@article {pmid41100700,
year = {2025},
author = {Braidy, N and Essa, MM and Poljak, A and Selvaraju, S and Al-Adawi, S and Manivasagm, T and Thenmozhi, AJ and Ooi, L and Sachdev, P and Guillemin, GJ},
title = {Retraction: Consumption of pomegranates improves synaptic function in a transgenic mice model of Alzheimer's disease.},
journal = {Oncotarget},
volume = {16},
number = {},
pages = {758},
doi = {10.18632/oncotarget.28773},
pmid = {41100700},
issn = {1949-2553},
}

@article {pmid41100474,
year = {2025},
author = {Akman, TC and Simsek, S and Erken, İN and Yildiztekin, KG and Tasci, H and Türkoğlu, Hİ and Dilek, E},
title = {Phytochemical Profile, Antioxidant, Anticholinesterase, and Antiproliferative Activities of Endemic Onosma discedens: In Vitro and In Silico Approaches.},
journal = {Chemistry & biodiversity},
volume = {},
number = {},
pages = {e02147},
doi = {10.1002/cbdv.202502147},
pmid = {41100474},
issn = {1612-1880},
support = {1919B012111191//The Scientific and Technological Research Council of Türkiye (TUBITAK) 2209-A University Students Research Projects Support Program/ ; },
abstract = {This study presents the first comprehensive analysis of the phytochemical profile and biological activities of root and stalk extracts from endemic Onosma discedens Hausskn. ex Bornm. (OD). The extracts of OD were analyzed by liquid chromatography-electrospray ionization-tandem mass spectrometry (LC-ESI-MS/MS), and 16 phenolics, including vanillic acid (2077.1332 µg/g extract in root) and hesperidin (1185.3621 µg/g extract in stalk), were detected. In antioxidant activity tests, DPPH• radical scavenging activity of root extract (IC50: 60.69 µg/mL) was found to be higher than stalk extract (IC50: 95.66 µg/mL), but both extracts showed lower activity than standard antioxidants. In antiproliferative activity assays, the OD extract exhibited low cytotoxicity against MCF7 cell lines, with an IC50 value exceeding 500 µg/mL. The stem extract was more effective on the butyrylcholinesterase (BChE) enzyme (IC50: 546.09 ± 0.533 µg/mL) than on the acetylcholinesterase (AChE) enzyme (IC50: 721.156 ± 0.410 µg/mL). When the plant is evaluated as a whole, it has a dual inhibitory effect on both cholinesterase enzymes. Molecular docking analyses confirmed the interactions of vanillic acid and hesperidin with target enzymes. As a result, it was revealed that OD, which has a rich structure in phenolic compounds and significant bioactivity due to its cholinesterase inhibitory effect, can be utilized to treat neurodegenerative illnesses like Alzheimer's.},
}

@article {pmid41100427,
year = {2025},
author = {Zheng, Q and Luo, M and Ren, Z and Guo, Y},
title = {Life's Crucial 9 Score and Cognitive Performance in Older Adults: The Mediating Role of Biological Aging.},
journal = {Dementia and geriatric cognitive disorders},
volume = {},
number = {},
pages = {1-18},
doi = {10.1159/000548982},
pmid = {41100427},
issn = {1421-9824},
abstract = {BACKGROUND: Cognitive decline is a pressing public health concern in older adults. The recently proposed Life's Crucial 9 (LC9) score, which integrates cardiovascular and mental health metrics, may offer a novel framework for predicting cognitive impairment.

METHODS: We analyzed data from 2,180 participants aged ≥ 60 years from 2011 to 2014 National Health and Nutrition Examination Survey (NHANES). LC9 was computed based on eight cardiovascular health metrics and depressive symptoms. Cognitive performance was assessed using the Animal Fluency Test (AFT), Consortium to Establish a Registry for Alzheimer's Disease (CERAD) test, and Digit Symbol Substitution Test (DSST). Biological Age (BA) and Biological Age Acceleration (BAcel) were derived using a validated algorithm. Weighted logistic regression, receiver operating characteristic (ROC), restricted cubic spline (RCS) models, and mediation analyses were performed to evaluate the associations.

RESULTS: Higher LC9 scores were significantly associated with lower odds of poor performance on the AFT (P = 1.5 x 10-2) and DSST (P = 1.4 x 10-2), but not CERAD (P = 1.2 x 10-1). ROC analysis showed that LC9 significantly outperformed Life's Essential 8 (LE8) in predicting low AFT and DSST performance (AUC: 0.599 vs. 0.588 for AFT; 0.632 vs. 0.614 for DSST). The RCS models indicated no statistically significant nonlinear relationship between the LC9 and cognitive performance. Mediation analysis revealed that BA and BAcel accounted for 7.48% and 4.53% of the total effect of LC9 on DSST performance, respectively. The subgroup and sensitivity analyses confirmed the robustness of these findings.

CONCLUSION: LC9 is significantly associated with cognitive performance in older adults. This association with DSST is partially mediated by biological aging.},
}

@article {pmid41100281,
year = {2025},
author = {van der Landen, SM and Rhodius-Meester, HFM and Postema, MC and Jutten, RJ and Tewolde, ME and Bohnen, CV and van Harten, AC and Teunissen, CE and Ponds, RWH and Schalet, BD and van der Flier, WM and Sikkes, SAM},
title = {The relationship between cognitive domains and everyday functioning in Alzheimer's disease.},
journal = {Neuropsychology},
volume = {},
number = {},
pages = {},
doi = {10.1037/neu0001038},
pmid = {41100281},
issn = {1931-1559},
support = {//Netherlands Organisation for Health Research and Development/ ; //Alzheimer Nederland/ ; //Netherlands Organisation for Scientific Research; Netherlands Organisation for Health Research and Development/ ; //European Union/ ; //European Union; IHI/ ; //Hersenstichting CardioVascular Onderzoek Nederland/ ; //Health∼Holland, Topsector Life Sciences and Health/ ; //Stichting Dioraphte/ ; //Gieskes-Strijbis Fonds/ ; //Stichting Equilibrio/ ; //Edwin Bouw Fonds/ ; //Pasman Stichting/ ; //Stichting Alzheimer and Neuropsychiatrie Foundation/ ; //Philips/ ; //Biogen MA Inc/ ; //Novartis-NL/ ; //Life-MI/ ; //AVID/ ; //Roche BV/ ; //Fujifilm/ ; //Eisai/ ; //Combinostics/ ; //Innovative Health Initiative Joint Undertaking (IHI JU)/ ; },
abstract = {OBJECTIVE: Alzheimer's disease (AD) causes increasing cognitive and functional impairments, yet if and how cognition impacts functioning remains unclear. Here, we assessed the relationship between cognitive domains and everyday functioning in participants with AD.

METHOD: In this cross-sectional study, we included participants with biomarker-confirmed AD with subjective cognitive decline (SCD), mild cognitive impairment (MCI), or dementia from the Amsterdam Dementia Cohort. Cognition was assessed with a standardized neuropsychological test battery divided into domains using exploratory factor analysis (EFA). These were used as input for structural equation modeling (SEM) to calculate the unique associations with everyday functioning, measured with the well-validated study partner-based Amsterdam Instrumental Activities of Daily Living Questionnaire (A-IADL-Q). Model fit of the SEM and its associations were described in standardized paths (std.lv).

RESULTS: A total of 613 participants were included, mean age ± SD = 65 ± 8 years, 310(51%) female, with a mean A-IADL-Q of 50.2 ± 9.3. The majority had a diagnosis of dementia (n = 443, 72%), followed by MCI (n = 100, 16%) and SCD (n = 70, 11%). SEM analysis, χ²(137, N = 613) = 1072.17, p < .001, showed that, of the four cognitive domains identified using EFA, "memory" (std.lv = 0.33) and "visual attention, mental flexibility, and visuoconstruction" (std.lv = 0.29) were related to A-IADL-Q, while "working memory, shifting, fluency, and inhibition" and "naming" were not.

CONCLUSIONS: Lower performance in memory and visual attention, mental flexibility, and visuoconstruction was related to more difficulties in everyday functioning. A better understanding of how cognition relates to everyday functioning has important implications for personalized care strategies and trial outcomes. (PsycInfo Database Record (c) 2025 APA, all rights reserved).},
}

@article {pmid41100182,
year = {2025},
author = {Woo, E and Datta, D and Bathla, S and Beatty, HE and Caglayan, PB and Albizu, AK and Lam, TT and Kanyo, J and Joyce, MKP and Leslie, SN and Uchendu, S and DeLong, JH and Guan, QS and Li, J and Abramson, E and Herman, AL and Cooper, DC and Licznerski, P and Horvath, TL and Jonas, EA and Nairn, AC and Arnsten, AF and Sansing, LH},
title = {Ryanodine receptor 2-mediated calcium leak is associated with increased glyoxalase I in the aging brain.},
journal = {JCI insight},
volume = {},
number = {},
pages = {},
doi = {10.1172/jci.insight.184041},
pmid = {41100182},
issn = {2379-3708},
abstract = {Alzheimer's disease (AD) is characterized by plaques and tangles, including calcium dysregulation and glycated products produced by reactive carbonyl compounds. AD brains have increased glyoxalase I (GLO1), a major scavenger of inflammatory carbonyl compounds, at early, but not later, stages of disease. Calcium dysregulation includes calcium leak from phosphorylated ryanodine receptor 2 (pS2808-RyR2), seen in aged macaques and AD mouse models, but the downstream consequences of calcium leak remain unclear. Here, we show that chronic calcium leak is associated with increased GLO1 expression and activity. In macaque, we found age-related increases in GLO1 expression in prefrontal cortex (PFC), correlating with pS2808-RyR2, and localized to dendrites and astrocytes. To examine the relationship between GLO1 and RyR2, we used S2808D-RyR2 mutant mice exhibiting chronic calcium leak through RyR2, and found increased GLO1 expression and activity in the PFC and hippocampus as early as 1-month and as late as 21-months of age, with a bell-shaped aging curve. These aged S2808D-RyR2 mice demonstrated impaired working memory. As with macaques, GLO1 was expressed in astrocytes and neurons. Proteomics data generated from S2808D-RyR2 synaptosomes confirmed GLO1 upregulation. Altogether, these data suggest potential association between GLO1 and chronic calcium leak, providing resilience in early stages of aging.},
}

@article {pmid41099975,
year = {2025},
author = {Gangan, N and Rosenthal, M and Arabshomali, A and Holmes, E and Banahan, BF and Shah, R and Bentley, JP},
title = {Does the relationship between stress and quality of life differ among informal caregivers of older adults with Alzheimer's disease and children with autism spectrum disorder? Results from a cross-sectional survey.},
journal = {Journal of patient-reported outcomes},
volume = {9},
number = {1},
pages = {121},
pmid = {41099975},
issn = {2509-8020},
}

@article {pmid41099939,
year = {2025},
author = {Dembitskaya, Y and Popov, A},
title = {Astrocytes in maintaining neuronal health and brain function: interplay of aging, diet, and environment.},
journal = {Metabolic brain disease},
volume = {40},
number = {8},
pages = {291},
pmid = {41099939},
issn = {1573-7365},
support = {24-14-00379//Russian Science Support Foundation/ ; 24-14-00379//Russian Science Support Foundation/ ; },
mesh = {Humans ; *Astrocytes/metabolism/physiology ; *Aging/physiology/metabolism ; Animals ; *Brain/physiology/metabolism ; *Neurons/metabolism/physiology ; *Diet ; *Environment ; Neurodegenerative Diseases/metabolism ; },
abstract = {Astrocytes are pivotal modulators of neuronal health and brain function through their roles in metabolic support, synaptic regulation, neurotransmitter recycling, and the maintenance of the blood-brain barrier. However, aging and environmental challenges compromise astrocytic function, setting the stage for neurodegeneration. Recent findings reveal that age-related astrocyte senescence-characterized by mitochondrial decline, structural atrophy, and a pro-inflammatory shift-undermines their capacity to support neurons, leading to cognitive decline and neurodegenerative conditions such as Alzheimer's disease. Environmental factors, notably dietary influences, further modulate astrocytic behavior. High-fat diets may initially enhance aspects of astrocytic function, such as glutamate clearance; yet prolonged exposure often triggers maladaptive metabolic shifts and neuroinflammation. In contrast, caloric restriction promotes metabolic flexibility and exerts anti-inflammatory effects, thereby preserving astrocytic integrity. Sleep also plays a crucial role by facilitating glymphatic clearance and synaptic maintenance, whereas sleep deprivation disrupts calcium signaling and exacerbates inflammatory processes. This review synthesizes recent advances in the metabolic, immune, and intercellular mechanisms underlying astrocytic dysfunction in aging. By integrating these insights, we highlight the therapeutic potential of targeting astrocyte-mediated processes to preserve cognitive resilience and counteract neurodegeneration.},
}

Humans
*Astrocytes/metabolism/physiology
*Aging/physiology/metabolism
Animals
*Brain/physiology/metabolism
*Neurons/metabolism/physiology
*Diet
*Environment
Neurodegenerative Diseases/metabolism

@article {pmid41099783,
year = {2025},
author = {Alavian, F and Hajimohammadi, A},
title = {Interplay between gut Microbiome and glymphatic system in cognitive function and memory regulation.},
journal = {Molecular biology reports},
volume = {52},
number = {1},
pages = {1038},
pmid = {41099783},
issn = {1573-4978},
mesh = {*Gastrointestinal Microbiome/physiology ; Humans ; *Cognition/physiology ; *Glymphatic System/metabolism/physiology ; *Memory/physiology ; Animals ; Brain/metabolism ; Neurodegenerative Diseases/metabolism ; Dysbiosis ; Aquaporin 4/metabolism ; },
abstract = {The glymphatic system, a network of perivascular channels in the brain, clears toxins and metabolic products such as amyloid-β (Aβ), supporting cognitive function and preventing neurodegenerative diseases. The gut microbiome also affects brain health and cognitive functions by producing anti-inflammatory metabolites and neurotransmitters. In this narrative review study, recently published articles from reputable scientific databases were collected and analyzed. Characteristics related to the gut microbiome, its metabolites, and their impact on the glymphatic system and ultimately cognitive function were examined. These findings indicate that microbial metabolites such as short-chain fatty acids (SCFAs) and neurotransmitters such as serotonin and melatonin reduce brain inflammation and improve sleep quality and synaptic plasticity, which are essential for memory stabilization. Disruption of the gut microbiome (dysbiosis) leads to increased inflammation and dysfunction of the glymphatic system, resulting in the accumulation of toxic proteins and decreased cognitive function. Proper polarization of aquaporin-4 (AQP4), a water channel protein critical for fluid homeostasis in the brain, in astrocytes is essential for the effective functioning of this system, and its disruption is associated with diseases such as Alzheimer's disease (AD) and Parkinson's disease (PD). Understanding the interaction between the gut microbiome and the glymphatic system presents a new pathway for regulating memory and cognitive health, which could be an important target for the prevention and treatment of neurodegenerative diseases. Enhancing the gut microbiome through probiotics and a healthy diet may improve glymphatic system function and brain health, thereby preventing cognitive disorders.},
}

*Gastrointestinal Microbiome/physiology
Humans
*Cognition/physiology
*Glymphatic System/metabolism/physiology
*Memory/physiology
Animals
Brain/metabolism
Neurodegenerative Diseases/metabolism
Dysbiosis
Aquaporin 4/metabolism

@article {pmid41099730,
year = {2025},
author = {Polu, PR and Mishra, S},
title = {Genetic convergence in brain aging and neurodegeneration: from cellular mechanisms to therapeutic targets.},
journal = {Journal of neurogenetics},
volume = {},
number = {},
pages = {1-20},
doi = {10.1080/01677063.2025.2571127},
pmid = {41099730},
issn = {1563-5260},
abstract = {The distinction between normal brain aging and neurodegeneration has traditionally been viewed as a binary classification, yet emerging evidence reveals a complex continuum of shared genetic mechanisms underlying both processes. This review synthesises current understanding of conserved molecular pathways that contribute to age-related neural decline across the spectrum from healthy aging to pathological neurodegeneration. We examine how fundamental cellular processes including protein quality control, mitochondrial dysfunction, inflammation, and synaptic maintenance are genetically regulated and become progressively dysregulated during aging. Key genetic pathways, such as insulin/IGF signalling, autophagy-lysosomal networks, and stress response mechanisms demonstrate remarkable conservation from model organisms to humans, suggesting evolutionary constraints on neural aging processes. The review highlights how genetic variants in these pathways can determine individual trajectories along the aging-neurodegeneration continuum, influencing susceptibility to diseases like Alzheimer's, Parkinson's, and ALS. We discuss evidence from comparative studies in C. elegans, Drosophila, rodents, and human populations that illuminate shared vulnerability genes and protective factors. Understanding these convergent mechanisms offers unprecedented opportunities for therapeutic intervention, as strategies targeting fundamental aging processes may simultaneously address multiple neurodegenerative conditions. This integrated perspective challenges traditional disease-centric approaches and supports the development of unified therapeutic strategies for promoting healthy brain aging while preventing neurodegeneration.},
}

@article {pmid41099572,
year = {2025},
author = {Grainger, L},
title = {Improvements in Dementia Symptoms Through Personalized Music.},
journal = {Journal of gerontological nursing},
volume = {},
number = {},
pages = {1-7},
doi = {10.3928/00989134-20251008-01},
pmid = {41099572},
issn = {0098-9134},
abstract = {PURPOSE: Routinely listening to personalized music selections has been shown to reduce agitation, the most common symptom of Alzheimer's disease and related dementias. The purpose of the current study was to assess changes in participant agitation by providing a 6-week personalized music listening (PML) intervention of 30 minutes to 10 nursing home residents with dementia.

METHOD: The Cohen-Mansfield Agitation Inventory (CMAI) was administered every 2 weeks throughout the study period. The objective was to see if PML would reduce symptoms of agitation, as measured by participants' CMAI scores.

RESULTS: Results from a one-way repeated measures analysis of variance showed improvement in CMAI scores pre- versus post-intervention. Using a Greenhouse-Geisser correction, CMAI score reduction was statistically significant at different time points of the study (F [1.487, 13.886] = 4.63, p = 0.044).

CONCLUSION: Results suggest that PML can be an effective and low-cost means for improving dementia-related agitation in the short term.},
}

@article {pmid41099373,
year = {2025},
author = {Arshad, F and Alladi, S},
title = {Disease-Modifying Drugs for Alzheimer's Disease: Bending the Curve.},
journal = {Annals of Indian Academy of Neurology},
volume = {},
number = {},
pages = {},
doi = {10.4103/aian.aian_748_25},
pmid = {41099373},
issn = {0972-2327},
abstract = {Alzheimer's disease (AD) is the most prevalent form of dementia worldwide and the leading cause of disability in the aging population. While several disease-modifying therapies, particularly anti-amyloid monoclonal antibodies, have recently gained approval, their clinical accessibility remains limited, especially in low- and middle-income countries (LMICs). A major prerequisite for initiating these treatments is a biomarker-based diagnosis, typically involving cerebrospinal fluid (CSF) analysis or amyloid/tau positron emission tomography (PET) imaging. However, these biomarkers are often costly, invasive, or unavailable in resource-constrained settings, emphasizing the urgent need for affordable, scalable, and validated biomarkers to enable early and accurate diagnosis and intervention. This review critically examined the current landscape of approved disease-modifying drugs for AD, their efficacy, safety profiles, and implementation challenges in LMICs. It also explored emerging therapeutic strategies beyond amyloid- and tau-targeting agents, including plasma exchange, synaptic modulators, and gene-based approaches. Finally, it discussed the future trajectory of AD therapeutics, emphasizing the necessity of strengthening healthcare systems and developing globally inclusive research frameworks to ensure equitable access to disease-modifying treatments.},
}

@article {pmid41099251,
year = {2025},
author = {Munan, S and Mondal, A and Tiwari, S and Yadav, R and Pareek, N and Samanta, A},
title = {Engineering fluorescent probes for tracking lysosomal pH in β-amyloid-induced microglial activation and phagocytosis.},
journal = {Journal of materials chemistry. B},
volume = {},
number = {},
pages = {},
doi = {10.1039/d5tb00968e},
pmid = {41099251},
issn = {2050-7518},
abstract = {Alzheimer's disease (AD) is primarily associated with the aggregation of amyloid-β (Aβ) due to insufficient clearance of Aβ peptides. This leads to deposition of fibrillar Aβ (fAβ), contributing to AD progression. Microglia, the brain's resident immune cells, are central to the phagocytotic-fusion of fAβ. Notably, fAβ itself can activate microglia via toll-like receptor signaling, triggering a phagocytic response. Previous studies have shown that activated microglia exhibit efficient phagocytotic-fusion of fAβ, primarily through lysosomal acidification compared to resting microglia. Therefore, distinguishing microglial activation states is vital for understanding and potentially modulating Aβ clearance mechanisms in AD. Herein, we systematically modified the structure to develop fluorescent probes (FPs), PS-Mor and PM-DMor based on morpholine-conjugated pyrylium and pyridinium derivatives of indigenous "IndiFluors". These probes exhibit strong fluorescence enhancement in lysosomal pH windows by modulating photoinduced electron transfer (PET). The turn-on behavior of the probes was further supported by TD-DFT/PCM theoretical calculations. Confocal imaging revealed that PM-DMor selectively localizes to lysosomes, while PS-Mor targets mitochondria in activated human microglia. PM-DMor effectively monitors intracellular pH changes (ΔpHi) during drug-induced apoptosis and discriminates activated from resting microglial using both fluorescence microscopy and flow cytometry. Importantly, PM-DMor also tracks Aβ-induced microglial activation and subsequent phagocytosis of Aβ. Overall, PM-DMor offers a valuable tool for probing lysosomal dynamics in microglia and holds promise for early-stage therapeutic strategies targeting Aβ clearance in Alzheimer's disease.},
}

@article {pmid41099215,
year = {2025},
author = {Yih, T and Yang, Y and Yang, M and Liu, H and Huang, L},
title = {Identifying novel linguistic biomarkers of mild cognitive impairment in Mandarin-speaking older adults: A quantitative syntactic approach.},
journal = {Clinical linguistics & phonetics},
volume = {},
number = {},
pages = {1-27},
doi = {10.1080/02699206.2025.2571660},
pmid = {41099215},
issn = {1464-5076},
abstract = {Mild Cognitive Impairment (MCI) is an early symptom of Alzheimer's disease, commonly observed in older adults. The use of low-cost language biomarkers is becoming an emerging trend. This study aims to investigate whether recently proposed measures in the field of Quantitative Syntax and their combinations have the potential to serve as biomarkers for distinguishing between the MCI and cognitively normal (CN) groups. A portion of the Chinese corpus MCGD (CN = 25, MCI = 16) was used. The elderly participants performed a sequential picture description task to produce connected speech. The transcription and annotation were semi-automatically conducted and manually checked. Eleven dependency-based syntactic features were calculated. We assessed the discriminability of both univariate features and multivariate feature combinations using support vector machine. Results show that all features can be grouped into four clusters. Most measures within the largest cluster demonstrate high intercorrelations and are statistically significant in distinguishing between the MCI and CN groups. Among these, mean dependency distance (MDD) exhibits the strongest discriminative ability (AUC = 0.791 [0.610, 0.944]). Two hierarchical features have relatively weaker performance, while dependency direction indicators show almost no group differentiability. Several feature combinations identified slightly improved performance, but the difference was not statistically significant. Our findings suggest that the classic syntactic biomarker MDD remains the best-performing measure for distinguishing between MCI and CN for Mandarin-speaking older adults, while most dependency-based syntactic measures can serve as alternative markers. In the future, combining MDD with features in other domains holds promising potential for early diagnosis.},
}

@article {pmid41099201,
year = {2025},
author = {Bolzetta, F and Durante, G and Tessari, A and Lazzarin, M and Busonera, F and Pontarin, A and Villanova, M and Vernuccio, L and Saccaro, C and Custodero, C and Portincasa, P and Barbagallo, M and Veronese, N},
title = {A simple nomogram to predict the onset of dementia in mild cognitive impairment: A retrospective study.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877251379898},
doi = {10.1177/13872877251379898},
pmid = {41099201},
issn = {1875-8908},
abstract = {BackgroundCurrently there is no effective treatment to reverse Alzheimer's disease, thus prevention is crucial. Patients with mild cognitive impairment (MCI) have higher rate of progression to dementia. Two commonly used cognitive tests, Mini-Mental State Examination (MMSE) and Clock Drawing Test (CDT), have only modest accuracy at predicting conversion from MCI to dementia, whereas other potentially predicting factors are difficult to implement in clinical practice.ObjectiveThe aim of this study was to assess the performance of a combination of simple cognitive tests and routine clinical data to predict onset clinical dementia over 3-year follow-up in a cohort of outpatients with MCI.MethodsMedical history was collected, and an advanced neuropsychological assessment was performed at baseline and at follow-up.Results98 participants were included (mean age 76.6 ± 4.5 years), and 49 developed dementia. Participants who developed dementia had significantly lower MMSE and CDT scores, as well as higher presence of hypercholesterolemia at the baseline evaluation. In the multivariate binary logistic regression analysis, the OR were 0.71 (CI95% 0.58-0.87) for MMSE, 0.77 (CI95% 0.65-0.93) for CDT, and 3.9 (CI95% 1.4-10.9) for hypercholesterolemia. The ROC curve combining these three factors obtained a value of AUC of 0.825 (CI95% 0.74-0.91). A nomogram was then developed for the risk of evolution from MCI to dementia at 3 years.ConclusionsCombining history of hypercholesterolemia with CDT and MMSE tests, may result in a simple prediction model to predict the onset of dementia over 3 years.},
}

@article {pmid41099145,
year = {2025},
author = {García Ribas, G and Ferrer-Picón, E},
title = {Tolerability of rivastigmine transdermal patch in patients with Alzheimer's disease: a narrative review.},
journal = {Expert opinion on drug safety},
volume = {},
number = {},
pages = {},
doi = {10.1080/14740338.2025.2576520},
pmid = {41099145},
issn = {1744-764X},
abstract = {INTRODUCTION: The rivastigmine transdermal patch was developed to provide similar efficacy to oral rivastigmine in the treatment of Alzheimer's disease (AD), but with improved tolerability.

AREAS COVERED: Randomized clinical trials and observational studies reporting on the tolerability of the rivastigmine transdermal patch in patients with AD, identified through a systematic literature search.

EXPERT OPINION: Rivastigmine was the first cholinesterase inhibitor for which a transdermal formulation was developed; consequently, there is a substantial body of evidence on its efficacy and tolerability. The incidence of gastrointestinal AEs is markedly reduced with the transdermal patch compared with oral rivastigmine, while the efficacy of the patch remains similar to that of the oral formulation. Application site reactions are generally mild and do not cause much discomfort for the patient, and the risk of can be reduced by simple measures such as site rotation and good skin care. Tolerability of the patch improves over time, including at the highest dose level. Overall, the available evidence supports transdermal rivastigmine being generally well tolerated at doses up to 13.3 mg/24 h in patients with AD.},
}

@article {pmid41099066,
year = {2025},
author = {Exarchos, TP and Dimakopoulos, GA and Lazaros, K and Krokidis, M and Vrahatis, A and Grammenos, G and Avramouli, A and Skolariki, K and Adams, R and Mahairaki, V and Oh, ES and Leoutsakos, J and Rosenberg, PB and Lyketsos, CG and Vlamos, P},
title = {Five-year dementia prediction and decision support system based on real-world data.},
journal = {Frontiers in aging neuroscience},
volume = {17},
number = {},
pages = {1670609},
pmid = {41099066},
issn = {1663-4365},
abstract = {INTRODUCTION: This work presents a machine learning (ML) based risk prediction model for Alzheimer's disease and related dementias, utilizing real-world electronic health record (EHR) clinical data. While significant research has been conducted on dementia risk prediction, most studies rely on volunteer-based research cohorts rather than real-world clinical data. Using raw EHR data offers more realistic insights but poses challenges due to the extensive effort required to convert real-world EHR clinical data into a decision support system for daily clinical use.

