toward earlier detection, including in asymptomatic individuals. Here, we propose a multidisciplinary framework, integrating scientific evidence, ethical principles, and value-based health care, to guide the responsible development and deployment of early detection programs for AD.},
}

*Alzheimer Disease/diagnosis
Humans
*Early Diagnosis
*Mass Screening/ethics/methods
Biomarkers

@article {pmid41240853,
year = {2025},
author = {Dang, K and Zheng, Q and Zhou, T and Wang, Y and Pan, D and Du, L and Suo, S and Dang, Y and Ma, L and Gao, X},
title = {Enhancing cognitive function with biopeptides from porcine brain hydrolysates via key targets: Keap1, p38α, AChE, and BACE1.},
journal = {Food chemistry},
volume = {497},
number = {},
pages = {147028},
doi = {10.1016/j.foodchem.2025.147028},
pmid = {41240853},
issn = {1873-7072},
abstract = {Previous research has reported the efficacy of porcine brain hydrolysate (PBH) in improving Alzheimer's disease (AD). Nevertheless, the identification and screening of peptides with memory-enhancing effects within PBH remains ambiguous. The memory-enhancing effect of PBH was evaluated through animal and human experiments. Peptides with potential memory-enhancement effects were screened using molecular docking based on key target proteins (Keap1, BACE1, AChE, and p38α), and confirmed through cellular experiments. Results showed a significant reduction in behavioral errors of mice and marked improvements in the memory scores of humans. Five peptides with potential memory-enhancing effects were identified and screened. Cell experiments demonstrated that the cell activities were increased to 89.83 % and 78.14 % respectively for FPLHP and WGQKPW. Furthermore, the two peptides could reduce the contents of the four target proteins, thereby exhibiting the potential of memory enhancement. These findings offer a novel strategy for the discovery of peptides, which contribute to the development of memory-enhancing.},
}

@article {pmid41240623,
year = {2025},
author = {Raghuvanshi, R and Wakudkar, SC and Manda, S and Bharate, SB},
title = {Design, synthesis, and biological evaluation of kenpaullone derivatives as potential dual inhibitors of cholinesterases and glycogen synthase kinase-3β.},
journal = {Bioorganic chemistry},
volume = {167},
number = {},
pages = {109232},
doi = {10.1016/j.bioorg.2025.109232},
pmid = {41240623},
issn = {1090-2120},
abstract = {Alzheimer's disease (AD) is a multifaceted neurodegenerative disorder that demands therapeutic approaches targeting multiple pathological pathways. Among these, the cholinergic deficit, amyloid-β (Aβ) aggregation, and tau hyperphosphorylation are recognized as key contributors to disease progression. This study aimed to develop multitarget-directed ligands (MTDLs) by rationally modifying the potent but poorly soluble glycogen synthase kinase 3β (GSK-3β) inhibitor, kenpaullone 17b, to simultaneously inhibit cholinesterases (ChEs) and GSK-3β while improving physicochemical properties. Initial substitution of the C9-bromo group in 17b with a sulfonamide moiety produced compound 17m, which retained strong GSK-3β inhibition (IC50 = 0.35 μM) and acquired modest acetylcholinesterase (AChE) inhibitory activity (IC50 = 20 μM). Further elongation of the C9 substituent with a cyclohexylaminopropyl chain yielded compound 18o, exhibiting balanced dual inhibition of AChE (IC50 = 1.7 μM), butyrylcholinesterase (BChE) (IC50 = 5.3 μM), and GSK-3β (IC50 = 5.7 μM). Compound 18o also inhibited Aβ1-42 self-aggregation by 21 % at 10 μM and demonstrated blood-brain barrier (BBB) permeability with a 100-fold improvement in aqueous solubility compared with 17b. Molecular docking and molecular dynamics simulations revealed stable dual binding conformations within the AChE and GSK-3β active sites, supported by key hydrogen bonds and hydrophobic interactions. Overall, the structurally flexible analog 18o represents a promising dual ChE/GSK-3β inhibitor with improved drug-like characteristics, warranting further preclinical evaluation as a potential therapeutic lead for AD.},
}

@article {pmid41240614,
year = {2025},
author = {Khan, U and Ahmad, M and Tuba, M and Naaz, R and Qayum, F and Khatoon, S and Sanobar, and Ahamad, S and Saquib, M and Hussain, MK},
title = {Natural alkaloids with therapeutic potential against Alzheimer's disease through cholinesterase inhibition.},
journal = {European journal of medicinal chemistry},
volume = {302},
number = {Pt 2},
pages = {118371},
doi = {10.1016/j.ejmech.2025.118371},
pmid = {41240614},
issn = {1768-3254},
abstract = {Alzheimer's disease (AD) is a progressive neurodegenerative disorder in which the decline of cholinergic neurotransmission plays a central role in cognitive impairment. Cholinesterase inhibition remains an established therapeutic approach to enhance acetylcholine levels and provide symptomatic relief. Natural alkaloids have long served as an important source of cholinesterase inhibitors, offering diverse molecular scaffolds, stereochemical complexity, and strong biological relevance. This review provides a comprehensive overview of natural alkaloids reported as acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) inhibitors, highlighting their structural diversity, mechanisms of inhibition, and structure-activity relationships. In addition, the review presents a brief analysis on the emerging pseudo-natural product (PNP) framework as a complementary strategy for designing new alkaloid-inspired potential inhibitors that combine nature-derived functionality with synthetic innovation. Overall, the manuscript underscores the enduring significance of alkaloids in cholinesterase inhibitor discovery and their potential in developing next-generation therapeutics for AD.},
}

@article {pmid41240472,
year = {2025},
author = {Nada, H and Yuan, S and El Gaamouch, F and Cho, S and Kuncewicz, K and Calvo-Barreiro, L and Gabr, MT},
title = {TREM2 activation by first-in-class direct small molecule agonists: DEL screening, optimization, biophysical validation, and functional characterization.},
journal = {European journal of medicinal chemistry},
volume = {302},
number = {Pt 3},
pages = {118358},
doi = {10.1016/j.ejmech.2025.118358},
pmid = {41240472},
issn = {1768-3254},
abstract = {Triggering receptor expressed on myeloid cells 2 (TREM2) is a key regulator of microglial function, and its loss-of-function variants are linked to Alzheimer's disease (AD) and neurodegenerative disorders. While TREM2 activation is a promising therapeutic strategy, no small molecule agonists acting via direct TREM2 binding have been reported to date. Here, we describe the discovery of first-in-class, direct small molecule TREM2 agonists identified through DNA-encoded library (DEL) screening. The DEL hit (4a) demonstrated TREM2 binding affinity, as validated by three biophysical screening platforms (TRIC, MST, and SPR), induced Syk phosphorylation, luciferase assay and enhanced microglial phagocytosis. Pre-liminary optimization yielded 4i, which maintained TREM2 engagement with improved selectivity over TREM1 and no cytotoxicity. Molecular dynamics simulations predicted that 4a stabilizes a transient binding pocket on TREM2, indicating the possibility of a novel mechanism for receptor activation. These findings provide the first proof-of-concept for direct pharmacological TREM2 agonism, offering a foundation for developing therapeutics against AD and related disorders.},
}

@article {pmid41240389,
year = {2025},
author = {Jahanmehr, D and Ahmadi, A and Fadaei, M and Sangi Nasab Lahijan, A and Shafiee Sabet, M and Kalantari Dehaghi, H and Asadi-Golshan, R},
title = {The Ketogenic Diet: A Possible Intervention for Improving Hippocampal Function in Neurological Disorders.},
journal = {Nutrition reviews},
volume = {},
number = {},
pages = {},
doi = {10.1093/nutrit/nuaf210},
pmid = {41240389},
issn = {1753-4887},
abstract = {With a focus on the hippocampus, in this review we examined the emerging role of the ketogenic diet (KD) in treating neurological disorders. There are multiple pathways through which various versions of the KD influence the hippocampus: energy metabolism shifts, neurotransmitter modulation, neuroinflammation control, and synaptic plasticity and epigenetic regulation modifications. Both animal studies and clinical research, with emphasis on epilepsy and Alzheimer disease, have revealed the therapeutic potential of KDs. By modifying energy metabolism and lowering neuroinflammation, KDs may have therapeutic uses such as treatment of epilepsy and Alzheimer disease. In addition, ketones may stabilize hippocampal neuronal networks and reduce amyloid-beta toxicity. Individualized factors and the duration and timing of KD intervention play critical roles in achieving optimal outcomes, such as enhanced hippocampal function and neuroprotection. While preclinical studies have demonstrated enhanced hippocampal synaptic plasticity and neuroprotection, the long-term neurological and metabolic effects of KDs require further clinical validation. There are still a number of important research gaps, especially with regard to the application of animal findings to humans. Future studies should concentrate on long-term human trials using standardized designs to investigate how KDs can affect the nervous system.},
}

