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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

DESIGN: Retrospective cohort study.

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

@article {pmid41134415,
year = {2025},
author = {Chen, KY and Chan, HC and Chan, CM},
title = {Does retinal vascular occlusion increase the risk of dementia? A pioneering systematic review and meta-analysis.},
journal = {Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology},
volume = {},
number = {},
pages = {},
pmid = {41134415},
issn = {1590-3478},
abstract = {INTRODUCTION: Retinal vascular occlusion (RVO), a common eye condition, has been hypothesized as a potential indicator of neurodegenerative risk. This systematic review and meta-analysis aimed to quantitatively assess the association between RVO and the subsequent development of dementia.

METHODS: A comprehensive search of major databases was conducted to identify cohort studies investigating the association between RVO and dementia. Data on hazard ratios (HRs) and odds ratios (ORs) for all-cause dementia, Alzheimer's disease, and vascular dementia were extracted. Pooled effect estimates were calculated using a random-effects model.

RESULTS: Six cohort studies with a pooled sample size of 4,638,720 participants were included. The pooled odds ratio for developing dementia in patients with RVO was 1.54 (95% CI (0.95, 2.47), p = 0.08; I² = 62%). The pooled hazard ratio for all-cause dementia was 1.04 (95% CI (0.92, 1.16), p = 0.56; I² = 93%). For Alzheimer's disease, the pooled HR was 1.01 (95% CI (0.91, 1.13), p = 0.83; I² = 78%). Notably, the pooled hazard ratio for vascular dementia showed a statistically significant increased risk in patients with RVO at 1.15 (95% CI (1.04, 1.28), p = 0.008; I² = 40%).

CONCLUSION: This meta-analysis suggests a significant association between RVO and increased vascular dementia risk, highlighting RVO as a potential marker for vascular-related cognitive decline, warranting further investigation.},
}

@article {pmid41134126,
year = {2025},
author = {Xu, Y and Li, X and Zhao, Q and Xu, X},
title = {The role of neutrophils, red blood cells, and platelets in the pathology of Alzheimer's disease.},
journal = {Annals of medicine},
volume = {57},
number = {1},
pages = {2575110},
doi = {10.1080/07853890.2025.2575110},
pmid = {41134126},
issn = {1365-2060},
mesh = {Humans ; *Alzheimer Disease/pathology/blood/immunology ; *Blood Platelets/metabolism/pathology ; *Neutrophils/metabolism/pathology ; *Erythrocytes/metabolism ; Blood-Brain Barrier/pathology/metabolism ; Amyloid beta-Peptides/metabolism ; Animals ; },
abstract = {INTRODUCTION: Alzheimer's disease (AD), the most prevalent form of neurodegenerative dementia, is characterized by core neuropathological hallmarks including abnormal deposition of β-amyloid forms neuroinflammatory plaques, hyperphosphorylated tau protein-driven neurofibrillary tangles, synaptic dysfunction, and progressive neuronal loss.

DISCUSSION: Emerging evidence transcends the traditional central nervous system (CNS)-centric perspective, revealing that neutrophils, red blood cells (RBCs), and platelets may play critical roles in AD pathogenesis by modulating systemic inflammatory responses, disrupting blood-brain barrier integrity, and participating in the CNS-peripheral interactions.

CONCLUSION: This review synthesizes recent advances in understanding the contributions of neutrophils, RBCs and platelets to AD pathology, which is promising to provide a transformative perspective and evidence for the in-depth understanding of the pathogenesis of AD and developing precision interventions against AD.},
}

Humans
*Alzheimer Disease/pathology/blood/immunology
*Blood Platelets/metabolism/pathology
*Neutrophils/metabolism/pathology
*Erythrocytes/metabolism
Blood-Brain Barrier/pathology/metabolism
Amyloid beta-Peptides/metabolism
Animals

@article {pmid41134110,
year = {2025},
author = {Volkmer, A and Boll, Y and Dibben, M and Ward, V and Townsend, R and Warren, JD and Hardy, CJD and , },
title = {The emotional journey through the stages of primary progressive aphasia: seven co-produced care pathway recommendations for clinical practice.},
journal = {Brain impairment : a multidisciplinary journal of the Australian Society for the Study of Brain Impairment},
volume = {26},
number = {4},
pages = {},
doi = {10.1071/IB25013},
pmid = {41134110},
issn = {1839-5252},
mesh = {Humans ; *Aphasia, Primary Progressive/therapy/psychology ; *Emotions/physiology ; *Caregivers/psychology ; Female ; Aged ; Male ; *Critical Pathways ; Middle Aged ; },
abstract = {Primary progressive aphasia (PPA) describes a group of language-led dementias associated with frontotemporal dementia and Alzheimer's disease. Speech and language therapy is the main intervention for PPA. Yet, there remains little guidance on the care requirements at the six stages of PPA (identified by Hardy et al. 2024a, 2024b). With the goal of generating care pathway recommendations, this co-produced study aimed to understand the opinions and perspectives of people affected by PPA (both people with PPA and their care partners). Informed by the People with Aphasia and Other Layperson Involvement framework for guiding patient and public involvement in aphasia research, this study used World Café methods to gather opinions and perspectives of people affected by PPA about a care pathway for PPA. Consequently, a survey was used to capture the emotional responses of care partners, also co-authors of the study. The World Café event highlighted the lack of awareness of PPA, and the need for timely access to relevant professionals from pre-diagnosis, during diagnosis, immediately after and then later post-diagnosis. The survey process enabled collaborators to reflect on their emotional responses to the six stages of PPA. From these, seven care pathway recommendations were synthesised. To better understand how we can meet the needs of people with PPA and their families it is essential that research is done with, rather than about them.},
}

Humans
*Aphasia, Primary Progressive/therapy/psychology
*Emotions/physiology
*Caregivers/psychology
Female
Aged
Male
*Critical Pathways
Middle Aged

@article {pmid41134085,
year = {2025},
author = {Xu, YJ and Wu, T and Lo, LT and Ko, CC and Wang, X and Ma, CHE},
title = {Microglial Deletion of Hrh4 Alleviates Alzheimer's Disease Pathologies by Enhancing Microglial Phagocytosis of Amyloid-β and Tau.},
journal = {Advanced science (Weinheim, Baden-Wurttemberg, Germany)},
volume = {},
number = {},
pages = {e05421},
doi = {10.1002/advs.202505421},
pmid = {41134085},
issn = {2198-3844},
support = {ITS/099/23FP//Innovation and Technology Commission of the Hong Kong Special Administrative Region (HKSAR) Government/ ; R1005-24F//Research Grant Council of the HKSAR Government/ ; CityU11100424//Research Grant Council of the HKSAR Government/ ; 08193956//Health and Medical Research Fund, Food and Health Bureau, HKSAR Government/ ; 32400807//National Natural Science Foundation of China/ ; },
abstract = {Amyloid-beta (Aβ) and hyperphosphorylated tau (p-tau) aggregation are hallmark pathogenic events in Alzheimer's disease (AD). Microglial clearance of these toxic aggregates is essential, yet the underlying mechanisms remain poorly understood. This study demonstrates that low-dose ionizing radiation (LDIR) provides protection against Aβ toxicity in vitro and rescues cognitive deficits in sporadic, young, and aged familial AD mouse models, including reductions in Aβ plaque, tauopathy, and microgliosis, while promoting microglial phagocytosis in aged 3xTg-AD mice. Transcriptomic analysis identifies VUF6002, a histamine H4 receptor (H4R) antagonist, which mimics the beneficial effects of LDIR by promoting microglial activity. VUF6002 treatment restores cognitive function in aged 3xTg-AD and APPswe/PSEN1dE9 mice and significantly increases Aβ and p-tau clearance by resident microglia. Mechanistically, deletion of Hrh4 in microglia, but not in neurons, reverses cognitive deficits and mitigates key AD pathogenesis by activating the cAMP/TGF-β1/Smad3 pathway. These beneficial effects are completely abolished by inhibition of TGF-β receptor 1 signaling, which is also downregulated in AD patients. Collectively, these findings reveal a H4R/cAMP/TGF-β1/Smad3 signaling axis involved in microglial phagocytosis and cognitive function, serving as a novel therapeutic target for AD.},
}

@article {pmid41133842,
year = {2025},
author = {Singh, B and Singh, K and Gupta, JK and Semwal, BC and Jain, D and Sharma, MC},
title = {Innovative Approaches in Molecular Docking for the Discovery of Novel Inhibitors Against Alzheimer's Disease.},
journal = {Current Alzheimer research},
volume = {},
number = {},
pages = {},
doi = {10.2174/0115672050386924250930184405},
pmid = {41133842},
issn = {1875-5828},
abstract = {INTRODUCTION: Alzheimer's disease (AD) is a debilitating neurodegenerative condition marked by progressive cognitive decline and memory impairment, affecting millions worldwide. Despite extensive research, no definitive cure exists, underscoring the need for innovative approaches to drug discovery and development.

METHODS: This review focuses on the application of molecular docking techniques in the context of AD drug discovery. The methodology involves the use of computational modeling tools to predict and analyze the interactions between small drug-like molecules and key protein targets implicated in AD pathogenesis, particularly amyloid-beta (Aβ) and tau proteins.

RESULTS: Molecular docking has enabled the virtual screening of large chemical libraries to identify potential inhibitors of Aβ aggregation and tau hyperphosphorylation. Numerous studies have validated docking-predicted interactions with in vitro and in vivo experiments, resulting in the discovery of novel compounds with promising pharmacological profiles. Docking has also aided in the optimization of ligand binding affinity and selectivity toward AD-relevant targets.

DISCUSSION: The integration of molecular docking with experimental techniques enhances the reliability and efficiency of the drug discovery process. Docking allows for the early identification of bioactive molecules, reducing time and cost compared to traditional methods. However, limitations such as rigid receptor assumptions and scoring function inaccuracies require further refinement.

CONCLUSION: Molecular docking stands out as a powerful computational tool in the quest for effective AD therapies. Simulating protein-ligand interactions accelerates the identification of potential drug candidates and supports the rational design of targeted interventions, paving the way for future clinical applications in combating Alzheimer's disease.},
}

@article {pmid41133841,
year = {2025},
author = {Yao, L and Ni, J and Wei, M and Li, T and Li, F and Wang, T and Xiao, W and Shi, J and Tian, J},
title = {Recent Advances in the Application of Artificial Intelligence in Alzheimer's Disease.},
journal = {Current Alzheimer research},
volume = {},
number = {},
pages = {},
doi = {10.2174/0115672050410489250930175402},
pmid = {41133841},
issn = {1875-5828},
abstract = {Artificial intelligence (AI) refers to a system that can simulate and execute the processes of human thinking and learning, and make informed decisions. Fueled by the development of AI, the quality and effectiveness of medical work have gained momentum. AI technology plays an increasingly important role in healthcare, exhibiting substantial potential in clinical practice and decision-making processes. In Alzheimer's disease (AD), where early diagnosis and treatment remain challenging due to clinical heterogeneity and insidious progression, AI could offer excellent solutions. AI models can integrate multi-modal data to identify pre-symptomatic biomarkers and stratify high-risk cohorts, improving diagnostic accuracy, assisting with personalizing treatment and care. Furthermore, AI can accelerate drug discovery and development through drug-target identification and predictive modeling of compound efficacy. However, data quality, supervision, transparency, privacy, and ethical concerns need to be addressed. By identifying and retrieving studies for the systematic review, this article provides a comprehensive overview of current progress and related AI applications in AD.},
}

@article {pmid41133799,
year = {2025},
author = {Estaún-Panzano, J and Dembitskaya, Y and Calaresu, I and Nandi, S and Gresil, Q and Doudnikoff, E and Leste-Laserre, T and Amédée, T and Cognet, L and Groc, L and Nägerl, UV and Bezard, E},
title = {Nanoscopic Mapping of the Extracellular Space in Amyloid Plaque-rich Cortex.},
journal = {Advanced science (Weinheim, Baden-Wurttemberg, Germany)},
volume = {},
number = {},
pages = {e15674},
doi = {10.1002/advs.202515674},
pmid = {41133799},
issn = {2198-3844},
support = {RGP0036/2020//Human Frontier Science Program/ ; 951294//H2020 European Research Council/ ; },
abstract = {A hallmark of Alzheimer's disease (AD) is the accumulation of amyloid plaques, primarily composed of misfolded amyloid β (Aβ) peptides. Complementary high-resolution imaging techniques are employed to investigate the plaque penetrability and the extracellular space (ECS) rheology in a mouse model of AD. Two-photon shadow imaging in vivo confirms that a dense ring of cells surrounds cortical amyloid plaques but highlights the diffusional penetrability of the amyloid core. Quantum dot tracking unveils that ECS diffusional parameters are heterogeneous in and around plaques, with an elevated diffusivity within and around plaques compared to wild-type-tissue. The amyloid core shows low nanoparticle density, varying by plaque phenotype. Carbon nanotube tracking confirms these altered local rheological properties at the level of the whole cortex of AD mice. Finally, the extracellular matrix is found to be dysregulated within the amyloid plaque, which may account for the observed alterations in diffusivity. This study provides fresh insights for understanding Aβ plaque penetration, a prerequisite for therapeutic development.},
}