METHODS: The dataset consists of a high-volume, ten-year export of raw EHR data from Epic, the Johns Hopkins (JH) Health System. In this study, we utilized multimodal JH EHR data to develop a patient-based model to predict dementia onset over a five-year period. The interpretable binary classification model identified prognostic rulesets for dementia based on clinical characteristics.

RESULTS: The model achieved a mean test accuracy of 0.722 (95% CI: 0.722-0.723) and an AUROC of 0.795 (95% CI: 0.794-0.795) using 5-fold cross-validation across different sample subsets.

DISCUSSION: Recognizing that neurodegenerative diseases are often driven by multiple contributing factors rather than a single cause, we identify risk pathways by leveraging multimodal data and modeling their combined effects, leading to accurate dementia predictions and improved clinical interoperability.},
}

@article {pmid41099060,
year = {2025},
author = {Lamoca, M and Rothenberg, S and Czornobil, R and Mamuyac, E and Korfmacher, K and Asllani, I and de Leon, J},
title = {Potential of low-field MRI for increasing participation of Filipino Americans and underrepresented populations in Alzheimer's and dementia research.},
journal = {Alzheimer's & dementia (New York, N. Y.)},
volume = {11},
number = {4},
pages = {e70168},
pmid = {41099060},
issn = {2352-8737},
abstract = {INTRODUCTION: Lack of racial and ethnic minority representation in Alzheimer's disease and related dementias (ADRD) research studies leads to inaccurate trial results and health outcomes disparities. This study examines barriers to ADRD research participation in under-studied Filipino American participants and explores the potential of low-field magnetic resonance imaging (LF-MRI) to mitigate these barriers.

METHODS: We utilized GIS mapping to analyze demographic differences across geographic distances from Alzheimer's Disease Research Centers (ADRCs) in the United States. The number of visits in racial and ethnic minority populations was examined using regression analysis of participant data from the National Alzheimer's Coordinating Center (NACC). Surveys and interviews were conducted with researchers and participants from the University of California, San Francisco Memory and Aging Center to identify barriers and explore LF-MRI's potential to increase Filipino American participation. We conclude with recommendations for LF-MRI implementation in ADRD research.

RESULTS: Location-based analysis demonstrates that LF-MRI may help diversify ADRD research participation by offering portable, cheap imaging modalities in satellite locations. Moreover, many racial and ethnic minority populations, particularly Asians, are underrepresented and less likely to have multiple ADRC visits compared to non-Hispanic and White individuals. Interviews and surveys identified participation barriers, including navigation, scheduling, fear of MRI, health-related stigma, and discomfort with conventional MRI procedures. It also suggested that LF-MRI may offer increased portability, reduced costs, improved physical comfort, and less anxiety. Additionally, researchers identified barriers to implementation, including lack of efficacy and reliability data for advanced imaging requirements, and logistical, privacy, and staff bandwidth concerns.

DISCUSSION: These findings contribute to improved understanding of clinical research participation barriers among racial and ethnic minority populations. LF-MRI implementation was explored as a potential way to mitigate these barriers. Future research should address scientific and infrastructural limitations and explore ways to leverage the benefits of LF-MRI in advancing diversity in ADRD research.

HIGHLIGHTS: Racial and ethnic minorities in Alzheimer's disease and related dementias (ADRD) research are underrepresented, including Asians.Expanding ADRD research access for Asian and minority groups needs broader outreach.Many minority populations are located beyond the typical travel distance from Alzheimer's Disease Research Centers (ADRCs).low-field magnetic resonance imaging (LF-MRI) may address comfort, cost, accessibility, and geographical barriers.LF-MRI implementation may lead to an increase in research participation.},
}

@article {pmid41098826,
year = {2025},
author = {Zhang, X and Huang, S and Xu, H and Hu, Y and Gao, L},
title = {Correction: Research progress on plant-derived natural compounds regulating the MAPK signaling pathway for the prevention and therapy of Alzheimer's disease.},
journal = {Frontiers in pharmacology},
volume = {16},
number = {},
pages = {1710820},
doi = {10.3389/fphar.2025.1710820},
pmid = {41098826},
issn = {1663-9812},
abstract = {[This corrects the article DOI: 10.3389/fphar.2025.1666082.].},
}

@article {pmid41098825,
year = {2025},
author = {Zhang, X and Huang, S and Xu, H and Hu, Y and Gao, L},
title = {Research progress on plant-derived natural compounds regulating the MAPK signaling pathway for the prevention and therapy of Alzheimer's disease.},
journal = {Frontiers in pharmacology},
volume = {16},
number = {},
pages = {1666082},
pmid = {41098825},
issn = {1663-9812},
abstract = {Alzheimer's disease (AD) is a progressive neurodegenerative disorder. It is characterised by the following: amyloid-β (Aβ) deposition, tau hyperphosphorylation, neuroinflammation and oxidative stress. Unfortunately, there is no curative treatment available. Recently, natural products have attracted growing interest as potential therapeutic agents for AD, thanks to their multi-target actions and favourable safety profiles. This review highlights recent advances in the use of various natural compounds, including flavonoids, phenolic compounds, saponins, terpenoids, alkaloids and coumarins, with a particular focus on how they modulate the mitogen-activated protein kinase (MAPK) signaling pathway. Representative agents such as myricetin, nobiletin, resveratrol, gallic acid, paeoniflorin, ganoderic acid A, huperzine A, triptolide, berberine, crocin, and ginsenosides have been shown to regulate MAPK subpathways (ERK, JNK, p38), thereby attenuating oxidative stress, neuroinflammation, synaptic dysfunction, and neuronal apoptosis. Preclinical studies suggest that these compounds improve cognitive function and ameliorate AD-related pathology, thereby supporting the idea that MAPK signaling is a critical therapeutic target. Nevertheless, current evidence is limited by short-term animal experiments, insufficient toxicological evaluations, and challenges related to bioavailability and blood-brain barrier penetration. Future studies should emphasize long-term efficacy, safety assessments, optimized drug delivery systems, and high-quality clinical trials. Overall, natural products represent a valuable source for AD drug discovery, and targeting MAPK signaling offers promising opportunities for novel therapeutic development.},
}

@article {pmid41098730,
year = {2025},
author = {Jin, Z and Cai, Z and Perveen, A and Barreto, GE and Yin, L and Wang, R and Liu, R},
title = {Editorial: Remedying the injured brain in cognitive impairment: potential neuroimmune communication signaling and therapeutic opportunities.},
journal = {Frontiers in immunology},
volume = {16},
number = {},
pages = {1705628},
pmid = {41098730},
issn = {1664-3224},
}

@article {pmid41098572,
year = {2025},
author = {Bertarini, L and Imbeni, F and Brighenti, V and Martusciello, I and Pellati, F and Alboni, S},
title = {Para-Cresol and the Brain: Emerging Role in Neurodevelopmental and Neurodegenerative Disorders and Therapeutic Perspectives.},
journal = {ACS pharmacology & translational science},
volume = {8},
number = {10},
pages = {3432-3452},
pmid = {41098572},
issn = {2575-9108},
abstract = {p-Cresol (pC) is a phenolic compound to which humans can be exposed through both environmental sources, such as a pollutant, and endogenous production by the gut microbiota. Among microbial contributors, Clostridioides difficile appears to be a major source of pC within the body. Once absorbed, pC is highly protein-bound in plasma and predominantly circulates in its hepatic conjugated forms: p-cresyl sulfate (pCS) and p-cresol glucuronide (pCG), which are mainly excreted in urine. Accumulation of these metabolites, particularly pCS, classified as a protein-bound uremic toxin, has been associated with the progression of chronic kidney disease (CKD) and related complications, due to its pro-oxidant, pro-inflammatory, and pro-apoptotic properties. CKD patients are at increased risk for cognitive impairment, affective disorders, and central nervous system (CNS) dysfunctions. In recent years, increasing evidence has suggested a potential role of pC and its metabolites in CNS diseases. Here, we summarize current knowledge on the involvement of these compounds in the pathogenesis and progression of autism spectrum disorder, Parkinson's disease, Alzheimer's disease, and post-traumatic stress disorder. We also discuss how modulating systemic levels of pC may represent a promising strategy to improve pathological phenotypes in the context of neurodevelopmental and neurodegenerative disorders.},
}

@article {pmid41098540,
year = {2025},
author = {Dafsari, HS and Schuler, J and Schober, E and Möller, B and Antebi, A and Fanto, M and Jungbluth, H},
title = {The space-time continuum in neurological disorders of the autophagosome-lysosome fusion machinery.},
journal = {Autophagy reports},
volume = {4},
number = {1},
pages = {2560903},
pmid = {41098540},
issn = {2769-4127},
abstract = {Autophagy is a highly conserved cellular pathway for the degradation and recycling of defective intracellular cargo and plays a vital role in the homeostasis of post-mitotic tissues, particularly the nervous system. Autophagosome-lysosome fusion represents the final critical step in macroautophagy with a tightly regulated process mediated by a complex molecular machinery of tethering vesicles for degradation. Since the first reports of human autophagy disorders, the scientific and clinical focus condensed on severe phenotypes with biallelic-truncating genotypes as monogenic models of near-complete autophagy perturbation. Recent reports suggest a much wider disease spectrum with defective autophagy, ranging from neurodevelopmental disorders to neurodegenerative phenotypes with later manifestation due to "milder" genotypes, including Alzheimer's disease (AD), Parkinson's disease (PD), and Amyotrophic Lateral Sclerosis-Frontotemporal Dementia (ALS-FTD). In addition, recent evidence identified molecular connections between physiological autophagy regulation during normal aging and pathophysiological hallmarks of aging-related disorders. These translational observations led to a more comprehensive understanding of autophagy at health and disease, in particular: 1) genetic location and allelism of pathogenic variants ("genomic space"); 2) protein-protein interaction in functional protein complexes ("proteomic space"); 3) metabolic autophagic flux with positive and negative regulators ("metabolomic space"); 4) age-related phenotypic progression over time. Here, we review the autophagosome-lysosome fusion machinery as a key structure both on the molecular level and with regards to the pathogenesis of the autophagy-related disease spectrum. We highlight the clinicopathological signature of disorders in the autophagosome-lysosome fusion machinery, in particular features warranting awareness from clinicians and geneticists to inform adequate diagnosis, surveillance, and patient guidance.},
}

@article {pmid41098384,
year = {2025},
author = {Deng, B and Zheng, Y and Gao, Y and Zhuang, Y and Ma, L and Cao, L},
title = {Evaluation of the diagnostic efficacy of core biomarkers in cerebrospinal fluid for Alzheimer's disease: a systematic review and meta-analysis.},
journal = {Frontiers in neurology},
volume = {16},
number = {},
pages = {1667402},
pmid = {41098384},
issn = {1664-2295},
abstract = {OBJECTIVE: Core cerebrospinal fluid (CSF) biomarkers serve as pivotal diagnostic indicators for Alzheimer's disease, yet their diagnostic efficacy varies substantially across different markers. This study employs a Bayesian meta-analytic approach to comprehensively evaluate the diagnostic accuracy of individual core CSF biomarkers for Alzheimer's disease (AD).

METHODS: A comprehensive literature search was conducted in Web of Science, PubMed, and other databases for English-language studies published between January 2013 and April 2025. Following predefined inclusion/exclusion criteria, eligible studies were selected for methodological quality assessment using standardized tools. Data extraction was subsequently performed, and statistical analyses were conducted using Meta-DiSc 1.4, Stata 15.1, and R 4.3.2 software packages.

RESULTS: This meta-analysis systematically evaluated the diagnostic value of eight core CSF biomarkers for AD, incorporating 23 eligible studies (2,187 AD cases and 2,019 non-AD). Key findings revealed: (1) Among individual biomarkers, p-tau217 demonstrated superior diagnostic performance, with sensitivity of 0.95 (95% CI: 0.92-0.97), specificity of 0.94 (95% CI: 0.88-0.98), area under the curve (AUC) of 0.99 (95% CI: 0.97-1.00), and an exceptionally high diagnostic odds ratio (DOR) of 395.28 (95% CI: 92.17-1,305.79), all parameters being significantly better than other biomarkers (p < 0.001). Both p-tau231 (AUC = 0.97) and p-tau181 (AUC = 0.90) also exhibited commendable diagnostic accuracy. (2) For biomarker ratios, the Aβ42/p-tau181 ratio showed optimal overall diagnostic efficacy, with sensitivity of 0.90 (95% CI: 0.86-0.94) and AUC of 0.93 (95% CI: 0.90-0.96), significantly outperforming other ratio combinations (p < 0.05).

CONCLUSION: This study demonstrates that among core CSF biomarkers for AD, p-tau217 exhibits the most outstanding diagnostic performance as a standalone biomarker, while the Aβ42/p-tau181 ratio shows superior diagnostic efficacy among biomarker combinations. Based on current evidence-based medical data, we recommend the combined use of p-tau217 and Aβ42/p-tau181 ratio as first-line core CSF biomarker panel for AD diagnosis, providing reliable laboratory evidence for early screening and differential diagnosis of AD in clinical practice.},
}

@article {pmid41098354,
year = {2025},
author = {Wang, H},
title = {Advancing Dementia Care Continuity: The 3A (Awareness, Attitude, Action) Framework.},
journal = {China CDC weekly},
volume = {7},
number = {38},
pages = {1209-1213},
pmid = {41098354},
issn = {2096-7071},
abstract = {In the context of World Alzheimer's Month 2025, this perspective article examines the current state of care continuity for people living with dementia in China and identifies critical gaps in this domain. The article further reviews existing global dementia action plans, highlighting the strategic approaches outlined in China's National Action Plan on Response to Dementia (2024-2030). To transform knowledge into meaningful change, this perspective proposes the 3A approach - Awareness, Attitude, and Action - as a comprehensive guiding framework to strengthen and advance the continuum of care.},
}

@article {pmid41098334,
year = {2025},
author = {Clark, AL and Hamlin, AM and Chikkala, A and Weigand, AJ and Tarraf, W and Sisco, S and Thomas, KR and Marsiske, M},
title = {The impact of tract- and county-level segregation on 10-year cognitive and everyday functioning outcomes of Black/African American older adults in the ACTIVE study.},
journal = {Alzheimer's & dementia. Behavior & socioeconomics of aging},
volume = {1},
number = {2},
pages = {},
pmid = {41098334},
issn = {2997-3805},
abstract = {OBJECTIVE: The present study used structural equation modeling (SEM) to examine the impact of tract- and county-level segregation on 10-year cognitive and functional outcomes of Black/African American older adults enrolled in the Advanced Cognitive Training for Independent and Vital Elderly study.

METHODS: Addresses for 695 participants were geocoded and linked with decennial census data to calculate segregation. Higher levels of segregation were indicated by higher levels of dissimilarity (uneven spatial distribution between Black and non-Hispanic White [NHW] residents) and lower levels of interaction (less exposure to NHW residents). Cognitive composites (memory, processing speed, and reasoning) and performance on an everyday functioning measure administered at baseline, post-intervention, 1-, 2-, 3-, 5-, and 10-year follow-up were the outcomes.

FINDINGS: Higher segregation, indicated by lower tract and county-level interaction, was associated with better cognitive and everyday functioning levels but faster rates of decline. Higher segregation, indicated by higher county-level dissimilarity, was associated with better cognitive and everyday functioning levels but accelerated rates of decline. No associations between segregation characterized by tract-level dissimilarity and outcomes were observed.

CONCLUSIONS: Segregation may restrict access to important resources, and this disadvantage may accelerate cognitive and everyday functioning declines. However, segregation may also increase cultural capital and social resources that have a positive impact on levels of cognitive and everyday functioning performance. Results also revealed that the magnitude and consistency of segregation effects differ across geospatial levels of analysis and highlight that targeted interventions at multiple levels may help reduce racial disparities in Alzheimer's disease and related dementias.},
}

@article {pmid41098319,
year = {2025},
author = {Jiang, W and Liu, J and Wu, Y and Li, J and Jin, H and Cui, Z and Chen, X and Lian, T and Lv, H and Han, B and Yu, D and Wang, C and Li, G and Chen, K and Li, S and Wang, L and Zhang, W and Wang, R and Zhang, G},
title = {Establishment and verification of reference intervals for Alzheimer's disease plasma biomarkers based on evaluation of pre-analytical procedures: a multicenter study.},
journal = {Alzheimer's & dementia (Amsterdam, Netherlands)},
volume = {17},
number = {4},
pages = {e70194},
pmid = {41098319},
issn = {2352-8729},
abstract = {INTRODUCTION: To establish and verify reference intervals (RIs) for Alzheimer's disease (AD) plasma biomarkers amyloid beta (Aβ) 40, Aβ42, phosphorylated tau 181 (p-tau181), p-tau217, and total tau (t-tau) after defining optimal pre-analytical procedures.

METHODS: Pre-analytical procedures were assessed, including storage of whole blood and plasma under different conditions and freeze-thaw times. RIs were established using 738 samples, with grouping by sex and age (≤ 44, 45 to 59, ≥60 years), and verified with 120 samples from four clinical centers.

RESULTS: Samples stored at 2°C to 8°C for 22 to 28 h or -20°C to -80°C for 30 days were stable. Though sex/age differences in biomarker levels existed, they did not require partitioning. RIs of Aβ40, Aβ42, p-tau181, p-tau217, and t-tau were 12.71 to 283.6, 2.313 to 25.96, 0.8342 to 18.36, 0.3351 to 4.310, and 0.8096 to 18.65 pg/mL, respectively. The verification rates of RIs with the multicenter cohort (n = 120) were 93.33% to 99.14%.

DISCUSSION: The established RIs for Chinese adults can potentially facilitate the early diagnosis of AD.

HIGHLIGHTS: Optimized pre-analytical procedures: Plasma levels of Aβ40, Aβ42, p-tau181, p-tau217, and t-tau are unstable at room temperature (25 ± 3°C) but remain stable for 22 to 28 h at 2°C to 8°C (fluctuation ≤10%). For long-term storage, -20°C to -80°C is suitable, with stability maintained for 30 days; ≤5 freeze-thaw cycles have minimal impact on biomarker levels.Established reference intervals (RIs) for healthy Chinese adults: Using non-parametric 2.5th to 97.5th percentiles, RIs were determined as follows: Aβ40 (12.71 to 283.6 pg/mL), Aβ42 (2.313 to 25.96 pg/mL), p-tau181 (0.8342 to 18.36 pg/mL), p-tau217 (0.3351 to 4.310 pg/mL), and t-tau (0.8096 to 18.65 pg/mL).Validated multicenter applicability: Verification with 120 samples from four clinical centers showed that 93.33% to 99.14% of samples fell within the established RIs, confirming broad applicability.No need for stratification by sex or age: Despite significant differences in some biomarkers between sexes (e.g., higher p-tau181/217 in males) and age groups (e.g., age-related increase in Aβ40), Harris-Boyd tests indicated no requirement for stratification, supporting combined RIs.Clinical value: These RIs and pre-analytical guidelines facilitate standardized early diagnosis, risk assessment, and therapeutic monitoring of AD in the Chinese population.},
}

@article {pmid41098318,
year = {2025},
author = {Singh, RK and Bekena, S and Zhu, Y and Cruchaga, C and Arnold, SE and Ances, BM and Babulal, GM},
title = {Plasma NfL and cognitive functioning in older adults: The moderating role of HDL cholesterol.},
journal = {Alzheimer's & dementia (Amsterdam, Netherlands)},
volume = {17},
number = {4},
pages = {e70205},
pmid = {41098318},
issn = {2352-8729},
abstract = {BACKGROUND AND OBJECTIVES: Plasma neurofilament light chain (NfL) is a marker of neuroaxonal injury associated with cognitive decline. High-density lipoprotein (HDL) cholesterol has neuroprotective properties, but its interaction with neurodegeneration remains unclear. This study examined whether HDL moderates the association between NfL and cognitive performance.

METHODS: Baseline data from 417 participants in the Aging Adult Brain Connectome study were analyzed. Plasma NfL and HDL were measured via Simoa and enzymatic assays; cognition was assessed using Montreal Cognitive Assessment (MoCA) and Preclinical Alzheimer Cognitive Composite (PACC). Generalized linear models were used to evaluate NfL and HDL interactions, adjusting for demographics. Sensitivity analyses included apolipoprotein E ε4, body mass index, total cholesterol, LDL, and triglycerides.

RESULTS: Significant interaction effects were observed: MoCA (β = -1.86×10[-4], P = 0.006) and PACC (β = -4.0×10[-5], P = 0.004), indicating HDL moderates the negative association between NfL and cognition.

DISCUSSION: These findings suggest that HDL modifies the cognitive impact of neurodegeneration, highlighting the importance of metabolic-neurological interactions.

HIGHLIGHTS: High-density lipoprotein (HDL) cholesterol moderates the negative association between plasma neurofilament light chain (NfL) and cognition.Higher HDL levels intensify the negative effect of NfL on cognitive performance.Findings challenge the assumption of HDL's uniformly protective role.Results support the integrated use of metabolic and neurodegenerative biomarkers.},
}

@article {pmid41098142,
year = {2025},
author = {Hart, DE},
title = {Research Advance Directives: Ethical Implications for Persons with Alzheimer's Disease, and for the Families of Elderly Dementia Patients.},
journal = {The Journal of law, medicine & ethics : a journal of the American Society of Law, Medicine & Ethics},
volume = {},
number = {},
pages = {1-9},
doi = {10.1017/jme.2025.10185},
pmid = {41098142},
issn = {1748-720X},
abstract = {As both human longevity and diagnostic ability improve, more individuals are being diagnosed with Alzheimer's dementia disease (Alzheimer's). Yet there is a paucity of new Alzheimer's research trials. One obstacle to research is the large number of Alzheimer's patients deemed incapable of providing informed consent for clinical research. Research advance directives (RADs) offer patients the opportunity to provide informed consent before incapacity occurs. However, critics question whether RADs guarantee informed consent, claiming that due to the nature of the disease, the consenting agent is no longer the same person after becoming incapacitated. This paper assesses the debate while using a conception of personhood, informed by the latest Alzheimer's research, which does not reduce the concept of personhood to psychological capacities. It explains how personal identity can persist despite Alzheimer's, such that RADs can and should suffice for informed consent.},
}

@article {pmid41098128,
year = {2025},
author = {Twiss, E and Weaver, DF},
title = {MARKETING SCIENCE: A MISSING PIECE IN THE FIGHT AGAINST ALZHEIMER'S.},
journal = {The Canadian journal of neurological sciences. Le journal canadien des sciences neurologiques},
volume = {},
number = {},
pages = {1-5},
doi = {10.1017/cjn.2025.10451},
pmid = {41098128},
issn = {0317-1671},
}

@article {pmid41097927,
year = {2025},
author = {Kowa, H and Sato, S and Kamiki, E and Nishimoto, T},
title = {[Significance of Amyloid Plaque Removal in Alzheimer's Disease Treatment: Development of Amyloid β-Targeting Antibody Drugs Based on the Amyloid Cascade Hypothesis].},
journal = {Brain and nerve = Shinkei kenkyu no shinpo},
volume = {77},
number = {10},
pages = {1129-1136},
doi = {10.11477/mf.188160960770101129},
pmid = {41097927},
issn = {1881-6096},
mesh = {*Alzheimer Disease/drug therapy/metabolism ; Humans ; *Plaque, Amyloid/drug therapy/metabolism ; *Amyloid beta-Peptides/immunology/metabolism ; *Antibodies/therapeutic use ; },
abstract = {In a hyper-aging society, taking measures against dementia, especially against dementia due to Alzheimer's disease, which accounts for about two thirds of dementia cases, is an important task socially and economically. Forty years have passed since amyloid β was isolated from a patient, 30 years have passed since the amyloid cascade hypothesis was proposed and antibody drugs based on this hypothesis have emerged, which has led to the new era of Alzheimer's disease treatment. This article reviews the significance of amyloid plaque removal with amyloid β-targeting antibody treatment for Alzheimer's disease. (Recieved October 17, 2024; Accepted June 6, 2025; Published October 1, 2025).},
}

*Alzheimer Disease/drug therapy/metabolism
Humans
*Plaque, Amyloid/drug therapy/metabolism
*Amyloid beta-Peptides/immunology/metabolism
*Antibodies/therapeutic use

@article {pmid41097916,
year = {2025},
author = {Sakai, N},
title = {[Sleep and Cerebrospinal Fluid].},
journal = {Brain and nerve = Shinkei kenkyu no shinpo},
volume = {77},
number = {10},
pages = {1059-1064},
doi = {10.11477/mf.188160960770101059},
pmid = {41097916},
issn = {1881-6096},
mesh = {Humans ; Animals ; *Sleep/physiology ; *Cerebrospinal Fluid/physiology ; Glymphatic System/physiology ; Alzheimer Disease ; Brain ; Aging/physiology ; },
abstract = {The discovery of the glymphatic system, a waste clearance pathway in the brain, has drawn increasing attention to the relationship between sleep and neurological diseases such as Alzheimer's disease. Recent studies have revealed the mechanisms of action during sleep in rodents. However, some aspects remain unclear, including their contribution to aging and disease development, and their potential for prevention and early therapeutic intervention.},
}

Humans
Animals
*Sleep/physiology
*Cerebrospinal Fluid/physiology
Glymphatic System/physiology
Alzheimer Disease
Brain
Aging/physiology

@article {pmid41097892,
year = {2025},
author = {Zou, X and Ren, Q and Li, W and Jiang, S and Wang, L and Yang, S and Zhao, M and Jiang, T and Zhang, H and Zheng, F and Xu, J and Jiang, J},
title = {Association Between Short-Term Blood Pressure Variability and the Alzheimer's Disease Continuum.},
journal = {Brain and behavior},
volume = {15},
number = {10},
pages = {e70990},
doi = {10.1002/brb3.70990},
pmid = {41097892},
issn = {2162-3279},
support = {2023ZD0505804//Scientific and Technological Innovation 2030/ ; 2024YFF0507500//National Key Research and Development Program of China/ ; 2021YFC2500100//National Key Research and Development Program of China/ ; 2021YFC2500103//National Key Research and Development Program of China/ ; 82471212//National Natural Science Foundation of China/ ; 8207118//National Natural Science Foundation of China/ ; 82360387//National Natural Science Foundation of China/ ; 81870821//National Natural Science Foundation of China/ ; 202301AS070037//Key Project of Yunnan Provincial Department of Science and Technology/ ; 202305AK340001//Key Project of Yunnan Provincial Department of Science and Technology/ ; },
mesh = {Humans ; *Alzheimer Disease/physiopathology/diagnostic imaging ; Male ; Female ; *Blood Pressure/physiology ; Aged ; Middle Aged ; Blood Pressure Monitoring, Ambulatory ; Neuropsychological Tests ; Aged, 80 and over ; Cognitive Dysfunction/physiopathology ; Biomarkers/cerebrospinal fluid ; Neuroimaging ; tau Proteins/cerebrospinal fluid ; Amyloid beta-Peptides/cerebrospinal fluid ; Risk Factors ; },
abstract = {BACKGROUND: Emerging evidence indicates that blood pressure variability (BPV) is a modifiable vascular risk factor for Alzheimer's disease (AD). Herein, we aimed to systematically evaluate the potential role of short-term BPV across the AD continuum.