@article {pmid41240365,
year = {2025},
author = {Zammit, MD and Bruzzone, H and Cody, KA and Morse, J and Wilson, R and Bettcher, BT and McLachlan, MJ and McVea, AK and DiFilippo, AH and Carey, FJ and Janelidze, S and Hansson, O and Price, JC and Laymon, CM and Minhas, DS and Luo, W and Rosas, HD and Lai, F and Lee, JH and Lao, PJ and Ances, BM and Krinsky-McHale, SJ and Hom, CL and Hartley, SL and Zaman, SH and Johnson, SC and Cohen, AD and Head, E and Mapstone, ME and Handen, BL and Christian, BT and Tudorascu, DL and Langhough, RE and Betthauser, TJ and , },
title = {The tau biomarker cascade is condensed in Down syndrome compared to sporadic Alzheimer's disease.},
journal = {Brain : a journal of neurology},
volume = {},
number = {},
pages = {},
doi = {10.1093/brain/awaf428},
pmid = {41240365},
issn = {1460-2156},
abstract = {Characterizing the timing and progression of Alzheimer's disease biomarker onset in Down syndrome (DS) and contrasting potential timing differences with neurotypical adults is needed to identify optimal Alzheimer's disease therapeutic treatment windows in DS. In this study, 198 adults with DS from the Alzheimer Biomarker Consortium - Down Syndrome and 172 neurotypical adults from the Wisconsin Registry for Alzheimer's Prevention with available longitudinal beta-amyloid PET, tau PET and plasma p-tau217 analyzed on Lilly MSD were included. Individuals with DS had a significantly higher lifetime risk of beta-amyloid plaque onset. Temporal modeling of longitudinal biomarker measures revealed earlier age at positivity of beta-amyloid plaques, p-tau217 and neurofibrillary tau tangles in DS relative to the neurotypical cohort. The onset of p-tau217 and tau PET positivity in DS occurred nearly simultaneously, roughly 4-6 years following beta-amyloid onset, whereas the neurotypical group displayed greater temporal latency between positivity of the two biomarkers. The early and simultaneous onset of these biomarkers in DS highlights the necessity for early therapeutic interventions in this population. This work, combined with the upcoming anti-amyloid safety and efficacy clinical trials for DS will help identify optimal treatment windows for these individuals.},
}

@article {pmid41240282,
year = {2025},
author = {Tatara, Y and Yamamoto, H and Terai, K and Matsuta, R and Kasai, S and Tamada, Y and Mikami, T and Murashita, K and Itoh, K},
title = {Multi-marker discovery for mild cognitive impairment in metabolomics using machine learning with a global surrogate model via partial least squares.},
journal = {Metabolomics : Official journal of the Metabolomic Society},
volume = {21},
number = {6},
pages = {164},
pmid = {41240282},
issn = {1573-3890},
support = {JPMJCE1302//Center of Innovation Program from the Japan Science and Technology Agency (JST, COI)/ ; JPMJPF2210//Center of Innovation Program from the Japan Science and Technology Agency (JST, COI-NEXT)/ ; },
mesh = {*Cognitive Dysfunction/metabolism/diagnosis/blood ; *Metabolomics/methods ; *Biomarkers/blood/metabolism ; Least-Squares Analysis ; Humans ; *Machine Learning ; Male ; Aged ; Female ; Principal Component Analysis ; Aged, 80 and over ; Algorithms ; },
abstract = {INTRODUCTION: Dementia can be prevented through early intervention; hence, there is an urgent need for biomarkers to help diagnose mild cognitive impairment (MCI).

OBJECTIVES: We aimed to develop a multi-marker panel composed of plasma metabolites to aid in the diagnosis of MCI.

METHODS: We performed an analysis of a multi-marker panel of MCI metabolites using a random forest algorithm with variable selection methods and a global surrogate with principal component analysis and partial least squares (PLS).

RESULTS: By incorporating variable selection methods, we constructed a predictive model that demonstrated robust performance, with an AUC of approximately 0.85 in both cross-validation and test evaluations, using only five metabolites (methionine, quinic acid, hypoxanthine, O-acetylcarnitine, and 2-oxoglutaric acid). However, owing to the limited number of selected metabolites, it was challenging to infer the biological meaning of this multi-marker panel. To interpret this multi-marker panel biologically, we constructed a global surrogate model using PLS. By examining the PLS loadings corresponding to the scores with intergroup differences, we identified a relationship between 14 metabolites involved in neuronal energy metabolism and neurotransmission. This suggests that the multi-marker panel constructed in this study is related to abnormalities in energy metabolism and neurotransmission in patients with MCI.

CONCLUSION: The method used in this study may be broadly applicable for analyzing multi-marker panels of metabolites and their biological interpretation. This study included an independent validation, and further larger-scale studies using additional external cohorts are warranted to confirm the generalizability of this approach.},
}

*Cognitive Dysfunction/metabolism/diagnosis/blood
*Metabolomics/methods
*Biomarkers/blood/metabolism
Least-Squares Analysis
Humans
*Machine Learning
Male
Aged
Female
Principal Component Analysis
Aged, 80 and over
Algorithms

@article {pmid41240244,
year = {2025},
author = {Jayathilaka, NS and Weththasinghe, AV and Amarasekara, CI and Amasha, EADH and Wijekoon, KJ and Firdous, SM},
title = {Targeting the Gut-Brain Axis Through Insulin-like Growth Factors: Therapeutic Implications and Future Directions.},
journal = {Journal of molecular neuroscience : MN},
volume = {75},
number = {4},
pages = {150},
pmid = {41240244},
issn = {1559-1166},
mesh = {Humans ; Animals ; *Brain/metabolism ; Gastrointestinal Microbiome ; *Somatomedins/metabolism ; *Neurodegenerative Diseases/metabolism/drug therapy/therapy ; *Insulin-Like Growth Factor I/metabolism ; *Brain-Gut Axis ; *Gastrointestinal Tract/metabolism ; Insulin-Like Peptides ; },
abstract = {The gut-brain axis represents a sophisticated bidirectional communication network connecting the gastrointestinal tract and central nervous system through neural, endocrine, and immune pathways. Insulin-like growth factors (IGFs), particularly IGF-1 and IGF-2, function as pivotal mediators within this communication framework. These polypeptide growth factors regulate intestinal barrier integrity, microbiota homeostasis, neurogenesis, and synaptic plasticity mechanisms. Clinical evidence from 1989 to 2024 demonstrates that gut microbiota-derived short-chain fatty acids enhance IGF-1 production through novel molecular mechanisms. This narrative review examines IGF roles in gut-brain communication and evaluates therapeutic potential for neurodegenerative diseases including Alzheimer's disease, Parkinson's disease, and depression, as well as inflammatory bowel disorders. Current clinical trials investigating IGF-based interventions show preliminary promising results, though studies remain limited in scope and patient numbers. Key therapeutic challenges include delivery mechanisms across biological barriers, oncogenic safety concerns related to cell proliferation, and substantial individual variability in treatment responses. Future directions emphasize development of tissue-specific IGF modulators, microbiome-targeted interventions, and precision medicine approaches utilizing advanced biomarkers. Understanding IGF-mediated gut-brain communication presents therapeutic opportunities for complex pathological conditions simultaneously affecting gastrointestinal and neurological systems.},
}

Humans
Animals
*Brain/metabolism
Gastrointestinal Microbiome
*Somatomedins/metabolism
*Neurodegenerative Diseases/metabolism/drug therapy/therapy
*Insulin-Like Growth Factor I/metabolism
*Brain-Gut Axis
*Gastrointestinal Tract/metabolism
Insulin-Like Peptides