@article {pmid41133666,
year = {2025},
author = {Glueck, J and Pluim McDowell, C and Quiroz, YT and Cronin-Golomb, A and Duffy, JF},
title = {Self-Reported Insomnia and Poor Sleep Quality Are Associated with Self-Reported Cognitive Changes in Older Adults.},
journal = {Clocks & sleep},
volume = {7},
number = {4},
pages = {},
doi = {10.3390/clockssleep7040056},
pmid = {41133666},
issn = {2624-5175},
support = {1T32HL007901-22/NH/NIH HHS/United States ; 1F31AG081066-22/NH/NIH HHS/United States ; 1R01AG066823-22/NH/NIH HHS/United States ; 1P30AG072978-22/NH/NIH HHS/United States ; 1R01HL148704-22/NH/NIH HHS/United States ; 1R01AG044416-22/NH/NIH HHS/United States ; },
abstract = {Older adults are vulnerable to changes in sleep with age. Poor sleep quality is associated with self-reported cognitive changes, which can occur before the onset of objective cognitive decline associated with Mild Cognitive Impairment and Alzheimer's disease. The objective of this study was to examine associations between self-reported sleep complaints, objective sleep quality, and self-reported cognitive changes and their relations to symptoms of depression and anxiety in a group of community-dwelling older adults. Adults aged ≥ 50 without dementia (n = 45) were recruited and completed 1-2 weeks of rest-activity monitoring using a wrist-worn device, underwent a test of global cognitive functioning (Mini-Mental State Examination; MMSE), and completed questionnaires assessing insomnia (Insomnia Severity Index; ISI), subjective sleep quality (Pittsburgh Sleep Quality Index; PSQI), self-reported cognitive changes (Cognitive Function Instrument; CFI), and symptoms of depression and anxiety (Beck Depression Inventory-II; BDI-II and Generalized Anxiety Disorder 7-item assessment; GAD-7). Pearson partial correlations assessed relations among subjective and objective sleep quality, insomnia ratings, CFI ratings, and global cognition, while controlling for BDI-II and GAD-7 ratings. Exploratory analyses examined the correlation between PSQI component scores and CFI ratings and global cognition. Greater ISI (r = 0.50, p ≤ 0.001) ratings significantly correlated with higher CFI scores. PSQI total ratings and actigraphy-based measures (n = 41) did not significantly correlate with CFI scores. Exploratory PSQI subscale analyses revealed that worse subjective sleep quality (r = 0.31, p = 0.048), shorter sleep duration (r = 0.32, p = 0.04), and greater use of sleep medications (r = 0.31, p = 0.048) correlated with higher CFI scores. Poorer sleep quality due to less time spent asleep, fragmented or disturbed sleep, and requiring medications to sleep, may be associated with greater memory concerns. Alternatively, worries about cognition may deleteriously affect sleep. Subjective measures of sleep quality may be useful to identify older adults at increased risk of cognitive decline.},
}

@article {pmid41133637,
year = {2025},
author = {Burles, F and Sallis, E and Kopala-Sibley, DC and Iaria, G and , },
title = {Mitigating Head Position Bias in Perivascular Fluid Imaging: LD-ALPS, a Novel Method for DTI-ALPS Calculation.},
journal = {NeuroSci},
volume = {6},
number = {4},
pages = {},
doi = {10.3390/neurosci6040101},
pmid = {41133637},
issn = {2673-4087},
support = {Wayfinding//Canadian Space Agency/ ; },
abstract = {BACKGROUND/OBJECTIVES: The glymphatic system is a recently characterized glial-dependent waste clearance pathway in the brain, which makes use of perivascular spaces for cerebrospinal fluid exchange. Diffusion tensor imaging analysis along the perivascular space (DTI-ALPS) offers a non-invasive method for estimating perivascular flow, but its biological specificity and susceptibility to methodological variation, particularly head position during MRI acquisition, remain as threats to the validity of this technique. This study aimed to assess the prevalence of current DTI-ALPS practices, evaluate the impact of head orientation on ALPS index calculation, and propose a novel computational approach to improve measurement validity.

METHODS: We briefly reviewed DTI-ALPS literature to determine the use of head-orientation correction strategies. We then analyzed diffusion MRI data from 172 participants in the Alzheimer's Disease Neuroimaging Initiative (ADNI) to quantify the influence of head orientation on ALPS indices computed using the conventional Unrotated-ALPS, a vecrec-corrected ALPS, and the new LD-ALPS method proposed within.

RESULTS: A majority of studies employed Unrotated-ALPS, which does not correct for head orientation. In our sample, Unrotated-ALPS values were significantly associated with absolute head pitch (r169 = -0.513, p < 0.001), indicating systematic bias. This relationship was eliminated using either vecreg or LD-ALPS. Additionally, LD-ALPS showed more sensitivity to cognitive status as measured by Mini-Mental State Examination scores.

CONCLUSIONS: Correcting for head orientation is essential in DTI-ALPS studies. The LD-ALPS method, while computationally more demanding, improves the reliability and sensitivity of perivascular fluid estimates, supporting its use in future research on aging and neurodegeneration.},
}

@article {pmid41133633,
year = {2025},
author = {Borgonovo, R and Nespoli, LM and Ceroni, M and Arnaud, LM and Morellini, L and Lissi, M and Sacco, L},
title = {Potential Genetic Intersections Between ADHD and Alzheimer's Disease: A Systematic Review.},
journal = {NeuroSci},
volume = {6},
number = {4},
pages = {},
doi = {10.3390/neurosci6040097},
pmid = {41133633},
issn = {2673-4087},
abstract = {BACKGROUND: attention-deficit/hyperactivity disorder (ADHD) and Alzheimer's disease (AD) are distinct neurological conditions that may share genetic and molecular underpinnings. ADHD, a neurodevelopmental disorder, affects approximately 5% of children and 3% of adults globally, while AD, a neurodegenerative disorder, is the leading cause of dementia in older adults. Emerging evidence suggests potential overlapping contributors, including pathways related to synaptic plasticity, neuroinflammation, and oxidative stress.

METHODS: this systematic review investigated potential genetic predispositions linking Attention-Deficit/Hyperactivity Disorder (ADHD) and Alzheimer's Disease (AD). Following PRISMA guidelines, a search was conducted in Web of Science, Embase, PsycINFO, and PubMed using keywords related to ADHD, AD, and genetic factors. Studies included were original human studies utilizing genetic analyses and ADHD polygenic risk scores (PRS), with AD confirmed using established diagnostic criteria. Exclusion criteria comprised non-original studies, animal research, and articles not addressing genetic links between ADHD and AD. Screening was conducted with Rayyan software (version 1.4.3), assessing relevance based on titles, abstracts, and full texts.

RESULTS: . The search identified 1450 records, of which 1092 were screened after duplicates were removed. Following exclusions, two studies met inclusion criteria. One study analyzed ADHD-PRS in 212 cognitively unimpaired older adults using amyloid-beta (Aβ) PET imaging and tau biomarkers. The findings revealed that ADHD-PRS was associated with progressive cognitive decline, increased tau pathology, and frontoparietal atrophy in Aβ-positive individuals, suggesting that ADHD genetic liability may exacerbate AD pathology. Another study assessed ADHD-PRS in a cohort of 10,645 Swedish twins, examining its association with 16 somatic conditions. The results showed modest risk increases for cardiometabolic, autoimmune, and neurological conditions, with mediation effects through BMI, education, tobacco use, and alcohol misuse, but no direct link between ADHD-PRS and dementia.

DISCUSSION AND CONCLUSIONS: this review highlights preliminary but conflicting evidence for a genetic intersection between ADHD and AD. One study suggests that ADHD genetic liability may exacerbate AD-related pathology in Aβ-positive individuals, whereas another large registry-based study finds no direct link to dementia, with associations largely mediated by lifestyle factors. The potential ADHD-AD relationship is likely complex and context-dependent, influenced by biomarker status and environmental confounders. Longitudinal studies integrating genetics, biomarkers, and detailed lifestyle data are needed to clarify this relationship.},
}

@article {pmid41133436,
year = {2025},
author = {},
title = {Correction to "Identification of 16 novel Alzheimer's disease loci using multi-ancestry meta-analyses".},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21},
number = {10},
pages = {e70854},
doi = {10.1002/alz.70854},
pmid = {41133436},
issn = {1552-5279},
}

@article {pmid41133401,
year = {2025},
author = {Doecke, JD and Stage, E and Fowler, C and Doré, V and Boehm, N and Kleinert, C and Challagundla, M and Feizpour, A and Ward, L and Fripp, J and Masters, CL and Rowe, C and Bannon, A},
title = {Multivariate models using NULISAseq and plasma p-tau217 for staging Alzheimer's disease.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21},
number = {10},
pages = {e70793},
doi = {10.1002/alz.70793},
pmid = {41133401},
issn = {1552-5279},
support = {//AbbVie/ ; //Eisai/ ; //Roche/ ; //Australian National Health/ ; /MRC_/Medical Research Council/United Kingdom ; //Enigma Australia/ ; //Alzheimer's Association Australia/ ; //Alzheimer's Drug Discovery Foundation/ ; //Bright Focus Foundation/ ; },
mesh = {Humans ; *Alzheimer Disease/blood/diagnostic imaging/diagnosis ; *tau Proteins/blood ; Female ; Male ; Biomarkers/blood ; Aged ; Positron-Emission Tomography ; Amyloid beta-Peptides ; Australia ; Multivariate Analysis ; Aged, 80 and over ; },
abstract = {INTRODUCTION: Plasma phospho-tau217 (p-tau217) has been shown to demonstrate equal performance to cerebrospinal fluid (CSF) to predict amyloid beta (Aβ) positivity. Although such high-performing plasma tests provide confirmatory information on Aβ status, further information is desperately needed to discern optimal blood-based biomarkers (BBMs) across the Alzheimer's disease (AD) stage.

METHODS: From the Australian Imaging, Biomarkers and Lifestyle study, 387 participants underwent [[18]F]NAV4694 (Aβ) and [[18]F]MK-6240 (tau) PET scans, a blood test to measure for p-tau217 (ALZpath and Lumipulse), and the Alamar Biosciences NULISASeq platform (120 central nervous system [CNS] and 250 inflammatory proteins). Individual p-tau217 assays were compared with selected biomarker sets from the Alamar panel to predict AD stage.

RESULTS: Using a panel of biomarkers was significantly better at predicting disease stage compared with p-tau217 alone; however, the difference was dependent upon p-tau217 assay.

DISCUSSION: Utility of extra BBMs in addition to p-tau217 provides useful information regarding overall disease burden during the separate stages of AD.

HIGHLIGHTS: Of the separate assays for p-tau217, the Lumipulse assay demonstrated significantly better performance than the ALZpath assay to separate disease stages. Multivariate blood-based biomarker (BBM) models are significantly better at predicting the presence of A/T from A-T- as compared with any p-tau217 assay. Multivariate BBM models have higher area under the curve values to predict disease stage than Alamar and ALZpath p-tau217, but not Lumipulse p-tau217 during later disease stage comparisons.},
}

Humans
*Alzheimer Disease/blood/diagnostic imaging/diagnosis
*tau Proteins/blood
Female
Male
Biomarkers/blood
Aged
Positron-Emission Tomography
Amyloid beta-Peptides
Australia
Multivariate Analysis
Aged, 80 and over

@article {pmid41133228,
year = {2025},
author = {Wang, S and Shi, Y and Xin, R and Kang, H and Xiong, H and Ren, J},
title = {Exploring the role of insulin resistance in bridging the metabolic syndrome and Alzheimer's disease-a review of mechanistic studies.},
journal = {Frontiers in endocrinology},
volume = {16},
number = {},
pages = {1614006},
pmid = {41133228},
issn = {1664-2392},
mesh = {*Insulin Resistance/physiology ; Humans ; *Alzheimer Disease/metabolism/pathology/etiology ; *Metabolic Syndrome/metabolism/pathology ; Animals ; Oxidative Stress ; Renin-Angiotensin System ; },
abstract = {The association between metabolic syndrome (MetS) and Alzheimer's disease (AD) has attracted widespread attention; nevertheless, the precise mechanism of action between the two is not yet fully elucidated. This review systematically explores the complex mechanisms of insulin resistance (IR) in MetS and AD. We first detail the intrinsic mechanisms of insulin resistance and emphasize its central role in the pathophysiology of MetS. Further, we reveal the underlying mechanisms by which insulin resistance in turn triggers AD through a multidimensional pathway that promotes the accumulation of pathological products, induces blood-brain barrier dysfunction, impairs neuroplasticity, induces neuroinflammatory responses, aberrantly activates the renin-angiotensin-aldosterone system, and exacerbates oxidative stress. In addition, we summarize potential strategies for targeting IR in AD treatment and demonstrate the promising prospects for improving insulin resistance in promoting cognitive recovery. This study offers a novel theoretical framework for elucidating the intricate relationship between MetS and AD. Furthermore, it provides a scientific foundation for the formulation of preventive and therapeutic strategies for metabolic and neurodegenerative diseases.},
}

*Insulin Resistance/physiology
Humans
*Alzheimer Disease/metabolism/pathology/etiology
*Metabolic Syndrome/metabolism/pathology
Animals
Oxidative Stress
Renin-Angiotensin System

@article {pmid41132837,
year = {2025},
author = {Jiang, S and Tian, Z and Yang, Y and Li, X and Zhou, F and Cheng, J and Lyu, J and Gao, T and Zhang, P and Han, H and Tong, Z},
title = {New insights into translational research in Alzheimer's disease guided by artificial intelligence, computational and systems biology.},
journal = {Acta pharmaceutica Sinica. B},
volume = {15},
number = {10},
pages = {5099-5126},
pmid = {41132837},
issn = {2211-3835},
abstract = {Alzheimer's disease (AD) is characterized by cognitive and functional deterioration, with pathological features such as amyloid-beta (Aβ) aggregates in the extracellular spaces of parenchymal neurons and intracellular neurofibrillary tangles formed by the hyperphosphorylation of tau protein. Despite a thorough investigation, current treatments targeting the reduction of Aβ production, promotion of its clearance, and inhibition of tau protein phosphorylation and aggregation have not met clinical expectations, posing a substantial obstacle in the development of drugs for AD. Recently, artificial intelligence (AI), computational biology (CB), and systems biology (SB) have emerged as promising methodologies in AD research. Their capacity to analyze extensive and varied datasets facilitates the identification of intricate patterns, thereby enriching our comprehension of AD pathology. This paper provides a comprehensive examination of the utilization of AI, CB, and SB in the diagnosis of AD, including the use of imaging omics for early detection, drug discovery methods such as lecanemab, and complementary therapies like phototherapy. This review offers novel perspectives and potential avenues for further research in the realm of translational AD studies.},
}

@article {pmid41132828,
year = {2025},
author = {Ren, L and Ma, X and Ye, J},
title = {A mechanism underlying the association of Aβ plaque and lipid droplets in Alzheimer's disease.},
journal = {Acta pharmaceutica Sinica. B},
volume = {15},
number = {10},
pages = {5486-5488},
pmid = {41132828},
issn = {2211-3835},
}