METHODS: This study included 263 patients on the AD continuum from the Chinese Imaging, Biomarkers, and Lifestyle study between January 1, 2023, and December 31, 2023. 24-h ambulatory blood pressure monitoring was performed to obtain blood pressure measurements and evaluate BPV. Partial Spearman's correlation and restricted cubic spline analysis were performed to assess the associations between BPV and neuropsychological tests, cerebrospinal fluid biomarkers, and multimodal neuroimaging measures, respectively. The mediating effects of multimodal neuroimaging measures on the association between BPV and neuropsychiatric symptoms (NPS) were analyzed.

RESULTS: The elevated standard deviation (SD) and average real variability of nightly diastolic blood pressure (DBP) were correlated with higher Neuropsychiatric Inventory (NPI) scores (r = 0.19, p = 0.034; r = 0.22, p = 0.013). The increased SD of nightly systolic blood pressure (SBP) was correlated with increased Hamilton Anxiety Scale (HAMA) scores and total tau levels (r = 0.20, p = 0.026; r = 0.17, p = 0.027), and elevated coefficient of variation (CV) of nightly SBP was correlated with higher HAMA scores and lower Aβ42/40 levels (r = 0.20, p = 0.026; r = -0.18, p = 0.021). The nightly variability of SBP showed an inverted U-shaped relationship with Montreal Cognitive Assessment scores (P for nonlinear = 0.008; P for nonlinear = 0.015; P for nonlinear = 0.021). The left cuneus volume mediated 29.41% of the association between the CV of nightly SBP and HAMA scores, while the right medial orbitofrontal thickness mediated 35.44% of the association between the CV of nightly DBP and NPI scores.

CONCLUSION: This study suggests that short-term BPV may play a role in the AD continuum. These findings provide evidence of a vascular pathway to AD, as well as a potential and accessible intervention target for patients on the AD continuum.},
}

Humans
*Alzheimer Disease/physiopathology/diagnostic imaging
Male
Female
*Blood Pressure/physiology
Aged
Middle Aged
Blood Pressure Monitoring, Ambulatory
Neuropsychological Tests
Aged, 80 and over
Cognitive Dysfunction/physiopathology
Biomarkers/cerebrospinal fluid
Neuroimaging
tau Proteins/cerebrospinal fluid
Amyloid beta-Peptides/cerebrospinal fluid
Risk Factors

@article {pmid41097470,
year = {2025},
author = {Gutierres, D and Pacheco, R and Reis, CP},
title = {The Role of Omega-3 and Omega-6 Polyunsaturated Fatty Acid Supplementation in Human Health.},
journal = {Foods (Basel, Switzerland)},
volume = {14},
number = {19},
pages = {},
doi = {10.3390/foods14193299},
pmid = {41097470},
issn = {2304-8158},
support = {UIDB/04138/2020, UIDP/04138/2020, UIDB/00645/2020 (https://doi.org/10.54499/UIDB/00645/2020) and UIDP/00645/2020 (https://doi.org/10.54499/UIDP/00645/2020). Centro de Química Estrutural is a Research Unit funded by the Fundação para a Ciência e Tecnologia//FCT/ ; },
abstract = {The concept "we are what we eat" is gaining increasing relevance as diet-related diseases and comorbidities continue to rise, while consumers place greater emphasis on healthy lifestyles and acknowledge the pivotal role of nutrition in disease prevention. Among dietary components, omega-3 (ω-3) and omega-6 (ω-6) polyunsaturated fatty acids stand out for their broad spectrum of health benefits. This review explores their potential roles in reducing triglyceride levels, delaying the onset of neurodegenerative disorders such as Alzheimer's and Parkinson's diseases, preventing depression, supporting infant brain development, modulating inflammatory processes, and contributing to cancer prevention. The mechanisms of action of these fatty acids are discussed, along with their potential adverse effects-particularly the risk of interactions with anticoagulant medications, which require cautious use. While ω-3 fatty acids are widely recognized for their anti-inflammatory properties, ω-6 fatty acids exhibit both pro- and anti-inflammatory effects, highlighting the importance of achieving a balanced intake. The recommended ω-6:ω-3 ratio, ideally between 4:1 and 1:1, is emphasized as a key element in promoting informed dietary choices. This review also discusses current legislation framework on food supplements, with a focus on challenges such as the lack of stringent regulation regarding supplement content. These gaps underline the need for improved nutritional literacy and stronger regulatory oversight. Ultimately, this review emphasizes the imperative for evidence-based dietary fat recommendations, integrative public health education strategies, the revision and standardization of nutritional guidelines, and the enforcement of robust regulatory frameworks and quality-control protocols across the food supplement industry.},
}

@article {pmid41097449,
year = {2025},
author = {Palmisani, J and Aresta, AM and Vergaro, V and Mancini, G and Mazzola, MC and Nisi, MR and Pastore, L and Pizzillo, V and De Vietro, N and Boncristiani, C and Ciccarella, G and Zambonin, C and de Gennaro, G and Di Gilio, A},
title = {Volatile Organic Compounds (VOCs) in Neurodegenerative Diseases (NDDs): Diagnostic Potential and Analytical Approaches.},
journal = {Molecules (Basel, Switzerland)},
volume = {30},
number = {19},
pages = {},
doi = {10.3390/molecules30194028},
pmid = {41097449},
issn = {1420-3049},
mesh = {Humans ; *Neurodegenerative Diseases/diagnosis/metabolism ; *Volatile Organic Compounds/analysis/metabolism ; Biomarkers/analysis/metabolism ; },
abstract = {Neurodegenerative diseases (NDDs) are a group of progressive diseases affecting neuronal cells in specific areas of the brain, causing cognitive decline and movement impairment. Nowadays, NDDs play a significant role in the global burden of disease, and their incidence is increasing, particularly due to population aging. NDD onset is multi-factorial; based on the current knowledge, genetic, environmental, and cellular factors are believed to contribute to their occurrence and progression. Taking into account that at an early stage, the symptoms are not clearly defined, and diagnosis may be delayed, the development of innovative and non-invasive methodological approaches for early diagnosis of NDDs is strategic for timely and tailored disease management, as well as for the overall improvement of patients' quality of life. The present review aims to provide, in the first part, an overview based on the current level of knowledge on the environmental risk factors that can explicate a role in the onset of the most common NDDs and on the main pathogenic mechanisms involved in disease initiation and progression. The second part aims to define the current state of the art regarding the significance of Volatile Organic Compounds (VOCs) in the volatome of different human biological matrices (exhaled breath, feces, and skin sebum) as candidate biomarkers of specific NDDs, with the aim of developing non-invasive diagnostic approaches for the early diagnosis and personalized management of the patients. A critical synthesis and discussion on the applied methodological approaches and on the relevant outcomes obtained across the studies is reported.},
}

Humans
*Neurodegenerative Diseases/diagnosis/metabolism
*Volatile Organic Compounds/analysis/metabolism
Biomarkers/analysis/metabolism

@article {pmid41097424,
year = {2025},
author = {Erdoğan, PM and Bilgili-Tetikoğlu, F and Çelik-Uzuner, S and Yıldız, O and Kolayli, S and Mossialos, D},
title = {Therapeutic Bioactivity Exerted by the Apis mellifera Bee Venom and Its Major Protein Melittin: A Scoping Review.},
journal = {Molecules (Basel, Switzerland)},
volume = {30},
number = {19},
pages = {},
doi = {10.3390/molecules30194003},
pmid = {41097424},
issn = {1420-3049},
mesh = {*Bee Venoms/chemistry/pharmacology/therapeutic use ; *Melitten/pharmacology/chemistry/therapeutic use ; Animals ; Bees/chemistry ; Humans ; Anti-Inflammatory Agents/pharmacology/chemistry/therapeutic use ; Antioxidants/pharmacology/chemistry/therapeutic use ; Antineoplastic Agents/pharmacology/chemistry/therapeutic use ; Anti-Infective Agents/pharmacology/chemistry/therapeutic use ; },
abstract = {Honey bee (Apis mellifera) products have been extensively utilized in traditional medicine. Bee venom (BV) is one of the major bee products with a high concentration of the small peptide melittin (MEL) and exerts bioactivity ranging from anti-microbial to anti-inflammatory and anti-cancer. This scoping review aims to sum up research articles on the bioactivity exerted by BV and MEL published in PubMed and Scopus from 2010 onwards. PRISMA guidelines were implemented to analyze the relevant literature; we ended up with 425 research articles. Bioactivity of BV and MEL was grouped as (i) anti-inflammatory (85), (ii) immunomodulatory (37), (iii) anti-microbial (179), (iv) anti-cancer (170), and (v) anti-oxidant (32). Although there is a significant body of research on the anti-cancer and anti-microbial activity of BV and MEL, their anti-oxidant, anti-inflammatory and immunomodulatory properties have received comparatively less attention. Many studies on the immunomodulatory effects of BV or MEL have focused on cancer. However, the effects on Parkinson's and Alzheimer's disease have not been extensively studied regarding the anti-inflammatory effects. Given the critical role of the immune system and inflammatory response in cancer, neurodegenerative diseases, senescence and against infections, it is paramount to further explore the immunomodulatory and anti-inflammatory potential of BV and MEL.},
}

*Bee Venoms/chemistry/pharmacology/therapeutic use
*Melitten/pharmacology/chemistry/therapeutic use
Animals
Bees/chemistry
Humans
Anti-Inflammatory Agents/pharmacology/chemistry/therapeutic use
Antioxidants/pharmacology/chemistry/therapeutic use
Antineoplastic Agents/pharmacology/chemistry/therapeutic use
Anti-Infective Agents/pharmacology/chemistry/therapeutic use

@article {pmid41097350,
year = {2025},
author = {Chakhari, S and Marco-Contelles, J and Iriepa, I and Carreiras, MDC and Chabchoub, F and Ismaili, L and Refouvelet, B},
title = {Multicomponent Synthesis of Multi-Target Quinazolines Modulating Cholinesterase, Oxidative Stress, and Amyloid Aggregation Activities for the Therapy of Alzheimer's Disease.},
journal = {Molecules (Basel, Switzerland)},
volume = {30},
number = {19},
pages = {},
doi = {10.3390/molecules30193930},
pmid = {41097350},
issn = {1420-3049},
mesh = {*Alzheimer Disease/drug therapy/metabolism ; *Oxidative Stress/drug effects ; *Quinazolines/chemical synthesis/pharmacology/chemistry ; *Amyloid beta-Peptides/metabolism/chemistry ; *Cholinesterase Inhibitors/pharmacology/chemical synthesis/chemistry ; Humans ; Antioxidants/pharmacology/chemical synthesis/chemistry ; Protein Aggregates/drug effects ; Acetylcholinesterase/metabolism ; *Cholinesterases/metabolism ; Peptide Fragments/metabolism/chemistry ; },
abstract = {Alzheimer's disease (AD) is a multifactorial neurodegenerative disorder characterized by extracellular accumulation of amyloid-beta (Aβ) peptide, intracellular neurofibrillary tangles (NFTs), severe neuronal loss, and a marked decline in cholinergic function. Due to the limited efficacy of currently available therapies, the search for new chemical scaffolds able to target multiple pathological mechanisms remains an urgent priority. Among the most promising strategies are heterocyclic frameworks that can simultaneously interact with cholinesterase (ChE) enzymes and inhibit amyloid-β (Aβ) aggregation while also exhibiting antioxidant activity. In this context, we report a series of quinazoline derivatives synthesized via a sequential, one-pot multicomponent reaction, in good yields. Several of these compounds demonstrated notable antioxidant properties, as well as inhibitory effects on ChE activity and Aβ1-42 self-aggregation, highlighting their potential as multifunctional agents for the treatment of neurodegenerative disorders. Notably, 2-ethyl-4-(3,4-Dimethoxyphenyl)aminoquinazoline (3h) demonstrated the most balanced biological profile among the tested compounds, exhibiting an ORAC value of 5.73 TE, an acetylcholinesterase (AChE) inhibition IC50 = 6.67 μM, and 36.68% inhibition of Aβ1-42 aggregation, closely approaching the activity of curcumin. These findings highlight compound 3h as a promising quinazoline-based hit for the development of multifunctional agents targeting AD.},
}

*Alzheimer Disease/drug therapy/metabolism
*Oxidative Stress/drug effects
*Quinazolines/chemical synthesis/pharmacology/chemistry
*Amyloid beta-Peptides/metabolism/chemistry
*Cholinesterase Inhibitors/pharmacology/chemical synthesis/chemistry
Humans
Antioxidants/pharmacology/chemical synthesis/chemistry
Protein Aggregates/drug effects
Acetylcholinesterase/metabolism
*Cholinesterases/metabolism
Peptide Fragments/metabolism/chemistry

@article {pmid41097218,
year = {2025},
author = {Dhakal, S and Ghimire, N and Bass, S},
title = {Association of Habitual Diet Quality and Nutrient Intake with Cognitive Performance in Community-Dwelling Older Adults: A Cross-Sectional Study.},
journal = {Nutrients},
volume = {17},
number = {19},
pages = {},
doi = {10.3390/nu17193139},
pmid = {41097218},
issn = {2072-6643},
mesh = {Humans ; Aged ; Cross-Sectional Studies ; Female ; Male ; *Independent Living ; *Cognition ; Aged, 80 and over ; *Diet ; *Feeding Behavior ; Cognitive Dysfunction ; *Eating ; *Diet, Healthy ; },
abstract = {Objectives: The rapid aging of the U.S. population has raised concerns about age-related cognitive decline and Alzheimer's disease. Therefore, we aimed to characterize diet quality, nutrient intake, and to examine the associations between specific dietary components and cognitive performance in older adults. Design: Cross-sectional observational study. Setting: Community-based recruitment. Participants: Data from 72 community-dwelling adults aged 65 years and older was analyzed. Measurements: Cognitive performance was assessed using subtests from the Consortium to Establish a Registry for Alzheimer's Disease (CERAD) battery, evaluating episodic memory (Word List Memory/Recall/Recognition), visuospatial skills (Constructional Praxis), and executive function (Verbal Fluency). A composite cognitive score was calculated from memory and visuospatial subtests. Habitual dietary intake was evaluated using structured 24-h recalls to calculate nutrient intake and the Healthy Eating Index score, supplemented by the Short HEI questionnaire. Demographics, health history, depressive symptoms (Patient Health Questionnaire-9), and sleep quality (Pittsburgh Sleep Quality Index) were also collected. Results: Participants demonstrated suboptimal diet quality (mean HEI score 62.9 ± 10.69; recommended >80), with only 9.7% meeting fiber recommendations, 11% meeting calcium or vitamin A recommendations, and 1.4% meeting vitamin D requirements. In bivariate comparisons, higher cognitive performance was observed in younger participants (75.5 vs. 79.5 years; p < 0.01) and females (78% vs. 50%; p = 0.024). Regression models identified significant positive associations between cognitive scores and intakes of dietary fiber (p = 0.007), unsaturated fats (mono- and polyunsaturated; p = 0.012-0.033), protein (p = 0.018), carotenoids (α-carotene, p = 0.001; β-carotene, p = 0.026; lutein + zeaxanthin, p = 0.016), vitamins A (p = 0.044) and E (p = 0.034), and minerals including magnesium (p = 0.006), potassium (p = 0.004), copper (p = 0.008), zinc (p = 0.024), and calcium (p = 0.035). Refined grain intake was inversely associated with cognition (p = 0.011). Conclusions: In this population, dietary components like fiber and micronutrients were positively associated with better cognitive function, and the overall nutrient intake shortfalls observed highlight the need for targeted dietary interventions to support healthy brain aging. Therefore, this work advances our understanding by highlighting potential modifiable nutritional targets for clinical trials focused on delaying or preventing cognitive decline.},
}

Humans
Aged
Cross-Sectional Studies
Female
Male
*Independent Living
*Cognition
Aged, 80 and over
*Diet
*Feeding Behavior
Cognitive Dysfunction
*Eating
*Diet, Healthy

@article {pmid41097203,
year = {2025},
author = {Mohib, O and Bomans, S and Jimenez Garcia, B and Leemans, L and Ligneel, C and De Waele, E and Beckwée, D and Janssens, P},
title = {Clinical Benefits of Exogenous Ketosis in Adults with Disease: A Systematic Review.},
journal = {Nutrients},
volume = {17},
number = {19},
pages = {},
doi = {10.3390/nu17193125},
pmid = {41097203},
issn = {2072-6643},
support = {G075423N//Research Foundation - Flanders/ ; },
mesh = {Humans ; *Ketosis ; *Ketone Bodies/therapeutic use/administration & dosage ; Adult ; Cardiovascular Diseases ; *Metabolic Diseases ; COVID-19 ; Mental Disorders/drug therapy ; Nervous System Diseases ; },
abstract = {BACKGROUND/OBJECTIVES: Ketone bodies are increasingly studied for their potential therapeutic effects, particularly through exogenous ketosis, in a variety of diseases. This systematic review aimed to rigorously assess the clinical efficacy of exogenous ketosis in adults with medical conditions.

METHODS: Following PRISMA guidelines, we systematically searched MEDLINE and Scopus databases. Our inclusion criteria were defined according to the PICOS framework, focusing on studies involving exogenous ketosis in adult patients with specific diseases. The study is registered in the International Prospective Register of Systematic Reviews (PROSPERO; CRD42023492846).

RESULTS: After a stringent selection process, fifty-one studies were analyzed. Twenty-two studies focused on neurological disorders, one on psychiatric disorders, twenty-two on metabolic disorders, five on cardiovascular disorders, and one on an inflammatory disorder. Exogenous ketosis demonstrated potential benefits across multiple conditions, including Alzheimer's disease, mild cognitive impairment, McArdle's disease, various forms of heart failure, cardiogenic shock, pulmonary hypertension, and COVID-19-related acute respiratory distress syndrome, although evidence is mostly limited to surrogate endpoints with insufficient hard outcome data. Subtherapeutic ketone concentrations induced by medium-chain triglycerides and limited follow-up periods often precluded firm conclusions regarding clinically meaningful outcomes.

CONCLUSIONS: Exogenous ketosis shows potential in neurological, metabolic, and cardiovascular disorders, while evidence in psychiatric and inflammatory conditions remains scarce and preliminary. Ketone esters appear preferable for effective and tolerable ketosis. Future research should focus on identifying responsive patient populations, optimizing treatment regimens, and conducting long-term clinical trials with hard endpoints to validate these findings.},
}

Humans
*Ketosis
*Ketone Bodies/therapeutic use/administration & dosage
Adult
Cardiovascular Diseases
*Metabolic Diseases
COVID-19
Mental Disorders/drug therapy
Nervous System Diseases

@article {pmid41097146,
year = {2025},
author = {Cantarero, I and Del Río, C},
title = {Role of Bioactive Compounds in Neuroprotection and Neurodegenerative Disease.},
journal = {Nutrients},
volume = {17},
number = {19},
pages = {},
doi = {10.3390/nu17193069},
pmid = {41097146},
issn = {2072-6643},
mesh = {Humans ; *Neurodegenerative Diseases/prevention & control/drug therapy ; *Neuroprotective Agents/therapeutic use/pharmacology ; *Neuroprotection ; Animals ; },
abstract = {The prevalence of neurological disorders, including neurodegenerative conditions such as Alzheimer's and Parkinson's disease and acute conditions like stroke, is increasing due to population aging [...].},
}

Humans
*Neurodegenerative Diseases/prevention & control/drug therapy
*Neuroprotective Agents/therapeutic use/pharmacology
*Neuroprotection
Animals

@article {pmid41097145,
year = {2025},
author = {Tuigunov, D and Sinyavskiy, Y and Nurgozhin, T and Zholdassova, Z and Smagul, G and Omarov, Y and Dolmatova, O and Yeshmanova, A and Omarova, I},
title = {Precision Nutrition and Gut-Brain Axis Modulation in the Prevention of Neurodegenerative Diseases.},
journal = {Nutrients},
volume = {17},
number = {19},
pages = {},
doi = {10.3390/nu17193068},
pmid = {41097145},
issn = {2072-6643},
support = {Grant No. AP23489983//This research is funded by the Science Committee of the Ministry of Science and Higher Education of the Republic of Kazakhstan/ ; },
mesh = {Humans ; *Neurodegenerative Diseases/prevention & control/microbiology ; *Gastrointestinal Microbiome/physiology ; *Brain ; *Precision Medicine/methods ; *Brain-Gut Axis/physiology ; Prebiotics/administration & dosage ; Probiotics/administration & dosage ; },
abstract = {In the recent years, the accelerating global demographic shift toward population aging has been accompanied by a marked increase in the prevalence of neurodegenerative disorders, notably Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, and multiple sclerosis. Among emerging approaches, dietary interventions targeting the gut-brain axis have garnered considerable attention, owing to their potential to modulate key pathogenic pathways underlying neurodegenerative processes. This review synthesizes current concepts in precision nutrition and elucidates neurohumoral, immune, and metabolic regulatory mechanisms mediated by the gut microbiota, including the roles of the vagus nerve, cytokines, short-chain fatty acids, vitamins, polyphenols, and microbial metabolites. Emerging evidence underscores that dysbiotic alterations contribute to compromised barrier integrity, the initiation and perpetuation of neuroinflammatory responses, pathological protein aggregations, and the progressive course of neurodegenerative diseases. Collectively, these insights highlight the gut microbiota as a pivotal target for the development of precision-based dietary strategies in the prevention and mitigation of neurodegenerative disorders. Particular attention is devoted to key bioactive components such as prebiotics, probiotics, psychobiotics, dietary fiber, omega-3 fatty acids, and polyphenols that critically participate in regulating the gut-brain axis. Contemporary evidence on the contribution of the gut microbiota to the pathogenesis of Alzheimer's disease, Parkinson's disease, and multiple sclerosis is systematically summarized. The review further discusses the prospects of applying nutrigenomics, chrononutrition, and metagenomic analysis to the development of personalized dietary strategies. The presented findings underscore the potential of integrating precision nutrition with targeted modulation of the gut-brain axis as a multifaceted approach to reducing the risk of neurodegenerative diseases and preserving cognitive health.},
}

Humans
*Neurodegenerative Diseases/prevention & control/microbiology
*Gastrointestinal Microbiome/physiology
*Brain
*Precision Medicine/methods
*Brain-Gut Axis/physiology
Prebiotics/administration & dosage
Probiotics/administration & dosage

@article {pmid41097131,
year = {2025},
author = {Ochocińska, AM and Podstawka, I and Kępka, A and Waszkiewicz, N},
title = {Diet as a Modulator of Gut Microbiota May Reduce Alzheimer's Disease Risk.},
journal = {Nutrients},
volume = {17},
number = {19},
pages = {},
doi = {10.3390/nu17193053},
pmid = {41097131},
issn = {2072-6643},
mesh = {Humans ; *Gastrointestinal Microbiome/physiology ; *Alzheimer Disease/prevention & control/microbiology ; Diet, Mediterranean ; Diet, Ketogenic ; Diet, Western/adverse effects ; Dysbiosis ; *Diet ; Risk Factors ; },
abstract = {The aging process, along with an inadequate diet and an inflammatory gut response resulting from dysbiosis, contributes to the pathogenesis of Alzheimer's disease (AD). Modifying the composition of the gut microbiota through appropriate pre/probiotic-rich diets may act as a preventive option for AD. The variety of functions performed by the gut microbiota makes this ecosystem one of the most important systems in the human body. The Mediterranean diet (MedDiet), the Dietary Approaches to Stop Hypertension (DASH), the Mediterranean-DASH Intervention for Neurodegenerative Delay diet (MIND), and the modified ketogenic-Mediterranean diet (MKD) positively affect the intestinal microflora and may reduce the risk of dementia. A ketogenic diet has a neuroprotective effect and improves cognitive function but leads to a significant decrease in the abundance and diversity of bacterial species in favor of harmful bacteria. A Western-style diet (Western diet, WD) rich in processed products, red meat, simple sugars, and saturated fatty acids has a negative impact on gut microbiota function, increasing the risk of AD. Our review supports the hypothesis that factors like a proper diet and a healthy gut microbiota have a positive impact on the prevention of neurodegenerative diseases, including AD. A thorough understanding of the role the microbiota plays in the proper functioning of the nervous system can aid in the prevention of AD by developing new dietary strategies and dietary lifestyles.},
}

Humans
*Gastrointestinal Microbiome/physiology
*Alzheimer Disease/prevention & control/microbiology
Diet, Mediterranean
Diet, Ketogenic
Diet, Western/adverse effects
Dysbiosis
*Diet
Risk Factors

@article {pmid41097093,
year = {2025},
author = {Massaccesi, L and Corsi Romanelli, MM and Galliera, E},
title = {Brain-Bone Axis in Physiological and Pathological Conditions.},
journal = {International journal of molecular sciences},
volume = {26},
number = {19},
pages = {},
doi = {10.3390/ijms26199822},
pmid = {41097093},
issn = {1422-0067},
mesh = {Humans ; *Bone and Bones/metabolism/physiology ; *Brain/metabolism/physiology ; Animals ; Central Nervous System/metabolism ; },
abstract = {The brain-bone axis has garnered increasing attention over the years, leading to numerous studies that have unraveled the intricate bidirectional communication between the central nervous system (CNS) and skeletal metabolism. This review explores this profound relationship, examining the complex mechanisms that regulate it, the key players involved, and the clinical implications of its dysfunction in various pathological situations affecting the CNS and skeletal system. Ultimately, it emphasizes the potential of ongoing research to develop diagnostic tools, therapeutic interventions, and preventive strategies aimed at enhancing skeletal and neurological health.},
}

Humans
*Bone and Bones/metabolism/physiology
*Brain/metabolism/physiology
Animals
Central Nervous System/metabolism

@article {pmid41097081,
year = {2025},
author = {Astorino, MF and Cipriano, GL and Anchesi, I and Lui, M and Raffaele, I and Calabrò, M and Crisafulli, C},
title = {Gene-Exercise Interactions in Amyloid Metabolism and Clearance: Implications for Alzheimer's Disease.},
journal = {International journal of molecular sciences},
volume = {26},
number = {19},
pages = {},
doi = {10.3390/ijms26199816},
pmid = {41097081},
issn = {1422-0067},
support = {RRC-2025-23686388//Ministero della Salute/ ; },
mesh = {Humans ; *Alzheimer Disease/metabolism/genetics/therapy ; *Exercise/physiology ; *Amyloid beta-Peptides/metabolism ; Animals ; Amyloid beta-Protein Precursor/metabolism/genetics ; },
abstract = {Alzheimer's disease (AD), the most prevalent form of dementia, poses a critical global health challenge as its incidence rises with aging populations. Despite extensive research into its genetic and molecular underpinnings, effective therapeutic strategies remain limited. Growing evidence suggests that physical exercise may offer neuroprotective benefits, potentially mitigating AD progression through multifactorial mechanisms. This review synthesizes current findings on the interplay between aerobic exercise and AD pathophysiology, with a focus on amyloid-β (Aβ) metabolism, gene expression, and neuroinflammation. We explore how exercise influences Aβ clearance, modulates amyloid precursor protein (APP) processing, and impacts the activity of key enzymes such as secretases and neprilysin. Further, we highlight the gene-exercise crosstalk identified through transcriptomic data, particularly in the entorhinal cortex-an early site of Aβ deposition. Our analysis also discusses how exercise-induced modulation of molecular pathways-including mitochondrial function, oxidative stress responses, and neuroinflammatory cascades-may confer cognitive resilience. By integrating molecular, genetic, and systems biology data, this review underscores the potential of structured physical activity as a non-pharmacological intervention to delay or attenuate AD pathology. These insights support a precision medicine approach, which combines lifestyle interventions with molecular profiling, to improve prevention strategies and therapeutic outcomes in AD.},
}