@article {pmid41240183,
year = {2025},
author = {García-Castro, P and Conejo, NM and González-Pardo, H},
title = {Transcranial photobiomodulation therapy in older women regarding cognitive functions: a systematic review.},
journal = {Lasers in medical science},
volume = {40},
number = {1},
pages = {480},
pmid = {41240183},
issn = {1435-604X},
mesh = {Humans ; *Low-Level Light Therapy/methods ; Female ; *Cognition/radiation effects ; Aged ; *Cognitive Dysfunction/therapy ; Animals ; Alzheimer Disease/therapy ; },
abstract = {Transcranial photobiomodulation therapy (tPBM) is a promising non-invasive treatment that uses red or near-infrared light to modulate biological functions and elicit therapeutic effects. This systematic review aimed to summarise the evidence on the effectiveness of tPBM in improving cognitive function in older women, in experimental animal models and in humans, by analyzing the optimal tPBM parameters and behavioral and neurobiological outcomes. tPBM offers advantages specific to older women as a non-invasive brain stimulation technique, applied to a sensitive population with increased risk of ageing-related brain dysfunction due to increased life expectancy. A comprehensive literature search was conducted in PubMed, Scopus, and PsycINFO databases, and only seven articles on older women were included in the review. Studies have shown that tPBM significantly improves cognitive impairment in Alzheimer's disease and related dementias, stroke, cognition and Parkinson's disease in older women. Despite the heterogeneity in the application parameters and limited number of studies, tPBM therapy was preliminarily found to be a safe, feasible, and effective non-pharmacological therapy for several neurological and mental health conditions in older women. Further research is required to establish standardized protocols for optimal therapeutic applications.},
}

Humans
*Low-Level Light Therapy/methods
Female
*Cognition/radiation effects
Aged
*Cognitive Dysfunction/therapy
Animals
Alzheimer Disease/therapy

@article {pmid41239890,
year = {2025},
author = {Pokorny, R and Ryan, JM and Abd-Elaziz, K and van den Berg, F and Rabiner, E and Searle, GE and Schneider, M and Wiessner, C and Stallaert, JF and Permanne, B and Quattropani, A and Beher, D},
title = {Safety, Tolerability, Pharmacokinetics, and Brain Target Occupancy of the OGA Inhibitor ASN90 in Healthy Participants.},
journal = {Movement disorders : official journal of the Movement Disorder Society},
volume = {},
number = {},
pages = {},
doi = {10.1002/mds.70104},
pmid = {41239890},
issn = {1531-8257},
abstract = {BACKGROUND: The OGA inhibitor ASN90/FNP-223 has the potential for disease modification in neurodegenerative diseases. A phase 1 clinical program in healthy participants was performed to determine its suitability for subsequent studies in movement disorders and Alzheimer's disease (AD) patients.

METHODS: Clinical Study 1: A randomized, double-blind, placebo-controlled, first-in-human study to assess the safety, tolerability, pharmacokinetics, pharmacodynamics, and food effect of single and multiple doses of orally administered ASN90 in healthy adult and elderly participants. Clinical Study 2: A phase 1, open-label, positron emission tomography (PET) study in healthy participants to determine the relationship between plasma concentration and brain target occupancy of ASN90 following a single oral dose.

OBJECTIVES: To assess the safety, tolerability, pharmacokinetics, pharmacodynamics, and central nervous system (CNS) target engagement of ASN90 in healthy participants.

RESULTS: ASN90 was considered safe and well tolerated with dose-proportional pharmacokinetics at steady-state up to oral doses of 500 mg twice daily. Cerebrospinal fluid-to-plasma ratios for mean peak and mean systemic exposures were in the range of 2.5%-4.6%. Investigation of CNS occupancy using a PET ligand demonstrated that target occupancy of greater than 98% in the brain of healthy participants can be achieved at doses that are clinically well tolerated.

CONCLUSIONS: The phase 1 results of ASN90 in healthy participants provide strong support for its further development in progressive supranuclear palsy (PSP) and AD. Currently, Ferrer Internacional, S.A. is conducting a phase 2 study, known as PROSPER (ClinicalTrials.gov ID: NCT06355531), to evaluate the efficacy, safety, and pharmacokinetics of ASN90 in slowing the progression of PSP. © 2025 International Parkinson and Movement Disorder Society.},
}

@article {pmid41239821,
year = {2025},
author = {Kronvold, C and Sperling, S and Möller, S and Grauslund, J and Stokholm, L},
title = {Primary open-angle glaucoma as a marker of upcoming Alzheimer's disease: A 20-year Danish National Registry-Based Study.},
journal = {Acta ophthalmologica},
volume = {},
number = {},
pages = {},
doi = {10.1111/aos.70039},
pmid = {41239821},
issn = {1755-3768},
support = {2410//P. Carl Petersen Foundation/ ; 24030032//Synoptik Foundation/ ; },
abstract = {PURPOSE: To investigate whether primary open-angle glaucoma (POAG) is associated with an increased long-term risk of developing Alzheimer's disease, given its shared neurodegenerative features.

METHODS: A 20-year longitudinal, registry-based matched cohort study was conducted using Danish national health registries from 1998 to 2018. Individuals aged 65 years or older with POAG identified by registration with the diagnostic code (ICD-10 = H40.1*) or at least four redeemed glaucoma prescriptions (ATC = S01E*) within 1 year entered the cohort. Each individual with POAG was randomly matched with five controls of the same sex and birth year. The outcome of Alzheimer's disease was defined by registration with the diagnostic code (ICD-10 = G30*, F00*). A Cox regression model adjusting for age, sex and systemic comorbidities estimated the hazard ratio (HR) for Alzheimer's disease and a Fine-Grey competing-risk model accounted for death as a competing event.

RESULTS: The study included 61 829 individuals with POAG and 306 794 matched controls (42.63% males, 57.37% females; median age 75.22 years, IQR: 70.35-80.63). Alzheimer's disease developed in 1.61% of individuals with POAG and 1.59% of controls. POAG did not appear to increase the risk of Alzheimer's disease (adjusted HR 0.98, 95% CI: 0.93-1.03). Competing risk analyses found a slightly increased risk of Alzheimer's disease observed among men with POAG (sHR 1.12, 95% CI: 1.03-1.21), whereas no association was found among women (sHR 1.00, 95% CI: 0.94-1.07).

CONCLUSION: In this nationwide matched cohort study, POAG was not clearly associated with an overall increased risk of developing Alzheimer's disease over 20 years.},
}

@article {pmid41239797,
year = {2025},
author = {Garg, N and Dhankhar, S and Dhariya, A and Parkash, C and Chauhan, S and Singh, TG},
title = {Role of Liposomes in the Treatment of Neurodegenerative Disorders: A Comprehensive Review.},
journal = {Central nervous system agents in medicinal chemistry},
volume = {25},
number = {4},
pages = {496-512},
pmid = {41239797},
issn = {1875-6166},
mesh = {Humans ; *Liposomes/metabolism/chemistry ; *Neurodegenerative Diseases/drug therapy/metabolism ; Animals ; *Drug Delivery Systems/methods ; *Neuroprotective Agents/administration & dosage/therapeutic use ; Blood-Brain Barrier/metabolism/drug effects ; },
abstract = {The complex etiology and limited therapy options of neurodegenerative illnesses pose daunting challenges to modern medicine. Nonetheless, novel treatment approaches have exciting new possibilities because of developments in nanotechnology. Liposomes have garnered a lot of interest as a potential treatment for neurological illnesses due to the fact that they are able to adapt to their role as nanocarriers. This review article discusses various uses of liposomes, including their ability to help treat neurodegenerative diseases such as Alzheimer's, Parkinson's, and Huntington's disease, as well as their diagnostic and neuroprotective uses. Liposomes allow for the targeted delivery of medicines to specific brain areas with minimal systemic side effects since they encapsulate and carry therapeutic molecules across the blood-brain barrier. Due to the fact that they are biocompatible, have surface features that can be adjusted, and have the ability to co-deliver many drugs, liposomes are excellent candidates for combination therapy and personalized medicine procedures. In spite of this, there is a growing body of research that suggests liposomes could serve as a versatile platform for the improvement of neurodegenerative disease treatment. This is a positive sign for the future results of patients and their quality of life.},
}

Humans
*Liposomes/metabolism/chemistry
*Neurodegenerative Diseases/drug therapy/metabolism
Animals
*Drug Delivery Systems/methods
*Neuroprotective Agents/administration & dosage/therapeutic use
Blood-Brain Barrier/metabolism/drug effects