@article {pmid41132791,
year = {2025},
author = {Wang, X and Wu, Z and Wei, S and Zhao, X and Lin, J and Zhao, F and Liu, X},
title = {Integrated transcriptomic and single-cell RNA sequencing identifies lysosomal ion channel genes as potential biomarkers for Alzheimer's disease.},
journal = {Frontiers in genetics},
volume = {16},
number = {},
pages = {1676565},
pmid = {41132791},
issn = {1664-8021},
abstract = {Previous research has highlighted lysosomal ion channel-related genes (LICRGs) as promising therapeutic targets for neurodegenerative diseases. This study aimed to identify and analyze LICRG-associated biomarkers for Alzheimer's disease (AD), elucidating their underlying biological mechanisms. Three datasets (GSE63061, GSE63060, GSE181279) were analyzed. In GSE63061, intersecting genes were identified by integrating differentially expressed genes (DEGs) from differential expression analysis with key module genes from Weighted Gene Co-expression Network Analysis (WGCNA). Candidate biomarkers were then selected using the MCODE plugin for PPI analysis (top 30 genes), two machine learning approaches, and cross-validation of gene expression profiles in GSE63061 and GSE63060. Single-cell RNA sequencing (scRNA-seq) analysis of GSE181279 identified key biomarkers and cell populations, followed by pseudo-temporal analysis of these cells. Nomogram construction, functional enrichment analysis, immune infiltration assessment, and RT-qPCR analysis were subsequently performed. scRNA-seq analysis revealed that SRP14, EIF3E, and COX7C were prominently expressed across most cell types, particularly in CD4[+] T cells, which were identified as key cells in AD. Pseudo-temporal analysis indicated that CD4[+] T cells from control subjects primarily resided in early differentiation stages, whereas those from patients with AD were predominantly found in later stages. The reduced expression of these biomarkers in AD CD4[+] T cells was consistent with transcriptomic data and further validated by RT-qPCR. A nomogram incorporating these biomarkers demonstrated strong predictive power for AD risk. Functional analysis linked the biomarkers to pathways such as "ribosome" and "oxidative phosphorylation." Immune infiltration analysis revealed 23 differentially abundant immune cell types, with significant correlations between all three biomarkers and memory CD4[+] T cells, mesangial cells, and other immune cell types. This study identified SRP14, EIF3E, and COX7C as novel biomarkers, underscoring CD4[+] T cells as pivotal in AD pathogenesis. These findings offer new mechanistic insights and potential therapeutic strategies for AD.},
}

@article {pmid41132780,
year = {2025},
author = {Hassanaly, R and Solal, M and Colliot, O and Burgos, N and , },
title = {Benchmarking 3D generative autoencoders for pseudo-healthy reconstruction of brain [18]F-fluorodeoxyglucose positron emission tomography.},
journal = {Journal of medical imaging (Bellingham, Wash.)},
volume = {12},
number = {5},
pages = {054005},
pmid = {41132780},
issn = {2329-4302},
abstract = {PURPOSE: Many deep generative models have been proposed to reconstruct pseudo-healthy images for anomaly detection. Among these models, the variational autoencoder (VAE) has emerged as both simple and efficient. Although significant progress has been made in refining the VAE within the field of computer vision, these advancements have not been extensively applied to medical imaging applications.

APPROACH: We present a benchmark that assesses the ability of multiple VAEs to reconstruct pseudo-healthy neuroimages for anomaly detection in the context of dementia. We first propose a rigorous methodology to define the optimal architecture of the vanilla VAE and select through random searches the best hyperparameters of the VAE variants. Relying on a simulation-based evaluation framework, we thoroughly assess the ability of 20 VAE models to reconstruct pseudo-healthy images for the detection of dementia-related anomalies in 3D brain F 18 -fluorodeoxyglucose (FDG) positron emission tomography (PET) and compare their performance.

RESULTS: This benchmark demonstrated that the majority of the VAE models tested were able to reconstruct images of good quality and generate healthy-looking images from simulated images presenting anomalies.

CONCLUSIONS: Even if no model clearly outperformed all the others, the benchmark allowed identifying a few models that perform slightly better than the vanilla VAE. It further showed that many VAE-based models can generalize to the detection of anomalies of various intensities, shapes, and locations in 3D brain FDG PET.},
}

@article {pmid41132687,
year = {2025},
author = {Billaud, CHA and Yu, J and , },
title = {Structure-function coupling using fixel-based analysis and functional magnetic resonance imaging in Alzheimer's disease and mild cognitive impairment.},
journal = {Network neuroscience (Cambridge, Mass.)},
volume = {9},
number = {3},
pages = {969-989},
pmid = {41132687},
issn = {2472-1751},
abstract = {Functional MRI (fMRI) and diffusion-weighted imaging (DWI) help explore correlations between structural connectivity (SC) and functional connectivity (FC; SC-FC coupling). Studies on mild cognitive impairment (MCI) and Alzheimer's disease (AD) observed coupling disruptions, co-occurring with cognitive decline. Advanced "fixel-based" analyses improved DWI's accuracy in assessing microstructural and macrostructural features of white matter (WM), but previous aging coupling studies commonly defined SC via tensor-based tractography and streamline counts, thereby missing fiber-specific information. We investigated different types of fixel-FC coupling and their relation to cognition in 392 participants (Agemean = 73; 207 females) from the ADNI. Two hundred twenty-five controls, 142 MCI, and 25 AD with diffusion-weighted and resting-state fMRI scans were analyzed. Structural connectomes were constructed using average fixel metrics (fiber density (FD), fiber-bundle cross-section log, and combined [FDC]) as edges. SC-FC coupling for each SC metric was calculated at overall network, edge, and node levels. Overall DMN, node- and edge-specific coupling differences were found across SC measures and groups. DMN nodal coupling significantly predicted Mini-Mental Status Examination score and verbal memory. In conclusion, different types of fixel-based coupling alterations can be observed across the neurocognitive aging spectrum, in particular, FD-FC and FDC-FC coupling between DMN regions are associated with cognitive functioning.},
}

@article {pmid41132659,
year = {2025},
author = {Mao, J and Wu, S and Yan, Z and Huang, G and Yu, Y},
title = {Neutrophil extracellular traps as therapeutics target in vascular aging.},
journal = {Frontiers in immunology},
volume = {16},
number = {},
pages = {1657938},
pmid = {41132659},
issn = {1664-3224},
mesh = {*Extracellular Traps/immunology/metabolism/drug effects ; Humans ; *Aging/immunology ; Animals ; *Neutrophils/immunology/metabolism ; Inflammation/immunology ; },
abstract = {Blood vessels are critical in systemic aging with arteries stiffening and calcifying due to chronic inflammation and oxidative stress, driving age-related cardiovascular and cerebrovascular diseases. In this review, neutrophil extracellular traps (NETs) -web-like structures composed of decondensed chromatin, histones, and antimicrobial proteins released by neutrophils-are explored as therapeutic targets in vascular aging. NETs are vital for pathogen defense, but their excessive activation leads to inflammation and vascular pathologies, promoting endothelial dysfunction, inflammatory aging, and vascular remodeling in diseases such as hypertension, atherosclerosis, myocardial infarction, heart failure, atrial fibrillation, ischemic stroke, and Alzheimer's disease. Increasing evidence supports that modulating NETs through inhibitors or scavengers can reduce inflammatory responses, preserve endothelial integrity, and improve prognosis. As a potential therapeutic target, growing attention has been directed toward exploring the balance between NET induction, inhibition, and degradation.},
}

*Extracellular Traps/immunology/metabolism/drug effects
Humans
*Aging/immunology
Animals
*Neutrophils/immunology/metabolism
Inflammation/immunology

@article {pmid41132583,
year = {2025},
author = {Zou, Z and Lei, D and Wang, X and Yin, Y and Li, H and Di, X and Li, X},
title = {Crocin Ameliorates Cognitive Impairment and Pathological Changes in Alzheimer's Disease Model Mice by Regulating Gut Microbiota.},
journal = {Food science & nutrition},
volume = {13},
number = {10},
pages = {e71117},
pmid = {41132583},
issn = {2048-7177},
abstract = {Alzheimer's disease (AD), a primary cause of dementia, places a significant strain on both patients and society due to the absence of effective treatments. Recent research suggests that the gut microbiota may play a role in the development of AD. Crocin, a compound derived from traditional medicine, has demonstrated potential in alleviating neurological disorders and influencing gut microbiota, yet its specific mechanisms in AD remain unclear. In this study, we administered Crocin or saline to 5xFAD mice and wild-type controls. We discovered that Crocin treatment led to notable improvements in cognitive function, as measured by the Morris water maze test, reduced beta-amyloid (Aβ) accumulation, and decreased neuroinflammation, as indicated by reduced microglial and astrocyte activation. Metagenomic sequencing revealed a significant increase in the gut microbiota diversity, specifically the abundance of Firmicutes, Verrucomicrobiota, and Akkermansia. Additionally, Crocin enhanced intestinal barrier function by upregulating tight junction proteins and Secretory immunoglobulin A, while improving the structure of the jejunal mucosa. These results suggest that Crocin may alleviate cognitive deficits and neuropathological changes in 5xFAD mice, possibly through modulation of the gut microbiota and strengthening the gut barrier, presenting it as a promising therapeutic approach for AD.},
}

@article {pmid41132573,
year = {2025},
author = {Sriramcharan, P and Ahmed, SS and Natarajan, J and Kumar, RR and Antony, J and Kumar, AP and Anjali, PB and Ganganagappa, N and Shah, RM and Madar, IH},
title = {Cerium oxide nanoparticles synthesized via green route exhibit neuroprotective effects in Alzheimer's-induced Albino Wistar rats.},
journal = {3 Biotech},
volume = {15},
number = {11},
pages = {398},
pmid = {41132573},
issn = {2190-572X},
abstract = {UNLABELLED: Green synthesis of cerium oxide nanoparticles emerges as a feasible therapeutic strategy for disorders like Alzheimer's to determine its antioxidant and cytotoxicity in the in vitro environment, following in vivo studies, safety and effectiveness were confirmed. This approach has gained increased reliability compared to physical and chemical methods due to its non-toxic and environmentally friendly nature. The synthesized nanoparticles are then characterized using Fourier transform infrared spectrometry (FTIR), particle size, scanning electron microscopy (SEM), X-ray diffraction (XRD), and Raman spectroscopy. Design optimization was applied to the selected variables to get the best-fit values of the experiment. FTIR spectroscopy revealed amide, carboxyl, and ester groups in the cerium oxide particles produced by Candida albicans, indicating their significance in nanoparticle stabilization. The particle size and zeta potential of cerium oxide nanoparticles were found to be 152 nm and - 15 mV, respectively. Various antioxidant studies, such as 2, 2-Diphenyl-2-Picryl Hydrazyl (DPPH), 2,2'-azino-bis (3-ethylbenzothiazoline-6-sulfonic acid (ABTS), anti-lipid peroxidation, and catalase, were conducted, revealing that synthesized nanoparticles had high antioxidant activity. SEM images produced high-quality, evenly distributed images. Cerium oxide nanoparticles effectively inhibited SK-N-SH human neuroblastoma cells, with an IC50 value of 65 µg/ml. An in vivo study was performed using an amyloid-beta-induced intracerebroventricular rat model. The finding demonstrates the induction of AD in rats led to spatial memory impairments, whereas the treatment with cerium oxide nanoparticles suggests a significant improvement in neuroprotective effect. This outcome was validated through Morris water maze behavioral assessment and histopathological analysis. The results indicated that the synthesized cerium oxide nanoparticles, optimizing using the Box-Behnken design, resulted in strong antioxidant and cytotoxic activities (65%).

SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s13205-025-04563-4.},
}

@article {pmid41132242,
year = {2025},
author = {Yanai, H and Adachi, H and Hakoshima, M and Katsuyama, H},
title = {Adenosine Monophosphate-Activated Protein Kinase Activation and Mammalian Target of Rapamycin Complex 1 Inhibition: A Mechanistic Rationale for Anti-Aging Therapy in Type 2 Diabetes.},
journal = {Journal of clinical medicine research},
volume = {17},
number = {9},
pages = {469-489},
pmid = {41132242},
issn = {1918-3003},
abstract = {Aging is a complicated biological process that induces a decline in the human organs' structure and function and elevates the risks of aging-related diseases such as Alzheimer's disease (AD) and type 2 diabetes. Type 2 diabetes accelerates all clinical manifestations of aging. Metabolic disorders in type 2 diabetes are unfavorably associated with all hallmarks of aging, such as inflammation and mitochondrial dysfunction. Adenosine monophosphate-activated protein kinase (AMPK) and the mammalian target of rapamycin complex 1 (mTORC1) are key players in cellular metabolism, and AMPK activation and mTORC1 inhibition improve all hallmarks of aging. AMPK activation and mTORC1 inhibition are favorably associated with diabetic complications. Nutritional interventions, such as caloric restriction, resveratrol, and astaxanthin, have AMPK-activating and mTORC1-inhibitory effects and improve metabolic abnormalities in type 2 diabetes. Anti-diabetic drugs, metformin, sodium-glucose cotransporter-2 inhibitors, and glucagon-like peptide 1 receptor agonists have been reported to have AMPK-activating and mTORC1-inhibiting effects and show prevention of aging-related diseases such as cardiovascular disease. The therapeutic interventions that activate AMPK and inhibit mTORC1 may be optimal treatments for type 2 diabetes from the perspective of anti-aging medicine. Furthermore, senolytics may be a promising, direct anti-aging therapeutic strategy specifically for type 2 diabetes and its complications.},
}