Humans
*Alzheimer Disease/metabolism/genetics/therapy
*Exercise/physiology
*Amyloid beta-Peptides/metabolism
Animals
Amyloid beta-Protein Precursor/metabolism/genetics

@article {pmid41097080,
year = {2025},
author = {Salarpour, F and Sévigny, J},
title = {P2Y2 Receptor Signaling in Health and Disease.},
journal = {International journal of molecular sciences},
volume = {26},
number = {19},
pages = {},
doi = {10.3390/ijms26199815},
pmid = {41097080},
issn = {1422-0067},
support = {PJT - 156205 and PJT - 178412/CAPMC/CIHR/Canada ; 30641//Fonds de recherche du Québec (FRQ) through the research centre grant for the CHU de Québec-Université Laval Re-search Center/ ; },
mesh = {Humans ; *Receptors, Purinergic P2Y2/metabolism ; *Signal Transduction ; Animals ; Alzheimer Disease/metabolism ; Inflammation/metabolism ; },
abstract = {P2Y2 receptors are a subclass of G protein-coupled receptors activated by the extracellular nucleotides ATP and UTP. These receptors are widely expressed in multiple tissues-including the brain, lungs, heart, and kidneys-and play pivotal roles in inflammation, wound healing, and cell migration. Through coupling with various G proteins, P2Y2 receptors initiate diverse intracellular signaling pathways that mediate calcium mobilization, cytokine release, and cytoskeletal reorganization. Recent studies highlight their dual roles in health and disease. In physiological contexts, P2Y2 receptors contribute to immune modulation and tissue repair. In pathological conditions, they are implicated in Alzheimer's disease by promoting non-amyloidogenic processing of amyloid precursor protein and in dry eye disease by enhancing mucin secretion while modulating ocular inflammation. They also influence chloride secretion and mucosal hydration in cystic fibrosis and contribute to inflammatory regulation and epithelial repair in inflammatory bowel disease. Additionally, P2Y2 receptors modulate breast cancer progression by regulating cell adhesion, migration, and matrix remodeling. Their involvement in blood pressure regulation via epithelial sodium channel modulation and their facilitative role in HIV-1 entry further underscore their clinical significance. These multifaceted functions position P2Y2 receptors as promising therapeutic targets for diverse diseases, warranting further investigation for translational applications.},
}

Humans
*Receptors, Purinergic P2Y2/metabolism
*Signal Transduction
Animals
Alzheimer Disease/metabolism
Inflammation/metabolism

@article {pmid41097067,
year = {2025},
author = {Soladogun, AS and Zhang, L},
title = {Preexisting Genetic Background Primes the Responses of Human Neurons to Amyloid β.},
journal = {International journal of molecular sciences},
volume = {26},
number = {19},
pages = {},
doi = {10.3390/ijms26199804},
pmid = {41097067},
issn = {1422-0067},
support = {32551015//Cecil H. and Ida Green Distinguished Chair fund/ ; },
mesh = {Humans ; *Amyloid beta-Peptides/metabolism/pharmacology ; *Neurons/metabolism/drug effects ; Male ; Female ; Alzheimer Disease/genetics/metabolism/pathology ; Induced Pluripotent Stem Cells/metabolism/cytology ; Neural Stem Cells/metabolism/cytology/drug effects ; Cell Movement/genetics/drug effects ; Cell Differentiation ; },
abstract = {The deposition of amyloid beta (Aβ) in the human brain is a hallmark of Alzheimer's disease (AD). Aβ has been shown to exert a wide range of effects on neurons in cell and animal models. Here, we take advantage of differentiated neurons from iPSC-derived neural stem cells of human donors to examine its effects on human neurons. Specifically, we employed two types of neurons from genetically distinct donors: one male carrying APO E2/E2 (M E2/E2) and one female carrying APO E3/E3 (F E3/E3). Genome-wide RNA-sequencing analysis identified 64 and 44 genes that were induced by Aβ in M E2/E2 and F E3/E3 neurons, respectively. GO and pathway analyses showed that Aβ-induced genes in F E3/E3 neurons do not constitute any statistically significant pathways whereas Aβ-induced genes in M E2/E2 neurons constitute a complex network of activated pathways. These pathways include those promoting inflammatory responses, such as IL1β, IL4, and TNF, and those promoting cell migration and movement, such as chemotaxis, migration of cells, and cell movement. These results strongly suggest that the effects of Aβ on neurons are highly dependent on their genetic background and that Aβ can promote strong responses in inflammation and cell migration in some, but not all, neurons.},
}

Humans
*Amyloid beta-Peptides/metabolism/pharmacology
*Neurons/metabolism/drug effects
Male
Female
Alzheimer Disease/genetics/metabolism/pathology
Induced Pluripotent Stem Cells/metabolism/cytology
Neural Stem Cells/metabolism/cytology/drug effects
Cell Movement/genetics/drug effects
Cell Differentiation

@article {pmid41097058,
year = {2025},
author = {Shen, X and Li, H and Zhang, B and Li, Y and Zhu, Z},
title = {Targeting Transferrin Receptor 1 for Enhancing Drug Delivery Through the Blood-Brain Barrier for Alzheimer's Disease.},
journal = {International journal of molecular sciences},
volume = {26},
number = {19},
pages = {},
doi = {10.3390/ijms26199793},
pmid = {41097058},
issn = {1422-0067},
mesh = {*Receptors, Transferrin/metabolism ; *Blood-Brain Barrier/metabolism/drug effects ; *Alzheimer Disease/drug therapy/metabolism ; Humans ; Animals ; *Drug Delivery Systems/methods ; Transferrin/metabolism ; Endocytosis ; Antigens, CD ; },
abstract = {Drug delivery to the brain faces a critical obstacle in the form of the blood-brain barrier (BBB), which severely limits therapeutic options for Alzheimer's disease (AD). Transferrin receptor 1 (TfR1) is abundantly expressed in brain capillary endothelial cells, offering a potential pathway for circumventing this barrier. Physiologically, TfR1 binds to iron-laden transferrin, leading to cellular uptake through clathrin-mediated endocytosis. Within acidic endosomes, the iron is released, and the receptor-apotransferrin complex recycles to the cell surface for further rounds of transport. Furthermore, studies in AD mouse models have demonstrated that TfR1 expression in brain microvessels remains stable, highlighting its suitability as a delivery target even in disease conditions. Based on this, various drug delivery strategies targeting TfR1 have been developed, including bispecific antibodies, antibody fragments, ligand conjugates, and nanoparticle-based carriers. While these approaches hold great promise, they face practical limitations such as competition with endogenous transferrin, receptor saturation, and inefficient intracellular trafficking. This review details the current understanding of TfR1-mediated BBB transport mechanisms, evaluates emerging delivery platforms, and argues that TfR1 represents an accessible gateway for brain-targeted therapeutics in AD. The insights presented will be of interest to researchers in molecular biology, pharmacology, and drug development.},
}

*Receptors, Transferrin/metabolism
*Blood-Brain Barrier/metabolism/drug effects
*Alzheimer Disease/drug therapy/metabolism
Humans
Animals
*Drug Delivery Systems/methods
Transferrin/metabolism
Endocytosis
Antigens, CD

@article {pmid41097011,
year = {2025},
author = {Campagnoli, LIM and Varesi, A and Fahmideh, F and Hakimizad, R and Petkovic, P and Barbieri, A and Marchesi, N and Pascale, A},
title = {From Diabetes to Degenerative Diseases: The Multifaceted Action of Metformin.},
journal = {International journal of molecular sciences},
volume = {26},
number = {19},
pages = {},
doi = {10.3390/ijms26199748},
pmid = {41097011},
issn = {1422-0067},
mesh = {Humans ; *Metformin/therapeutic use/pharmacology ; *Hypoglycemic Agents/therapeutic use/pharmacology ; *Diabetes Mellitus, Type 2/drug therapy/metabolism ; Animals ; *Neurodegenerative Diseases/drug therapy/metabolism ; AMP-Activated Protein Kinases/metabolism ; Oxidative Stress/drug effects ; Signal Transduction/drug effects ; },
abstract = {Metformin, an oral antihyperglycemic drug, represents the cornerstone of pharmacological treatment for type 2 diabetes mellitus (T2DM). Its primary glucose-lowering effects are well established, predominantly mediated through the activation of AMP-activated protein kinase (AMPK). This activation leads to a reduction in hepatic glucose production (primarily by inhibiting gluconeogenesis and glycogenolysis) and an increase in peripheral glucose uptake and utilization. Beyond its direct impact on glucose metabolism, metformin also improves insulin sensitivity and has beneficial effects on lipid profiles. Increasingly, research shows that metformin has pleiotropic effects. In addition to its recognized antihyperglycemic action, metformin is emerging as a regulator of cellular processes implicated in aging. Indeed, emerging evidence suggests a potential role of metformin in modulating pathways associated with longevity and ameliorating the symptoms of age-related diseases, including neurodegenerative disorders (such as Alzheimer's and Parkinson's diseases), cardiovascular diseases, age-related macular degeneration, and osteoporosis. The proposed mechanisms for these broader effects involve AMPK activation, modulation of the mTOR pathway, reduction of oxidative stress, and promotion of autophagy. After exploring the established role of metformin in T2D, this review provides a comprehensive investigation of its promising applications in the context of age-related diseases, offering valuable insights into its multifaceted therapeutic potential beyond glycemic control.},
}

Humans
*Metformin/therapeutic use/pharmacology
*Hypoglycemic Agents/therapeutic use/pharmacology
*Diabetes Mellitus, Type 2/drug therapy/metabolism
Animals
*Neurodegenerative Diseases/drug therapy/metabolism
AMP-Activated Protein Kinases/metabolism
Oxidative Stress/drug effects
Signal Transduction/drug effects

@article {pmid41097004,
year = {2025},
author = {Daponte, A and Koros, C and Skarlis, C and Siozios, D and Rentzos, M and Papageorgiou, SG and Anagnostouli, M},
title = {Neurofilament Biomarkers in Neurology: From Neuroinflammation to Neurodegeneration, Bridging Established and Novel Analytical Advances with Clinical Practice.},
journal = {International journal of molecular sciences},
volume = {26},
number = {19},
pages = {},
doi = {10.3390/ijms26199739},
pmid = {41097004},
issn = {1422-0067},
mesh = {Humans ; *Biomarkers/metabolism/blood ; *Neurofilament Proteins/metabolism/blood ; *Neurodegenerative Diseases/metabolism/diagnosis ; *Neuroinflammatory Diseases/metabolism/diagnosis ; Animals ; },
abstract = {Neuroaxonal damage underlies permanent disability in various neurological conditions, both neuroautoimmune and neurodegenerative. It is crucial to accurately quantify and monitor axonal injury using biomarkers to evaluate disease progression and treatment effectiveness and offer prognostic insights. Neurofilaments (NFs), and especially neurofilament light chain (NfL), show promise for this purpose, as their levels increase with neuroaxonal damage in both cerebrospinal fluid and blood, independent of specific causal pathways. Recent advances in ultrasensitive immunoassays enable the reliable detection of NFs in blood, transforming them from research tools into clinically applicable measures. In multiple sclerosis (MS), serum NfL correlates with disease activity, treatment response, and long-term disability, and may complement MRI in monitoring subclinical progression. In MS, NfL is primarily emerging as a marker of disease activity and treatment response; in amyotrophic lateral sclerosis (ALS), it has progressed further, being integrated into clinical trials as a pharmacodynamic endpoint and considered by regulatory agencies as a drug development tool. Additionally, NFs are increasingly being investigated in Alzheimer's disease, frontotemporal dementia, and other neurodegenerative disorders, though their disease specificity is limited. Ongoing challenges include older and novel assay harmonization, normative range interpretation, biological and analytical variability, and integration with other molecular and imaging biomarkers. This critical narrative review synthesizes the existing literature on NFs as diagnostic, prognostic, predictive, and pharmacodynamic biomarkers and discusses their role in therapeutic development and precision medicine in neuroautoimmune and neurodegenerative diseases.},
}

Humans
*Biomarkers/metabolism/blood
*Neurofilament Proteins/metabolism/blood
*Neurodegenerative Diseases/metabolism/diagnosis
*Neuroinflammatory Diseases/metabolism/diagnosis
Animals

@article {pmid41096935,
year = {2025},
author = {Klein, J},
title = {The Central Cholinergic Synapse: A Primer.},
journal = {International journal of molecular sciences},
volume = {26},
number = {19},
pages = {},
doi = {10.3390/ijms26199670},
pmid = {41096935},
issn = {1422-0067},
mesh = {Humans ; *Synapses/metabolism ; Animals ; Choline O-Acetyltransferase/metabolism ; *Acetylcholine/metabolism ; *Cholinergic Neurons/metabolism ; Acetylcholinesterase/metabolism ; Choline/metabolism ; Vesicular Acetylcholine Transport Proteins/metabolism ; Membrane Transport Proteins ; },
abstract = {The central cholinergic system is an important player in the control of motor function, appetite, the reward system, attention, memory and learning. Its participation in neurological diseases (e.g., Alzheimer's and Parkinson's disease, epilepsy) and in psychiatric diseases (e.g., schizophrenia, depression) makes it a preferred study subject for drug development. The present review summarizes salient features of the central cholinergic synapses that will guide future studies. Cholinergic synapses are defined by the presence of choline acetyltransferase (ChAT), the vesicular ACh transporter (VAChT), the high-affinity choline transporter CHT-1 and the presence of PRiMA-coupled acetylcholinesterase (AChE). The firing frequency of cholinergic fibers is reflected in high-affinity choline uptake activity, which also responds to variations in ChAT, VAChT and AChE activities conferring considerable plasticity to cholinergic responses. The availability of glucose and choline can limit ACh synthesis and release under conditions of high ACh turnover. Future studies will focus on rapid methods to measure ACh release and a deeper understanding of cholinergic plasticity during development, aging and dementia.},
}

Humans
*Synapses/metabolism
Animals
Choline O-Acetyltransferase/metabolism
*Acetylcholine/metabolism
*Cholinergic Neurons/metabolism
Acetylcholinesterase/metabolism
Choline/metabolism
Vesicular Acetylcholine Transport Proteins/metabolism
Membrane Transport Proteins

@article {pmid41096864,
year = {2025},
author = {Obregón-Mendoza, MA and Sánchez-Obregón, R and Tavera-Hernández, R and Pérez-González, LL and Nieto-Camacho, A and Rodríguez-Sotres, R and Escobedo-Martínez, C and Romero, I and Enríquez, RG},
title = {One Pot Synthesis of the C-3 Complex (Curcumin, Demethoxycurcumin, and Bis-Demethoxycurcumin): Their Joint and Independent Biological Actions.},
journal = {International journal of molecular sciences},
volume = {26},
number = {19},
pages = {},
doi = {10.3390/ijms26199599},
pmid = {41096864},
issn = {1422-0067},
support = {307152//CONAHCYT FOINS-PRONACES-/ ; IT200720 and IT202125//DGAPA-UNAM PAPIIT/ ; },
mesh = {*Curcumin/analogs & derivatives/chemical synthesis/chemistry/pharmacology ; *Diarylheptanoids/chemical synthesis/chemistry/pharmacology ; Curcuma/chemistry ; Antioxidants/chemical synthesis/chemistry/pharmacology ; Plant Extracts/chemistry ; },
abstract = {Curcumin (CUR) is the primary metabolite isolated from the Curcuma longa L. rhizome. Most synthetic and biological studies have focused mainly on the curcumin molecule due to its essential biological activity as an antioxidant, anti-cancer, and anti-Alzheimer's disease agent. However, the natural extract of turmeric also contains two essential curcuminoids (demethoxycurcumin (DMC) and bisdemethoxycurcumin (BDMC)), which altogether comprise the so-called C-3 complex. They are present in commercial compositions for treating biliary or digestive ailments. The vegetal rhizome's extraction typically leads to a mixture of the three main curcuminoids, CUR, DMC, and BDMC, in variable proportions, and each of these metabolites has reported specific synthetic routes. Herein, we have performed the synthesis and isolation of the three major curcuminoids using the method called scrambling of aldehydes followed by aldol di-condensation reactions. A density functional theory (DFT) approach supported the experimental results by inspecting the predicted energies for the aldol condensation. Thus, the di-condensation reaction is substantially favoured (ΔG° = -2685.9 kJ/mol) over the mono-condensation reaction (ΔG° = -1393.753 kJ/mol). Our approach allows us to mimic closely the proportions of these curcuminoids found in extracts from natural sources that follow the order CUR > DMC > BDMC, respectively. The proportion of aldehydes can be modified in the scrambling reaction with an adequate mixture of aldehydes to render the order DMC > CUR > BDMC. This is an advantageous way to increase the amount of the unsymmetric DMC metabolite.},
}

*Curcumin/analogs & derivatives/chemical synthesis/chemistry/pharmacology
*Diarylheptanoids/chemical synthesis/chemistry/pharmacology
Curcuma/chemistry
Antioxidants/chemical synthesis/chemistry/pharmacology
Plant Extracts/chemistry

@article {pmid41096835,
year = {2025},
author = {Nairuz, T and Heo, JC and Park, HJ and Lee, JH},
title = {Photobiomodulation at 660 nm Alleviates Alzheimer's Disease Pathology Through Amyloid-β Reduction and SIRT1 Upregulation in the Hippocampus of 5xFAD Mice.},
journal = {International journal of molecular sciences},
volume = {26},
number = {19},
pages = {},
doi = {10.3390/ijms26199569},
pmid = {41096835},
issn = {1422-0067},
support = {DBSD1-06,NRF-2022R1I1A307278, RS-2023-00237791,HI21C0977, RS-2021-KH118978, RS-2024-00433896,RS-2022-00166898,2020R1A6C101B189//Korea government (MSIT and Daegu Metropolitan City), the Basic Research Program through the National Research Foundation of Korea,Korea Health Technology R&D Project through the Korea Health Industry Development Institute (KHIDI), the Korea government (th/ ; },
mesh = {Animals ; *Alzheimer Disease/metabolism/pathology/radiotherapy/genetics/therapy ; *Sirtuin 1/metabolism/genetics ; *Hippocampus/metabolism/radiation effects/pathology ; *Low-Level Light Therapy/methods ; Mice, Transgenic ; *Amyloid beta-Peptides/metabolism ; Mice ; Disease Models, Animal ; Up-Regulation/radiation effects ; Male ; Humans ; },
abstract = {Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by amyloid-β (Aβ) accumulation, synaptic dysfunction, and cognitive decline. Current pharmacological treatments provide only symptomatic relief without altering disease progression. Photobiomodulation therapy (PBMT), a light-based intervention, has shown neuroprotective potential, although its exact neurobiological mechanisms in AD pathogenesis remain obscure. In this study, we investigated the effects of PBMT using a 660 nm wavelength light-emitting diode (LED) in 5xFAD transgenic mouse, a well-established model of early-onset AD. Mice were subjected to once daily PBMT sessions over a defined treatment period and outcomes were assessed through immunohistochemical analysis of hippocampal regions (CA1, CA2, CA3, and dentate gyrus) alongside behavioral testing using the Y-maze spontaneous alternation task. PBMT significantly reduced Aβ plaque load across hippocampal regions, accompanied by improved preservation of neuronal morphology. Furthermore, PBMT significantly upregulated SIRT1 expression, a critical regulator of synaptic plasticity and memory processes. Behaviorally, PBMT-treated mice displayed enhanced spatial working memory compared with controls, indicating a functional benefit linked to the observed molecular and structural changes. These findings suggest that 660 nm PBMT attenuates hallmark AD pathology, promotes neuroprotective pathways, and improves cognition, highlighting its potential as a disease-modifying therapy that warrants further preclinical and clinical investigation.},
}

Animals
*Alzheimer Disease/metabolism/pathology/radiotherapy/genetics/therapy
*Sirtuin 1/metabolism/genetics
*Hippocampus/metabolism/radiation effects/pathology
*Low-Level Light Therapy/methods
Mice, Transgenic
*Amyloid beta-Peptides/metabolism
Mice
Disease Models, Animal
Up-Regulation/radiation effects
Male
Humans

@article {pmid41096823,
year = {2025},
author = {Drescher, MJ and Drescher, DG and Khan, KM and Hatfield, JS and Hemani, D},
title = {Dysferlin Protein-Protein Interaction Pathways in the Organ of Corti and Spiral Ganglion Intersect with Alzheimer's Protein Pathways.},
journal = {International journal of molecular sciences},
volume = {26},
number = {19},
pages = {},
doi = {10.3390/ijms26199559},
pmid = {41096823},
issn = {1422-0067},
support = {DC004076, DC000156//Jain Foundation and NIH Grants/ ; },
mesh = {Humans ; *Dysferlin/metabolism ; Animals ; *Spiral Ganglion/metabolism ; *Alzheimer Disease/metabolism ; *Organ of Corti/metabolism ; *Protein Interaction Maps ; Calcium/metabolism ; Signal Transduction ; },
abstract = {Dysferlin direct protein-protein interactions (PPI) previously have been elucidated with surface plasmon resonance (SPR) and predicted to underlie membrane repair in mechanotransducing myofibrils. In mechanotransducing inner ear hair cells, dysferlin is detected with Z-stack confocal immunofluorescence in the stereocilia and their inserts in the tectorial membrane (TM) co-localizing with FKBP8, consistent with the SPR determination of tight, positively Ca[2+]-dependent interaction. FKBP8, a direct binding partner of mechanotransducing TMC1, when overexpressed, evokes an elevation in anti-apoptotic BCL2, inhibition of ryanodine receptor (RYR) activity, and a consequent reduction in Ca[2+] release. RYR3 has now been immunolocalized to the tip of the TM in close association with a third-row outer hair cell (OHC) stereociliary BCL2-positive insertion. Dysferlin, annexin A2, and Alzheimer's proteins BACE1 and amyloid precursor protein (APP) are also accumulated in these stereociliary insertions. RYR2 and RYR1 have been immunolocalized to the TM core, in position to influence TM Ca[2+]. Dysferlin PPI pathways also intersect with AD protein pathways in the spiral ganglion (SG). Dysferlin segregates with FKBP8, BACE1, and RYR3 in the interiors of SG type I cell bodies. RYR1, RYR2, PSEN1, BCL2, and caspase 3 are primarily confined to plasma membrane sites. RYR3 pathways traverse the plasma membrane to the cell body interior. Western analysis of dysferlinopathy proteins links FKBP8 and BCL2 overexpression with RYR inhibition, indicative of dysferlin targets that are ameliorative in AD.},
}

Humans
*Dysferlin/metabolism
Animals
*Spiral Ganglion/metabolism
*Alzheimer Disease/metabolism
*Organ of Corti/metabolism
*Protein Interaction Maps
Calcium/metabolism
Signal Transduction

@article {pmid41096819,
year = {2025},
author = {Leanza, MH and Storelli, E and D'Arco, D and de Leo, G and Kleiner, G and Arancio, L and Capodieci, G and Gulino, R and Bava, A and Leanza, G},
title = {Cerebellar Contributions to Spatial Learning and Memory: Effects of Discrete Immunotoxic Lesions.},
journal = {International journal of molecular sciences},
volume = {26},
number = {19},
pages = {},
doi = {10.3390/ijms26199553},
pmid = {41096819},
issn = {1422-0067},
mesh = {Animals ; Rats ; *Spatial Learning/physiology/drug effects ; *Cerebellum/drug effects/physiology/pathology ; Saporins ; Purkinje Cells/drug effects/metabolism ; Male ; Immunotoxins/toxicity ; *Memory/drug effects/physiology ; Maze Learning/drug effects ; Antibodies, Monoclonal/toxicity ; Cholinergic Neurons/drug effects ; },
abstract = {Evidence of possible cerebellar involvement in spatial processing, place learning and other types of higher order functions comes mainly from clinical observations, as well as from mutant mice and lesion studies. The latter, in particular, have reported deficits in spatial learning and memory following surgical or neurotoxic cerebellar ablation. However, the low specificity of such manipulations has often made it difficult to precisely dissect the cognitive components of the observed behaviors. Likewise, due to conflicting data coming from lesion studies, it has not been possible so far to conclusively address whether a cerebellar dysfunction is sufficient per se to induce learning deficits, or whether concurrent damage to other regulatory structure(s) is necessary to significantly interfere with cognitive processing. In the present study, the immunotoxin 192 IgG-saporin, selectively targeting cholinergic neurons in the basal forebrain and a subpopulation of cerebellar Purkinje cells, was administered to adult rats bilaterally into the basal forebrain nuclei, the cerebellar cortices or both areas combined. Additional animals underwent injections of the toxin into the lateral ventricles. Starting from two-three weeks post-lesion, the animals were tested on paradigms of motor ability as well as spatial learning and memory and then sacrificed for post-mortem morphological analyses. All lesioned rats showed no signs of ataxia and no motor deficits that could impair their performance in the water maze task. The rats with discrete cerebellar lesions exhibited fairly normal performance and did not differ from controls in any aspect of the task. By contrast, animals with double lesions, as well as those with 192 IgG-saporin given intraventricularly did manifest severe impairments in both reference and working memory. Histo- and immunohistochemical analyses confirmed the effects of the toxin conjugate on target neurons and fairly similar patterns of Purkinje cell loss in the animals with cerebellar lesion only, basal forebrain-cerebellar double lesions and bilateral intraventricular injections of the toxin. No such loss was by contrast seen in the basal forebrain-lesioned animals, whose Purkinje cells were largely spared and exhibited a normal distribution pattern. The results suggest important functional interactions between the ascending regulatory inputs from the cerebellum and those arising in the basal forebrain nuclei that would act together to modulate the complex sensory-motor and cognitive processes required to control whole body movement in space.},
}

Animals
Rats
*Spatial Learning/physiology/drug effects
*Cerebellum/drug effects/physiology/pathology
Saporins
Purkinje Cells/drug effects/metabolism
Male
Immunotoxins/toxicity
*Memory/drug effects/physiology
Maze Learning/drug effects
Antibodies, Monoclonal/toxicity
Cholinergic Neurons/drug effects

@article {pmid41096797,
year = {2025},
author = {Papaliagkas, V},
title = {Anti-Amyloid Therapies for Alzheimer's Disease: Progress, Pitfalls, and the Path Ahead.},
journal = {International journal of molecular sciences},
volume = {26},
number = {19},
pages = {},
doi = {10.3390/ijms26199529},
pmid = {41096797},
issn = {1422-0067},
mesh = {Humans ; *Alzheimer Disease/drug therapy/metabolism ; Biomarkers/metabolism ; *Amyloid beta-Peptides/metabolism/antagonists & inhibitors ; *Antibodies, Monoclonal/therapeutic use ; Animals ; },
abstract = {Anti-amyloid monoclonal antibodies have finally achieved their translational breakthrough after many years of unmet expectations. The FDA granted traditional approval to lecanemab in July 2023, and the European Medicines Agency approved it in late 2024 with specific genetic restrictions; meanwhile, donanemab received FDA approval in July 2024 and EMA marketing authorization just one month ago. These agents consistently clear cerebral amyloid and slow clinical decline modestly in early-stage, biomarker-confirmed Alzheimer's disease (AD). On the other hand, they also create significant safety risks, including amyloid-related imaging abnormalities (ARIA) and substantial operational requirements for health systems that are already under pressure. Therefore, precise risk management based on APOE genotyping and the presence of cerebral amyloid angiopathy and cerebral microbleeds should be performed before therapy is initiated. The near-term agenda should prioritize the following areas of study: (1) biomarker-driven front-end triage (including emerging plasma assays); (2) ARIA-aware care pathways and shared decision making; (3) outcome-based coverage and rational pricing; (4) clinical trials that layer anti-amyloid therapy into combinatorial strategies targeting tau protein, neuroinflammation, and synaptic resilience.},
}