@article {pmid41239791,
year = {2025},
author = {Bassi, P and Rana, S and Sapra, V and Raina, A and Kumar, P and Devi, S},
title = {Exploring Novel Therapeutic Avenues: Drug Repurposing for Neurodegenerative Movement Disorders.},
journal = {Current drug research reviews},
volume = {17},
number = {3},
pages = {375-393},
pmid = {41239791},
issn = {2589-9783},
mesh = {Humans ; *Drug Repositioning/methods ; *Neurodegenerative Diseases/drug therapy ; Animals ; *Movement Disorders/drug therapy ; },
abstract = {Neurodegenerative movement disorders, encompassing conditions such as Parkinson's disease, Huntington's disease, and amyotrophic lateral sclerosis, represent a significant burden on individuals, families, and healthcare systems globally. Traditional drug discovery approaches for these disorders have encountered challenges, including high costs and lengthy timelines. Drug repurposing has emerged in recent years as a promising approach to expedite the discovery of new treatments by leveraging existing drugs approved for other indications. This review explores the landscape of drug repurposed for neurodegenerative movement disorders, highlighting promising candidates, underlying mechanisms, and clinical implications. The rationale behind repurposing, including the advantages of utilizing existing pharmacological agents with established safety profiles and known pharmacokinetics, along with techniques utilized for repurposing (computational and experimental), have been elaborated. Several studies on the potential of pre-existing drugs such as isradipine, tetracycline, ambroxol, metformin, deferiprone, simvastatin, etc., which have been repurposed for neurodegenerative movement disorders, including Parkinson's disease, Huntington's disease, Alzheimer's disease, Multiple Sclerosis, etc. have been discussed. Further, the current scenario and future prospective of drug repurposing have also been touched upon.},
}

Humans
*Drug Repositioning/methods
*Neurodegenerative Diseases/drug therapy
Animals
*Movement Disorders/drug therapy

@article {pmid41239670,
year = {2025},
author = {He, L and Xing, C and Yang, X and Wang, S and Tian, B and Cheng, J and Yao, Y and Sui, B},
title = {Association between visceral adiposity index and cognitive dysfunction in US participants derived from NHANES data: A cross-sectional analysis.},
journal = {Medicine},
volume = {104},
number = {46},
pages = {e45814},
doi = {10.1097/MD.0000000000045814},
pmid = {41239670},
issn = {1536-5964},
mesh = {Humans ; Cross-Sectional Studies ; Male ; Female ; Nutrition Surveys ; *Cognitive Dysfunction/epidemiology/etiology ; Aged ; Middle Aged ; United States/epidemiology ; *Intra-Abdominal Fat ; *Obesity, Abdominal/epidemiology/complications ; Neuropsychological Tests ; Risk Factors ; },
abstract = {This study examines the cross-sectional association between the Visceral Adiposity Index (VAI) and domain-specific cognitive performance in US older adults. We analyzed data from 1323 participants aged ≥ 60 years in the National Health and Nutrition Examination Survey (NHANES) 2011 to 2014. Cognitive function was assessed with CERAD Word‑List Learning (memory/learning), Animal Fluency Test (semantic fluency/executive function), and the Digit Symbol Substitution Test (DSST; processing speed/attention). We fitted a sequence of multiple linear regression models: model 1 (crude), model 2 (adjusted for demographic covariates), model 3 (further adjusted for lifestyle factors), and model 4 (additionally adjusted for clinical comorbidities). Effect estimates are presented as β coefficients with 95% confidence intervals and P-values. VAI showed no significant link with composite cognition in age‑ and sex-unadjusted analyses (Model 1), while DSST approached significance (β = -0.16, 95% CI - 0.31 to - 0.02, P = .027). After adjusting for demographics (Model 2) DSST remained significant (β = -0.15, 95% CI - 0.29 to - 0.01, P = .031). Adding lifestyle factors (Model 3) gave a similar DSST effect (β = -0.15, P = .017) and also negative associations for immediate recall (β = -0.14, P = .039) and animal fluency (β = -0.18, P = .012). Full adjustment for sociodemographic and clinical comorbidities (Model 4) rendered these associations non‑significant (all P >.05), with Delayed Recall borderline (β = 0.15, P = .054). Sensitivity tests excluding clinical covariates partly restored the intermediate‑model effects, and removing the dyslipidemia covariate partly reversed attenuation, suggesting cardiometabolic comorbidities and overlap between VAI and lipid measures drive much of the attenuation. Age- and lifestyle-adjusted analyses showed inverse, domain‑specific links between higher VAI and cognition (most notably processing speed), but these weakened after full sociodemographic and clinical adjustment, suggesting measured sociodemographic and cardiometabolic factors largely explain the crude associations. Intermediate-model findings are hypothesis‑generating. Longitudinal studies with repeated measures, direct visceral-fat imaging, and mechanistic biomarkers are needed to separate confounding from mediation and to determine whether VAI or its metabolic components independently predict cognitive decline.},
}

Humans
Cross-Sectional Studies
Male
Female
Nutrition Surveys
*Cognitive Dysfunction/epidemiology/etiology
Aged
Middle Aged
United States/epidemiology
*Intra-Abdominal Fat
*Obesity, Abdominal/epidemiology/complications
Neuropsychological Tests
Risk Factors

@article {pmid41239587,
year = {2025},
author = {Chang, H},
title = {Epidemiological trends, attributable risks, decomposition analysis, and forecasts of Alzheimer's disease and other dementias burden in China, 1990 to 2036: A population-based observational study.},
journal = {Medicine},
volume = {104},
number = {46},
pages = {e45880},
doi = {10.1097/MD.0000000000045880},
pmid = {41239587},
issn = {1536-5964},
mesh = {Humans ; China/epidemiology ; *Alzheimer Disease/epidemiology/mortality ; Male ; Female ; Aged ; Risk Factors ; Incidence ; Middle Aged ; Aged, 80 and over ; Disability-Adjusted Life Years ; *Dementia/epidemiology ; Forecasting ; Global Burden of Disease/trends ; Cost of Illness ; Adult ; },
abstract = {This study analyzes the burden of Alzheimer disease and other dementias (ADOD) in China using Global Burden of Disease 2021 data. The data on ADOD in China from 1990 to 2021 was collected from the Global Burden of Disease 2021. The incidence rate, mortality and the number of disability adjusted life years (DALYs), and age-standardized rates of ADOD were analyzed. Use Joinpoint analysis to evaluate trends. Analyze the attribution ratio of risk factors such as smoking, high body mass index, and high fasting blood glucose (FPG) to the burden of ADOD disease. Evaluate the relative contributions of epidemiological changes, population growth, and population aging through decomposition analysis. Autoregressive Integrated Moving Average model is used to evaluate future trends. Age-standardized incidence rose from 121.11 (95% confidence interval: 105.5-137.99) to 151.47 (131.22-173.34) per 100,000, with an estimated annual percentage change (APC) of 0.41% (0.34-0.49%). Age-standardized mortality declined from 31.39 (7.6-83.63) to 30.82 (7.88-82.43) per 100,000, yet deaths increased by 3.92% annually (estimated APC: 3.79-4.04%). disability adjusted life years (DALYs) surged to 10.07 (4.95-22.22) million, with age-standardized DALY rate reaching 562.39 (271.16-1238.81) per 100,000. Joinpoint regression confirmed upward trends for age-standardized incidence (average APC = 0.60%, 0.46-0.74%) and age-standardized DALY rate (average APC = 0.10%, -0.01 to 0.22%). The incidence rate, mortality, and DALYs of ADOD in men and women mostly occur in the age group over 75 years old. FPG was the leading risk factor, attributing to 10.5% of DALYs, followed by smoking (8.0%) and high body mass index (0.2%). Decomposition analysis identified epidemiological changes as the primary driver of mortality increases (679,000 deaths, 45.6% contribution), exceeding aging (595,000 deaths) and population growth (214,000 deaths). Projections to 2036 indicate dramatic growth: cases rising to 7.46 (5.73-9.20) million, deaths to 1.12 (0.93-1.31) million, and DALYs to 23.76 (19.10-28.43) million. The ADOD burden in China has significantly increased, especially among women and the elderly population. It is worth noting that FPG is the primary risk factor for ADOD. The disease ADOD burden will continue to rise. Attention should be paid to the issue of population aging, and interventions targeting ADOD risk factors should be emphasized.},
}