@article {pmid41131969,
year = {2025},
author = {Matusz, EF and Fiala, J and Kiselica, AM and Rosselli, M and Armstrong, MJ and Holgerson, AA and Levy, SA and Arias, F and Vélez-Uribe, I and Duara, R and Curiel Cid, RE and Loewenstein, DA and Smith, GE and Marsiske, M and Asken, BM},
title = {Cognitive factor structure of the NACC UDS-3 neuropsychological battery across ethno-racial, linguistic, and cognitive status groups.},
journal = {The Clinical neuropsychologist},
volume = {},
number = {},
pages = {1-23},
doi = {10.1080/13854046.2025.2576154},
pmid = {41131969},
issn = {1744-4144},
abstract = {Objective: There are diagnostic disparities in dementia across ethno-racial communities. The potential contribution of measurement bias in cognitive assessments was investigated by examining the factor structure and measurement invariance of the Uniform Data Set neuropsychological battery (UDS3-NB) across ethno-racial groups as well as Spanish and English speakers along a cognitive continuum. Methods: Data were from the National Alzheimer's Coordinating Center (NACC) and the 1Florida Alzheimer's Disease Research Center (1FLADRC). Confirmatory factor analyses were conducted in NACC (n = 29,462; M age = 71.0, SD = 10.4; 58.5% female, M education = 15.8, SD = 3.0; 68.6% non-Hispanic White, 5.3% -primary Spanish speaking) to determine the UDS3-NB factor structure. Measurement invariance was tested in NACC and separately within 1FLADRC (n = 829; M age = 69.9, SD = 8.5; 56.5% female; M education = 14.6, SD = 3.5 years; 33.3% non-Hispanic White, 33.8% primary Spanish speaking), across ethno-racial (non-Hispanic White, Hispanic White, Black/African American), primary language (English, Spanish), and cognitive status (cognitively normal, mild cognitive impairment, dementia). Invariance was assessed at configural, metric, scalar, and strict levels. Results: A 4-factor model (memory, processing speed/executive functioning, language, attention) demonstrated acceptable to good fit in NACC (CFI = 0.97, TLI = 0.96, RMSEA = 0.07, SRMR = 0.03) and 1FLADRC (CFI = 0.97, TLI = 0.96, RMSEA = 0.05, SRMR = 0.04). Standardized factor loadings ranged from 0.43-0.87. Metric invariance was supported across all contrasts in both cohorts. Higher levels of invariance were cohort-dependent: CN vs. MCI achieved strict invariance in both cohorts, whereas non-Hispanic White vs. Hispanic White and English vs. Spanish only achieved strict invariance in NACC. Conclusions: The UDS3-NB demonstrates structural validity and metric equivalence across ethno-racial, linguistic, and cognitive status groups.},
}

@article {pmid41131967,
year = {2025},
author = {Javed, A and Mandal, P and Khan, I and Singh, A and Akhtar, J and Maheshwari, S and Prajapati, BG},
title = {Liposomal Drug Delivery for Neurological Disorders: Advances and Challenges.},
journal = {Central nervous system agents in medicinal chemistry},
volume = {25},
number = {3},
pages = {245-260},
pmid = {41131967},
issn = {1875-6166},
mesh = {Humans ; *Liposomes/chemistry/administration & dosage/metabolism ; *Drug Delivery Systems/methods/trends ; *Nervous System Diseases/drug therapy/metabolism ; Animals ; Blood-Brain Barrier/drug effects/metabolism ; *Neuroprotective Agents/administration & dosage ; },
abstract = {Liposomal drug delivery methods are becoming increasingly viable options for improving treatment outcomes for neurological illnesses. These systems provide a flexible framework for the formulation of medications intended for delivery to the brain, protecting the medication from enzymatic breakdown and enhancing its bioavailability. To maximize liposome-drug interactions and improve brain-targeted delivery efficiency, a variety of formulation strategies are used, such as surface modification and remote loading. By utilizing various pathways to cross the blood- -brain barrier (BBB), such as passive diffusion and receptor-mediated transcytosis, liposomes facilitate the effective transport of therapeutic drugs to the brain parenchyma. Liposomal formulations show potential for targeted drug delivery, reducing off-target effects, and improving treatment efficacy in neurological conditions like Parkinson's disease, Alzheimer's disease, stroke, multiple sclerosis, and brain cancers. For instance, in Parkinson's disease, liposomal delivery of neuroprotective agents can help maintain dopamine levels and protect dopaminergic neurons. In Alzheimer's disease, liposomes can be engineered to deliver drugs that reduce amyloid-beta plaques or tau tangles. For brain cancer, liposomal chemotherapy can target tumor cells more precisely while minimizing damage to surrounding healthy tissue. In stroke, liposomal delivery of neuroprotective agents can reduce the extent of brain damage, while in multiple sclerosis, liposomes can be used to deliver drugs that modulate the immune response. However, the clinical translation of liposomal drug delivery systems for brain diseases faces challenges related to scalability, stability, and immunogenicity, in addition to regulatory barriers. Scalability issues arise from the complex manufacturing processes required to produce liposomes consistently on a large scale. Stability concerns involve maintaining the integrity of liposomes during storage and after administration. Immunogenicity can be a problem if the liposomes trigger an unwanted immune response, potentially reducing their effectiveness or causing adverse effects. To overcome these obstacles, multidisciplinary cooperation is essential. Collaboration among materials scientists, pharmacologists, neurologists, and regulatory experts can drive the development of more robust liposomal formulations. Continuous research is needed to refine liposome designs, such as by optimizing lipid composition, surface charge, and size to improve stability and targeting capabilities. Advanced techniques like PEGylation (coating liposomes with polyethylene glycol) can help reduce immunogenicity and extend circulation time in the bloodstream. Despite these challenges, liposomal methods present intriguing prospects for transforming medication administration to the brain and offering effective treatments for neurological illnesses. The development of more sophisticated liposomal technologies, combined with a deeper understanding of their mechanisms of action, could lead to significant breakthroughs in the treatment of neurological disorders. For example, research into ligand- targeted liposomes, which use specific molecules to bind to receptors on the BBB, holds promise for enhancing delivery specificity and efficiency. To fully realize the therapeutic promise of these novel drug delivery systems, further advancements in liposomal technologies and a deeper understanding of their mechanisms are necessary. This includes not only technical improvements but also comprehensive preclinical and clinical studies to evaluate safety, efficacy, and long-term effects. As our knowledge expands and technology progresses, liposomal drug delivery could become a cornerstone of neurological disease treatment, providing new hope for patients with previously intractable conditions.},
}

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

@article {pmid41131676,
year = {2025},
author = {Lam, LCW and Chan, WC and Ikeda, M},
title = {Dementia care in old age psychiatry over 50 years.},
journal = {International review of psychiatry (Abingdon, England)},
volume = {},
number = {},
pages = {1-7},
doi = {10.1080/09540261.2025.2577393},
pmid = {41131676},
issn = {1369-1627},
abstract = {The global increase in number of people living with dementia and its mental health implications is closely linked to the development of Old Age Psychiatry (OAP) in the past 50 years. OAP focuses on addressing the complex psychiatric and physical needs of older adults, particularly those with dementia. Reflecting on the significance of early neuropsychiatric symptoms (NPS) in dementia, recent breakthroughs in early diagnostics and the amyloid targeting therapy (ATT) for Alzheimer's disease, it is time to examine the ongoing challenges and the role of OAP clinicians in managing dementia. The future of collaboration with medical, technological, and social experts presents opportunities for OAP to optimize dementia care beyond medication or social assistance, addressing the needs of people living with and their families along the whole disease spectrum.},
}

@article {pmid41131662,
year = {2025},
author = {Eijansantos, E and Allen, IE and de Leon, J and Grasso, S and Rogers, N and Bogley, R and Paramo, A and Ehrenberg, AJ and Montembeault, M and Sturm, V and Spina, S and Grinberg, LT and Seeley, WW and Rankin, KP and Kramer, JH and Rosen, HJ and Rabinovici, GD and Gorno-Tempini, ML and Miller, BL and Perry, DC and Miller, ZA},
title = {Burden of psychiatric disease inversely correlates with Alzheimer's age at onset.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21},
number = {10},
pages = {e70677},
doi = {10.1002/alz.70677},
pmid = {41131662},
issn = {1552-5279},
support = {AG048291//NIA/NIH/ ; AG052648//NIA/NIH/ ; AG053435//NIA/NIH/ ; AG023501//NIA/NIH/ ; AG019724//NIA/NIH/ ; AG062422//NIA/NIH/ ; AG045611//NIA/NIH/ ; AG080396//NIA/NIH/ ; DC018021//NIDCD/NIH/ ; DC015544//NIDCD/NIH/ ; NS050915//NINDS/NIH/ ; //Hellman Research Scientist Award/ ; //the Arking Foundation for Frontotemporal Dementia/ ; //the UCSF/ ; },
mesh = {Humans ; *Alzheimer Disease/epidemiology/psychology ; Age of Onset ; Female ; Male ; Aged ; Aged, 80 and over ; Comorbidity ; Retrospective Studies ; Stress Disorders, Post-Traumatic/epidemiology ; Depression/epidemiology ; *Mental Disorders/epidemiology ; Middle Aged ; Anxiety/epidemiology ; Prevalence ; },
abstract = {INTRODUCTION: Depression is regarded as a risk factor for Alzheimer's disease (AD). Associations between AD and other psychiatric disorders are less clear.

METHODS: We screened 1,500 AD UCSF Memory and Aging Center patients for prevalence of psychiatric disorders and compared results to 8,267 NACC AD participants.

RESULTS: AD with depression, anxiety, or post-traumatic stress disorder were significantly younger at age at onset than AD without (p < 0.001; p < 0.001; p < 0.05). Comorbidity of depression, anxiety and PTSD led to further decreases in AD age at onset. Within the NACC cohort, we further demonstrated an inverse relationship between the severity of depression and anxiety symptoms and AD age at onset.

DISCUSSION: Depression, anxiety, and post-traumatic stress disorder are inversely associated with AD age at onset. Age at onset further decreases with increasing number of psychiatric conditions and increasing severity of symptoms, suggesting that overall burden of psychiatric disease is highly relevant to AD.

HIGHLIGHTS: Retrospective chart review revealed that in patients with AD, those who also had depression, anxiety, or post-traumatic stress disorder were significantly younger at age at onset than those without. Increasing burden of psychiatric disease, both in severity of psychiatric symptoms and number of comorbid psychiatric conditions, produced serial decreases in the age at onset of AD. In patients with AD, those with depression were more likely to have autoimmune disease, and those with anxiety were more likely to have a history of seizures.},
}

Humans
*Alzheimer Disease/epidemiology/psychology
Age of Onset
Female
Male
Aged
Aged, 80 and over
Comorbidity
Retrospective Studies
Stress Disorders, Post-Traumatic/epidemiology
Depression/epidemiology
*Mental Disorders/epidemiology
Middle Aged
Anxiety/epidemiology
Prevalence

@article {pmid41131640,
year = {2025},
author = {Bhembre, N and Boskovic, Z and Willshaw, JL and Castello-Waldow, T and Bonthron, C and Paolino, A and Opazo, P},
title = {Direct evidence for dendritic spine compensation and regeneration in Alzheimer's disease models.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21},
number = {10},
pages = {e70829},
doi = {10.1002/alz.70829},
pmid = {41131640},
issn = {1552-5279},
support = {UKDRI-Edin0010//UK Dementia Research Institute/ ; APP1165504//National Health and Medical Research Council/ ; //Dementia Australia Research Foundation Back Block Bards Project/ ; },
mesh = {*Dendritic Spines/pathology/physiology ; Animals ; *Alzheimer Disease/pathology/physiopathology ; Disease Models, Animal ; Mice ; Mice, Transgenic ; Amyloid beta-Peptides/metabolism ; Optogenetics ; Neuronal Plasticity/physiology ; Synapses/pathology ; Neurons ; },
abstract = {INTRODUCTION: Dendritic spine loss in Alzheimer's disease (AD) strongly correlates with cognitive decline, whereas spine preservation is associated with cognitive resilience. Yet, whether and how neurons compensate for spine loss in AD remains largely unknown.

METHODS: We developed a chromophore-assisted light inactivation (CALI) strategy to selectively eliminate dendritic spines to model this key feature of AD. Two-photon microscopy was used to monitor the structural plasticity of spines over time after spine elimination. Validation experiments were conducted in amyloid beta (Aβ)-driven models of synapse loss, including APP/PS1 mice and intracortical delivery of oligomeric Aβ.

RESULTS: We discovered that dendritic spine elimination-induced either artificially or in Aβ models-triggers a two-stage compensatory response: rapid enlargement of remaining spines followed by delayed spine regeneration.

DISCUSSION: These findings provide direct evidence that neurons retain an intrinsic capacity to reverse early synaptic loss in AD, potentially contributing to cognitive resilience.

HIGHLIGHTS: We developed a targeted optogenetic tool to selectively eliminate individual dendritic spines in live neurons, both in vitro and in vivo. We discovered a two-stage compensatory response to spine loss: rapid enlargement of surviving spines followed by delayed regeneration. We showed that the compensatory enlargement of dendritic spines depends on N-methyl-D-aspartate receptor activation and protein synthesis. We validated across multiple Alzheimer's disease models, demonstrating that similar compensatory plasticity occurs after amyloid beta oligomer-induced synapse loss. We postulate that synaptic resilience is an active neuronal program rather than a passive byproduct of pathology.},
}

*Dendritic Spines/pathology/physiology
Animals
*Alzheimer Disease/pathology/physiopathology
Disease Models, Animal
Mice
Mice, Transgenic
Amyloid beta-Peptides/metabolism
Optogenetics
Neuronal Plasticity/physiology
Synapses/pathology
Neurons

@article {pmid41131557,
year = {2025},
author = {Buchanan, RA and Kramer, AT and Calipari, ES and Bowman, AB and Nobis, WP and Harrison, FE},
title = {Differential impact of manganese on glutamate clearance, electroencephalography, and sleep in Alzheimer's disease.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21},
number = {10},
pages = {e70821},
doi = {10.1002/alz.70821},
pmid = {41131557},
issn = {1552-5279},
support = {DK135073/DK/NIDDK NIH HHS/United States ; DK020593/DK/NIDDK NIH HHS/United States ; //FEH and ABB/ ; T32 ES007028/ES/NIEHS NIH HHS/United States ; P50 HD103537/HD/NICHD NIH HHS/United States ; HD103537//Eunice Kennedy Shriver National Institute of Child Health and Human Development/ ; R01 ES031401/ES/NIEHS NIH HHS/United States ; R01 ES035518/ES/NIEHS NIH HHS/United States ; ES007028/ES/NIEHS NIH HHS/United States ; },
mesh = {Animals ; *Alzheimer Disease/metabolism/physiopathology ; *Manganese/toxicity/metabolism/pharmacology ; Electroencephalography ; *Glutamic Acid/metabolism ; Mice ; Mice, Transgenic ; Disease Models, Animal ; *Sleep/drug effects ; Amyloid beta-Protein Precursor/genetics ; Presenilin-1/genetics ; Male ; *Brain/drug effects/metabolism ; Mice, Inbred C57BL ; },
abstract = {INTRODUCTION: Underlying glutamate dysregulation in Alzheimer's disease can be worsened by environmental factors like manganese (Mn) exposure. This study examined how excess Mn affects glutamatergic signaling and neurotransmission in a beta-amyloid mouse model.