Humans
*Alzheimer Disease/drug therapy/metabolism
Biomarkers/metabolism
*Amyloid beta-Peptides/metabolism/antagonists & inhibitors
*Antibodies, Monoclonal/therapeutic use
Animals

@article {pmid41096792,
year = {2025},
author = {Athanasaki, A and Tsantzali, I and Theodorou, A and Michalopoulou, A and Constantinides, VC and Boufidou, F and Tzartos, JS and Tsalouchidou, PE and Zompola, C and Paraskevas, SG and Bonakis, A and Giannopoulos, S and Tsivgoulis, G and Kapaki, E and Paraskevas, GP},
title = {The Biomarker Profile of Alzheimer's Disease for Disease-Modifying Treatment Eligibility: Questions and Debates.},
journal = {International journal of molecular sciences},
volume = {26},
number = {19},
pages = {},
doi = {10.3390/ijms26199531},
pmid = {41096792},
issn = {1422-0067},
mesh = {*Alzheimer Disease/metabolism/diagnosis/drug therapy/therapy/blood ; Humans ; *Biomarkers/blood/metabolism ; tau Proteins/metabolism/blood ; Amyloid beta-Peptides/metabolism ; },
abstract = {Alzheimer's disease (AD) is the most common cause of cognitive decline; currently, anti-amyloid monoclonal antibodies are available for clinical use as disease-modifying treatments, while many other substances are being tested in clinical trials. Molecular biomarkers for AD have been studied for more than two decades, and various guidelines and diagnostic recommendations have been published. However, there are still questions and controversies about the biomarker profile needed to confirm AD and the eligibility for such established treatments and clinical trials. Is amyloid positivity sufficient for eligibility, or is a biomarker for tau biochemistry/pathology also needed? What is the role of hybrid ratios combining amyloid and tau? Should we rely on plasma biomarkers alone? This review aimed to describe and discuss such questions and controversies.},
}

*Alzheimer Disease/metabolism/diagnosis/drug therapy/therapy/blood
Humans
*Biomarkers/blood/metabolism
tau Proteins/metabolism/blood
Amyloid beta-Peptides/metabolism

@article {pmid41096772,
year = {2025},
author = {Jackson, DC and Hall, MK and Sudweeks, SN},
title = {The Human Alpha3 Beta2 Neuronal Nicotinic Acetylcholine Receptor Can Form Two Distinguishable Subtypes.},
journal = {International journal of molecular sciences},
volume = {26},
number = {19},
pages = {},
doi = {10.3390/ijms26199506},
pmid = {41096772},
issn = {1422-0067},
support = {internal funding//Brigham Young University/ ; },
mesh = {Humans ; *Receptors, Nicotinic/metabolism/genetics ; Animals ; Xenopus laevis ; Acetylcholine/metabolism/pharmacology ; Oocytes/metabolism ; Hippocampus/metabolism ; Rats ; RNA, Messenger/genetics/metabolism ; },
abstract = {Diverse neuronal nicotinic acetylcholine receptor (nAChR) subtypes are expressed in hippocampal interneurons. Single-cell analysis of mRNA expression previously revealed prominent co-expression of the α3 and β2 subunits within rat interneurons in the CA1 region. Although the α3 subunit (traditionally expressed together with β4) is usually associated with the peripheral nervous system, its significant co-expression with the β2 subunit in hippocampal interneurons suggests a distinct, potentially novel central nervous system nAChR subtype. We demonstrate that the human α3 and β2 subunits injected into Xenopus laevis oocytes can assemble into at least two functionally distinct subtypes of nAChRs based on different subunit stoichiometries. These subtypes exhibit similar reversal potentials but differ significantly in their desensitization kinetics and acetylcholine (ACh) affinities. The response obtained from a 1:5 α3:β2 mRNA injection ratio shows a higher affinity for ACh and significantly greater desensitization during prolonged ACh application compared to the response obtained from a 5:1 α3:β2 mRNA injection ratio. The identification of distinct functional α3β2 subtypes, characterized by differential desensitization kinetics and ACh affinity, could represent novel targets for the potential development of highly selective cognitive therapeutics for conditions such as Alzheimer's disease, autism spectrum disorder, and attention deficit hyperactivity disorder, where hippocampal nAChRs are implicated.},
}

Humans
*Receptors, Nicotinic/metabolism/genetics
Animals
Xenopus laevis
Acetylcholine/metabolism/pharmacology
Oocytes/metabolism
Hippocampus/metabolism
Rats
RNA, Messenger/genetics/metabolism

@article {pmid41096746,
year = {2025},
author = {Ferrari, I and Limiti, E and Giannitelli, SM and Trombetta, M and Rainer, A and D'Amelio, M and La Barbera, L and Gori, M},
title = {Microfluidic-Based Technologies for Crossing the Blood-Brain Barrier Against Alzheimer's Disease: Novel Strategies and Challenges.},
journal = {International journal of molecular sciences},
volume = {26},
number = {19},
pages = {},
doi = {10.3390/ijms26199478},
pmid = {41096746},
issn = {1422-0067},
support = {Project "NanoProAD" in the framework of "Strategic University Projects"//Campus Bio-Medico University of Rome (UCBM)/ ; },
mesh = {*Blood-Brain Barrier/metabolism/drug effects ; *Alzheimer Disease/drug therapy/metabolism/pathology ; Humans ; Animals ; *Microfluidics/methods ; Drug Delivery Systems/methods ; Lab-On-A-Chip Devices ; },
abstract = {Alzheimer's disease (AD) represents the major cause of dementia worldwide, involving different etiopathogenetic mechanisms, but with no definitive cure. The efficacy of new AD drugs is limited by the multifactorial disease nature that involves several targets, but also by the difficult penetration across the blood-brain barrier (BBB) for reaching the target area at therapeutic doses. Thus, the inability of many compounds to efficiently bypass the BBB makes it arduous to treat the disease. Furthermore, the lack of more representative BBB in vitro models than conventional 2D cultures, and xenogeneic animal models that recapitulate AD pathogenesis, makes it even more difficult to develop definitive cures. In this context, microfluidics has emerged as a promising tool, offering advanced strategies for simulating the BBB, investigating its crossing mechanisms, and developing nanocarriers that successfully pass the BBB for brain-targeting, with particular interest in pathological states. The advantages of microfluidic platforms for studying the BBB role in pathophysiological conditions might herald more tailored and effective approaches based on functionalized nanosystems for treating AD. Here, we provide an overview of the latest advances in microfluidic-based technologies both for the synthesis of nanodrug delivery systems, and for developing advanced models of the BBB-on-a-chip to simulate this biological barrier, facing open challenges in AD, and improving our understanding of the disease.},
}

*Blood-Brain Barrier/metabolism/drug effects
*Alzheimer Disease/drug therapy/metabolism/pathology
Humans
Animals
*Microfluidics/methods
Drug Delivery Systems/methods
Lab-On-A-Chip Devices

@article {pmid41096715,
year = {2025},
author = {Mima, Y and Yamamoto, M and Iozumi, K},
title = {Review of Promising Off-Label Use of Deucravacitinib.},
journal = {International journal of molecular sciences},
volume = {26},
number = {19},
pages = {},
doi = {10.3390/ijms26199447},
pmid = {41096715},
issn = {1422-0067},
mesh = {Humans ; *Off-Label Use ; *Protein Kinase Inhibitors/therapeutic use/pharmacology ; Animals ; *TYK2 Kinase/antagonists & inhibitors/metabolism ; Signal Transduction/drug effects ; Clinical Trials as Topic ; Psoriasis/drug therapy ; Bridged-Ring Compounds ; Pyrimidines ; },
abstract = {Tyrosine kinase 2 (TYK2) mediates the signaling pathways of proinflammatory cytokines such as interleukin (IL)-12, IL-23, and type I interferons (IFNs) and plays a pivotal role in the pathogenesis of psoriasis and various other immune-mediated diseases. Deucravacitinib, a selective oral TYK2 inhibitor, has been approved for the treatment of psoriasis and demonstrated high efficacy and a favorable safety profile. This review summarizes the potential for expanding deucravacitinib indications based on case reports, clinical trials, and preclinical studies. Diseases in which TYK2 pathway has been demonstrated to be involved and for which clinical benefit of deucravacitinib has been reported include discoid lupus erythematosus, systemic lupus erythematosus, alopecia areata, lichen planus, palmoplantar pustulosis, psoriatic arthritis, systemic sclerosis, interstitial pneumonia, inflammatory bowel disease, and chronic recurrent multifocal osteomyelitis. Furthermore, emerging research suggests potential therapeutic applications in neurodegenerative diseases such as Alzheimer's disease, and malignancies such as type 1 diabetes, vascular calcification in chronic kidney disease, T-cell acute lymphoblastic leukemia, and multiple sclerosis. Deucravacitinib may exert therapeutic effects by broadly suppressing cytokine signaling in a diverse range of inflammatory disorders. Ongoing clinical trials and mechanistic studies are required to clarify the efficacy and support its future indications.},
}

Humans
*Off-Label Use
*Protein Kinase Inhibitors/therapeutic use/pharmacology
Animals
*TYK2 Kinase/antagonists & inhibitors/metabolism
Signal Transduction/drug effects
Clinical Trials as Topic
Psoriasis/drug therapy
Bridged-Ring Compounds
Pyrimidines

@article {pmid41096712,
year = {2025},
author = {Ivanova, AV and Kutuzova, AD and Kuzmichev, IA and Abakumov, MA},
title = {Alzheimer's Disease: From Molecular Mechanisms to Promising Therapeutic Strategies.},
journal = {International journal of molecular sciences},
volume = {26},
number = {19},
pages = {},
doi = {10.3390/ijms26199444},
pmid = {41096712},
issn = {1422-0067},
support = {registration number EGISU NIOKTR 1024110600012-8-3.2.25;3.2.26;3.2.12..//The work was carried out within the framework of the State assignment "Creation of a radio-pharmaceutical drug for the diagnosis of Alzheimer's disease using the tetrapeptide HAEE as a vector molecule",/ ; },
mesh = {*Alzheimer Disease/metabolism/therapy/pathology/etiology/drug therapy/diagnostic imaging ; Humans ; Animals ; Amyloid beta-Peptides/metabolism ; tau Proteins/metabolism ; Oxidative Stress ; Brain/metabolism/pathology ; },
abstract = {Alzheimer's disease (AD) is the most common cause of dementia worldwide, and there are still no strategies to slow or prevent its clinical progression. Significant financial and research resources have been invested into studying the pathology of AD. However, its pathogenesis is not fully understood. This review provides a comprehensive analysis of current understanding of AD pathogenesis, including classical hypotheses (amyloid cascade, tau pathology, neuroinflammation, oxidative stress), emerging mechanisms (cellular senescence, endoplasmic reticulum stress, ubiquitin-proteasome system dysfunction), and alternative mechanisms (cholinergic dysfunction, glutamate excitotoxicity, disruption of the microbiota-gut-brain axis, and autophagy). Schematic illustrations summarize the relationships between the hypotheses and their role in the pathogenesis of AD. Particular attention is paid to the systematization of promising biological targets and the analysis of modern ligands of various nature, including small molecules, peptides, antibodies and their fragments, natural compounds, as well as innovative hybrid and multifunctional structures. A separate section is devoted to radiopharmaceuticals for PET imaging (Florbetaben, Flortaucipir, etc.) and promising therapeutic agents. Thus, in this review we (1) systematize modern concepts of AD pathogenesis, including classical, emerging mechanisms and alternative hypotheses; (2) conduct a comparative analysis of ligand classes (small molecules, peptides, antibodies, etc.) and their therapeutic potential; and (3) discuss the clinical prospects of radiopharmaceuticals for PET imaging and targeted therapy. The work provides a comprehensive analysis of modern approaches, which can help in the development of more effective drugs against AD.},
}

*Alzheimer Disease/metabolism/therapy/pathology/etiology/drug therapy/diagnostic imaging
Humans
Animals
Amyloid beta-Peptides/metabolism
tau Proteins/metabolism
Oxidative Stress
Brain/metabolism/pathology

@article {pmid41096702,
year = {2025},
author = {Alarcón-Elizalde, S and Lora-Castellanos, A and Santillán-Morales, V and Reséndiz-Gachús, MA and Estrada-Reyes, R and Oikawa-Sala, J and Muñoz-Estrada, J and Mayagoitia-Novales, L and Constantino-Jonapa, LA and Martín-Higueras, C and Acebes, Á and Benítez-King, G},
title = {Impaired Formation of Primary Cilia in Olfactory Neuronal Precursors Is Associated with Decreased Proliferation and Maturation in Individuals with Hyposmia.},
journal = {International journal of molecular sciences},
volume = {26},
number = {19},
pages = {},
doi = {10.3390/ijms26199435},
pmid = {41096702},
issn = {1422-0067},
support = {FOSISS-290526 and CBF-2023-2024-457 to GBK. AEI/10.13039/501100011033 to A.A.//CONACYT and SECIHTI grant to GBK, Mexico. Spanish AEI Grant to A.A./ ; },
mesh = {Humans ; *Cilia/metabolism/pathology ; Cell Proliferation ; *Olfactory Receptor Neurons/metabolism/pathology ; Male ; Female ; Adult ; *Olfactory Mucosa/metabolism/pathology ; Middle Aged ; Cell Differentiation ; *Anosmia/pathology/metabolism ; Aged ; Young Adult ; *Neural Stem Cells/metabolism/pathology ; },
abstract = {Smell dysfunction affects quality of life and is considered an early clinical sign of Alzheimer's and Parkinson's diseases. Olfactory loss increases with age and is associated with certain ciliopathies, a group of genetic disorders characterized by a wide spectrum of multisystemic disturbances. The dysfunction of mature olfactory sensory neurons (OSNs) in the olfactory neuronal pathway remains poorly understood. Previous evidence suggests that primary cilia proteins are involved in the maturation of olfactory sensory neurons (OSNs). In this study, we obtained olfactory neuronal precursors (ONPs) from the olfactory mucosa of young and older healthy volunteers who reported smell impairment (hyposmia) without neurological deficits or underlying airflow issues (conductive olfactory loss) and from normosmic individuals. In vitro analysis of ONPs showed that these cells can form primary cilia in normosmic individuals, while in hyposmic participants, there is a reduction in cilia frequency and a shorter length. In addition, ONPs from hyposmic individuals had a decrease in proliferation and cell differentiation. Our data indicate that alterations in molecular pathways related to primary cilia formation and the proliferation of ONPs lead to defects in neuronal maturation. These changes may hinder the differentiation of olfactory sensory neurons OSNs and contribute, at least in part, to olfactory loss.},
}

Humans
*Cilia/metabolism/pathology
Cell Proliferation
*Olfactory Receptor Neurons/metabolism/pathology
Male
Female
Adult
*Olfactory Mucosa/metabolism/pathology
Middle Aged
Cell Differentiation
*Anosmia/pathology/metabolism
Aged
Young Adult
*Neural Stem Cells/metabolism/pathology

@article {pmid41096677,
year = {2025},
author = {Șerban, M and Toader, C and Covache-Busuioc, RA},
title = {CRISPR and Artificial Intelligence in Neuroregeneration: Closed-Loop Strategies for Precision Medicine, Spinal Cord Repair, and Adaptive Neuro-Oncology.},
journal = {International journal of molecular sciences},
volume = {26},
number = {19},
pages = {},
doi = {10.3390/ijms26199409},
pmid = {41096677},
issn = {1422-0067},
mesh = {Humans ; *Artificial Intelligence ; *Precision Medicine/methods ; Gene Editing/methods ; *CRISPR-Cas Systems ; Animals ; *Spinal Cord Regeneration ; *Clustered Regularly Interspaced Short Palindromic Repeats ; *Nerve Regeneration/genetics ; },
abstract = {Repairing the central nervous system (CNS) remains one of the most difficult obstacles to overcome in translational neurosciences. This is due to intrinsic growth inhibitors, extracellular matrix issues, the glial scar-form barrier, chronic neuroinflammation, and epigenetic silencing. The purpose of this review is to bring together findings from recent developments in genome editing and computational approaches, which center around the possible convergence of clustered regularly interspaced short palindromic repeats (CRISPR) platforms and artificial intelligence (AI), towards precision neuroregeneration. We wished to outline possible ways in which CRISPR-based systems, including but not limited to Cas9 and Cas12 nucleases, RNA-targeting Cas13, base and prime editors, and transcriptional regulators such as CRISPRa/i, can be applied to potentially reactivate axon-growth programs, alter inhibitory extracellular signaling, reprogram or lineage transform glia to functional neurons, and block oncogenic pathways in glioblastoma. In addition, we wanted to highlight how AI approaches, such as single-cell multi-omics, radiogenomic prediction, development of digital twins, and design of adaptive clinical trials, will increasingly be positioned to act as system-level architects that allow translation of complex datasets into predictive and actionable therapeutic approaches. We examine convergence consumers in spinal cord injury and adaptive neuro-oncology and discuss expanse consumers in ischemic stroke, Alzheimer's disease, Parkinson's disease, and rare neurogenetic syndromes. Finally, we discuss the ethical and regulatory landscape around beyond off-target editing and genomic stability of CRISPR, algorithmic bias, explainability, and equitable access to advanced neurotherapies. Our intent was not to provide a comprehensive inventory of possibilities but rather to provide a conceptual tool where CRISPR acts as a molecular manipulator and AI as a computational integrator, converging to create pathways towards precision neuroregeneration, personalized medicine, and adaptive neurotherapeutics that are ethically sound.},
}

Humans
*Artificial Intelligence
*Precision Medicine/methods
Gene Editing/methods
*CRISPR-Cas Systems
Animals
*Spinal Cord Regeneration
*Clustered Regularly Interspaced Short Palindromic Repeats
*Nerve Regeneration/genetics

@article {pmid41096667,
year = {2025},
author = {Skarlis, C and Angelopoulou, E and Rentzos, M and Papageorgiou, SG and Anagnostouli, M},
title = {Monoclonal Antibodies as Therapeutic Agents in Autoimmune and Neurodegenerative Diseases of the Central Nervous System: Current Evidence on Molecular Mechanisms and Future Directions.},
journal = {International journal of molecular sciences},
volume = {26},
number = {19},
pages = {},
doi = {10.3390/ijms26199398},
pmid = {41096667},
issn = {1422-0067},
mesh = {Humans ; *Antibodies, Monoclonal/therapeutic use/pharmacology ; *Neurodegenerative Diseases/drug therapy/immunology ; Animals ; *Central Nervous System Diseases/drug therapy/immunology ; Neuromyelitis Optica/drug therapy ; Central Nervous System/drug effects/immunology ; Multiple Sclerosis/drug therapy ; },
abstract = {Monoclonal antibodies (mAbs) have revolutionized the treatment landscape for neurological diseases, providing targeted, mechanism-based therapies for conditions ranging from autoimmune demyelinating disorders to neurodegenerative diseases. In multiple sclerosis (MS), mAbs against CD20, CD52, and α4-integrins offer disease-modifying efficacy by altering immune responses, depleting B cells, or blocking leukocyte migration into the central nervous system (CNS). Similarly, novel agents under investigation, such as frexalimab and foralumab, modulate T and B cell interactions and regulatory immunity. In neuromyelitis optica spectrum disorder (NMOSD), mAbs targeting IL-6, the complement cascade, and B cell lineage have demonstrated significant clinical benefit in preventing relapses and disability. In Alzheimer's disease (AD), several anti-amyloid mAbs have gained regulatory approval. Anti-tau and anti-α-synuclein antibodies, though promising, have shown limited efficacy to date in AD and parkinson's disease (PD), respectively. The evolving armamentarium of mAbs reflects a paradigm shift toward personalized neuroimmunology and neurodegeneration-targeted treatments, based on ongoing clarification of molecular and neuroinflammatory mechanisms. In this context, the present review summarizes current evidence on mAbs used in CNS disorders, with an emphasis on their pathophysiological targets, molecular mechanisms, clinical efficacy, and safety.},
}

Humans
*Antibodies, Monoclonal/therapeutic use/pharmacology
*Neurodegenerative Diseases/drug therapy/immunology
Animals
*Central Nervous System Diseases/drug therapy/immunology
Neuromyelitis Optica/drug therapy
Central Nervous System/drug effects/immunology
Multiple Sclerosis/drug therapy

@article {pmid41096666,
year = {2025},
author = {Świątek, G and Nowakowska-Gołacka, J and Słomińska-Wojewódzka, M and Glac, W and Harackiewicz, O and Kurowska-Rucińska, E and Wrona, D},
title = {Minocycline Treatment Improves Memory and Reduces Anxiety by Lowering Levels of Brain Amyloid Precursor Protein and Indoleamine 2,3-Dioxygenase in a Rat Model of Streptozotocin-Induced Alzheimer's Disease.},
journal = {International journal of molecular sciences},
volume = {26},
number = {19},
pages = {},
doi = {10.3390/ijms26199397},
pmid = {41096666},
issn = {1422-0067},
mesh = {Animals ; *Indoleamine-Pyrrole 2,3,-Dioxygenase/metabolism ; *Alzheimer Disease/drug therapy/metabolism/chemically induced ; Male ; *Minocycline/pharmacology/therapeutic use ; Rats ; *Anxiety/drug therapy/metabolism ; Streptozocin ; Rats, Wistar ; Disease Models, Animal ; *Memory/drug effects ; *Amyloid beta-Protein Precursor/metabolism ; Brain/metabolism/drug effects ; Hippocampus/metabolism/drug effects ; Maze Learning/drug effects ; },
abstract = {Minocycline (MINO), a classic antibiotic, may have psychotropic activity related to the modulation of the tryptophan-kynurenine pathway. In this study, we investigated the effects of MINO on (1) memory and anxiety behaviors, (2) the modulation of brain levels of amyloid precursor protein (APP) and 2,3-indoleamine dioxygenase (IDO1) levels, and (3) peripheral inflammatory markers in a streptozotocin (STZ)-induced rat model of sporadic Alzheimer's disease (sAD). After repeated treatment with a dose of 35 mg/kg MINO for seven consecutive days, male Wistar rats with sAD showed (1) improvements in early (29 days after injection, probe test) reference memory (decreased latency to reach the platform, increased time in the critical quadrant of the Morris water maze) and anxiety disorders (increased time in the open arms of the elevated plus maze; increased exploration and entrances in the center of the white-light illuminated open field) 45-46 and 90-91 days after STZ injection; (2) reduced APP and IDO1 levels in the hippocampus and prefrontal cortex; and (3) induction of anti-inflammatory response in blood (increased TCD4[+] lymphocyte number and interleukin-10 production). This suggests that MINO, due to its anti-inflammatory action, improves memory and anxiety behavior related to sAD, indicating its neuroprotective and psychotropic properties.},
}

Animals
*Indoleamine-Pyrrole 2,3,-Dioxygenase/metabolism
*Alzheimer Disease/drug therapy/metabolism/chemically induced
Male
*Minocycline/pharmacology/therapeutic use
Rats
*Anxiety/drug therapy/metabolism
Streptozocin
Rats, Wistar
Disease Models, Animal
*Memory/drug effects
*Amyloid beta-Protein Precursor/metabolism
Brain/metabolism/drug effects
Hippocampus/metabolism/drug effects
Maze Learning/drug effects

@article {pmid41096642,
year = {2025},
author = {Mochol, M and Jablonowski, L and Pawlik, A and Rasławska-Socha, J and Chamarczuk, A and Lipski, M and Mazurek-Mochol, M},
title = {The Role of Vitamin C in Selected Autoimmune and Immune-Mediated Diseases: Exploring Potential Therapeutic Benefits.},
journal = {International journal of molecular sciences},
volume = {26},
number = {19},
pages = {},
doi = {10.3390/ijms26199375},
pmid = {41096642},
issn = {1422-0067},
mesh = {Humans ; *Autoimmune Diseases/drug therapy/metabolism/immunology ; *Ascorbic Acid/therapeutic use/pharmacology ; Antioxidants/therapeutic use ; Animals ; Dietary Supplements ; *Immune System Diseases/drug therapy ; Oxidative Stress/drug effects ; },
abstract = {Autoimmune diseases are characterized by immune response dysregulation against self-components, leading to chronic inflammation and tissue damage. Vitamin C (VitC), a water-soluble vitamin with established functions in antioxidant defence and collagen synthesis, has also been of interest based on its potential immunomodulatory effects. This review discusses the role of VitC in the course and progression of (A) autoimmune diseases (multiple sclerosis, rheumatoid arthritis, Sjögren's disease, type 1 diabetes, Hashimoto's thyroiditis, pernicious anaemia, antiphospholipid syndrome), (B) other immune-mediated diseases (Crohn's disease, periodontitis), and (C) Alzheimer's disease, a neurodegenerative disorder with autoimmune features. Results from clinical, observational, and experimental trials show that VitC deficiency is common in many of these diseases and may contribute to increased oxidative stress and immune disequilibrium. Supplementation has been associated with improved antioxidant levels, control of inflammatory mediators, and, in some cases, clinical outcomes like disease activity decrease or symptom load. Although findings vary across conditions and few large, randomized trials are available, the overall evidence indicates that maintaining good VitC status can be useful in maintaining immune homeostasis and reducing inflammation. VitC should be viewed as an adjunct to be employed safely, perhaps and ideally within larger treatment regimens, but not in place of effective therapies. Further research, including large-scale clinical trials, will be required to determine more clearly optimal dosing, timing of treatment, and patient population most likely to benefit. By integration of current knowledge, this review recognizes both promise in VitC for treatment of autoimmune/immune-mediated disease and promise in its potential use within future treatment regimens.},
}

Humans
*Autoimmune Diseases/drug therapy/metabolism/immunology
*Ascorbic Acid/therapeutic use/pharmacology
Antioxidants/therapeutic use
Animals
Dietary Supplements
*Immune System Diseases/drug therapy
Oxidative Stress/drug effects