Humans
China/epidemiology
*Alzheimer Disease/epidemiology/mortality
Male
Female
Aged
Risk Factors
Incidence
Middle Aged
Aged, 80 and over
Disability-Adjusted Life Years
*Dementia/epidemiology
Forecasting
Global Burden of Disease/trends
Cost of Illness
Adult

@article {pmid41239516,
year = {2025},
author = {Shi, Y and Li, Y and Ci, R and Yan, S and Tian, T and Zheng, N and Zhu, W and Qin, Y},
title = {Dynamic functional connectivity and transcriptomic signatures reveal stage-dependent brain network dysfunction in Alzheimer's disease spectrum.},
journal = {Alzheimer's research & therapy},
volume = {17},
number = {1},
pages = {247},
pmid = {41239516},
issn = {1758-9193},
support = {2022YFC2406903//National Key Research and Development Program of China/ ; 81873890//National Natural Science Foundation of China/ ; },
mesh = {Humans ; *Alzheimer Disease/physiopathology/genetics/diagnostic imaging ; Male ; Female ; Magnetic Resonance Imaging ; Cross-Sectional Studies ; Aged ; *Cognitive Dysfunction/physiopathology/diagnostic imaging/genetics ; *Brain/physiopathology/diagnostic imaging/metabolism ; *Transcriptome ; *Nerve Net/physiopathology/diagnostic imaging ; Middle Aged ; Neuropsychological Tests ; Disease Progression ; },
abstract = {BACKGROUND: Alzheimer's Disease Spectrum (ADS) progresses from preclinical stages to dementia, with dynamic functional connectivity (dFC) changes emerging early. This study aimed to investigate the dynamic changes in brain networks across different stages of ADS and their underlying molecular mechanisms.

METHODS: This cross-sectional study included 239 participants: 69 Healthy Controls (HC), 83 with Subjective Cognitive Decline (SCD), 56 with Mild Cognitive Impairment (MCI), and 31 with Alzheimer's disease (AD). All participants underwent neuropsychological testing and resting-state functional magnetic resonance imaging (rs-fMRI). Leading Eigenvector Dynamics Analysis (LEiDA), a data-driven method that captures time-resolved whole-brain dFC, was applied to identify transient brain states and calculated their occupancy rate, dwell time, and transition probabilities. Group differences in these dynamic metrics were assessed using a General Linear Model (GLM), and their correlations with cognitive performance were examined. To explore the molecular basis of significant dFC alterations, we performed gene-category enrichment analysis. This analysis integrated the spatial maps of altered brain states with regional gene expression data from the Allen Human Brain Atlas (AHBA), using spin permutations to ensure statistical robustness.

RESULTS: We identified ten recurring brain states and characterized how their transition patterns, stability, and frequency differed as a function of disease severity. Specifically, early disruptions appeared as altered transition probabilities between states, while later stages showed pronounced changes in the dwell time and occurrence rates of specific states, closely associated with cognitive decline. Notably, one brain state marked by synchronized activity in attention, salience, and default mode networks emerged as a critical hub linked to both cognitive deterioration and excitatory-inhibitory imbalance. Genes associated with this state were enriched in glycine-mediated synaptic pathways and expressed in both excitatory and inhibitory neurons, showing spatial and temporal patterns that extended from early development into late disease stages.

CONCLUSIONS: Our study uncovered the stage-dependent dFC changes and their molecular underpinnings of brain network dysfunction across the ADS.},
}

Humans
*Alzheimer Disease/physiopathology/genetics/diagnostic imaging
Male
Female
Magnetic Resonance Imaging
Cross-Sectional Studies
Aged
*Cognitive Dysfunction/physiopathology/diagnostic imaging/genetics
*Brain/physiopathology/diagnostic imaging/metabolism
*Transcriptome
*Nerve Net/physiopathology/diagnostic imaging
Middle Aged
Neuropsychological Tests
Disease Progression

@article {pmid41239142,
year = {2025},
author = {Eva, TA and Shenoy, A and Gupta, VB and Palanivel, V and Salkar, A and Nasab, SN and Chitranshi, N and Mirzaei, M and You, Y and Graham, SL and Basavarajappa, D and Gupta, V},
title = {The Dynamic Roles of Repressor Element 1-Silencing Transcription Factor (REST): A Double-Edged Sword in Neural Health and Disease.},
journal = {Molecular neurobiology},
volume = {63},
number = {1},
pages = {46},
pmid = {41239142},
issn = {1559-1182},
mesh = {Humans ; Animals ; *Repressor Proteins/metabolism/genetics ; *Neurodegenerative Diseases/metabolism/pathology/genetics ; *Neurons/metabolism/pathology ; *Health ; },
abstract = {The repressor element 1-silencing transcription factor (REST), or neuron-restrictive silencer factor (NRSF), is crucial for gene regulation since it binds to chromatin and recruits chromatin-modifying enzymes. Acting as a regulatory hub, REST orchestrates neurogenesis, neuronal differentiation, and the preservation of neuronal identity by regulating a broad network of target genes across stem cells, non-neuronal cells, and neurons. These targets influence critical processes such as axonal growth, vesicular transport, neurotransmitter release, and ion conductance. An important feature of normal aging in cortical and hippocampal neurons is REST induction, where it contributes to extended longevity by repressing genes linked to neuronal excitability and stress vulnerability. However, REST's role in neurodegenerative diseases remains complex and context dependent. Variations in its expression and subcellular localization, including cytoplasmic translocation or loss, have been implicated in the pathology of disorders like Alzheimer's disease, Parkinson's disease, Huntington's disease, schizophrenia, and epilepsy. Given its broad regulatory functions, REST has emerged as an attractive therapeutic target. Strategies such as microRNA modulation, small molecule inhibitors, and complex-disrupting compounds have been explored, each offering unique opportunities and challenges. Understanding REST's molecular mechanisms and disease-specific functions is critical for identifying novel therapeutic interventions. This review provides a comprehensive analysis of REST's role in aging and neurodegeneration, highlighting its regulatory networks, disease relevance, and recent therapeutic strategies targeting REST, with an emphasis on their potential for clinical translation.},
}

Humans
Animals
*Repressor Proteins/metabolism/genetics
*Neurodegenerative Diseases/metabolism/pathology/genetics
*Neurons/metabolism/pathology
*Health

@article {pmid41239092,
year = {2025},
author = {Kong, W and Miao, X and Dang, R and Jiang, P and Feng, L},
title = {Mechanisms and Clinical Significance of Endosomal Toll-Like Receptors in Neurological Diseases.},
journal = {Molecular neurobiology},
volume = {63},
number = {1},
pages = {54},
pmid = {41239092},
issn = {1559-1182},
support = {82373585//National Natural Science Foundation of China/ ; 2023M741364//the China Postdoctoral Science Foundation/ ; ZR2022MH007//the Natural Science Foundation of Shandong Province/ ; 2022YXNS124//the Jining Key R&D Projects/ ; 2022YXNS137//the Jining Key R&D Projects/ ; 202304040457//the Medical and Health Science and Technology Development Project of Shandong Province/ ; },
mesh = {Humans ; *Toll-Like Receptors/metabolism ; *Endosomes/metabolism ; Animals ; *Nervous System Diseases/metabolism ; Signal Transduction ; Clinical Relevance ; },
abstract = {Neurological diseases such as Alzheimer's disease, Parkinson's disease, multiple sclerosis, and epilepsy constitute a major global public health burden, affecting millions of patients. Recent studies have shown that the complex interactions between the immune system and the nervous system play a significant role in these diseases, especially Toll-like receptors (TLRs), among which endosomal TLRs (TLR3, TLR7, TLR8, and TLR9) are crucial in neuroinflammation and disease progression. This review systematically elaborates on the biological characteristics of endosomal TLRs, their distribution, and signaling pathways within the central nervous system, with a particular focus on their "double-edged sword" effect in specific disease contexts: on the one hand, they may provide neuroprotection, while on the other hand, they can exacerbate neural injury and neurodegeneration during immune dysregulation. Furthermore, this article evaluates the potential and challenges of utilizing endosomal TLRs as early diagnostic biomarkers. It summarizes research progress in targeted regulatory strategies as emerging therapeutic approaches, along with the encountered bottlenecks in clinical translation. The review aims to systematically integrate fundamental mechanistic research with clinical application prospects, emphasizing the critical importance of in-depth elucidation of the mechanistic roles of endosomal TLRs in neurological disorders and their translational value in diagnosis and treatment. Clinical trial number: not applicable.},
}