METHODS: APP/PSEN1 and control mice were exposed to systemic Mn subcutaneously. Gene expression, glutamate clearance dynamics, electroencephalography (EEG) activity, and sleep architecture were analyzed using quantitative polymerase chain reaction (qPCR), Western blot, ex vivo hippocampal slices, and EEG recordings.

RESULTS: Mn exposure elevated brain Mn levels and altered glutamate dynamics in both WT and APP/PSEN1 mice. Wild-type (WT) mice showed faster glutamate clearance, increased spiking, disrupted sleep, and brain wave changes. APP/PSEN1 mice exhibited slower glutamate clearance, altered gene expression, increased glial fibrillary acidic protein (GFAP), and changes in non-rapid eye movement (NREM) delta and rapid eye movement (REM) alpha power.

DISCUSSION: Mn exposure altered glutamate clearance and brain activity, particularly in WT mice. APP/PSEN1 mice showed impaired clearance, limited gene expression changes, and altered EEG patterns, suggesting distinct or pre-existing compensatory mechanisms.

HIGHLIGHTS: Manganese exposure significantly alters glutamate clearance dynamics differentially in wild-type and APP/PSEN1 mouse models of Alzheimer's disease. Acute manganese treatment disrupts sleep architecture, evidenced by changes in electroencephalography (EEG) patterns and vigilance states. APP/PSEN1 mice exhibit slower glutamate clearance and altered gene expression compared to wild-type mice following manganese exposure. Distinct brain wave frequency shifts were observed in response to manganese treatment, particularly affecting delta, theta, and alpha rhythms. Findings suggest a potential exacerbation of excitatory/inhibitory imbalances due to environmental manganese exposure in Alzheimer's pathology.},
}

Animals
*Alzheimer Disease/metabolism/physiopathology
*Manganese/toxicity/metabolism/pharmacology
Electroencephalography
*Glutamic Acid/metabolism
Mice
Mice, Transgenic
Disease Models, Animal
*Sleep/drug effects
Amyloid beta-Protein Precursor/genetics
Presenilin-1/genetics
Male
*Brain/drug effects/metabolism
Mice, Inbred C57BL

@article {pmid41131417,
year = {2025},
author = {Aiello, EN and Curti, B and De Luca, G and Moreschi, A and Crispiatico, V and Maranzano, A and Menichelli, A and Cattaruzza, T and Manganotti, P and Silani, V and Ticozzi, N and Verde, F and Poletti, B},
title = {Telephone-based cognitive screening in neurodegenerative MCI and dementia: preliminary findings from the TBCS Study.},
journal = {Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology},
volume = {},
number = {},
pages = {},
pmid = {41131417},
issn = {1590-3478},
support = {Ministero della Salute//Ministero della Salute/ ; },
abstract = {BACKGROUND: This study aimed to provide preliminary information on the clinical usability of a set of Italian telephone-based cognitive screening (TBCS) tests in patients with neurodegenerative MCI and dementia.

METHODS: Eighty-one patients with MCI (N = 32) and dementia (N = 49) due to Alzheimer's disease, frontotemporal lobar degeneration and Lewy body disease and 100 healthy controls (HCs) were administered a battery of TBCS tests assessing global cognition (Telephone Interview for Cognitive Status), executive functioning (Telephone-based Frontal Assessment Battery), verbal fluency (Telephone-based Phonemic and Semantic Verbal Fluency), working memory (Telephone-based Backward Digit Span) and language (Telephone Language Screener). For each test, we assessed their (1) applicability, (2) construct validity against in-person first- and second-level cognitive measures, (3) ecological validity against the Amsterdam IADL Questionnaire-Short Version (A-IADL-Q-SV), (4) capability to discriminate MCI and dementia patients from HCs and (5) to discriminate MCI from dementia.

RESULTS: TBCS tests could be completed by the majority of patients (75-96%), with applicability rates being higher in MCI than in dementia. Moderate-to-strong correlations were detected between TBCS tests and both in-person cognitive measures and the A-IADL-Q-SV. All TBCS tests - except for the Backward Digit Span - optimally-to-excellently discriminated HCs from both MCI and dementia, by nevertheless being less accurate in discriminating between these two entities.

CONCLUSIONS: Italian TBCS tests are valid and accurate measures for the detection of MCI and dementia due to neurodegenerative etiologies, thus prompting further research on the topic and their use in clinical practice and research.},
}

@article {pmid41131361,
year = {2025},
author = {Sheehan, PW and Fass, SB and Sapkota, D and Kang, S and Hollis, HC and Lawrence, JH and Park, S and Sharma, A and Schafer, DP and Anafi, RC and Dougherty, JD and Fryer, JD and Musiek, ES},
title = {A glial circadian gene expression atlas reveals cell-type and disease-specific reprogramming in response to amyloid pathology or aging.},
journal = {Nature neuroscience},
volume = {},
number = {},
pages = {},
pmid = {41131361},
issn = {1546-1726},
support = {R01AG054517//U.S. Department of Health & Human Services | National Institutes of Health (NIH)/ ; R00AG061231//U.S. Department of Health & Human Services | National Institutes of Health (NIH)/ ; R01AG068577//U.S. Department of Health & Human Services | National Institutes of Health (NIH)/ ; R01AG068577//U.S. Department of Health & Human Services | National Institutes of Health (NIH)/ ; T32AG058518//U.S. Department of Health & Human Services | NIH | National Institute on Aging (U.S. National Institute on Aging)/ ; R01AG054517//U.S. Department of Health & Human Services | NIH | National Institute on Aging (U.S. National Institute on Aging)/ ; R01NS102272//U.S. Department of Health & Human Services | NIH | National Institute of Neurological Disorders and Stroke (NINDS)/ ; },
abstract = {While circadian rhythm disruption may promote neurodegenerative disease, the impact of aging and neurodegenerative pathology on circadian gene expression patterns in different brain cell types remains unknown. Here we used a translating ribosome affinity purification to identify the circadian translatomes of astrocytes, microglia and bulk tissue in healthy mouse cortex and in the settings of amyloid-β plaque pathology or aging. We show that glial circadian translatomes are highly cell-type-specific and exhibit profound, context-dependent reprogramming in response to amyloid pathology or aging. Transcripts involved in glial reactivity, immunometabolism and proteostasis, as well as nearly half of all Alzheimer's disease risk genes, displayed circadian oscillations, many of which were altered by pathology. Microglial oxidative stress and amyloid phagocytosis showed temporal variation in gene expression and function. Thus, circadian rhythms in gene expression are cell-dependent and context dependent, and provide important insights into glial function in health, Alzheimer's disease and aging.},
}

@article {pmid41131191,
year = {2025},
author = {Pitts, J and Wang, S and Bhatt, T},
title = {Neuromechanistic causes of timber falls in older adults with mild cognitive impairment: Is response initiation or motor execution the problem?.},
journal = {GeroScience},
volume = {},
number = {},
pages = {},
pmid = {41131191},
issn = {2509-2723},
support = {R01AG073152/AG/NIA NIH HHS/United States ; },
abstract = {Older adults with mild cognitive impairment (OAwMCI) show reactive balance deficits compared to cognitively intact older adults (CIOA), which could increase the likelihood of 'Timber' falls (i.e., backward falls caused by extremely delayed reactive stepping). This study investigated potential neuromechanistic causes of Timber falls in OAwMCI, including delayed muscle onset latencies and/or altered muscle synergies during reactive stepping. 36 OAwMCI, 38 CIOA, and 20 young adults were exposed to a large anterior stance perturbation, with electromyography collected from the biceps femoris (BF), vastus lateralis (VL), medial gastrocnemius (MG), and tibialis anterior (TA). Timber falls were identified by falling (> 30% weight in harness) without initiating stepping within 430 ms (perturbation duration). Timber falls only occurred in OAwMCI, who were subcategorized into MCI: Timber (36%) or MCI: Step (intact stepping, 64%). MCI: Timber had higher fall rate, lower reactive stability, shorter step length, and longer step initiation time compared to groups with intact stepping (p < 0.05), and delayed onsets of stepping limb muscles and the stance limb MG (p ≤ 0.03). MCI: Timber also showed many structural differences in muscle synergies (M1-6), such as recruiting a unique synergy (M4) which might affect coordination of the stepping limb MG, and failing to recruit M6, which might be involved in taking a long recovery step (stepping limb VL). These results suggest that reactive balance deficits in OAwMCI may be related to problems with both initiating and executing reactive stepping, possibly due to neural pathology and sensorimotor processing deficits which delay response initiation and/or affect motor command execution.},
}

@article {pmid41131113,
year = {2025},
author = {Yanez-Perez, R and Habich, A and Toledo, JB and Barroso, J and Ferreira, D},
title = {The cognitive connectome in dementia with lewy bodies undergoes early alterations already at the mild cognitive impairment stage.},
journal = {Scientific reports},
volume = {15},
number = {1},
pages = {37162},
pmid = {41131113},
issn = {2045-2322},
mesh = {Humans ; *Cognitive Dysfunction/physiopathology ; *Connectome/methods ; *Lewy Body Disease/physiopathology/psychology ; Female ; Male ; Aged ; Cross-Sectional Studies ; Alzheimer Disease/physiopathology ; *Cognition/physiology ; Aged, 80 and over ; Neuropsychological Tests ; Middle Aged ; Brain/physiopathology ; },
abstract = {Cognitive impairment is required to diagnose mild cognitive impairment with Lewy bodies (MCI-LB). However, associations of impairments across cognitive domains remain unclear. In this cross-sectional study, we investigated these associations by assessing the cognitive connectome of MCI-LB patients compared with healthy controls (HC), mild cognitive impairment due to Alzheimer's disease (MCI-AD), and dementia with Lewy bodies (DLB). Using the National Alzheimer's Coordinating Center database, we built cognitive connectomes for MCI-LB (n = 88), HC (n = 3703), MCI-AD (n = 1789), and DLB (n = 104) by correlating 24 cognitive measures. We compared global and nodal network measures of centrality (importance of cognitive measure), integration (communication across cognitive measures), and segregation (specialisation of cognitive measures) between groups. For global measures, MCI-LB showed lower segregation than HC, with no significant differences from MCI-AD, and lower integration) and higher segregation than DLB. For nodal measures, MCI-LB compared with HC and MCI-AD showed differences in executive and memory measures, respectively. MCI-LB showed several nodal differences compared with DLB, involving executive, processing speed/attention, and language measures. Our findings suggest that MCI-LB involves early changes in the cognitive connectome, particularly reduced segregation that becomes more pronounced at the DLB stage and shows overlap with MCI-AD, offering insights into cognitive impairment in MCI-LB.},
}

Humans
*Cognitive Dysfunction/physiopathology
*Connectome/methods
*Lewy Body Disease/physiopathology/psychology
Female
Male
Aged
Cross-Sectional Studies
Alzheimer Disease/physiopathology
*Cognition/physiology
Aged, 80 and over
Neuropsychological Tests
Middle Aged
Brain/physiopathology

@article {pmid41131017,
year = {2025},
author = {Revand, R and Puskar, P and Thondala, B and Netam, RK and Jain, S},
title = {Capsaicin evoked cardiopulmonary reflexes and heart rate variability responses are attenuated in a rat model of dementia induced by streptozotocin.},
journal = {Scientific reports},
volume = {15},
number = {1},
pages = {37008},
pmid = {41131017},
issn = {2045-2322},
support = {CRG/2022/008816/BHS//Science and Engineering Research Board (SERB), Department of Science and Technology (DST), Government of India, under the Core Research Grant (CRG) scheme in Biomedical and Health Sciences (BHS)/ ; },
mesh = {Animals ; *Capsaicin/pharmacology ; Male ; *Heart Rate/drug effects ; Disease Models, Animal ; Streptozocin/toxicity ; Rats ; Rats, Wistar ; *Reflex/drug effects ; *Alzheimer Disease/physiopathology/chemically induced ; *Dementia/chemically induced/physiopathology ; },
abstract = {Alzheimer's dementia (AD) principally a degenerative ailment of nervous system, also impacts systemic functions, including cardiopulmonary (CP) dynamics. Capsaicin-induced nociceptive CP reflexes play a defensive role against infective and inflammatory pathologies, yet their modulation in preclinical (early-stage) AD remains unclear. Therefore, this study investigates the modulation of capsaicin-evoked protective CP reflexes in streptozotocin-induced preclinical AD rat models as compared to Sham rats. Twelve adult Wistar male rats were assigned to AD and Sham groups, wherein preclinical AD was induced via bilateral intracerebroventricular streptozotocin injections using stereotaxic coordinates. Jugular vein cannulation enabled administration of capsaicin to evoke the nociceptive reflex CP responses, while femoral artery cannulation allowed continuous recording of blood pressure. Lead II electrocardiogram and breathing movements were also recorded. Hippocampal sections were stained with cresyl violet to evaluate neuronal cytoarchitecture, to confirm the induction of preclinical AD. Capsaicin evoked immediate hypotension, hyperventilation, tachypnea, and bradycardia in both AD and Sham groups, but were significantly attenuated (mean arterial pressure from 28 to 11%; respiratory rate from 44 to 15%; minute ventilation from 201 to 28%; heart rate from 30 to 7% of baseline) in AD rats. In addition, capsaicin-evoked heart rate variability alterations were significantly attenuated in the AD rats. Immunofluorescence analysis demonstrated amyloid β and phosphorylated Tau proteins deposition in the paraventricular nucleus of hypothalamus as well as key brainstem autonomic nuclei. To conclude, diminished nociceptive CP reflex responses in preclinical AD may be associated with AD-related pathologies in hypothalamus and brainstem, harboring the CP autonomic regulatory centers.},
}