@article {pmid41096572,
year = {2025},
author = {Zhang, X and Fu, Y and Li, X and Zhang, Y and Li, L and Yi, T and Jiang, H and Lu, Y},
title = {Phlorizin Ameliorates Amyloid-β Toxicity and Enhances Fatty Acid β-Oxidation in Caenorhabditis elegans via NHR-49-Dependent Pathway.},
journal = {International journal of molecular sciences},
volume = {26},
number = {19},
pages = {},
doi = {10.3390/ijms26199303},
pmid = {41096572},
issn = {1422-0067},
support = {7252230//Beijing Municipal Science & Technology Commission/ ; },
mesh = {Animals ; *Caenorhabditis elegans/metabolism/drug effects/genetics ; *Amyloid beta-Peptides/toxicity/metabolism ; *Caenorhabditis elegans Proteins/metabolism/genetics ; *Fatty Acids/metabolism ; Oxidation-Reduction/drug effects ; Reactive Oxygen Species/metabolism ; Alzheimer Disease/metabolism/drug therapy ; Lipid Metabolism/drug effects ; Longevity/drug effects ; Signal Transduction/drug effects ; Disease Models, Animal ; Receptors, Cytoplasmic and Nuclear ; },
abstract = {Phlorizin (PHZ) is a glucoside of phloretin, belonging to the dihydrochalcone class within flavonoids; It is one of the active ingredients of the plant Cynomorium, and it has been shown that PHZ can regulate lipid metabolism disorders as well as having anti-aging properties. However, no studies have investigated whether PHZ ameliorates Aβ-induced toxicity in Alzheimer's disease (AD) by regulating fatty acid β-oxidation. This study aims to investigate the effects of PHZ on the regulation of fatty acid β-oxidation and resistance to Aβ-associated toxicity on the AD Caenorhabditis elegans and the mechanisms of action. Wild-type N2 and AD model CL4176 C. elegans were used; lifespan, heat stress resistance, chronic paraquat stress, reactive oxygen species (ROS), behavioral performance, and lipofuscin accumulation assays were examined to evaluate the anti-aging effects; and non-esterified fatty acid (NEFA), triglyceride (TG) and lipidomic contents were quantified after PHZ treatment. The detection of genes related to fatty acid β-oxidation pathways was performed using qRT-PCR. nhr-49 knockout mutant RB1716; and GFP-binding mutants PMD150 WBM170 were used to observe the effect of PHZ on NHR-49 pathways, and molecular docking studies were performed by combining PHZ with NHR-49 proteins. Results showed that PHZ improved worms' survival and delayed senescence, as demonstrated by enhanced performance in lifespan, heat stress, ROS, and paraquat assays and chronic paraquat assays; PHZ also reduced lipid accumulation in worms, affected the unsaturated fatty acid pathway, and significantly increased the expression of fatty acid metabolism-related genes nhr-49, acs-2, and cpt-5, and can be tightly coupled to NHR-49 targets. PHZ may play an anti-Aβ toxicity role by regulating lipid metabolism disorders through the NHR-49-related pathway and anti-aging in AD worms.},
}

Animals
*Caenorhabditis elegans/metabolism/drug effects/genetics
*Amyloid beta-Peptides/toxicity/metabolism
*Caenorhabditis elegans Proteins/metabolism/genetics
*Fatty Acids/metabolism
Oxidation-Reduction/drug effects
Reactive Oxygen Species/metabolism
Alzheimer Disease/metabolism/drug therapy
Lipid Metabolism/drug effects
Longevity/drug effects
Signal Transduction/drug effects
Disease Models, Animal
Receptors, Cytoplasmic and Nuclear

@article {pmid41096552,
year = {2025},
author = {Schulten, W and Czaniera, NJ and Buschheuer, AL and Liermann, A and Wiegand, A and Kaltschmidt, B and Kaltschmidt, C},
title = {Pluripotent Cells Expressing APOE4 Exhibit a Pronounced Pro-Apoptotic Phenotype Accompanied by Markers of Hyperinflammation and a Blunted NF-κB Response.},
journal = {International journal of molecular sciences},
volume = {26},
number = {19},
pages = {},
doi = {10.3390/ijms26199283},
pmid = {41096552},
issn = {1422-0067},
mesh = {*NF-kappa B/metabolism ; *Apolipoprotein E4/metabolism/genetics ; Humans ; *Apoptosis/genetics ; *Inflammation/metabolism/genetics/pathology ; *Induced Pluripotent Stem Cells/metabolism ; Signal Transduction ; Biomarkers/metabolism ; Octamer Transcription Factor-3/metabolism/genetics ; Alzheimer Disease/metabolism/genetics/pathology ; Chemokine CXCL10/metabolism/genetics ; Cyclooxygenase 2/metabolism/genetics ; Chemokine CCL2/metabolism/genetics ; Phenotype ; Cell Line ; Apolipoprotein E3/metabolism/genetics ; Tumor Necrosis Factor-alpha/metabolism ; },
abstract = {Alzheimer's disease (AD) is a progressive neurodegenerative disorder that poses an increasing burden on society. It is characterized by the presence of neurofibrillary tangles (NFTs) and amyloid-beta (Aβ) plaques. AD is a multifactorial disease, with one of the strongest genetic risk factors being the APOE4 allele. In this study, we investigated the impact of APOE4 on NF-κB signaling in induced pluripotent stem (iPS) cells. Our results indicate that APOE4 may influence the subcellular localization of the pluripotency marker OCT4, showing a predominantly nuclear localization in APOE4 cells, whereas it appears cytoplasmic in APOE3 cells. Additionally, NF-κB activation via its canonical subunits is blunted in APOE4 cells. Interestingly, APOE4 cells still exhibit increased transcription of key hyperinflammatory markers CCL2, CXCL10 and COX2, which are known NF-κB target genes, and exhibit a significantly higher rate of apoptosis compared to APOE3 cells-independent of TNF-α stimulation. Moreover, an elevated incidence of DNA double-strand breaks was observed in APOE4 cells. However, the precise molecular mechanisms by which APOE4 suppresses NF-κB activation while simultaneously promoting inflammation and apoptosis remain unclear. Further research is required to elucidate these underlying pathways.},
}

*NF-kappa B/metabolism
*Apolipoprotein E4/metabolism/genetics
Humans
*Apoptosis/genetics
*Inflammation/metabolism/genetics/pathology
*Induced Pluripotent Stem Cells/metabolism
Signal Transduction
Biomarkers/metabolism
Octamer Transcription Factor-3/metabolism/genetics
Alzheimer Disease/metabolism/genetics/pathology
Chemokine CXCL10/metabolism/genetics
Cyclooxygenase 2/metabolism/genetics
Chemokine CCL2/metabolism/genetics
Phenotype
Cell Line
Apolipoprotein E3/metabolism/genetics
Tumor Necrosis Factor-alpha/metabolism

@article {pmid41096551,
year = {2025},
author = {Zia Ul Haq, M and Zhao, X and Obeng Apori, S and Singh, B and Tian, F},
title = {Molecular Biomarkers for Early Detection of Alzheimer's Disease and the Complementary Role of Engineered Nanomaterials: A Systematic Review.},
journal = {International journal of molecular sciences},
volume = {26},
number = {19},
pages = {},
doi = {10.3390/ijms26199282},
pmid = {41096551},
issn = {1422-0067},
mesh = {*Alzheimer Disease/diagnosis/metabolism ; Humans ; *Biomarkers/metabolism ; *Nanostructures/chemistry ; Amyloid beta-Peptides ; Early Diagnosis ; Metal Nanoparticles/chemistry ; },
abstract = {Alzheimer's disease (AD) instantly requires affordable diagnostic tools for targeting the responsible molecular biomarkers. In this review, we briefly discussed the overview of the AD population, performance of different analytical techniques and nanoparticles/composites, molecular biomarkers, and the interest of countries towards the detection of AD biomarkers during 2012-2025. The desired result was attained by lateral flow assay, surface-enhanced Raman scattering, and colorimetric sensor techniques with nanoparticles of magnetic, gold, and carbon-containing silver, and iridium oxide nanoparticles, upon biomarkers of dopamine, amyloid beta41, and Apolipoprotein E, individually. Additionally, the outstanding performance of nanoparticles including gold nanoparticles, carbon-containing nanoparticles, and manganese dioxide with their particle size of 5.7 nm, 35 nm, 37.3 nm, 120 nm, and 220 nm, respectively, has been discussed. Moreover, the percentages of AD-related biomarkers including amyloid beta42 having research articles of 21.2%, amyloid beta1-42 12.1%, amyloid beta oligomer 12.1%, phosphorylated Tau detection 12.1%, amyloid beta1-40 9.09%, Dopamine 9.09%, amyloid beta40 9.17%, apolipoprotein 6.06%, etc., have also been included. Additionally, LOD comparison with respect to applied analytical techniques, investigated through a timeline and electrochemical sensor, was found most suitable. Finally, a portable molecular diagnostic device to combine amyloid beta1-42, amyloid beta1-40, and phosphorylated Tau detection in non-invasive bodily fluid was proposed for the future and clinical diagnosis.},
}

*Alzheimer Disease/diagnosis/metabolism
Humans
*Biomarkers/metabolism
*Nanostructures/chemistry
Amyloid beta-Peptides
Early Diagnosis
Metal Nanoparticles/chemistry

@article {pmid41096446,
year = {2025},
author = {Quadalti, C},
title = {One Health, Two Species: Linking Domestication to Cognitive Aging in Dogs and Humans.},
journal = {Animals : an open access journal from MDPI},
volume = {15},
number = {19},
pages = {},
doi = {10.3390/ani15192851},
pmid = {41096446},
issn = {2076-2615},
abstract = {This commentary explores the parallel neuroanatomical and neurobiological evolution that ultimately led to modern dogs and humans, through domestication and self-domestication, respectively. The selective pressures for benignness and enhanced prosociality have reshaped brain anatomy and cognitive architecture in both Canis familiaris and Homo sapiens, leading to analogous changes including a reduction in limbic system volume and expansion of the prefrontal cortex, critical for executive control and social cognition. From a molecular point of view, shared genetic and epigenetic underpinnings of these adaptations and their implications gave rise to parallel trajectories in brain aging; notably, the emergence of canine cognitive dysfunction. Interestingly, this canine age-related cognitive decline presents significant overlaps with Alzheimer's disease in terms of both behavioral presentation and underlying pathology. In the context of a One Health perspective, the profound influence of shared environmental exposures, such as urbanization, pollutants, and stressors, on neurodevelopment, cognitive aging, and disease susceptibility offers a compelling translational model for understanding brain health within intertwined ecological and social contexts.},
}

@article {pmid41096196,
year = {2025},
author = {Siwecka, N and Golberg, M and Świerczewska, D and Filipek, B and Pendrasik, K and Bączek-Grzegorzewska, A and Stasiołek, M and Świderek-Matysiak, M},
title = {Sleep Disorders in Neurodegenerative Diseases with Dementia: A Comprehensive Review.},
journal = {Journal of clinical medicine},
volume = {14},
number = {19},
pages = {},
doi = {10.3390/jcm14197119},
pmid = {41096196},
issn = {2077-0383},
abstract = {Dementia is a growing problem of global relevance, currently affecting over 55 million people worldwide. The number of new dementia cases is still increasing, primarily due to the aging of society. Dementia is defined as a substantial decline in cognitive function, and it is inherently associated with neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, dementia with Lewy bodies, frontotemporal dementia, and vascular dementia. Of note, most patients suffering from neurodegenerative conditions, in addition to cognitive impairment, often experience various types of sleep disorders, including insomnia, rapid eye movement sleep behavior disorder, sleep-disordered breathing, and circadian rhythm disturbances. There is increasing evidence of a bidirectional interaction between sleep disturbances and mental health. Disrupted sleep may directly aggravate neuropsychiatric symptoms, like depression, anxiety, agitation, and hallucinations, and conversely, such symptoms can make sleeping more difficult. This creates a feedback loop that inevitably leads to disease progression and deterioration in quality of life. In this review, we provide an up-to-date overview of the nature and mechanisms behind sleep disorders in major neurodegenerative diseases, summarize treatment strategies for handling sleep disturbances, and discuss the clinical relevance of sleep-mental health interactions in the context of neurodegeneration-associated dementia. Neurodegeneration is a complex problem on the border between neurology and psychiatry, and it poses a challenge to the healthcare system, as it requires multidisciplinary approaches for optimal management. Understanding the connection between sleep and neuropsychiatric symptoms offers further opportunities for better symptom control, improved quality of life, and slower cognitive decline.},
}

@article {pmid41095945,
year = {2025},
author = {Jo, S and Park, JH and Kim, KW},
title = {Frank's Sign as a Dose-Dependent Marker of White Matter Burden in CADASIL: A Brain MRI Study.},
journal = {Journal of clinical medicine},
volume = {14},
number = {19},
pages = {},
doi = {10.3390/jcm14196865},
pmid = {41095945},
issn = {2077-0383},
support = {HI09C1379 (A092077)//Korean Health Technology R&D Project, Ministry of Health and Welfare, Republic of Korea/ ; RS-2020-KH095941//Korea Dementia Research Project through the Korea Dementia Research Center (KDRC), funded by the Ministry of Health & Welfare and Ministry of Science and ICT, Republic of Korea/ ; },
abstract = {Background/Objectives: Frank's sign, a diagonal earlobe crease, may reflect systemic microvascular dysfunction. We investigated whether Frank's sign serves as a clinical marker of white matter hyperintensity (WMH) burden in Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy (CADASIL), a monogenic model of pure cerebral small vessel disease. Methods: We analyzed 81 genetically confirmed CADASIL patients (61.8 ± 12.6 years, 40.7% female) and 54 age/sex-matched controls (70.3 ± 6.6 years, 48.1% female). Frank's sign was detected using deep learning from brain MRI-reconstructed 3D facial surfaces. WMH volumes were automatically quantified and adjusted for confounders using Random Forest regression residuals. We compared Frank's sign prevalence between groups, assessed within-CADASIL associations, and evaluated dose-response relationships across WMH tertiles. Results: Frank's sign prevalence was significantly higher in CADASIL versus controls (66.7% vs. 42.6%, p = 0.020), with strengthened association after multivariate adjustment (OR = 4.214, 95% CI: 1.128-15.733, p = 0.032). Within CADASIL, Frank's sign-positive patients showed 72% greater WMH burden (51.5 ± 27.1 vs. 30.0 ± 26.1 mL, p < 0.001) and lower Consortium to Establish a Registry for Alzheimer's Disease (CERAD) total scores (57.7 ± 19.6 vs. 71.2 ± 22.8, p = 0.006), but similar lacunes, microbleeds, and hippocampal volumes. A robust dose-response relationship emerged across WMH tertiles, with Frank's sign prevalence increasing from 37.0% (lowest) to 74.1% (highest tertile; adjusted OR = 3.571, 95% CI: 1.134-11.253, p = 0.030). Conclusions: Frank's sign represents an accessible biomarker of WMH burden in CADASIL, demonstrating disease-specificity and dose-response characteristics independent of vascular risk factors. The automated MRI-based detection method of Frank's sign enables retrospective analysis of existing neuroimaging databases, transforming a bedside observation into a quantifiable neuroimaging biomarker for genetic small vessel disease stratification.},
}

@article {pmid41095775,
year = {2025},
author = {Tatarciuc, D and Curca, FR and Virvescu, DI and Butnaru, OM and Goriuc, A and Bida, S and Luchian, I and Surlari, Z and Scurtu, M and Ursu, RG and Budala, DG},
title = {Alzheimer's Disease and Oral Health from Clinical Challenges to Interdisciplinary Care: A Narrative Review.},
journal = {Journal of clinical medicine},
volume = {14},
number = {19},
pages = {},
doi = {10.3390/jcm14196696},
pmid = {41095775},
issn = {2077-0383},
abstract = {The link between oral health and Alzheimer's disease (AD) has gained increasing attention in recent years. Emerging evidence suggests that this association is bidirectional, involving both biological mechanisms and behavioral consequences that reinforce one another over time. Literature Review: A narrative synthesis of systematic reviews, meta-analyses, and scoping reviews published between January 2010 and March 2024 was conducted. Searching was performed in four electronic databases (PubMed, Scopus, the Web of Science, and the Cochrane Library), using a combination of MeSH terms and free-text keywords related to dementia and oral health. Inclusion criteria targeted human studies published in English with full-text access and a clear focus on the interplay between oral status and Alzheimer's disease. Results: The reviewed literature indicates that periodontal disease, tooth loss, and oral microbiome alterations may contribute to neuroinflammation and cognitive decline, potentially influencing the onset and progression of AD. Conversely, Alzheimer's disease negatively affects oral health through impaired self-care, reduced motor coordination, salivary changes, and altered pain perception. Conclusions: By mapping out these interconnections, the findings support a shift in perspective; oral health should be considered a relevant factor in both the prevention and management of Alzheimer's disease. Dentistry and neurology must move closer together in clinical practice, particularly in the care of older adults. Promoting oral health is not just about preserving teeth; it may be part of preserving cognitive function and quality of life.},
}

@article {pmid41094623,
year = {2025},
author = {Yu, F and Todd, M and Salisbury, D and Maxfield, M and Pruzin, J and Joseph, RP and Su, Y and Li, D and Baena, E and Coon, D},
title = {Precision exercise in older adults with early Alzheimer's disease: The study protocol of the FIT-AD Sequential, Multiple Assignment, Randomized Trial (SMART).},
journal = {Trials},
volume = {26},
number = {1},
pages = {416},
pmid = {41094623},
issn = {1745-6215},
support = {R01AG076566-01A1/AG/NIA NIH HHS/United States ; },
mesh = {Humans ; *Alzheimer Disease/psychology/therapy/physiopathology/diagnosis ; Aged ; Randomized Controlled Trials as Topic ; Cognition ; *Exercise Therapy/methods ; Female ; Male ; Treatment Outcome ; Time Factors ; *Exercise ; High-Intensity Interval Training ; Biomarkers/blood ; Resistance Training ; Age Factors ; Aged, 80 and over ; Physical Fitness ; },
abstract = {BACKGROUND: Aerobic exercise is promising for preventing Alzheimer's disease (AD) and AD-related dementia (ADRD), but exercise trials have shown mixed results. An important, understudied factor potentially contributing to mixed results is individual differences in aerobic fitness responses to moderate-intensity continuous training (MICT). This trial will test the effects and mechanisms of 6 months of aerobic exercise tailored on aerobic fitness response to MICT in community-dwelling older adults with early symptomatic AD. We aim to (I) test the effects of aerobic exercise on aerobic fitness, white matter hyperintensity volume (WMHv), and patient-centered outcomes in older adults with early symptomatic AD; (II) determine the best exercise to improve aerobic fitness and reduce non-responses over 6 months; and (III) examine the mechanisms of aerobic exercise's action on cognition.

METHODS: This stage II trial is a Sequential, Multiple Assignment, Randomized Trial (SMART). The hypothesis is that MICT augmented with high-intensity interval training (HIIT) or combined aerobic and resistance exercise (CARE) will improve aerobic fitness, WMHv, and AD/ADRD plasma biomarkers. This trial will enroll 108 dyads (participants and their study partners). Participants (n = 108) are randomized using a 2:1 allocation ratio to 3-month MICT or 6-month stretching control. After the initial 3-month intervention period for participants assigned to MICT, aerobic fitness is measured with peak oxygen consumption (VO2peak) from a cycle-ergometer exercise testing and the shuttle walk test to identify non-response (< 5% increase). Non-responders are subsequently re-randomized (1:1) to either HIIT or CARE for 3 months. Responders continue MICT. All participants are followed for an additional 6 months post-intervention. Primary outcomes are VO2peak measured at 0, 3, 6, 9, and 12 months and WMHv at 0, 6, and 12 months. Secondary outcomes include memory, physical function, behavioral and psychological symptoms of dementia (BPSD), quality of life (QoL), caregiver burden, and AD plasma biomarkers. This trial has 80% power, assuming 18% and 25% attrition at 6 and 12 months, respectively, to detect changes in aerobic fitness.

DISCUSSION: Individual differences in VO2peak responses were reported in older adults with AD/ADRD previously but how this affects response to exercise interventions is unknown, Precision exercise tailored to VO2peak is critical to advance exercise research in AD.

TRIAL REGISTRATION: ClinicalTrials.gov NCT05877196. Registered on May 25, 2023.},
}

Humans
*Alzheimer Disease/psychology/therapy/physiopathology/diagnosis
Aged
Randomized Controlled Trials as Topic
Cognition
*Exercise Therapy/methods
Female
Male
Treatment Outcome
Time Factors
*Exercise
High-Intensity Interval Training
Biomarkers/blood
Resistance Training
Age Factors
Aged, 80 and over
Physical Fitness

@article {pmid41094207,
year = {2025},
author = {Chen, Z and Ma, S and Wang, C and Liu, J and Yang, X},
title = {A ratio electrochemiluminescence sensor for monitoring amyloid-beta based on g-C3N4-heme with luminol as the internal standard.},
journal = {Mikrochimica acta},
volume = {192},
number = {11},
pages = {737},
pmid = {41094207},
issn = {1436-5073},
support = {ZR2023MB083//Natural Science Foundation of Shandong Province/ ; },
mesh = {*Luminol/chemistry ; *Amyloid beta-Peptides/analysis/blood ; *Electrochemical Techniques/methods ; *Biosensing Techniques/methods ; Aptamers, Nucleotide/chemistry ; *Luminescent Measurements/methods ; Humans ; Graphite/chemistry ; Limit of Detection ; *Nitriles/chemistry ; Metal Nanoparticles/chemistry ; Electrodes ; Gold/chemistry ; Aniline Compounds/chemistry ; Tin Compounds/chemistry ; },
abstract = {Monitoring of the amyloid-beta (Aβ) peptide is crucial for the diagnosis and treatment of Alzheimer's disease. Here, a label-free, signal-on ratiometric electrochemiluminescence (ECL) aptasensor was fabricated for the detection of Aβ peptide. Specifically, graphite-like carbon nitride (g-C3N4) nanosheets and luminol served as the cathodic and anodic ECL emitters, respectively. K2S2O8 and H2O2 were used as the coreactants for the two emitters. Luminol was first coated on the indium tin oxide (ITO) electrode and used as the internal standard in the ratiometric biosensor. Polyaniline was then electrodeposited on the surface of the luminol-modified electrode to improve the biocompatibility and conductivity of the sensing interfaces. Gold nanoparticles were subsequently modified on the surface of polyaniline to immobilize a DNA aptamer. g-C3N4-heme incubated with different concentrations of Aβ solution to form g-C3N4-heme-Aβ complex, in which Aβ could specifically bind to the DNA aptamer and thus introduce g-C3N4 into the system. As a result, it was observed that the ratio value of ECL intensity (I1/I2) significantly increased with the increase of Aβ concentration. Under the optimized conditions, the biosensor has a good linear response in the range 10 fM to 10 nM with a detection limit of 4.2 fM. Consequently, the ratiometric ECL sensor, characterized by high sensitivity and favorable stability, offers a reliable method for the determination of Aβ.},
}

*Luminol/chemistry
*Amyloid beta-Peptides/analysis/blood
*Electrochemical Techniques/methods
*Biosensing Techniques/methods
Aptamers, Nucleotide/chemistry
*Luminescent Measurements/methods
Humans
Graphite/chemistry
Limit of Detection
*Nitriles/chemistry
Metal Nanoparticles/chemistry
Electrodes
Gold/chemistry
Aniline Compounds/chemistry
Tin Compounds/chemistry

@article {pmid41094020,
year = {2025},
author = {Makinde, IA and Hammed, SO and Kumar, N and Kuthi, NA and Umar, HI and Hassan, TA and Kehinde, IO and Bello, RO and Aborode, AT and Jimoh, TO and Mahamat, AO and Khalid, M and Almohammed, OA},
title = {Identification of novel DYRK1A inhibitors as treatment options for alzheimer's disease through comprehensive in silico approaches.},
journal = {Scientific reports},
volume = {15},
number = {1},
pages = {36114},
pmid = {41094020},
issn = {2045-2322},
support = {ORF-2025-77//King Saud University/ ; },
mesh = {Dyrk Kinases ; *Protein-Tyrosine Kinases/antagonists & inhibitors/chemistry/metabolism ; *Protein Serine-Threonine Kinases/antagonists & inhibitors/chemistry/metabolism ; *Alzheimer Disease/drug therapy ; Quantitative Structure-Activity Relationship ; *Protein Kinase Inhibitors/chemistry/pharmacology/therapeutic use ; Humans ; Molecular Dynamics Simulation ; Molecular Docking Simulation ; Benzimidazoles/pharmacology/chemistry ; Computer Simulation ; Aminopyridines/pharmacology/chemistry ; },
abstract = {This study aims to identify potential DYRK1A inhibitors from a curated database and utilize a QSAR model to predict the bioactivity of drug compounds in inhibiting the enzyme involved in tau protein oligomerization, a key process in AD pathology. 192 compounds were sourced from the SuperNatural 3.0 database and docked against DYRK1A using Maestro 12.5. The top five lead compounds and the reference drug Abemaciclib underwent ADMET profiling via the AI Drug Lab Server and a 200 nanosecond molecular dynamics simulation using Desmond. A machine learning-based Quantitative Structure-Activity Relationship (QSAR) analysis was then performed to predict their biological activity based on pIC50 values. The top five compounds, identified as 45,934,388, CNP0344929, CNP0360040, CNP0309850, and CNP0426983, demonstrated binding affinities of -13.337, -12.746, -11.712, -11.656, and - 11.416 kcal/mol, respectively, outperforming Abemaciclib (-6.528 kcal/mol). None of the compounds violated Lipinski's Rule of Five, and all exhibited favorable ADMET profiles, including optimal blood-brain barrier penetration and structural stability. The QSAR model successfully predicted the pIC50 values of the hit compounds (6.16, 5.758, 5.752, 6.003, 5.982), comparable to Abemaciclib (6.32). These findings highlight five promising DYRK1A inhibitors with potential therapeutic applications for AD.},
}

Dyrk Kinases
*Protein-Tyrosine Kinases/antagonists & inhibitors/chemistry/metabolism
*Protein Serine-Threonine Kinases/antagonists & inhibitors/chemistry/metabolism
*Alzheimer Disease/drug therapy
Quantitative Structure-Activity Relationship
*Protein Kinase Inhibitors/chemistry/pharmacology/therapeutic use
Humans
Molecular Dynamics Simulation
Molecular Docking Simulation
Benzimidazoles/pharmacology/chemistry
Computer Simulation
Aminopyridines/pharmacology/chemistry

@article {pmid41093842,
year = {2025},
author = {Xu, Z and Kiani Shabestari, S and Barannikov, S and Bieniek, KF and Blurton-Jones, M and Palavicini, JP and Han, X},
title = {Microglia-specific regulation of lipid metabolism in Alzheimer's disease revealed by microglial depletion in 5xFAD Mice.},
journal = {Nature communications},
volume = {16},
number = {1},
pages = {9156},
pmid = {41093842},
issn = {2041-1723},
support = {AG085545//U.S. Department of Health & Human Services | NIH | National Institute on Aging (U.S. National Institute on Aging)/ ; AG061872//U.S. Department of Health & Human Services | NIH | National Institute on Aging (U.S. National Institute on Aging)/ ; AG061729//U.S. Department of Health & Human Services | NIH | National Institute on Aging (U.S. National Institute on Aging)/ ; AG066546//U.S. Department of Health & Human Services | NIH | National Institute on Aging (U.S. National Institute on Aging)/ ; AG013319//U.S. Department of Health & Human Services | NIH | National Institute on Aging (U.S. National Institute on Aging)/ ; AG044271//U.S. Department of Health & Human Services | NIH | National Institute on Aging (U.S. National Institute on Aging)/ ; OT2-OD030544//Foundation for the National Institutes of Health (Foundation for the National Institutes of Health, Inc.)/ ; },
mesh = {*Alzheimer Disease/metabolism/pathology/genetics ; *Microglia/metabolism/pathology ; Animals ; *Lipid Metabolism ; Humans ; Mice ; Disease Models, Animal ; Mice, Transgenic ; Brain/metabolism/pathology ; Lipidomics ; Plaque, Amyloid/metabolism/pathology ; Astrocytes/metabolism ; Male ; Oxidative Stress ; Female ; },
abstract = {Abnormal lipid metabolism is observed in Alzheimer's disease (AD), but its contribution to disease progression remains unclear. Genetic studies indicate that microglia, the brain's resident immune cells, influence lipid processing during AD. Here, we show that microglia-the brain's resident immune cells-selectively regulate lipid accumulation that associated with disease pathology in both AD mouse models and human postmortem brains. Using lipidomics and histological analysis, we identify a striking buildup of arachidonic acid-containing bis(monoacylglycero)phosphate in response to amyloid plaques, which depends on microglial activity and the AD risk gene GRN. In contrast, lysophosphatidylcholine and lysophosphatidylethanolamine accumulate independently of microglia, correlating instead with astrocyte activation and oxidative stress. These results connect dysregulated lipid metabolism in AD to distinct brain cell types and molecular pathways. Our findings highlight microglial lipid homeostasis as a potential therapeutic target for modifying disease progression in AD.},
}