Humans
*Toll-Like Receptors/metabolism
*Endosomes/metabolism
Animals
*Nervous System Diseases/metabolism
Signal Transduction
Clinical Relevance

@article {pmid41239049,
year = {2025},
author = {Ma, H and Cong, C},
title = {Insights and advances of theranostic nanoscale metal-organic frameworks.},
journal = {Mikrochimica acta},
volume = {192},
number = {12},
pages = {809},
pmid = {41239049},
issn = {1436-5073},
mesh = {*Metal-Organic Frameworks/chemistry ; Humans ; *Theranostic Nanomedicine/methods ; Contrast Media/chemistry ; Animals ; },
abstract = {As one class of multifunctional materials, metal-organic frameworks (MOFs) with virtues like large surface area, high porosity, and tailorability have been found in many applications. Particularly, the investigation on health is rapidly growing. Accurate diagnosis and efficient treatment of diseases are increasingly important but challenging. Nanoplatforms based on MOFs are receiving much attention, which has made significant progress in imaging and drug delivery during the past few years. This review article will summarize and discuss the latest development of nanoscale MOFs in the following topics: contrast agents for magnetic resonance imaging (MRI); X-ray computed tomography imaging (CT); optical imaging (OI); photoacoustic imaging (PAI); photothermal imaging (PTI); positron emission tomography (PET); single-photon emission computed tomography (SPECT); and multimodal imaging (MI). In addition, targeting drug delivery by MOFs to treat diseases will be categorized into the followings: cancers; lung diseases; bone diseases; diabetes; infections; wound healing; bowel diseases; Alzheimer's disease; ocular diseases; and atherosclerosis.},
}

*Metal-Organic Frameworks/chemistry
Humans
*Theranostic Nanomedicine/methods
Contrast Media/chemistry
Animals

@article {pmid41238997,
year = {2025},
author = {Chen, Y and Wang, Z and Chen, H and Xu, J and Li, H and Li, S and , },
title = {CSF Glucose-6-Phosphate Isomerase Is a Tau-Related Biomarker Associated with Neurodegeneration and Cognitive Impairment in Alzheimer's Disease.},
journal = {Molecular neurobiology},
volume = {63},
number = {1},
pages = {47},
pmid = {41238997},
issn = {1559-1182},
support = {82471199//the National Natural Science Foundation of China/ ; },
mesh = {Humans ; Female ; *Alzheimer Disease/cerebrospinal fluid/complications/pathology ; *tau Proteins/cerebrospinal fluid ; Biomarkers/cerebrospinal fluid ; Aged ; Male ; *Cognitive Dysfunction/cerebrospinal fluid/complications ; *Glucose-6-Phosphate Isomerase/cerebrospinal fluid ; *Nerve Degeneration/cerebrospinal fluid ; Cross-Sectional Studies ; Amyloid beta-Peptides/cerebrospinal fluid ; Aged, 80 and over ; Magnetic Resonance Imaging ; Cohort Studies ; },
abstract = {Skeletal diseases are closely linked to Alzheimer's disease (AD) in terms of epidemiology and pathogenesis. Glucose-6-phosphate isomerase (GPI), a critical enzyme in the glycolytic pathway that participates in various skeletal disorders, has unclear effects on AD pathological progression in humans. This cross-sectional study included 601 participants from the Alzheimer's Disease Neuroimaging Initiative (ADNI) [260 (43.3%) women; 288 (47.9%) APOE ε4 carriers]. The cohort comprised 151 cognitively normal (CN) participants [mean age 74.7 (5.9) years] and 450 cognitively impaired (CI) participants [mean age 72.8 (7.8) years]. We assessed CSF GPI levels, AD biomarkers (CSF β-amyloid [Aβ]42, phosphorylated Tau [p-Tau]181), magnetic resonance imaging-based neurodegenerative changes, and cognitive function. Associations between CSF GPI levels and AD pathology, neurodegeneration, and cognition were evaluated using linear regression models. Mediation models were employed to investigate the potential mechanism of how CSF GPI affects AD pathology. Findings were validated in two independent external cohorts using autopsy-confirmed Braak staging (n = 419; mean age 84.1 [6.6] years; 195 [46.5%] women) and cross-platform validation (n = 36). Among the total cohort (N = 601), CSF GPI levels were significantly elevated among participants with tau pathology (T+ group), regardless of Aβ status, and correlated positively with CSF p-Tau181 but not with Aβ42. Higher CSF GPI levels were also associated with downstream events of tau pathology, including reduced hippocampal volume and worse cognitive performance. Mediation analyses revealed that CSF GPI partially mediated tau pathology's effects on hippocampal volume reduction and cognitive impairment. Moreover, CSF GPI exhibited excellent diagnostic accuracy in distinguishing tau-positive/negative (T+/-) participants (area under the curve [AUC] = 0.833), with even higher accuracy when combined with demographic indicators (AUC = 0.862). In the external cohort, we used Braak staging of neuropathologies found at autopsy to indicate tau pathology and validated its positive association with CSF GPI levels (p < 0.001), with cross-platform validation demonstrating strong concordance of GPI measurements between different analytical methods (r = 0.817, p < 0.001). CSF GPI shows associations with tau pathology independent of amyloid status and may partially mediate relationships between tau pathological changes and neurodegeneration. These findings indicate that CSF GPI may serve as a potential biomarker reflecting tau-related pathological processes. However, further validation studies are required to establish its utility for clinical diagnostic evaluation or therapeutic monitoring.},
}

Humans
Female
*Alzheimer Disease/cerebrospinal fluid/complications/pathology
*tau Proteins/cerebrospinal fluid
Biomarkers/cerebrospinal fluid
Aged
Male
*Cognitive Dysfunction/cerebrospinal fluid/complications
*Glucose-6-Phosphate Isomerase/cerebrospinal fluid
*Nerve Degeneration/cerebrospinal fluid
Cross-Sectional Studies
Amyloid beta-Peptides/cerebrospinal fluid
Aged, 80 and over
Magnetic Resonance Imaging
Cohort Studies

@article {pmid41238954,
year = {2025},
author = {Augusto-Oliveira, M and Arrifano, GP and Leal-Nazaré, CG and Soares-Silva, I and Lopes-Araujo, A and Santos-Sacramento, L and Crespo-Lopez, ME},
title = {Lifestyle Drives Astroglial Plasticity Toward Cognitive Improvement: Roles of Physical Exercise, Environmental Enrichment, Diet, and Sleep.},
journal = {Molecular neurobiology},
volume = {63},
number = {1},
pages = {42},
pmid = {41238954},
issn = {1559-1182},
support = {444791/2023-0//Conselho Nacional de Desenvolvimento Científico e Tecnológico/ ; 427784/2018-2//Conselho Nacional de Desenvolvimento Científico e Tecnológico/ ; },
mesh = {Humans ; *Neuronal Plasticity/physiology ; *Astrocytes/physiology ; *Cognition/physiology ; Animals ; *Sleep/physiology ; *Exercise/physiology ; *Life Style ; *Diet ; *Environment ; },
abstract = {Lifestyle, including physical exercise, diet, intellectual and social engagement, and sleep, represents a powerful nonpharmacological alternative to improve cognitive performance or mitigate cognitive decline associated with ageing or neuropathological conditions. Among brain cells, astrocytes, the most abundant glial cell, are involved in virtually all brain functions, from neurogenesis and synaptogenesis to brain homeostasis, defence, and cognition. Recent studies demonstrate that astrocytes are very sensitive to lifestyle changes, undergoing morphological, molecular, and functional remodelling. These adaptations include enhanced astrocyte complexity, increased synaptic coverage, modulation of inflammatory pathways, and changes in gene expression. Such modifications, accompanied by cognitive improvements, are observed in models of Alzheimer's and Parkinson's, depression, and cerebral ischaemia, as well as in sleep quality and dietary patterns-making astrocytes key elements in lifestyle-induced neural plasticity driving brain health and cognitive improvements. Here, we discuss astroglial roles in translating lifestyle benefits into cognitive improvements; such mechanisms may represent a therapeutic target to prevent or even mitigate cognitive dysfunction associated with ageing or neurological conditions, ultimately contributing to quality of life.},
}