Animals
*Capsaicin/pharmacology
Male
*Heart Rate/drug effects
Disease Models, Animal
Streptozocin/toxicity
Rats
Rats, Wistar
*Reflex/drug effects
*Alzheimer Disease/physiopathology/chemically induced
*Dementia/chemically induced/physiopathology

@article {pmid41130790,
year = {2025},
author = {Zhang, J and Soleimani-Meigooni, DN and Koeppe, R and Ackley, S and Schonhaut, DR and Lin, ZE and Maiti, P and Yballa, C and Rocha, S and Shankar, R and Amuiri, A and Bourgeat, P and Doré, V and Carrillo, MC and Dickerson, BC and Apostolova, LG and Harrison, TM and Grinberg, LT and Spina, S and Seeley, WW and Rabinovici, GD and La Joie, R and Blazhenets, G and , },
title = {Exploring Centiloid Robustness: Impact of Sample Size and Image Resolution on Centiloid Conversion Accuracy.},
journal = {Journal of nuclear medicine : official publication, Society of Nuclear Medicine},
volume = {},
number = {},
pages = {},
doi = {10.2967/jnumed.125.270607},
pmid = {41130790},
issn = {1535-5667},
abstract = {As Centiloids are increasingly used in trials and clinical settings to quantify amyloid-β (Aβ) PET, better characterization of sources of measurement error is essential. We examined 2 potential factors driving it: variability in the estimated coefficients in the SUV ratio-to-Centiloid conversion equation related to random sampling of the calibration dataset and PET image resolution. Methods: First, we analyzed [[11]C]PiB scans in 200 participants with a clinical diagnosis of Alzheimer disease (cAD) and 114 Aβ-negative participants. PET scans were processed using the standard Centiloid pipeline and a nonstandard MRI-based pipeline (native space, cerebellar cortex as reference). We split data into training and test datasets (n = 157 each) to compare conversion equations in subsamples with an n of 10-30 Aβ-negative and 15-50 cAD participants. Second, all [[11]C]PiB images, along with 604 [[18]F]florbetaben and 538 [[18]F]florbetapir images, were reduced from high (6/7 mm[3]) to medium (8 mm[3]) and low (10 mm[3]) resolution and resulting Centiloids were compared between resolutions. rPOP and CapAIBL, 2 PET-only processing pipelines, were used to explore the effects of the PET spatial resolution across different pipelines. Results: In the smallest required sample of 15 cAD and 10 Aβ-negative participants, conversion error was 1.7 Centiloids at 25 Centiloids and 3.4 Centiloids at 100 Centiloids. Error decreased to 1.0 Centiloid at 25 Centiloids and 2.0 Centiloids at 100 Centiloids, when including 50 cAD and 30 Aβ-negative participants. Lower image resolution was associated with a systematic difference in Centiloids, especially in highly positive [[11]C]PiB scans: a scan estimated as 100 Centiloids in high resolution was quantified as 94.2 Centiloids and 84.9 Centiloids at medium and low resolution. When a [[11]C]PiB scan was quantified as 25 Centiloids in its high resolution, lowering its resolution resulted in reduced values of 23.5 Centiloids and 20.6 Centiloids for medium and low resolution, respectively. Similar trends were observed for [[18]F]florbetaben and [[18]F]florbetapir scans. Conclusion: A relatively accurate SUV ratio-to-Centiloid conversion equation for level 2 analyses can still be achieved with a minimally required datasets. Increasing the number of cAD participants reduced error at higher values, whereas adding Aβ-negative participants had little effect. Image resolution significantly impacts Centiloids in highly positive scans and should be considered when interpreting data acquired with different settings. Errors remain minimal at 25 Centiloids, the typical cutoff for determining Aβ positivity.},
}

@article {pmid41130542,
year = {2025},
author = {Wang, J and Jiang, B and Lin, X and Zhang, J and Xiong, L and Feng, Y and Cheang, WS and Xu, B},
title = {Genistein ameliorates glucose-induced β-amyloid toxicity, oxidative stress, and aging in the C. elegans model of Alzheimer's disease.},
journal = {Free radical biology & medicine},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.freeradbiomed.2025.10.263},
pmid = {41130542},
issn = {1873-4596},
abstract = {Alzheimer's disease (AD) has been considered a kind of diabetic encephalopathy due to the shared molecular mechanisms found between type 2 diabetes mellitus (T2DM) and AD. However, the specific mechanism and therapy of diabetic encephalopathy remain underexplored, particularly the neuroprotective potential of dietary polyphenols in conditions of glucose enrichment. In this study, glucose enrichment-induced potentially harmful effects regarding (neuro)toxicity, apoptosis, oxidative stress, and impaired lipid metabolism were reported for the first time in the AD Caenorhabditis elegans model (CL4176 and CL2355). Genistein intervention prolonged the lifespan and mitigated AD-like symptoms in C. elegans. Further results from network pharmacology, RNA sequencing, RT-qPCR, and lipidomic analysis revealed that the anti-aging, antioxidative, and neuroprotective effects of genistein involve the regulation of sphingolipids, glycerophospholipids, and glycerolipids, which are likely mediated via the PI3K/AKT signaling pathway. These findings provide novel insights into the role of dietary polyphenols in preventing cognitive impairment and aging.},
}

@article {pmid41130534,
year = {2025},
author = {Condado, JG and Recuero, IV and Elorriaga, IT and Birkhenbil, C and Carrigan, M and Diez, I and Buckley, RF and Erramuzpe, A and Cortes, JM and , },
title = {Aging as an active player in Alzheimer's Disease Classification: Insights from feature selection in BrainAge Models.},
journal = {NeuroImage},
volume = {},
number = {},
pages = {121548},
doi = {10.1016/j.neuroimage.2025.121548},
pmid = {41130534},
issn = {1095-9572},
abstract = {BACKGROUND: BrainAge models estimate the biological age of the brain using neuroimaging or clinical features, making them promising tools for studying neurodegenerative diseases like Alzheimer's disease. However, the reliance of BrainAge models on neuroimaging features such as grey matter volume and hippocampal atrophy, can introduce biases linked to individuals' ages as these features are influenced both by normal aging and Alzheimer's disease progression. The potential presence of such age-biases raises a critical question: can BrainAge models trained to estimate biological brain aging make meaningful contributions to Alzheimer's diagnosis, or does any introduced age-bias conflate aging effects with disease pathology? Understanding how deliberate feature selection impacts this confounding effect is essential for developing reliable age-related biomarkers.

METHODOLOGY: We ranked neuroimaging and neuropsychological features based on their mutual information with age and their discriminative power across four clinical groups: cognitively normal, Mild Cognitive Impairment, Alzheimer's Disease, stable Mild Cognitive Impairment and progressive Mild Cognitive Impairment. Iteratively, we trained BrainAge models using different subsets of these features, some optimized for predicting aging and others for discrimination of clinical Alzheimer's disease stages. We assess the error in BrainAge delta, the difference between predicted biological age and chronological age, and evaluate its classification performance across clinical groups. Finally, we compare using deltas for classification with a logistic regression model directly trained on the neuroimaging features used in the BrainAge models.

RESULTS: Neuroimaging features are more strongly correlated with aging, while neuropsychological features exhibit greater discriminative power for Alzheimer's disease classification. BrainAge models optimized for age prediction yield deltas that are suboptimal when used for classifying Alzheimer´s disease, whereas models trained to generate deltas optimized to be used for classifying Alzheimer's disease have reduced age prediction accuracy. This trade-off suggests that BrainAge models may not optimally separate aging-related changes from disease-specific alterations. BrainAge models have varying classification accuracy as compared to direct utilization of features in logistic regression. However, BrainAge provides a continuous measure, offering a single output that can be used across clinical stages, in contrast to classification approaches that require explicit labels for each disease stage.

CONCLUSION: Aging significantly affects BrainAge-based classification of Alzheimer's disease. Feature selection plays a critical role in mitigating this effect, as the outputs of models trained to predict age, the deltas, may fail in Alzheimer´s disease classification. These findings underscore the need for task-specific feature selection and model design to ensure that BrainAge models are appropriately applied in neurodegenerative disease research.},
}

@article {pmid41130466,
year = {2025},
author = {El Sayed, AM and El Hawary, S and Elimam, H and El Raey, MA and Mouhamed, AA and Zokalih, AH and Bassam, SM and Mohyeldin, MM},
title = {Green synthesized Gmelina arborea Roxb leaves ZnO nanoparticles: DNA fingerprinting, phytochemistry, greenness and biological activities.},
journal = {Fitoterapia},
volume = {187},
number = {},
pages = {106943},
doi = {10.1016/j.fitote.2025.106943},
pmid = {41130466},
issn = {1873-6971},
abstract = {This study focused on the green synthesis of zinc oxide nanoparticles (ZnONPs) using Gmelina arborea Roxb (GA) leaf extract. Both the extract and the green-synthesized ZnONPs (GSNPs) were evaluated for their biological activities against key health conditions; Alzheimer's disease, diabetes, and inflammation. Standard reference drugs;donepezil, sitagliptin, and ibuprofen were included in the respective assays. Successful synthesis of GSNPs was confirmed and characterized using SEM, TEM, FTIR, X-ray diffraction, UV spectroscopy, and zeta potential analysis. The nanoparticles were spherical, with sizes ranging from 8.01 to 18.79 nm, and some agglomerates measuring between 50.27 and 72.50 nm. FTIR analysis indicated effective capping by flavonoids and cinnamic acid derivatives. Zeta potential values ranged from -31.3 to -49.9 mV, suggesting good colloidal stability. GSNPs demonstrated significant anti-acetylcholinesterase (AChE) activity (p < 0.001) compared to donepezil. The IC50 values for GA leaf extract, GSNPs, and donepezil were 113.24 ± 7.39, 105.1 ± 3.62, and 49.70 ± 2.50 μg/mL, respectively. The GSNPs also exhibited a notable anti-inflammatory effect (p < 0.0001), outperforming the GA leaf extract, while the anti-diabetic activity was moderate. HPLC analysis revealed a rich content of phenolics and flavonoids, which are likely involved in the nanoparticle synthesis and biological activities. The environmental sustainability of the entire process-from synthesis to analysis-was evaluated using AGREE software, yielding a high score of 0.88, indicating strong adherence to green chemistry principles. In conclusion, the green synthesis of ZnONPs using Gmelina arborea leaf extract presents an economical and eco-friendly approach, with promising potential for developing therapeutic agents against inflammation-related diseases.},
}

@article {pmid41130380,
year = {2025},
author = {Vrbjar, N and Radosinska, D and Radosinska, J},
title = {The involvement of Na,K-ATPase enzyme in the development of Alzheimer's disease.},
journal = {Experimental neurology},
volume = {},
number = {},
pages = {115526},
doi = {10.1016/j.expneurol.2025.115526},
pmid = {41130380},
issn = {1090-2430},
abstract = {The sodium‑potassium pump (Na,K-ATPase) is an essential membrane-bound enzyme that maintains electrochemical gradients across the plasma membrane in animal cells. Growing evidence implicates its dysfunction in the pathogenesis of Alzheimer's disease (AD). This review summarizes findings from studies utilizing postmortem human brain tissue, rodent models of AD, and in vitro systems to explore the role of Na,K-ATPase in AD and the potential for its modulation by naturally occurring compounds. The link between Na,K-ATPase and AD can be explained through several mechanisms. First, the enzyme may serve as a downstream target of oxidative stress, a well-known hallmark of AD. Second, amyloid-beta (Aβ) peptides bind to Na,K-ATPase even under normal physiological conditions; however, in AD, where Aβ levels are abnormally elevated, this interaction may impair enzyme activity. Third, Na,K-ATPase contributes to cerebrospinal fluid dynamics, potentially influencing Aβ clearance from the brain. A larger body of evidence supports the involvement of Na,K-ATPase in AD progression, though inconsistencies in the literature likely reflect differences in experimental models and methodologies. Importantly, Na,K-ATPase activity also shows promise as a biomarker for assessing AD risk or progression, particularly in readily accessible biological materials such as blood. In addition, naturally occurring antioxidants from fruits, vegetables, and medicinal plants have been shown to protect Na,K-ATPase activity, suggesting a potential therapeutic strategy to slow or mitigate cognitive decline associated with AD.},
}

@article {pmid41130360,
year = {2025},
author = {Rabie, MA and Madry, H and Cucchiarini, M and El-Sayed, NS},
title = {The brain-joint axis: links between osteoarthritis and neurodegenerative disorders in aging.},
journal = {Journal of advanced research},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.jare.2025.10.023},
pmid = {41130360},
issn = {2090-1224},
abstract = {BACKGROUND: Osteoarthritis (OA) and neurodegenerative disorders such as Alzheimer's and Parkinson's diseases are prevalent age-related conditions that severely impair quality of life in the elderly. Growing evidence suggests shared pathological drivers, including chronic low-grade inflammation, oxidative stress, mitochondrial dysfunction, and cellular senescence, link the degeneration of articular cartilage with neuronal loss in the aging brain.

AIM OF REVIEW: This review introduces and defines the emerging concept of the "brain-joint axis" as a bidirectional communication network integrating neural, endocrine, and immune signaling between the central nervous system (CNS) and joint tissues. By consolidating evidence of systemic crosstalk between OA and neurodegenerative disorders, we highlight how aging-related biological processes simultaneously influence joint and brain homeostasis.