*Alzheimer Disease/metabolism/pathology/genetics
*Microglia/metabolism/pathology
Animals
*Lipid Metabolism
Humans
Mice
Disease Models, Animal
Mice, Transgenic
Brain/metabolism/pathology
Lipidomics
Plaque, Amyloid/metabolism/pathology
Astrocytes/metabolism
Male
Oxidative Stress
Female

@article {pmid41093813,
year = {2025},
author = {Akasaka, T and Watanabe, H and Ono, M},
title = {Novel BODIPY-Based Fluorescent Probes with Improved Aqueous Solubility for Selective Detection of Soluble Aβ Aggregates.},
journal = {ACS chemical neuroscience},
volume = {},
number = {},
pages = {},
doi = {10.1021/acschemneuro.5c00525},
pmid = {41093813},
issn = {1948-7193},
abstract = {Soluble amyloid β (Aβ) aggregates have attracted attention as therapeutic targets and biomarkers of Alzheimer's disease. We previously reported a fluorescent probe, BAOP-16, which targets soluble Aβ aggregates. However, its limited aqueous solubility has hindered its application in biological assays. In this study, we developed aqueous-soluble fluorescent probes that target soluble Aβ aggregates. Among the synthesized candidates, sBAOP-2-3, which is substituted with two CH2C[-]Tf2 groups and a diphenyl amino group, exhibited markedly improved aqueous solubility compared with BAOP-16. It also showed a marked increase in fluorescence intensity in the presence of Aβ oligomers, and the highest selectivity for Aβ oligomers over Aβ fibrils. During the aggregation process of Aβ, sBAOP-2-3 detected soluble Aβ aggregates in an early phase. Furthermore, staining experiments using mouse brain sections suggested that sBAOP-2-3 selectively stained soluble Aβ aggregates in mouse brains. These results suggest that sBAOP-2-3 shows promise as a probe for the selective detection of soluble Aβ aggregates in biological systems.},
}

@article {pmid41093507,
year = {2025},
author = {Li, R and Wang, M and Song, Q and Liu, D and Jiang, L and Wen, Y and Chen, L and Chen, S and Lu, D and Zheng, J and Liu, T},
title = {Illuminating Fe[3+] spatiotemporal dynamics in Alzheimer's disease via a lipid-activated ultrasensitive probe.},
journal = {Analytica chimica acta},
volume = {1377},
number = {},
pages = {344635},
doi = {10.1016/j.aca.2025.344635},
pmid = {41093507},
issn = {1873-4324},
mesh = {*Alzheimer Disease/metabolism/diagnostic imaging ; Humans ; *Lipids/chemistry ; *Fluorescent Dyes/chemistry/chemical synthesis ; Animals ; *Iron/analysis/metabolism ; Microscopy, Fluorescence ; Mice ; *Ferric Compounds/analysis ; Optical Imaging ; Cell Line, Tumor ; },
abstract = {Abnormal iron metabolism is recognized as one of the pathological factors underlying Alzheimer's disease (AD). However, the precise relationship between Fe[3+] and the AD progression remains incompletely understood. In this study, we introduce a lipid-activated probe, NRA, specifically designed for the detection of Fe[3+]. NRA exhibits excellent stability, high selectivity for Fe[3+], and a distinct lipid-targeting capability. By using this probe, in the AD cell models successfully induced and constructed with various stimulants, it has been demonstrated that the level of Fe[3+] gradually increases in AD. More importantly, in vivo studies have shown a significant correlation between Fe[3+] and amyloid plaques, and its distribution is spatially correlated with lipid enriched regions. Fluorescence lifetime imaging microscopy (FLIM) further revealed that Fe[3+] exhibits unique distribution patterns across different stages of AD and various brain regions, suggesting an important role in AD pathogenesis. Collectively, these findings provide a novel perspective on the role of Fe[3+] in AD pathogenesis.},
}

*Alzheimer Disease/metabolism/diagnostic imaging
Humans
*Lipids/chemistry
*Fluorescent Dyes/chemistry/chemical synthesis
Animals
*Iron/analysis/metabolism
Microscopy, Fluorescence
Mice
*Ferric Compounds/analysis
Optical Imaging
Cell Line, Tumor

@article {pmid41093210,
year = {2025},
author = {Manzoor, SI and Ahanger, IA and Kamli, MR and Malik, MA and Dar, TA},
title = {Nano-conjugation of small molecule modulators of protein aggregation: Enhancing the therapeutic precision.},
journal = {International journal of biological macromolecules},
volume = {},
number = {},
pages = {148293},
doi = {10.1016/j.ijbiomac.2025.148293},
pmid = {41093210},
issn = {1879-0003},
abstract = {Protein aggregation is a central hallmark of several neurodegenerative and systemic diseases, including Alzheimer's, Parkinson's, cataract and type 2 diabetes. Consequently, targeting protein aggregation is emerging as a promising therapeutic strategy for these diseases. Small molecule modulators have exhibited considerable potential in stabilizing native protein conformations and promoting the dissolution of toxic aggregates, leading to delayed disease progression. Some also target proteostatic pathways, promoting clearance of misfolded proteins to prevent further aggregation. Despite being promising, their clinical efficacy often faces challenges due to poor bioavailability, limited stability, and lack of specificity. Recent advances in nanotechnology have introduced nano-conjugation as a potential strategy for maximizing the therapeutic efficacy of these small molecule modulators. By ensuring targeted delivery, increased availability, improved stability and controlled tissue release, nano-conjugation has not only overcome the limitations but also acts as a future pathway to precision medicine in protein aggregation diseases. The present review article provides a comprehensive overview of small molecule modulators of protein aggregation and explores how nano-conjugation enhances their therapeutic efficacy. Moreover, it highlights emerging clinical trials and explores future directions in the application of nano-conjugated small molecule modulators as a potential treatment strategy for protein aggregation diseases.},
}

@article {pmid41093165,
year = {2025},
author = {León-Arcia, K and Andrade-Guerrero, J and Martínez-Orozco, H and Villegas-Rojas, MM and Pérez-Segura, I and Ramírez, IL and Vilches-Flores, A and Guerra-Crespo, M and Díaz-Cintra, SY and Soto-Rojas, LO},
title = {First unified time-course of Alzheimer's-like pathology in the intracerebroventricular streptozotocin-rat model: A Systematic Review.},
journal = {Ageing research reviews},
volume = {},
number = {},
pages = {102918},
doi = {10.1016/j.arr.2025.102918},
pmid = {41093165},
issn = {1872-9649},
abstract = {This systematic review investigates the timeline of Alzheimer's disease (AD)-like changes in the intracerebroventricular streptozotocin (ICV-STZ) rat model, a key tool for studying sporadic, non-genetic forms of AD. Following PRISMA guidelines, we analyzed 402 studies to characterize the progression of key pathological features, including cognitive deficits, insulin resistance, neurodegeneration, neuroinflammation, oxidative stress, tau pathology, amyloid aggregation, blood-brain barrier (BBB) dysfunction, and alterations in the gut-brain axis. Most studies used young male Wistar rats, revealing a sex and age bias. Results show cognitive impairment beginning within the first 24hours after ICV-STZ administration and persisting beyond 121 days, accompanied by early molecular changes, including disrupted insulin signaling, apoptosis (on day 1), and oxidative stress (on day 7). These events triggered a cascade of neuroinflammation, synaptic loss, tau hyperphosphorylation, amyloid plaque formation/accumulation, and neuronal death that closely resemble human AD. This work provides the first unified time-course of these alterations, confirming the model's ability to mimic the complexity of AD, while also identifying important gaps, such as its limited use of female and aged rats, underexplored areas like the BBB and gut-brain axis, and specific brain regions that require further investigation. The sporadic AD rat model induced by ICV-STZ serves as a powerful and versatile platform for dissecting the multifactorial nature of AD, identifying early biomarkers, and accelerating the development of targeted and disease-modifying therapies.},
}

@article {pmid41093142,
year = {2025},
author = {Marizzoni, M and Mombelli, E and Alboni, S and Rosa, M and Moretti, DV and Mirabelli, P and Coppola, L and Luongo, D and Salamone, D and Saleri, S and Piazza, F and Begni, V and Salvatore, M and Frisoni, GB and Cattaneo, A},
title = {Microbiota-gut-brain axis dysregulation in Alzheimer's disease and its modulation through probiotic supplementation.},
journal = {Brain, behavior, and immunity},
volume = {},
number = {},
pages = {106138},
doi = {10.1016/j.bbi.2025.106138},
pmid = {41093142},
issn = {1090-2139},
abstract = {BACKGROUND: The microbiota-gut-brain axis (MGBA) has been implicated in the pathophysiology of Alzheimer's Disease (AD).Probiotics reduced the progression of ADin different mouse models, possibly through MGBA modulation, but human data are still limited.

OBJECTIVE: Here, we evaluated whether differences in the gut microbiome (GM), pro-inflammatory markers and other MGBA mediators were associated with probable AD (pAD). We also assessed the impact of a 12-week probiotic treatment on MGBA.

METHODS: Forty-five pAD patients and 47 healthy subjects (HC) were recruited at IRCCS Istituto Centro San Giovanni di Dio Fatebenefratelli of Brescia (Italy). An uncontrolled clinical investigation was performed to test the effects of 12-week probiotic supplementation in the pAD group. Fecal microbiota composition, intestinal and blood inflammatory markers, and microbiota-related metabolites were assessed before supplementation in all participants and after only in pAD.

RESULTS: pAD patients showed intestinal inflammation, an altered GM profile, blood changes in the tryptophan metabolism, and reduced glutamate levels compared with HC (p-value < 0.049). Probiotic supplementation partially modulated these alterations, determining a reduction in several pro-inflammatory mediators, and an increase of GM-related protective factors, such as butyrate (p-value < 0.040) in pAD.

CONCLUSIONS: These findings confirmed the presence of MGBA alterations in AD and suggested a potential beneficial effect of probiotic supplementation through modulation of GM functionality rather than composition. Further research is required to confirm these results and their clinical relevance.},
}

@article {pmid41093133,
year = {2025},
author = {Kosidou, S and Zannas, Z and Ofrydopoulou, A and Lambropoulou, DA and Tsoupras, A},
title = {Psychotropic and neurodegenerative drugs modulate platelet activity via the PAF pathway.},
journal = {Neurochemistry international},
volume = {},
number = {},
pages = {106073},
doi = {10.1016/j.neuint.2025.106073},
pmid = {41093133},
issn = {1872-9754},
abstract = {Mild psychiatric conditions such as anxiety and depression, as well as severe disorders like schizophrenia and neurodegenerative diseases, are increasingly recognized as systemic inflammatory conditions. Platelets possess both hemostatic and immunomodulatory roles in these situations, with sharing key molecular pathways with the central nervous system, offering thus a valuable peripheral model for evaluating psychotropic drug effects. Platelet-activating factor (PAF), a potent thrombo-inflammatory mediator, has emerged as a potential link between the two systems, yet its involvement in drug responses remains understudied. This study systematically investigates the effects of psychotropic drugs (i.e. antidepressants, antipsychotics and anxiolytics), and neuroprotective (anti-Alzheimer's/Anti-Parkinson's) drugs on platelet aggregation, focusing on PAF-pathway in comparison to a control platelet agonist, ADP. Using ex vivo light transmission aggregometry, we determined IC50 values for each drug and analyzed the impact of selected drug combinations, in which the NSAID diclofenac was also included. Results revealed that most of the compounds assessed inhibited more effectively the PAF-induced aggregation of platelets compared to their effect on the ADP-pathway, with perphenazine showing the greatest anti-PAF potency. Several drug combinations, notably those including alprazolam and diclofenac, demonstrated significant synergistic effects. These findings suggest that commonly prescribed psychotropic drugs and medications for neurodegenerative disorders can influence platelet activity, mostly through the PAF-pathway, and that their interactions with NSAIDs may amplify their efficacy. Nevertheless, some drugs and their combinations induced lysis of platelets at much higher concentrations than their IC50 values, which stems safety concerns for their use.},
}

@article {pmid41093115,
year = {2025},
author = {Shen, Z and Wu, M and Sun, S and Ling, Y and Chen, X and Zhang, J and Zhou, X and Zhou, C},
title = {Lingguizhugan decoction improves cognitive impairment in APP/PS1 mice by promoting meningeal lymphatic drainage based on fatty acid degradation pathway.},
journal = {Journal of ethnopharmacology},
volume = {},
number = {},
pages = {120748},
doi = {10.1016/j.jep.2025.120748},
pmid = {41093115},
issn = {1872-7573},
abstract = {Lingguizhugan Decoction (LGZG), a classic traditional Chinese medicine formula, has been demonstrated in numerous studies to possess therapeutic potential for Alzheimer's disease (AD). However, it remains unclear whether its mechanism of action involves the meningeal lymphatic system.

AIM OF THE STUDY: Investigate if LGZG improves cognition in APP/PS1 mice by restoring mLVs drainage.

MATERIALS AND METHODS: Assessed cognitive behavior and pathology in LGZG-treated APP/PS1 mice. Used tracers and immunofluorescence (LYVE-1/TR-d3) to evaluate mLVs drainage and markers. Conducted untargeted brain metabolomics and dura mater micro-proteomics. Performed molecular docking and functional analysis focusing on fatty acid pathways.

RESULTS: LGZG ameliorated cognitive impairment and Aβ deposition in mice. Improved Aβ clearance correlated with enhanced mLVs function (confirmed by tracing). Metabolomics and micro-proteomics identified impaired fatty acid degradation as a key pathological factor. LGZG, at clinically relevant doses, restored mLVs drainage and rescued cognition by activating the fatty acid degradation pathway.

CONCLUSION: Lingguizhugan Decoction ameliorates AD-like pathologies and cognitive deficits in APP/PS1 mice by enhancing Aβ clearance via regulating the "fatty acid degradation-meningeal lymphatic axis." This finding reveals a novel multi-target mechanism of LGZG and offers a fresh perspective on metabolic intervention for AD treatment.},
}

@article {pmid41093093,
year = {2025},
author = {Tuo, C and Sui, X and Cui, C and Han, F and Jiao, J and Cai, H and Wu, M},
title = {Pramipexole improves cognitive deficits and synaptic plasticity impairments in 3xTg-AD mice through enhancing autophagy.},
journal = {Experimental neurology},
volume = {},
number = {},
pages = {115503},
doi = {10.1016/j.expneurol.2025.115503},
pmid = {41093093},
issn = {1090-2430},
abstract = {Autophagy dysfunction plays important roles in the pathogenesis of Alzheimer's disease (AD), and activation of autophagy might be a potential strategy in AD treatment. Although some autophagy inducers play beneficial roles in AD, no autophagy inducer has been available in AD clinical treatment due to lack of efficacy or obvious side effects. A recent study demonstrated that pramipexole (PPX) can activate autophagy in the brain without interfering with protein synthesis, thereby avoiding the side effects associated with prolonged use of an autophagy inducer. However, whether PPX can exert neuroprotective effects on AD and whether its potential mechanism is related to autophagy remains unclear. In the present study, the effects of PPX on the cognitive function of 3xTg-AD mice were observed using multiple behavioral tests, then synaptic plasticity was evaluated through in vivo hippocampal electrophysiological recordings and by measuring synaptic proteins, while Aβ and tau pathologies were detected using immunofluorescence staining and western blot. Finally, autophagy was detected and the potential target was predicted using bioinformatics analysis, qRT-PCR and molecular docking. Results demonstrated that PPX significantly improved cognitive deficits and hippocampal long-term potentiation (LTP) depression, increased the expression of PSD95, reduced Aβ deposition and tau hyperphosphorylation, activated autophagy by increasing LC3-II/LC3-I ratios and decreasing p62 levels, and restored Beclin1 expression. Bioinformatics analysis identified MAPK1 as a key target in PPX-ameliorated AD by enhancing autophagy. These findings suggest that PPX alleviates AD-related cognitive deficits and neuropathologies through increased autophagy, emphasising its potential as a disease-modifying therapeutic strategy for AD.},
}

@article {pmid41093092,
year = {2025},
author = {Kim, D and Shim, K and Kim, J and Ko, G and Tan, M and Chang, KA and An, SSA},
title = {Potential anti-amyloid beta oligomerization effects of PD166793 in Alzheimer's disease.},
journal = {Experimental neurology},
volume = {},
number = {},
pages = {115504},
doi = {10.1016/j.expneurol.2025.115504},
pmid = {41093092},
issn = {1090-2430},
abstract = {Alzheimer' disease (AD), the most common neurodegenerative disorder, is driven in aggregation of amyloid-beta (Aβ) oligomers, which cause neuronal damage and cognitive decline. Despite advancements in AD drug development, many treatments remain expensive and often lack long-term efficacy. This highlights the urgent need for small-molecule therapeutics that can specifically target Aβ oligomers, with drug repositioning emerging as a promising strategy. In this study, we investigate the repositioned compound PD166793 for its effects on Aβ oligomers and AD pathology. A screening of bioactive molecules or compounds identified that PD166793 as a potent inhibitor of Aβ42 aggregation and significantly reduced Aβ42 oligomerization. Its direct interaction with Aβ42 was confirmed by surface plasmon resonance and computational docking system. The PD166793 recovered Aβ42-induced toxicity and improved the mitochondrial functions in SH-SY5Y cells. AD therapeutic potentials of PD166793 were assessed in 5xFAD (B6SJL) transgenic mice. In these mice, PD166793 significantly improved cognitive performance, reduced Aβ plaque deposition, and decreased neuroinflammation and apoptosis in the brain, including reduced microglial activation and caspase-3 expression. These findings supported that PD166793 was a potent inhibitor of Aβ42 oligomerization, exhibiting neuroprotective effects in both cellular and animal models. Its ability to reduce Aβ plaque formation, alleviate neuroinflammation, and protect neurons from apoptosis underscores its potential as a repositioned therapeutic agent for AD.},
}

@article {pmid41093091,
year = {2025},
author = {Lee, JY and Lee, KJ and Jang, YJ and Park, S and Kook, KH and Yoo, BJ and Jung, WB and Park, SA},
title = {A high-fat diet disrupts neural tracts in apolipoprotein E mouse models.},
journal = {Experimental neurology},
volume = {395},
number = {},
pages = {115501},
doi = {10.1016/j.expneurol.2025.115501},
pmid = {41093091},
issn = {1090-2430},
abstract = {Diet-induced obesity is becoming increasingly prevalent, and its impact on brain pathology is gaining recognition. Apolipoprotein E (ApoE), a key regulator of lipid transport, exhibits isoform-specific differences in its relationship with brain disorders. This study examined how high-fat diet (HFD)-induced obesity affects brain function and structure across ApoE isoforms. Male knock-in (ApoE3, ApoE4) and knockout (KO) mice were fed an HFD for 6 months starting at 3 months of age. All genotypes experienced weight gain and elevated blood glucose levels. Diffusion tensor imaging (DTI) revealed reduced fractional anisotropy (FA) in the corpus callosum of all HFD-fed mice, with an additional FA reduction in the cingulum of ApoE3 mice. Immunohistochemical analysis of the corpus callosum showed diminished remyelinating oligodendrocytes in KO mice compared to their regular-diet counterparts and ApoE3 mice. In the cortex, Western blotting revealed a diet-specific trend toward reduced axonal skeletal proteins (β3-tubulin) in ApoE3 mice, leading to a significant difference between ApoE3 and ApoE4 mice on HFD. Conversely, lower levels of myelin basic protein (MBP) in ApoE3 mice compared to ApoE4 mice at baseline became negligible when HFD was introduced, due to an overall increase in MBP levels in ApoE3 mice. These findings indicate that neural tracts are the primary brain substrate affected by HFD-induced obesity in human ApoE mouse models, with more pronounced effects in ApoE3 and KO mice than in ApoE4 mice. Specifically, ApoE3 mice exhibited axon skeletal damage, while KO mice showed impaired remyelination.},
}

@article {pmid41092898,
year = {2025},
author = {Theriault, JE and Katsumi, Y and Reimann, HM and Zhang, J and Deming, P and Dickerson, BC and Quigley, KS and Barrett, LF},
title = {It's not the thought that counts: Allostasis at the core of brain function.},
journal = {Neuron},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.neuron.2025.09.028},
pmid = {41092898},
issn = {1097-4199},
abstract = {In psychology and neuroscience, scientific questions are often framed in terms of mental activity (e.g., cognition, emotion, and perception); however, the brain is an organ with a particular function that only it can fulfill. Converging evidence suggests that this function is allostasis: the predictive regulation of competing demands from internal bodily systems. We review evidence for a distributed allostatic system that organizes whole-brain signaling, scaffolds psychological phenomena, and places bodily regulation at the core of brain structure. We also demonstrate, with an example from Alzheimer's disease, how an "allostasis-first" perspective might transform hypothesis generation in the context of neurological health and disease. In sum, the common conception that the brain is primarily for thinking, or other cognitive processes, is potentially misleading, and neuroscience may benefit from a theoretical structure that centers on basic questions of how the brain coordinates and efficiently regulates the body.},
}

@article {pmid41092895,
year = {2025},
author = {Gertie, JA and Chung, H},
title = {Alzheimer's alphabet soup: Find the letters "Z-DNA-ZBP1-RIPK1".},
journal = {Immunity},
volume = {58},
number = {10},
pages = {2367-2369},
doi = {10.1016/j.immuni.2025.09.010},
pmid = {41092895},
issn = {1097-4180},
mesh = {*Alzheimer Disease/metabolism/immunology ; Humans ; Animals ; *Microglia/metabolism/immunology ; Signal Transduction ; *DNA-Binding Proteins/metabolism ; *Receptor-Interacting Protein Serine-Threonine Kinases/metabolism ; Mitochondria/metabolism ; Mice ; *RNA-Binding Proteins/metabolism ; Inflammation/immunology ; },
abstract = {Neuroinflammation contributes to Alzheimer's disease (AD), but the molecules and pathways that initiate inflammation are unclear. In this issue of Immunity, Song et al. demonstrate that ZBP1-RIPK1 signaling in microglia can drive AD, wherein ZBP1 is activated by left-handed Z-DNA leaking from mitochondria, presenting new molecular targets for AD therapeutics.},
}

*Alzheimer Disease/metabolism/immunology
Humans
Animals
*Microglia/metabolism/immunology
Signal Transduction
*DNA-Binding Proteins/metabolism
*Receptor-Interacting Protein Serine-Threonine Kinases/metabolism
Mitochondria/metabolism
Mice
*RNA-Binding Proteins/metabolism
Inflammation/immunology

@article {pmid41092763,
year = {2025},
author = {Vilor-Tejedor, N and Rodrigo, A and Genius, P and Rodríguez-Fernández, B and Anastasi, F and Pelkmans, W and Navarro, A and Adams, HH and Wisse, L and Gispert, JD and Evans, TE and , },
title = {Genetic drivers of hippocampal atrophy highlight the role of APOE functional variants and AD polygenicity in Mild Cognitive Impairment.},
journal = {NeuroImage. Clinical},
volume = {48},
number = {},
pages = {103889},
doi = {10.1016/j.nicl.2025.103889},
pmid = {41092763},
issn = {2213-1582},
abstract = {The hippocampus, crucial in cognitive aging and Alzheimer's disease (AD), shows early atrophy during disease progression. This study investigated 5-year trajectories of hippocampal volumes across AD stages, focusing on genetic predisposition to AD, captured through the polygenic risk score for AD (PRS-AD) and APOE, and their impact on hippocampal atrophy. Analyzing data from 1,051 participants in the ADNI, we found that AD genetic risk accelerates a reduction in hippocampal volume, particularly in individuals with mild cognitive impairment (MCI). Effects were primarily driven by cerebrospinal fluid protein quantitative trait loci of APOE. Excluding the APOE region from analyses negated these effects, underscoring its critical role. This stage-specific effect suggested that AD genetic factors, particularly the APOE region, exert their influence primarily before or during the transition to MCI, highlighting the hippocampus's increased vulnerability during this period. These findings underscored the importance of targeting the MCI stage for early detection and intervention in AD. Further research is warranted to elucidate these dynamics and their potential clinical applications.},
}

@article {pmid41092496,
year = {2025},
author = {Liu, C and Shi, Y and Hu, Q and Chu, Y and Guo, Y and Song, C and Jia, J and He, C},
title = {DIA proteomic analysis revealed the molecular characteristics of aluminum-induced hippocampal injury in rats.},
journal = {Journal of trace elements in medicine and biology : organ of the Society for Minerals and Trace Elements (GMS)},
volume = {92},
number = {},
pages = {127779},
doi = {10.1016/j.jtemb.2025.127779},
pmid = {41092496},
issn = {1878-3252},
abstract = {BACKGROUND: Aluminum is widely used in production and daily life due to its excellent properties. However, aluminum can damage neurons and cause cognitive impairment. Therefore, studying the neurotoxic mechanism of aluminum is of great significance.

OBJECTIVE: This study established a subchronic aluminum exposure model in Sprague Dawley rats and systematically investigated the neurotoxic effects and molecular mechanisms of aluminum.

METHODS: The experimental animals were randomly divided into a control group (0.9 % saline) and an aluminum exposure group ﹛20 μmol/kg maltol aluminum [Al(mal)3]﹜. Both groups were given intraperitoneal injections every other day for 90 days. After the administration, the rats received a series of behavioral tests. Subsequently, the rat hippocampus was subjected to data independent acquisition proteomic sequencing.

RESULT: Through Morris water maze and electron microscopy analysis of hippocampal tissue, it was confirmed that rats exposed to aluminum exhibited significant learning and memory impairments, accompanied by hippocampal neuron damage. The bioinformatics results showed that 188 differentially expressed proteins were screened out. And aluminum exposure mainly damages mitochondrial function (such as oxidative phosphorylation and ATP synthesis). It is worth noting that pathway enrichment analysis suggests a common pathogenic mechanism between aluminum induced neurotoxicity and Alzheimer's disease.