Humans
*Neuronal Plasticity/physiology
*Astrocytes/physiology
*Cognition/physiology
Animals
*Sleep/physiology
*Exercise/physiology
*Life Style
*Diet
*Environment

@article {pmid41238774,
year = {2025},
author = {Cerman, J and Škorvagová, A and Vyhnálek, M and Veverová, K and Dvořák, K and Kozák, Š and Kavka, A and Hort, J},
title = {Concordance between amyloid PET and CSF biomarkers in clinical setting: a cross-platform comparison and in-depth analysis of discordant cases.},
journal = {Scientific reports},
volume = {15},
number = {1},
pages = {39963},
pmid = {41238774},
issn = {2045-2322},
mesh = {Humans ; *Biomarkers/cerebrospinal fluid ; *Alzheimer Disease/cerebrospinal fluid/diagnostic imaging/diagnosis/metabolism ; Male ; *Amyloid beta-Peptides/cerebrospinal fluid/metabolism ; Female ; *Positron-Emission Tomography/methods ; Aged ; tau Proteins/cerebrospinal fluid ; Middle Aged ; Peptide Fragments/cerebrospinal fluid ; *Amyloid/metabolism ; Aged, 80 and over ; Enzyme-Linked Immunosorbent Assay ; Apolipoprotein E4/genetics ; },
abstract = {Reliable detection of amyloid pathology is essential for Alzheimer's disease (AD) diagnosis and treatment. We directly compared routine ELISA assays and the automated Lumipulse platform against quantitative amyloid PET in a real-world memory clinic cohort. In 153 participants, flutemetamol amyloid PET and CSF biomarkers were assessed across platforms. Concordance with PET and predictors of discordance were evaluated. PET visual reads and Centiloids showed near-perfect agreement (AUC = 0.99). The p-tau181/Aβ42 ratio achieved the highest concordance with PET (OPA 87% ELISA, 92% Lumipulse), while the Lumipulse Aβ42/40 ratio reached 93%. About 6% of participants showed consistent discordance between CSF and PET, associated with APOE ε4 and mixed or non-AD pathologies. Automated CSF assays align strongly with amyloid PET and support biomarker standardization. Persistent discrepancies between CSF and PET likely reflect underlying biological heterogeneity such as mixed or non-AD pathologies and APOE ε4 carriage.},
}

Humans
*Biomarkers/cerebrospinal fluid
*Alzheimer Disease/cerebrospinal fluid/diagnostic imaging/diagnosis/metabolism
Male
*Amyloid beta-Peptides/cerebrospinal fluid/metabolism
Female
*Positron-Emission Tomography/methods
Aged
tau Proteins/cerebrospinal fluid
Middle Aged
Peptide Fragments/cerebrospinal fluid
*Amyloid/metabolism
Aged, 80 and over
Enzyme-Linked Immunosorbent Assay
Apolipoprotein E4/genetics

@article {pmid41238639,
year = {2025},
author = {Esteve, M and Martinez-Gracia, A and Rodríguez-Sala, JJ and Brotons-Mas, JR and Falcó, A},
title = {A novel approach integrating topological deep learning from EEG Data in Alzheimer's disease.},
journal = {Scientific reports},
volume = {15},
number = {1},
pages = {39942},
pmid = {41238639},
issn = {2045-2322},
support = {TED2021-129347B-C22//Ministerio de Ciencia e Innovación/ ; TED2021-129347B-C22//Ministerio de Ciencia e Innovación/ ; TED2021-129347B-C22//Ministerio de Ciencia e Innovación/ ; TED2021-129347B-C22//Ministerio de Ciencia e Innovación/ ; },
mesh = {Humans ; *Alzheimer Disease/diagnosis/physiopathology ; *Electroencephalography/methods ; *Deep Learning ; Male ; Female ; Aged ; Neural Networks, Computer ; Support Vector Machine ; Middle Aged ; Frontotemporal Dementia/diagnosis/physiopathology ; },
abstract = {High-throughput analysis of EEG data has significantly contributed to understanding neural dynamics in Alzheimer's disease diagnosis. However, the complexity and high dimensionality of EEG signals pose challenges for traditional classification methods, which often fail to capture intricate patterns. To address this, we propose a hybrid approach integrating Topological Deep Learning (TDL) with machine learning models-including Support Vector Machines (SVM), Random Forest (RF), Neural Networks (NN), and Logistic Regression (LR)-for Alzheimer's disease classification. By leveraging TDL, our method extracts topological and neural features from EEG data, enhancing the identification of disease-specific patterns that conventional models may overlook. The dataset consists of EEG recordings from 88 individuals, categorized into AD patients, FTD patients, and CN, providing a robust foundation for model evaluation. Our findings demonstrate that NN augmented by TDL achieve the highest classification accuracy, reaching up to 90% in distinguishing AD, FTD, and CN cases. These results highlight the potential of TDL-enhanced deep learning models in clinical applications, offering a more accurate and detailed tool for Alzheimer's disease diagnosis and differentiation from other neurodegenerative conditions. This work is presented as a proof-of-concept demonstrating that persistence-based topological descriptors can enhance EEG classification; multicenter validation on larger, diverse cohorts will be required to confirm generalizability.},
}

Humans
*Alzheimer Disease/diagnosis/physiopathology
*Electroencephalography/methods
*Deep Learning
Male
Female
Aged
Neural Networks, Computer
Support Vector Machine
Middle Aged
Frontotemporal Dementia/diagnosis/physiopathology

@article {pmid41238601,
year = {2025},
author = {Alzarea, SI},
title = {Identification of novel neuraminidase 1 modulators as potential therapeutics for Alzheimer's disease using virtual screening and molecular dynamics simulations.},
journal = {Scientific reports},
volume = {15},
number = {1},
pages = {39901},
pmid = {41238601},
issn = {2045-2322},
support = {KSRG-2024-340//King Salman Center for Disability Research/ ; },
mesh = {*Neuraminidase/antagonists & inhibitors/metabolism/chemistry ; *Alzheimer Disease/drug therapy/enzymology/metabolism ; Molecular Dynamics Simulation ; Molecular Docking Simulation ; Humans ; *Enzyme Inhibitors/pharmacology/chemistry ; Drug Evaluation, Preclinical ; },
abstract = {Alzheimer's disease (AD) is a neurodegenerative disorder caused by the accumulation of β-amyloid (Aβ) plaques and neurofibrillary tangles, resulting in neuronal dysfunction and cognitive decline. The neuraminidase isoenzyme NEU1 is a most ubiquitous mammalian enzyme, involved in various cellular mechanisms. The deficiency of NEU1 has been implicated in the pathophysiology of AD, significantly in amyloid precursor protein (APP) metabolism and Aβ clearance. Despite extensive research, no potent NEU1 modulator has been developed to regulate its activity for therapeutic intervention in AD. The present work aims to identify potential NEU1 modulators from a library of seaweed Metabolites Database through molecular docking, ADMET analysis, and molecular dynamics (MD) simulations. A library of 1,077 seaweed metabolites was screened, identifying 20 active compounds, of which 4 met Lipinski's Rule of Five criteria. ADMET profiling revealed favorable pharmacokinetic properties for BE003, BS032, and RG007, with good blood-brain barrier permeability and bioavailability. Molecular docking demonstrates that BE003, BS032, RG007, and BD039 metabolites exhibited the highest binding affinities for the NEU1 active site. Additionally, MD simulation and MM-GBSA validated the stability of the metabolite-protein complex, with BE003 demonstrating the most stable interactions. Comparative docking against a natural substrate (Neu5Ac) and a NEU1 inhibitor (17f) revealed that BE003 shares significant interaction, RMSD stability profiles with the substrate and loop conformational dynamics while differing from the inhibitor. Our findings emphasize the potential of this modulator as a novel therapeutic target against NEU1 in AD treatment. Further experimental validation and preclinical studies are needed to confirm its efficacy in modulating NEU1 activity.},
}

*Neuraminidase/antagonists & inhibitors/metabolism/chemistry
*Alzheimer Disease/drug therapy/enzymology/metabolism
Molecular Dynamics Simulation
Molecular Docking Simulation
Humans
*Enzyme Inhibitors/pharmacology/chemistry
Drug Evaluation, Preclinical