We discuss how proinflammatory cytokines (e.g., interleukin-1β, tumor necrosis factor-α) and metabolic stress mediators propagate systemic inflammation that exacerbates both cartilage degradation and neuronal damage. Furthermore, we propose that OA is not merely a localized musculoskeletal disorder but part of a broader systemic neuro-immuno-endocrine network whose dysfunction contributes to neurodegeneration. Indeed, this work delineates the mechanistic framework of the brain-joint axis, emphasizing its translational potential as a therapeutic target to simultaneously mitigate OA progression and neurodegenerative decline.},
}

@article {pmid41130349,
year = {2025},
author = {Petrič, B and Kramberger, MG and Dolžan, V and Emeršič, A and Goličnik, M and Leonardi, A and Križaj, I and Bavec, A},
title = {The Role of Age and Sex in Paraoxonase 1 Activity in Patients with Alzheimer's Dementia.},
journal = {Chemico-biological interactions},
volume = {},
number = {},
pages = {111787},
doi = {10.1016/j.cbi.2025.111787},
pmid = {41130349},
issn = {1872-7786},
abstract = {The enzyme paraoxonase 1 (PON1) is present in high density lipoprotein (HDL) particles in blood plasma and in cerebrospinal fluid (CSF). Its activity has been investigated in several oxidative-stress-related conditions, including Alzheimer's disease (AD). There is convincing evidence that PON1 activity in blood is lower in AD patients than in healthy controls, but it is less clear whether there is a difference between the precursor stage of AD, known as mild cognitive impairment (MCI AD), and the dementia stage of AD. In the present study, we assessed PON1 status in blood plasma and cerebrospinal fluid (CSF) of 32 patients with MCI AD, 56 patients with AD dementia, and 74 patients with non-AD dementia. We measured PON1 concentration as well as rates of hydrolysis and Michaelis-Menten kinetic parameters Km and Vmax of PON1 for lactonase, arylesterase and arildialkylphosphatase activities in all the samples. There was no significant difference between AD dementia and MCI AD patients in any of the parameters measured. Within the AD group, we found that in blood plasma, rates of hydrolysis and Vmax negatively correlated with age in the case of lactonase and arylesterase. In CSF, the negative correlation with age for these parameters was even more pronounced. The correlation between age and PON1 status was more prominent in men for blood plasma and in women for CSF. The correlation between age and PON1 status was mostly absent in patients with other kinds of dementia, suggesting that PON1 activity decline is a part of development of AD pathology.},
}

@article {pmid41130191,
year = {2025},
author = {Man, VH and He, X and Nguyen, PH and Gao, J and Wang, J},
title = {Aberrant S293 Phosphorylation Drives Oligomerization of Tau Repeat R2: Insights from Molecular Dynamics Simulations.},
journal = {ACS chemical neuroscience},
volume = {},
number = {},
pages = {},
doi = {10.1021/acschemneuro.5c00734},
pmid = {41130191},
issn = {1948-7193},
abstract = {Aberrant phosphorylation, which is absent in healthy brains but present exclusively in the brains of individuals with Alzheimer's disease (AD), plays a critical role in AD development. It causes the dissociation of tau protein from microtubules, followed by the aggregation of tau protein into brain-toxic oligomers and fibrils. In our previous study, we investigated the impact of abnormal phosphorylation at S289 (pS289) on the oligomerization of tau repeat R2 peptides. In this work, we continue to investigate the effect of aberrant phosphorylation at residue S293 (pS293) on the R2 peptides. Our result indicated that pS293 also promotes oligomerization, which is similar to pS289. Both the phosphorylation-enhanced intramolecular and intermolecular interactions and β-sheet formation of phosphorylated R2 compared to that of the wild type. We observed that Na[+] can bridge two pS293 residues to form pS293--Na[+]-pS293 triad in the R2 dimer, a phenomenon also observed for the pS289 R2 dimer. However, the impact of pS293 was different from that of pS289 in terms of the secondary structural profile of both monomeric and dimeric R2 peptides. Our findings suggest that phosphorylation at S293 should be taken into consideration in the inhibitor screening of tau oligomerization.},
}

@article {pmid41129981,
year = {2025},
author = {Wang, B and Chang, Y and Shen, L and Ma, Y and Zhang, Z and Du, J and Wang, Y and Li, Y and Zhao, F and Wang, J and Pang, X and Fan, W and Du, L and Yan, L},
title = {Multifunctional near-infrared fluorescent probe for imaging of hydrogen peroxide and photodynamic therapy of amyloid-β aggregation in Alzheimer's disease.},
journal = {Talanta},
volume = {298},
number = {Pt B},
pages = {129009},
doi = {10.1016/j.talanta.2025.129009},
pmid = {41129981},
issn = {1873-3573},
abstract = {Photodynamic therapy (PDT) has shown significant potential in eliminating amyloid-β (Aβ) aggregates, the characteristic pathological marker of Alzheimer's disease (AD). However, traditional photosensitizers have limitations such as off-target oxidation and single functionality, which severely hinder their specificity and therapeutic efficiency in clearing Aβ plaques. Given the complexity of AD's pathological mechanisms, the development of novel photosensitizers with both targeting ability and multifunctionality has become an urgent priority. In this study, a H2O2-responsive near-infrared (NIR) fluorescent probe ENBS-P was designed and synthesized. By integrating the dual functions of H2O2 visualization and precise photodynamic therapy, it has achieved efficient application in both in vitro and in vivo models. ENBS-P could be specifically activated by H2O2 to release ENBS, resulting in a significant enhancement of fluorescence signal at 720 nm (λex = 640 nm), thus realizing highly sensitive in situ detection of H2O2 (LOD = 0.2 μM). In addition, benefiting from a more efficient intersystem crossing (ISC) process from S1 to T1, the therapeutic molecule ENBS, generated after the specific activation of ENBS-P by H2O2, could produce superoxide radical anions (O2[-•], Type I photoreaction) under NIR light excitation. Importantly, through imaging-guided PDT, it could effectively inhibit the aberrant aggregation of Aβ42 and promote the dissociation of formed aggregates. This study overcomes the limitations of traditional photosensitizers by providing an innovative "diagnosis-treatment" integrated strategy for the early diagnosis and therapy of AD, holding significant promise for advancing precision medicine in AD.},
}

@article {pmid41129723,
year = {2025},
author = {Ben Zaken, K and Mesfin, S and Bloch, N and Samson, AO},
title = {Virtual screening of drugs against multiple targets of Alzheimer's disease.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877251387167},
doi = {10.1177/13872877251387167},
pmid = {41129723},
issn = {1875-8908},
abstract = {BackgroundDrug repurposing offers a rapid, cost-effective approach for discovering therapies against multiple targets.ObjectiveHere, we screen virtual ligand libraries consisting of 3468 approved drugs against 11 protein targets associated with Alzheimer's disease (AD).MethodsWe employ blind molecular docking, and target amyloid-β (Aβ), microtubule-associated protein tau (MAPT), Apolipoprotein E4 (APOE4), acetylcholinesterase (AChE), butyrylcholinesterase (BChE), amyloid-β protein precursor (AβPP), β-secretase (BACE1), brain-derived neurotrophic factor (BDNF), presenilin 1 (PSEN1) and 2 (PSEN2), and α-synuclein (SNCA) proteins using AutoDock Vina.ResultsNotably, multitarget binding recurs among the top-10 ligands with Ergotamine and Dihydroergotamine potentially binding 8; Dutasteride 7; Drospirenone and Nilotinib 6; Adapalene and Conivaptan 5; Bromocriptine 4; and Rolapitant, Irinotecan, Plerixafor, Saquinavir, and Telmisartan 3, out of 11 protein targets. As such, we reveal potential binding sites for ergot alkaloids, steroids, retinoids, antivirals, angiotensin receptor blockers, and Neurokinin 1 (NK1) receptor antagonists on multiple AD targets. Importantly, the therapeutic potential of the top-scoring ligands is confounded by pharmacokinetics and adverse-effects. For example, poor blood-brain barrier (BBB) penetration, and vasoconstriction, discount ergot-alkaloid use in AD. Likewise, potential toxicity limits prolonged use of steroids, Nilotinib, Adapalene, and Irinotecan. Conversely, BBB penetration, neuronal protection, oral availability, anti-inflammation, and anti-hypertension, admit Angiotensin receptor blockers (ARB), (Telmisartan/Candesartan); Antidiuretic hormone (ADH) inhibitors (Conivaptan/Tolvaptan); and of the NK1 receptors antagonists (Rolapitant/Netupitant) use in AD.ConclusionsOur multitarget screening identifies selective synergistic AD modulators, such as ARB, ADH and NK1 receptor inhibitors, and simplifies drug discovery by focusing on the most promising candidates for experimental validation.},
}

@article {pmid41129721,
year = {2025},
author = {Drzymalla, E and Avery, C and Palta, P and Reiner, AP and Sun, Q and Raffield, LM},
title = {Association between neutrophil to lymphocyte ratio and Alzheimer's disease in large biobank cohorts.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877251386813},
doi = {10.1177/13872877251386813},
pmid = {41129721},
issn = {1875-8908},
abstract = {BackgroundNeutrophil to lymphocyte ratio (NLR) is an inflammatory biomarker for chronic disease that also may provide evidence for peripheral innate immune activation in Alzheimer's disease (AD) pathogenesis.ObjectiveThe objective of this study is to assess the association between NLR and AD as a biomarker or potential causal step for AD pathogenesis.MethodsCohorts used for analysis include the UK Biobank (n = 207100; n = 2198 AD cases) and the All of Us research program (AoU, n = 45202; n = 263 AD cases) which allowed for a larger sample size than most previous studies. Cox proportional hazard models were used to assess the association between NLR and AD, including in models adjusting for factors in the UK Biobank Dementia Risk Score. A Mendelian randomization analysis was performed to assess the potential causality between NLR and AD.ResultsNLR was associated with AD in the UK Biobank (HR: 1.03 per 1 SD, 95% CI: 1.01-1.05) but not in AoU (HR: 1.02, 95% CI: 0.92-1.14). A fixed effects model resulted in a pooled HR: 1.03 (95% CI: 1.02-1.05). These effects were robust to adjustment for C-reactive protein, APOE ε4 genotype status, APOE ε2 genotype status, and other AD risk factors. The MR analysis was performed with 214 NLR-associated variants but was not significant (IVW estimate: -0.001, p: 0.99).ConclusionsFindings provide evidence for NLR as a biomarker for AD but not as a causal risk factor.},
}

@article {pmid41129705,
year = {2025},
author = {Pink, A and Krell-Roesch, J and Syrjanen, JA and Vassilaki, M and Fields, JA and Iglseder, B and Aigner, E and Kremers, WK and Jack, CR and Racette, SB and Petersen, RC and Geda, YE},
title = {The longitudinal association between dyslipidemia and cognitive trajectory.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877251385255},
doi = {10.1177/13872877251385255},
pmid = {41129705},
issn = {1875-8908},
abstract = {BackgroundThe literature on dyslipidemia and cognitive trajectories among cognitively unimpaired (CU) persons remains inconclusive.ObjectiveTo investigate the association between baseline dyslipidemia and change in global and domain specific (i.e., memory, language, attention/executive function, and visuospatial skills) cognition in a population-based setting and whether the association differs by sex, age, or APOE ɛ4 carrier status.MethodsWe conducted a longitudinal study derived from the Mayo Clinic Study of Aging, involving 4236 CU persons aged ≥ 50 years. We ran linear mixed-effect models to examine baseline dyslipidemia in predicting longitudinal cognitive global and domain-specific z-scores adjusted for age, sex, education, medical comorbidity, repeated cognitive testing, and APOE ɛ4. We examined interactions among dyslipidemia, years since baseline, and separately by sex, age, and APOE ɛ4 carrier status.ResultsOver a median follow-up period of 6.4 years, CU individuals with dyslipidemia showed faster decline in z-scores of all domains, i.e., memory, language, attention/executive function, visuospatial and global cognition relative to CU individuals without dyslipidemia. Three-way interactions showed that dyslipidemia's effect on decline in z-scores of global cognition, attention and visuospatial skills was less pronounced in males than females. Higher age increased dyslipidemia's effect on decline in z-scores of attention but not global cognition or any other domain. APOE ɛ4 carrier status did not modify the effect of dyslipidemia on cognitive z-scores.ConclusionsDyslipidemia was associated with faster global and domain-specific cognitive decline over time in older community-dwelling individuals who were cognitively unimpaired at baseline. The effect of dyslipidemia on cognitive trajectories may be sex-influenced.},
}

@article {pmid41129700,
year = {2025},
author = {Wu, X and Tsuchiya, I and Aung, KZ and Qiao, Q and Fardo, DW and Nelson, PT and Abner, EL and James, BD and Norris, CM and Katsumata, Y},
title = {Genetic association analyses of cognitive performance across multi-ancestry older adults: Application of Tobit models.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877251385220},
doi = {10.1177/13872877251385220},
pmid = {41129700},
issn = {1875-8908},
abstract = {BackgroundPrevious studies investigating associations between genetic variants and late-onset Alzheimer's disease (LOAD)-related cognitive functions included primarily European-ancestry individuals and utilized linear models on neuropsychological test scores with ceiling effects.ObjectiveInvestigate associations between LOAD-related single nucleotide polymorphisms (SNPs) and neuropsychological test scores by applying the superior approach, Tobit (versus linear) regression models, to identify population-specific SNPs associated with cognitive performance across multiple genetic ancestry groups.MethodsNational Alzheimer's Coordinating Center (NACC) Uniform Data Set (UDS) and Alzheimer's Disease Genetics Consortium (ADGC) provided phenotype and genotype data on Alzheimer's Disease Research Center (ADRC) participants, respectively. Using the ADGC genotype data, genetic ancestry groups were identified for ADRC participants, including non-Hispanic White (NHW), African American (AA), Hispanic, and Asian. Tobit and linear models were applied to examine genetic associations of 84 LOAD-related SNPs with cognitive performance at the most recent visit, utilizing the NACC UDS data.ResultsGenetic architectures varied across genetic ancestry groups. The Tobit model detected the association of TMEM106B-rs13237518(A) missed by the linear model. APOE-rs429358(C) was negatively associated with global cognitive function across ancestry groups. Subgroup analyses recognized associations among participants with a cognitive status of dementia: ADAMTS1-rs2830489(T) for Asians and SHARPIN-rs34173062(A) for Hispanics.ConclusionsTobit models demonstrated superior model fit for genetic association analyses of global cognition and language test scores exhibiting ceiling effects.},
}