CONCLUSION: This study confirms that subchronic aluminum exposure leads to cognitive decline by mediating a large amount of protein expression dysregulation. The core mechanism is to impair mitochondrial energy metabolism and synaptic plasticity.},
}

@article {pmid41092455,
year = {2025},
author = {Barba, T and Bagley, BA and Steyaert, S and Carrillo-Perez, F and Sadée, C and Iv, M and Gevaert, O},
title = {DUNE: a versatile neuroimaging encoder captures brain complexity across 3 major diseases: cancer, dementia, and schizophrenia.},
journal = {GigaScience},
volume = {14},
number = {},
pages = {},
doi = {10.1093/gigascience/giaf116},
pmid = {41092455},
issn = {2047-217X},
support = {R01 CA260271/CA/NCI NIH HHS/United States ; /NH/NIH HHS/United States ; },
mesh = {Humans ; *Schizophrenia/diagnostic imaging/pathology ; *Neuroimaging/methods ; *Magnetic Resonance Imaging/methods ; *Brain/diagnostic imaging/pathology ; *Dementia/diagnostic imaging/pathology ; Male ; Female ; Machine Learning ; Image Processing, Computer-Assisted/methods ; Middle Aged ; *Neoplasms/diagnostic imaging ; Algorithms ; Aged ; },
abstract = {BACKGROUND: Magnetic resonance imaging (MRI) of the brain contains complex data that pose significant challenges for computational analysis. While models proposed for brain MRI analyses yield encouraging results, the high complexity of neuroimaging data hinders generalizability and clinical application. We introduce DUNE, a neuroimaging-oriented workflow that transforms raw brain MRI scans into standardized compact patient-level embeddings through integrated preprocessing and deep feature extraction, thereby enabling their processing by basic machine learning algorithms. A UNet-based autoencoder was trained using 3,814 selected scans of morphologically normal (healthy volunteers) or abnormal (glioma patients) brains, to generate comprehensive compact representations of the full-sized images. To evaluate their quality, these embeddings were utilized to train machine learning models to predict a wide range of clinical variables.

RESULTS: Embeddings were extracted for cohorts used for the model development (21,102 individuals), along with 3 additional independent cohorts (Alzheimer's disease, schizophrenia, and glioma cohorts, 1,322 individuals), to evaluate the model's generalization capabilities. The embeddings extracted from healthy volunteers' scans could predict a broad spectrum of clinical parameters, including volumetry metrics, cardiovascular disease (area under the receiver operating characteristic curve [AUROC] = 0.80) and alcohol consumption (AUROC = 0.99), and more nuanced parameters such as the Alzheimer's predisposing APOE4 allele (AUROC = 0.67). Embeddings derived from the validation cohorts successfully predicted the diagnoses of Alzheimer's dementia (AUROC = 0.92) and schizophrenia (AUROC = 0.64). Embeddings extracted from glioma scans successfully predicted survival (C-index = 0.608) and IDH molecular status (AUROC = 0.92), matching the performances of previous task-oriented models.

CONCLUSION: DUNE efficiently represents clinically relevant patterns from full-size brain MRI scans across several disease areas, opening ways for innovative clinical applications in neurology.},
}

Humans
*Schizophrenia/diagnostic imaging/pathology
*Neuroimaging/methods
*Magnetic Resonance Imaging/methods
*Brain/diagnostic imaging/pathology
*Dementia/diagnostic imaging/pathology
Male
Female
Machine Learning
Image Processing, Computer-Assisted/methods
Middle Aged
*Neoplasms/diagnostic imaging
Algorithms
Aged

@article {pmid41092385,
year = {2025},
author = {Lassell, R and Metaxas, A and Wang, K and Hantgan, S and Gottipati, P and Zwerling, S and Pena, T and Pollak, C and Gitlin, L and Jariwala, S},
title = {Applying the Human-Centered Innovation Biodesign Framework to the Development and Piloting of a Program to Mitigate Risk for Cognitive Decline Among Historically Underrepresented Individuals: Case Study.},
journal = {JMIR formative research},
volume = {9},
number = {},
pages = {e64930},
doi = {10.2196/64930},
pmid = {41092385},
issn = {2561-326X},
mesh = {Humans ; *Cognitive Dysfunction/prevention & control ; Pilot Projects ; *Program Development/methods ; Male ; Female ; *Exercise ; Aged ; Dementia/prevention & control ; *User-Centered Design ; Risk Factors ; Needs Assessment ; },
abstract = {BACKGROUND: Physical inactivity is a modifiable risk factor for dementia. Past physical activity interventions often overlook the voices of the end user in the design process, particularly minoritized groups living with dementia or memory challenges. To develop physical activity interventions, we use the principles of human-centered design.

OBJECTIVE: We applied human-centered design using the innovation biodesign framework to develop a physical activity intervention, Nurturing Aging Through Uplifting Activities in a Restorative Environment (NATURE) program for minoritized individuals as a use case.

METHODS: The innovation biodesign framework has three domains: (1) problem space, (2) invention, and (3) solution space. Each domain includes several activities. The problem space involves a needs assessment, needs screening, evidence-based literature review, review of existing models of programs, and iterative feedback from partners, leading to an invention. The solution space encompasses the implementation and validation of the invention and outcomes. We applied this framework in 3 steps: (1) identifying the problem: we used data points from multiple sources to identify needs and mapped them onto the problem space. These sources included reviews of the literature to identify existing interventions, findings from other nature programs to surmise gaps, and focus groups to iteratively identify unmet needs. (2) Designing the invention: we developed NATURE with Hispanic or Latino people with memory challenges and identified their preferred outcomes. (3) Mapping the pilot study. We added the study protocol and planned outcomes to the solution space.

RESULTS: In step 1, three evidence-based programs guided the development of NATURE to address physical inactivity and related risks of decreased well-being and dementia. We received 50 referrals for focus group participants, 22 were eligible and completed consent, and 21 (n=6 Hispanic or Latino people with memory challenges and care partners, n=8 outdoor professionals, and n=7 health care providers) participants completed the focus groups. We received feedback from participants on local nature activities, program frequency, duration, and delivery mode, a referral pathway, and outcomes using 5 focus groups and 2 interviews. In step 2, the 12-week NATURE program was developed to promote an active lifestyle and well-being, using nature activities that a person enjoys. NATURE accounts for a person's preferences, needs, and daily situation and includes 4-6 sessions with 2 phone check-ins. Preferred outcomes were well-being, sleep, and social connections. In step 3, we mapped the plan to pilot NATURE using activity tracker technology to measure sleep, heart rate, and activity (well-being), and validated questionnaires.

CONCLUSIONS: The framework provided a systematic approach for mapping the development of NATURE to address the needs of Hispanic or Latino people with memory challenges, using human-centered design principles. Application of the framework can be a helpful tool to map the development of other interventions for minoritized populations.

TRIAL REGISTRATION: ClinicalTrials.gov NCT06403345; https://clinicaltrials.gov/study/NCT06403345.},
}

Humans
*Cognitive Dysfunction/prevention & control
Pilot Projects
*Program Development/methods
Male
Female
*Exercise
Aged
Dementia/prevention & control
*User-Centered Design
Risk Factors
Needs Assessment

@article {pmid41092251,
year = {2025},
author = {Ong, JJH and Leow, YJ and Qiu, B and Tanoto, P and Zailan, FZ and Sandhu, GK and Kandiah, N},
title = {Association of Enlarged Perivascular Spaces With Early Serum and Neuroimaging Biomarkers of Alzheimer Disease Pathology.},
journal = {Neurology},
volume = {105},
number = {9},
pages = {e214339},
doi = {10.1212/WNL.0000000000214339},
pmid = {41092251},
issn = {1526-632X},
}

@article {pmid41091921,
year = {2025},
author = {Besser, LM and Baig, M and Henriquez, AM and Tolea, M and O'Shea, DM and Chrisphonte, S and Joshi, M and Kleiman, MJ and Galvin, JE},
title = {Sociodemographic correlates of cognition and Alzheimer's disease and vascular biomarkers among middle to older age participants in the Healthy Brain Initiative.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877251386378},
doi = {10.1177/13872877251386378},
pmid = {41091921},
issn = {1875-8908},
abstract = {BackgroundKey sociodemographics (e.g., nativity) plausibly related to Alzheimer's disease and related dementia (ADRD) risk have been investigated less frequently in relation to cognitive function, brain imaging, and blood-based biomarkers.ObjectiveTo examine associations between multiple sociodemographics and ADRD/vascular outcomes among middle- to older-age adults.MethodsWe used cross-sectional data on 341 Healthy Brain Initiative participants. Outcomes included cognitive domain scores (e.g., episodic memory, language), magnetic resonance imaging (MRI) (e.g., hippocampal and white matter hyperintensity volume), and blood-based biomarkers (e.g., Aβ42/40, pTau-217, NfL, GFAP). Sociodemographics included age, sex, racial group, Hispanic ethnicity, primary language, nativity, socioeconomic position, area deprivation, and living alone. Multivariable linear regression examined associations between sociodemographics and brain health outcomes.ResultsMean age was 69 ± 9 and 71% were women. Older individuals, women, Black and Hispanic individuals, those of lower socioeconomic position, and those born outside the US performed worse across various cognitive domains, while those who primarily spoke Spanish (versus English) scored better on episodic memory. Older individuals, women, and Hispanic individuals had worse brain health, and those identifying as other racial group and born outside of the US had better brain health measured via MRI. Older and Hispanic individuals had worse brain health and Black individuals and women had better brain health as measured via blood-based biomarkers.ConclusionsThis study contributes to the growing number of studies identifying differences in ADRD/vascular biomarkers by sociodemographics. Additional studies are needed to assess whether social and economic determinants of health are associated with longitudinal change in ADRD/vascular biomarkers.},
}

@article {pmid41091896,
year = {2025},
author = {Kelsey, PT and Selbæk, G and Lövheim, H and Åsvold, BO and Hveem, K and Wolford, BN and Skjellegrind, HK},
title = {Helicobacter pylori and Alzheimer's disease risk: The HUNT study.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877251386015},
doi = {10.1177/13872877251386015},
pmid = {41091896},
issn = {1875-8908},
abstract = {BackgroundInfections may contribute to Alzheimer's disease (AD) pathogenesis. Prior studies on the relationship between Helicobacter pylori (H. pylori) infection and AD or dementia have shown differing results.ObjectiveWe investigated whether H. pylori serology is associated with the risk of AD and dementia in the Trøndelag Health Study (HUNT).MethodsThe HUNT cohort study measured serum H. pylori antibody titers using the Pyloriset EIA-IgG test. 22 years after baseline serum sampling, cognitive assessments were conducted using standardized tests and proxy interviews. We performed logistic regression (n = 1364) adjusted for sex and age to estimate odds ratios for cognitive outcomes. Subgroup analyses were stratified by sex, age, Apolipoprotein E4 (APOE ε4) carrier status and high sensitivity serum C-reactive protein levels and sensitivity analyses further adjusted for lifestyle and co-morbidity risk factors. Cox regression models (n = 4689) were used to estimate hazard ratios for all-cause mortality.ResultsH. pylori titers were not associated with AD (OR 0.99 per 1 SD higher titer, 95% CI 0.82-1.20) or dementia (OR 0.98, 95% CI 0.84-1.15). There were no associations between H. pylori seropositivity (≥ 300 titers) and AD (OR 1.10, CI 0.75-1.63) or dementia (OR 0.96, CI 0.68-1.32). Stratifications by sex, age, CRP, or APOE ε4 genotype and adjusting for additional covariates showed no associations. All-cause mortality was higher with H. pylori positivity (HR 1.07, CI 1.03-1.11).ConclusionsH. pylori was not associated with later AD or dementia in this study. The relationship between specific versus multi-pathogenic infection burden and neurodegenerative diseases warrants further clarification.},
}

@article {pmid41091855,
year = {2025},
author = {de la Fuente, J and Londoño-Correa, D and Tucker-Drob, EM},
title = {Distinguishing Specific from Broad Genetic Associations between External Correlates and Common Factors.},
journal = {Bioinformatics (Oxford, England)},
volume = {},
number = {},
pages = {},
doi = {10.1093/bioinformatics/btaf568},
pmid = {41091855},
issn = {1367-4811},
abstract = {MOTIVATION: Within the Genomic SEM framework, common factors are often used to index shared genetic etiology across constellations of GWAS phenotypes. A standard common pathway model, in which a genetic association is estimated between an external GWAS phenotype and a common factor, assumes that all genetic associations between the external GWAS phenotype and the individual indicator phenotypes are mediated through the factor. This assumption can be tested using the QTrait statistic, which compares the common pathway model to an independent pathways model that allows for direct genetic associations between the external GWAS phenotype and the individual indicators of the factor. However, QTrait is not designed to identify either the magnitude or the source of this heterogeneity.

RESULTS: We expand upon the QTrait approach by describing an effect size index that quantifies the degree to which the common pathways model is violated, and we provide a systematic approach for empirically identifying specific direct pathways between an external trait and indicator traits. Our method comprises a series of omnibus tests and outlying indicator detection algorithms indexing the heterogeneity of associations between the genetic component of external traits and the individual indicators of common factors. We provide a set of automated functions which we apply to investigate the patterns of genetic associations across a set of external correlates with respect to indicators of general cognitive ability and case-control and proxy GWAS indices of Alzheimer's disease.

AVAILABILITY: The Genomic SEM R package and the QTrait function is available at https://github.com/GenomicSEM/GenomicSEM. The QTrait function tutorial is available at https://github.com/GenomicSEM/GenomicSEM/wiki/8.-Tutorials. To ensure reproducibility of the analyses presented in this manuscript, the exact version of the QTrait function used, along with input data and scripts, has been archived on Zenodo (DOI: https://doi.org/10.5281/zenodo.17186083).

SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.},
}

@article {pmid41091821,
year = {2025},
author = {Yang, J and Zhao, H and Huang, Y},
title = {A review of studies on vascular dementia and iron metabolism.},
journal = {Science progress},
volume = {108},
number = {4},
pages = {368504251387230},
doi = {10.1177/00368504251387230},
pmid = {41091821},
issn = {2047-7163},
mesh = {Humans ; *Dementia, Vascular/metabolism/drug therapy/pathology ; *Iron/metabolism ; Animals ; Oxidative Stress ; Iron Chelating Agents/therapeutic use ; Lipid Peroxidation ; },
abstract = {Vascular dementia (VaD) is recognized as the second most prevalent form of dementia after Alzheimer's disease, with its pathogenesis intricately associated with cerebrovascular pathologies, including chronic hypoperfusion, oxidative stress, and neuroinflammation. Recent studies have highlighted dysregulated iron metabolism as a pivotal factor in the pathogenesis of VaD; however, the precise mechanisms and therapeutic implications of this dysregulation remain insufficiently elucidated. In this article, we synthesize clinical and basic research to systematically explore the interaction between iron metabolism and VaD. Aberrant iron metabolism contributes to neuronal damage by exacerbating oxidative stress, lipid peroxidation, and ferroptosis, while cerebrovascular injuries, such as blood-brain barrier disruption and chronic inflammation, further compromise iron metabolism, thereby perpetuating a detrimental cycle. From a diagnostic standpoint, imaging modalities such as susceptibility-weighted imaging, alongside biomarkers like ferritin and soluble transferrin receptors, serve as effective instruments for detecting iron-related pathologies in VaD. At the therapeutic level, the use of chelating agents such as deferoxamine and deferiprone, in combination with antioxidants and innovative nanomaterials, has exhibited neuroprotective effects in animal models by alleviating iron-induced oxidative damage. Nevertheless, further validation is required to establish their clinical efficacy and safety. This is a narrative review. This article investigates the influence and significance of iron metabolism in the pathophysiology of VaD and explores potential therapeutic targets associated with iron metabolism, offering implications for future clinical applications.},
}

Humans
*Dementia, Vascular/metabolism/drug therapy/pathology
*Iron/metabolism
Animals
Oxidative Stress
Iron Chelating Agents/therapeutic use
Lipid Peroxidation

@article {pmid41091796,
year = {2025},
author = {Bayıl, S and Özdemir Tozlu, Ö and Karagul, B},
title = {Synthesized boron compounds: Neurotoxic and oxidative effects in an in vitro model of Alzheimer's disease.},
journal = {Science progress},
volume = {108},
number = {4},
pages = {368504251384830},
doi = {10.1177/00368504251384830},
pmid = {41091796},
issn = {2047-7163},
mesh = {Humans ; *Alzheimer Disease/drug therapy/metabolism/pathology ; *Boron Compounds/pharmacology/chemical synthesis/chemistry ; *Oxidative Stress/drug effects ; Amyloid beta-Peptides/metabolism ; *Antioxidants/pharmacology/chemical synthesis/chemistry ; Cell Line, Tumor ; *Neuroprotective Agents/pharmacology/chemical synthesis/chemistry ; Cell Survival/drug effects ; Peptide Fragments/metabolism ; },
abstract = {ObjectiveAlzheimer's disease (AD) is characterized by amyloid-beta (Aβ1-42) aggregation, oxidative stress, and neuronal loss, necessitating novel therapeutic agents to mitigate these pathological hallmarks.MethodThis study investigates the neuroprotective and antioxidant properties of newly synthesized borenium (compounds 1-4) and borinium (compounds 5-8) derivatives in an in vitro AD model using differentiated SH-SY5Y neuroblastoma cells exposed to Aβ1-42. Furthermore, automated Total Antioxidant Capacity assays were conducted using commercially available kits on culture media collected from cell cultures following 24 h of incubation. 3-(4,5-dimethylthiazol-2-yl)-2,5 diphenyltetrazolium bromide and lactate dehydrogenase tests were done to determine the cytotoxicity of boron compounds after application to the exposed cell lines of Aβ1-42.ResultsIt was determined that the boron compounds applied to the cell lines at different concentrations did not show any neurotoxic effect at a concentration of 50 μM in 24 h of incubation. All boron compounds were determined to have antioxidant properties. It was found that the borinium compounds are much more neuroprotective than the borenium.ConclusionThese findings highlight the therapeutic potential of borenium and borinium compounds as neuroprotective and antioxidant agents for AD, warranting further mechanistic and in vivo studies.},
}

Humans
*Alzheimer Disease/drug therapy/metabolism/pathology
*Boron Compounds/pharmacology/chemical synthesis/chemistry
*Oxidative Stress/drug effects
Amyloid beta-Peptides/metabolism
*Antioxidants/pharmacology/chemical synthesis/chemistry
Cell Line, Tumor
*Neuroprotective Agents/pharmacology/chemical synthesis/chemistry
Cell Survival/drug effects
Peptide Fragments/metabolism

@article {pmid41091740,
year = {2025},
author = {Tong, Q and Wu, J and Jiao, Q and Wu, H and Gong, J and Wu, Q},
title = {Global burden of Alzheimer's disease and other dementias attributable to smoking in 204 countries and territories, 1990-2021.},
journal = {PloS one},
volume = {20},
number = {10},
pages = {e0334619},
pmid = {41091740},
issn = {1932-6203},
mesh = {Humans ; Male ; Female ; *Alzheimer Disease/epidemiology/etiology ; Aged ; Global Burden of Disease/trends ; Aged, 80 and over ; Disability-Adjusted Life Years ; *Smoking/adverse effects/epidemiology ; Global Health ; Middle Aged ; *Dementia/epidemiology/etiology ; Risk Factors ; Quality-Adjusted Life Years ; },
abstract = {BACKGROUND: Alzheimer's disease and other dementias (ADD) are significant global public health challenges. Smoking is a clearly established modifiable risk factor for dementia.

OBJECTIVE: This study aims to systematically elucidate the burden of ADD attributable to smoking from 1990 to 2021.

METHODS: We obtained data on Disability Adjusted Life Years (DALYs) and age-standardized DALYs rate (ASDRs) associated with ADD attributable to smoking from the Global Burden of Disease (GBD) database for the years 1990-2021. These data were disaggregated by gender, age, sociodemographic index (SDI), and region. Temporal trends in the burden of smoking-induced ADD were examined by calculating the average annual percentage changes.

RESULTS: From 1990-2021, global ASDR of smoking-attributed ADD declined 21.3% (EAPC = -0.88%) while DALYs increased 93% to 1.53 million. Females showed faster ASDR decline (EAPC = -1.50% vs male -0.73%). DALYs peaked at 65-85 years with accelerated crude rates post-75. Regionally, East Asia (611760.52, 262060.15-1401979.1), Western Europe (184593.67, 78898.94-420812.86), High-income North America (164283.74, 72809.79-373190.34) had highest 2021 DALYs; East Asia (29.95, 12.67-68.10), High income North America (23.32, 10.39-52.46), Tropical Latin America (20.81, 9.05-48.62) had highest ASDR. Nationally, China, United States of America and Lebanon led burdens. Steepest declines occurred in Mexico (EAPC = -3.14%), South Africa (-3.14%), and Sri Lanka (-2.84%). ASDR correlated with SDI (r = 0.44, p < 0.001) showing bimodal peaks at SDI = 0.5 and 0.8. Frontier analysis revealed peak heterogeneity in Alzheimer's disease ASDR around SDI 0.75, with the largest effectiveness disparities observed primarily in Middle-High SDI countries, indicating urgent needs for targeted health interventions despite declining trends in high-SDI nations.

CONCLUSION: Despite declining dementia ASDR, global DALYs rose absolutely. The burden disproportionately impacted older populations, males, and high-middle-income nations. Mitigation requires context-adapted interventions including enhanced tobacco control, equitable healthcare access, and targeted health education.},
}

Humans
Male
Female
*Alzheimer Disease/epidemiology/etiology
Aged
Global Burden of Disease/trends
Aged, 80 and over
Disability-Adjusted Life Years
*Smoking/adverse effects/epidemiology
Global Health
Middle Aged
*Dementia/epidemiology/etiology
Risk Factors
Quality-Adjusted Life Years

@article {pmid41091591,
year = {2025},
author = {Magham, SV and Shanavas, S and Pindiprolu, SSSKS and Nagappan, K and More, S and Chaudhury, D and Ramakkamma, AR and Singh, MT and Wadhwani, A and Bose, B and Thaggikuppe Krishnamurthy, P},
title = {Targeting GSK-3β to Modulate the Wnt Pathway: A Promising Neuroprotective Strategy for Alzheimer's Disease.},
journal = {Molecular pharmaceutics},
volume = {},
number = {},
pages = {},
doi = {10.1021/acs.molpharmaceut.5c00329},
pmid = {41091591},
issn = {1543-8392},
abstract = {Alzheimer's disease (AD) is marked by amyloid-β plaques and neurofibrillary tangles. Glycogen synthase kinase-3β (GSK-3β) is a promising therapeutic target for mitigating several AD-related pathologies via modulation of the Wnt pathway. However, nonspecific GSK-3β inhibition by indirubin-3'-oxime (IMX) may result in significant off-target effects, necessitating the development of brain-targeted delivery systems. Solid lipid nanoparticles (SLNs) are biocompatible nanocarriers for brain-targeted delivery of therapeutics. Polysorbate 80 (PS80) and stearic acid (SA)-modified SLNs encapsulating IMX (PS80-SA SLNs-IMX) were prepared using the solvent injection method. The formula was optimized using full factorial design (FFD). The optimized formulation was biophysically characterized. The neuroprotective efficacy of PS80-SA SLNs-IMX was then evaluated in vitro using cell lines (IMR-32 & N2a). Biodistribution study was carried out in Wistar rats to evaluate the site-specific distribution of IMX and SLNs. The optimized PS80-SA SLNs-IMX exhibited a particle size of 185.7 ± 2.7 nm, a polydispersity index of 0.22 ± 0.01, a ζ potential of -21.02 ± 1.53 mV, and an entrapment efficiency of 99.4 ± 0.12%. Surface morphology analysis revealed that they are spherical in shape, and in vitro release study revealed the sustained release of PS80-SA SLNs-IMX until 48 h. Accelerated stability study results revealed the formulation stability with negligible changes in the PS, PDI, and ZP up to 6 months. MTT assay results have shown that PS80-SA SLNs-IMX has a negligible cytotoxic effect. ROS and neuroprotective assays have demonstrated antioxidant and neuroprotective effects of PS80-SA SLNs-IMX against OKA-induced neurotoxicity. ELISA depicted a significant reduction in Aβ1-42 and p-tau upon treatment with PS80-SA SLNs-IMX. Western blot analysis confirmed the effect of PS80-SA SLNs-IMX on the inhibition of GSK-3β and the activation of the Wnt pathway. Biodistribution study results revealed that PS80-SA SLNs-IMX has a significant increase in brain concentration when compared to naïve IMX, indicating the brain-specific distribution of PS80-SA SLNs-IMX. In conclusion, PS80-SA SLNs-IMX demonstrated enhanced neuronal cell uptake and significant neuroprotective activity in vitro. To our knowledge, this is the first report of PS80-SA SLNs-IMX with high entrapment and robust neuroprotection in an okadaic acid (OKA)-induced tauopathy model, underscoring the translational potential for AD therapy.},
}

@article {pmid41091545,
year = {2025},
author = {Pérez-Toro, PA and J Ferrante, F and Pérez, G and Tee, BL and de Leon, J and Nöth, E and Schuster, M and Maier, A and Slachevsky, A and Gorno-Tempini, ML and Ibáñez, A and Orozco-Arroyave, JR and García, A},
title = {Automated Speech Markers of Alzheimer Dementia: Test of Cross-Linguistic Generalizability.},
journal = {Journal of medical Internet research},
volume = {27},
number = {},
pages = {e74200},
doi = {10.2196/74200},
pmid = {41091545},
issn = {1438-8871},
mesh = {Humans ; *Alzheimer Disease/diagnosis/physiopathology ; Female ; Male ; Aged ; *Speech ; *Linguistics ; Language ; Aged, 80 and over ; Middle Aged ; },
abstract = {BACKGROUND: Automated speech and language analysis (ASLA) is gaining momentum as a noninvasive, affordable, and scalable approach for the early detection of Alzheimer disease (AD). Nevertheless, the literature presents 2 notable limitations. First, many studies use computationally derived features that lack clinical interpretability. Second, a significant proportion of ASLA studies have been conducted exclusively in English speakers. These shortcomings reduce the utility and generalizability of existing findings.

OBJECTIVE: To address these gaps, we investigated whether interpretable linguistic features can reliably identify AD both within and across language boundaries, focusing on English- and Spanish-speaking patients and healthy controls (HCs).

METHODS: We analyzed speech recordings from 211 participants, encompassing 117 English speakers (58 patients with AD and 59 HCs) and 94 Spanish speakers (47 patients with AD and 47 HCs). Participants completed a validated picture description task from the Boston Diagnostic Aphasia Examination, eliciting natural speech under controlled conditions. Recordings were preprocessed and transcribed before extracting (1) speech timing features (eg, pause duration, speech segment ratios, and voice rate) and (2) lexico-semantic features (lexical category ratios, semantic granularity, and semantic variability). Machine learning classifiers were trained with data from English-speaking patients and HCs, and then tested (1) in a within-language setting (with English-speaking patients and HCs) and (2) in a between-language setting (with Spanish-speaking patients and HCs). Additionally, the features were used to predict cognitive functioning as measured by the Mini-Mental State Examination (MMSE).

RESULTS: In the within-language condition, combined speech timing and lexico-semantic features yielded maximal classification (area under the receiver operating characteristic curve [AUC]=0.88), outperforming single-feature models (AUC=0.79 for timing features; AUC=0.80 for lexico-semantic features). Timing features showed the strongest MMSE prediction (R=0.43, P<.001). In the between-language condition, speech timing features generalized well to Spanish speakers (AUC=0.75) and predicted Spanish-speaking patients' MMSE scores (R=0.39, P<.001). Lexico-semantic features showed lower performance (AUC=0.64) and no significant MMSE prediction (R=-0.31, P=.05). The combined model did not improve results (AUC=0.65; R=0.04, P=.79).

CONCLUSIONS: These results suggest that while both timing and lexico-semantic features are informative within the same language, only speech timing features demonstrate consistent performance across languages. By focusing on clinically interpretable features, this approach supports the development of clinically usable ASLA tools.},
}

Humans
*Alzheimer Disease/diagnosis/physiopathology
Female
Male
Aged
*Speech
*Linguistics
Language
Aged, 80 and over
Middle Aged