@article {pmid41238324,
year = {2025},
author = {Soulier, T and Burgos, N and Hassanaly, R and Pitombeira, M and Solal, M and Roy, H and Hamzaoui, M and Yazdan-Panah, A and de Paula Faria, D and Louapre, C and Bodini, B and Bottlaender, M and Ayache, N and Colliot, O and Stankoff, B},
title = {Artificial intelligence in presymptomatic neurological diseases: Bridging normal variation and prodromal signatures.},
journal = {Revue neurologique},
volume = {181},
number = {9},
pages = {944-950},
doi = {10.1016/j.neurol.2025.07.011},
pmid = {41238324},
issn = {0035-3787},
mesh = {Humans ; *Prodromal Symptoms ; *Artificial Intelligence/trends ; *Nervous System Diseases/diagnosis ; Early Diagnosis ; Deep Learning ; Machine Learning ; Cognitive Dysfunction/diagnosis ; },
abstract = {Presymptomatic neurological diseases are marked by early pathological changes that occur before overt clinical symptoms. These stages, which include prodromes such as REM sleep behavior disorder in Parkinson's or mild cognitive impairment in Alzheimer's, offer critical opportunities for early intervention. However, their detection remains challenging due to the subtlety of changes and the overlap with normal interindividual variability. Artificial intelligence (AI), especially machine learning (ML) and deep learning (DL), offers new tools to uncover hidden signatures in complex biomedical data. First, we explore how supervised ML models can detect known prodromal patterns across diverse modalities, including EEG, cognitive scores, and structural imaging. Depending on the input, various model types - such as tree-based algorithms for structured data and convolutional or transformer networks for images and signals - can extract predictive features of early neurodegeneration. These approaches have demonstrated success in identifying at-risk individuals before clinical thresholds are reached. Yet, detecting only known patterns limits the scope of early intervention. Many individuals who will go on to develop neurological disease may not yet exhibit any recognized prodromal syndrome. Bridging this gap requires moving beyond predefined labels toward models capable of identifying subtle, unknown anomalies in individuals still considered healthy. Second, we address the detection of latent anomalies among individuals not yet considered at risk without identifiable known prodromal patterns. By mining clinical records, free-text medical notes, and population-level health databases (e.g., UK Biobank, EDS-AP-HP), and by analyzing sensor data from smartphones or wearables, AI can flag deviations from healthy patterns long before symptom onset or formal diagnosis. This approach holds promise for scalable, low-burden, ecological screening. Finally, we introduce the concept of pseudo-healthy twins - synthetic, personalized baselines generated from structural data such as MRI, to improve anomaly detection. These models predict a patient's expected healthy signal in another modality, such as PET, enabling the subtraction of normal anatomical and physiological variability to isolate disease-specific effects. Generative models like GANs and VAEs have shown promise in producing these cross-modal references, enhancing early anomaly detection in diseases like Alzheimer's and multiple sclerosis. Together, these approaches show how AI can bridge the gap between normal variation and early pathology, enabling more sensitive, personalized, and population-scalable detection of presymptomatic neurological disease.},
}

Humans
*Prodromal Symptoms
*Artificial Intelligence/trends
*Nervous System Diseases/diagnosis
Early Diagnosis
Deep Learning
Machine Learning
Cognitive Dysfunction/diagnosis

@article {pmid41238323,
year = {2025},
author = {Cohen, M},
title = {Digital health in presymptomatic diseases.},
journal = {Revue neurologique},
volume = {181},
number = {9},
pages = {937-943},
doi = {10.1016/j.neurol.2025.06.017},
pmid = {41238323},
issn = {0035-3787},
mesh = {Humans ; *Nervous System Diseases/diagnosis ; Telemedicine/trends ; Early Diagnosis ; Parkinson Disease/diagnosis ; *Asymptomatic Diseases/therapy ; *Prodromal Symptoms ; Digital Health ; },
abstract = {Most of widely available consumer devices like smartphones and tablets are equipped with various sensors that allow for detection of subtle and undetectable neurological impairment of various neurological functions like motricity, coordination, cognition, visual function or eye movements. This opens the perspective of earlier diagnosis of neurological diseases, even at the preclinical stage, which could allow for earlier therapeutic intervention and improved long term outcomes. In this article, we review how technology can enhance the clinician's examination skills and the current level of evidence in the field of preclinical diseases detection, in diseases like Parkinson's disease, Alzheimer's disease or multiple sclerosis. Many studies reported subtle impairment regarding fine motricity, eye movements, cognition, voice features and speech. We will also discuss current limitations regarding scientific evidence and practical implementation in the daily practice, as well as future perspectives.},
}

Humans
*Nervous System Diseases/diagnosis
Telemedicine/trends
Early Diagnosis
Parkinson Disease/diagnosis
*Asymptomatic Diseases/therapy
*Prodromal Symptoms
Digital Health

@article {pmid41238322,
year = {2025},
author = {Dupont, S},
title = {Late-onset epilepsy as a prodromal symptom.},
journal = {Revue neurologique},
volume = {181},
number = {9},
pages = {929-936},
doi = {10.1016/j.neurol.2025.07.007},
pmid = {41238322},
issn = {0035-3787},
mesh = {Humans ; *Prodromal Symptoms ; *Epilepsy/diagnosis/epidemiology/etiology ; Age of Onset ; Alzheimer Disease/diagnosis/complications/epidemiology ; Risk Factors ; Stroke/diagnosis/complications ; Aged ; },
abstract = {Late-onset epilepsy (LOE) of unknown etiology accounts for 15-30% of all LOE cases. A critical question is whether these unexplained seizures represent a prodromal manifestation of an underlying neurological disorder - most notably, stroke or Alzheimer's disease (AD). Growing evidence suggests that seizures may be an early sign of subclinical cerebrovascular disease, serving as a warning signal for future stroke, or an early symptom of a neurodegenerative disorder, particularly AD, reflecting initial pathological changes such as amyloid-β and tau deposition. An alternative hypothesis proposes that shared risk factors - especially cardiovascular ones - underlie all three conditions: LOE, stroke, and AD. As a result, it is recommended that patients with LOE of unknown etiology undergo comprehensive cardiovascular evaluation and receive appropriate management of any identified risk factors. However, it remains unclear whether this approach is sufficient to prevent future strokes. Cognitive assessment is also essential in these patients. In this context, prodromal seizures may provide an opportunity to identify individuals suitable for early, targeted interventions aimed at slowing neurodegeneration.},
}

Humans
*Prodromal Symptoms
*Epilepsy/diagnosis/epidemiology/etiology
Age of Onset
Alzheimer Disease/diagnosis/complications/epidemiology
Risk Factors
Stroke/diagnosis/complications
Aged

@article {pmid41238317,
year = {2025},
author = {Wallon, D and Garnier-Crussard, A},
title = {The challenging concept of preclinical Alzheimer's disease.},
journal = {Revue neurologique},
volume = {181},
number = {9},
pages = {881-892},
doi = {10.1016/j.neurol.2025.07.016},
pmid = {41238317},
issn = {0035-3787},
mesh = {Humans ; *Alzheimer Disease/diagnosis/therapy/pathology ; *Prodromal Symptoms ; Biomarkers/analysis ; Prognosis ; tau Proteins ; },
abstract = {Alzheimer's disease (AD) is increasingly recognized as a decades-long process that begins before any first cognitive symptoms. Neuropathology and in vivo biomarker studies have revealed a silent preclinical phase. However, its precise definition and boundaries remain debated. Elucidating the biological events and temporal sequence that characterize this stage is essential, while researchers try to identify the optimal window to prevent or postpone cognitive decline. At the same time, "preclinical AD" raises unresolved challenges in diagnosis, prognosis, therapeutic intervention and ethics. This narrative review synthesizes the current evidence, from clinical characterization to prevention trials and societal considerations, with an emphasis on original findings for amyloid, tau and neurodegeneration biomarkers. We critically contrast the two principal research frameworks that structure the field and examine how each shapes patient classification and trial design. By integrating these lines of evidence, we explore persistent gaps in prognostic modeling and in the clinical efficacy of disease-modifying strategies. The review aims to provide a concise but comprehensive overview of the preclinical concept for clinicians and researchers developing the next generation of preventive interventions for AD.},
}

Humans
*Alzheimer Disease/diagnosis/therapy/pathology
*Prodromal Symptoms
Biomarkers/analysis
Prognosis
tau Proteins