@article {pmid41129692,
year = {2025},
author = {Schäffler, M and Wales, DJ and Strodel, B},
title = {Energy Landscape and Kinetic Analysis of Molecular Dynamics Simulations for Intrinsically Disordered Proteins.},
journal = {The journal of physical chemistry. B},
volume = {},
number = {},
pages = {},
doi = {10.1021/acs.jpcb.5c05390},
pmid = {41129692},
issn = {1520-5207},
abstract = {Understanding the conformational dynamics of biomolecules requires methods that go beyond structural sampling and provide a quantitative description of thermodynamics and kinetics. For intrinsically disordered proteins (IDPs), energy landscape characterization is particularly crucial to unravel their complex conformational behavior. Here, we present a comprehensive protocol for analyzing molecular dynamics (MD) simulations in terms of energy landscapes, metastable states, and transition pathways. Our approach is based on the distribution of reciprocal interatomic distances (DRID) for dimensionality reduction, followed by clustering and kinetic modeling. Free energy surfaces and transition state barriers are computed directly from the simulation data and visualized using disconnectivity graphs. The method integrates two Python packages, DRIDmetric and freenet, with standard energy landscape tools based on kinetic transition networks, including PATHSAMPLE and disconnectionDPS. We demonstrate this workflow for simulations of the intrinsically disordered, aggregation-prone Alzheimer's amyloid-β peptide in physiologically relevant environments. This modular framework offers a robust and interpretable way to extract thermodynamic and kinetic insights from MD data and is especially valuable for characterizing the diverse conformational states of IDPs.},
}

@article {pmid41126283,
year = {2025},
author = {Chandra, PK and Panner Selvam, MK and Zulfiquar, TN and Rutkai-Green, I and Sikka, SC and Braun, SE and Rappaport, J and Busija, DW},
title = {Plasma circulating extracellular vesicles reveal dysregulation of synaptic signaling in SHIV-infected rhesus macaque.},
journal = {Cell communication and signaling : CCS},
volume = {23},
number = {1},
pages = {455},
pmid = {41126283},
issn = {1478-811X},
support = {R01NS136041/GF/NIH HHS/United States ; R21/R33AI110158/GF/NIH HHS/United States ; R56AG075988/GF/NIH HHS/United States ; },
abstract = {BACKGROUND: Antiretroviral therapy suppresses human immunodeficiency virus (HIV) replication; however, nearly 50% of HIV infected patients suffer from HIV-associated neurocognitive disorders (HAND). Recently, we reported that proteins in plasma circulating extracellular vesicles (EVs) of either simian human immunodeficiency virus (SHIV) infected rhesus macaques (RMs) or HIV-infected patients show a link to neuropathogenesis. In this study, we show that proteins in circulating EVs of SHIV-infected RMs (SHIV-EVs) were associated with dysregulation of the synaptic signaling pathway.

METHODS: Plasma circulating EVs were isolated from SHIV-infected (SHIV-EVs) and uninfected (CTL-EVs) RMs and characterized by the ZetaView analyzer (n = 5/group) and transmission electron microscopy. Several EV-associated markers were detected by western blotting. Proteomic analysis of the isolated EVs (n = 3/group) was performed using liquid chromatography/mass spectrometry. Using ingenuity pathway analysis (IPA), the differentially expressed proteins (DEPs) involved in the dysregulation of different synaptic signaling pathways were assessed.

RESULTS: Interestingly, proteins in SHIV-EVs were involved in synaptogenesis signaling deactivation, synaptic long-term potentiation/depression, and glutamate receptor signaling, as well as activation of semaphorin neuronal repulsive signaling pathways. Intriguingly, we observed that several proteins, which are involved in synaptic vesicle (SV) assembly and SV fusion, were abundantly under-expressed in SHIV-EVs compared with EVs of uninfected RMs. Dysregulated proteins in SHIV-EVs show possible deactivation of (a) SV priming, docking, and fusion in presynaptic neurons; and (b) synaptic spine development/density and synapse stabilization in postsynaptic neurons. Conversely, the activation of semaphorin neuronal repulsive signaling pathway in SHIV-EVs showed possible activation of cytoskeleton contraction/rearrangement, microtubule stabilization, and action repulsion, as well as deactivation of microtubule polymerization and action generation/outgrowth in SHIV-infected RMs. Dysregulated synaptic signaling-related proteins in SHIV-EVs were involved in several neuropathology-related disorders/diseases, including early/progressive neurological disorder, cognitive impairment, degenerative dementia, and Alzheimer’s disease.

CONCLUSIONS: Our novel findings suggest that plasma circulating EVs can be a useful noninvasive technique to elucidate the mechanisms involved in the development of central nervous system dysfunction and the progression of neurological diseases such as HAND.

SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s12964-025-02464-w.},
}

@article {pmid41129691,
year = {2025},
author = {Tang, J and Feng, D and Guan, L and Qi, B and Zou, Y},
title = {Computational Insights into the Destabilization of Baicalein on the Tau Protofibrils Associated with Alzheimer' s Disease and Chronic Traumatic Encephalopathy.},
journal = {The journal of physical chemistry. B},
volume = {},
number = {},
pages = {},
doi = {10.1021/acs.jpcb.5c05778},
pmid = {41129691},
issn = {1520-5207},
abstract = {Tauopathies are a subgroup of neurodegenerative diseases pathologically typified as tau protein aggregate deposits in the brain, including Alzheimer's disease (AD) and chronic traumatic encephalopathy (CTE). AD is the most common cause of dementia, and CTE is a unique tauopathy affecting contact sports athletes, such as those active in American football and boxing, among others. It is revealed that the three-dimensional configurations of the protofibrils in AD and CTE-specific tau filaments are rather similar. Baicalein (BA) is a natural polyphenol extracted from Scutellaria baicalensis Georgia and was confirmed to disaggregate the preformed tau fibrils in vitro. However, the atomic effects and underlying mechanisms of BA on the AD- and CTE-specific tau protofibrils are largely unknown. In this study, we conducted all-atom molecular dynamics (MD) simulations on the two types of protofibrils without and with BA. The results revealed that BA could decrease the structural stability and reduce the β-sheet structure probability of the two types of protofibrils. BA extended the three-dimensional conformations of the AD-type protofibril in the vertical axis direction while it extended the CTE-type protofibril in the horizontal axis direction. BA preferentially bound with the β-sheet fragments of the two types of protofibrils through hydrophobic, H-bonding, and π-π stacking interactions, while the binding sites showed many differences. In addition, the cation-π interaction only existed between BA and the AD-type protofibril. Our work provides useful theoretical implications for the design of drugs to prevent or delay the development of AD and CTE.},
}

@article {pmid41129661,
year = {2025},
author = {Wu, CS and Huang, WL and Wang, SH and Wu, MS and Chen, KS and Cheng, SH and Chiu, YM},
title = {Association Between Autoimmune Diseases, Treatments, and Dementia Risk: A Population-Based Case-Control Study From Taiwan.},
journal = {The Journal of clinical psychiatry},
volume = {86},
number = {4},
pages = {},
doi = {10.4088/JCP.25m15774},
pmid = {41129661},
issn = {1555-2101},
mesh = {Humans ; Taiwan/epidemiology ; Female ; Male ; *Autoimmune Diseases/epidemiology/drug therapy/complications ; *Dementia/epidemiology/etiology ; Middle Aged ; Aged ; Case-Control Studies ; Comorbidity ; Prevalence ; Aged, 80 and over ; Risk Factors ; Immunosuppressive Agents/therapeutic use ; },
abstract = {Objectives: This study aimed to assess the risk of dementia associated with specific autoimmune diseases and the impact of related pharmacologic treatments. Methods: Patients 55 years or older diagnosed with dementia by neurologists or psychiatrists between 2010 and 2021 were identified using claims data from Taiwan's National Health Insurance program. We examined 22 autoimmune diseases for their associations with dementia, controlling for age, gender, urbanization level, and comorbidities. Results: Dementia prevalence was higher among individuals with autoimmune diseases (10.5% in cases vs. 8.7% in comparisons). Thirteen autoimmune diseases were linked with an elevated dementia risk, particularly Behçet disease, multiple sclerosis, and systemic lupus erythematosus. Associations with vascular dementia were stronger than with Alzheimer disease. Although overall dementia risk was higher in women, no significant sex differences were observed for specific autoimmune diseases. Nonsteroidal anti-inflammatory drugs and corticosteroids did not significantly alter dementia risk among individuals with autoimmune diseases; however, immunosuppressants were associated with a reduced risk when used for more than 180 days. Conclusions: Certain autoimmune diseases are significantly associated with an increased risk of dementia, particularly vascular dementia, highlighting the distinct role of inflammation. Effective prevention or treatment of autoimmune diseases may reduce dementia incidence by 0.8%. While immunosuppressants show potential for risk reduction, further prospective studies are needed to confirm this effect.},
}

Humans
Taiwan/epidemiology
Female
Male
*Autoimmune Diseases/epidemiology/drug therapy/complications
*Dementia/epidemiology/etiology
Middle Aged
Aged
Case-Control Studies
Comorbidity
Prevalence
Aged, 80 and over
Risk Factors
Immunosuppressive Agents/therapeutic use

@article {pmid41129511,
year = {2025},
author = {Cornitius, CP and Perez, EK and Lee, SC},
title = {Microbial links to Alzheimer's disease.},
journal = {PLoS pathogens},
volume = {21},
number = {10},
pages = {e1013599},
doi = {10.1371/journal.ppat.1013599},
pmid = {41129511},
issn = {1553-7374},
mesh = {*Alzheimer Disease/microbiology/etiology/pathology ; Humans ; Animals ; },
abstract = {Alzheimer's disease (AD) is a common chronic neurodegenerative disease that is characterized by (1) plaques, (2) neuronal death, (3) hyperphosphorylation of tau proteins, and (4) memory deficits. Despite extensive research, the underlying cause of AD is not fully understood. Evidence that infectious pathogens may trigger AD has been documented for decades. There are notable correlations between microbes (including bacteria, viruses, and fungi) and AD pathologies. Although it is yet to be determined if pathogenic microbes are the causative agent or a contributing factor to AD, the role of infections in the pathogenesis of AD should not be ignored. Even though the pathogens may not cause AD, they may play a direct role in the triggering or exacerbation of AD progression. In this mini review, the current status of pathogens' role in AD etiology will be presented.},
}

*Alzheimer Disease/microbiology/etiology/pathology
Humans
Animals

@article {pmid41129489,
year = {2025},
author = {, },
title = {Editorial Note: Complete Phenotypic Recovery of an Alzheimer's Disease Model by a Quinone-Tryptophan Hybrid Aggregation Inhibitor.},
journal = {PloS one},
volume = {20},
number = {10},
pages = {e0335097},
doi = {10.1371/journal.pone.0335097},
pmid = {41129489},
issn = {1932-6203},
}

@article {pmid41129427,
year = {2025},
author = {Park, C and Kim, C},
title = {A Novel Chain-of-Thought Reasoning Approach for Alzheimer's Disease Detection Using Large Language and Vision-Language Models.},
journal = {IEEE transactions on neural systems and rehabilitation engineering : a publication of the IEEE Engineering in Medicine and Biology Society},
volume = {PP},
number = {},
pages = {},
doi = {10.1109/TNSRE.2025.3624762},
pmid = {41129427},
issn = {1558-0210},
abstract = {In response to the rapid onset of super-aged societies and the growing prevalence of dementia, our research proposes a multimodal, on-device large language model (LLM)-based agent designed for comprehensive elderly care. Unlike traditional models focused only on dementia diagnosis, our approach leverages a compact, privacy-preserving LLM as the core technology, enabling a wide range of support functions-including cognitive assessment- directly on the device. The pipeline begins with automatic speech recognition (ASR) to convert user speech into text, followed by a vision-language model (VLM) that generates contextual cues from provided images through visual question answering (VQA). We then employ Chain-of-Thought (CoT) reasoning during supervised fine-tuning (SFT) of the LLM, using the generated cues to improve the classification of Alzheimer's disease (AD) versus non-AD cases. A linear layer is added to the LLM for final binary classification. Our results show a 16.7% relative improvement in performance when CoT reasoning is applied compared to when it is not. This multimodal, on-device strategy enables real-time, comprehensive support for the elderly-such as early intervention and integrated cognitive assessment-without reliance on cloud services, thereby laying the groundwork for advanced, privacy-friendly care solutions tailored to super-aged societies.},
}

@article {pmid41129388,
year = {2025},
author = {Gavett, BE and Mungas, D and Fletcher, E and Robles, I and Widaman, K and Fan, A and DeCarli, C and Whitmer, RA and Tomaszewski Farias, S},
title = {Domain-specific changes in everyday cognition: Associations with diagnosis change and gray matter volume change.},
journal = {Neuropsychology},
volume = {},
number = {},
pages = {},
doi = {10.1037/neu0001043},
pmid = {41129388},
issn = {1931-1559},
support = {/AG/NIA NIH HHS/United States ; },
abstract = {OBJECTIVE: Declines in everyday cognitive functioning are a common occurrence in late life. The present study sought to understand how informant-rated everyday cognitive abilities related to memory, language, spatial skills, planning, organization, and divided attention-as measured by the Everyday Cognition (ECog) scale-change over time in a diverse sample of older adults.

METHOD: Participants (N = 891) from the University of California Davis Alzheimer's Disease Research Center longitudinal cohort (Mage = 76.1, SDage = 7.4) were followed for an average of 4.4 years with annual ECog assessments. Multilevel beta regression was used to model ECog scores as a function of time, cognitive domain, diagnosis change, and-in a neuroimaging subsample (N = 264)-cross-sectional and longitudinal total gray matter and hippocampus volume.

RESULTS: ECog domains changed at different rates when modeled as a function of diagnosis change; differences in domain were most apparent in the stable mild cognitive impairment (MCI)-to-MCI and MCI-to-dementia conversion groups. By contrast, ECog domains changed at the same rate when modeled as a function of baseline gray matter volume and longitudinal gray matter volume change, corresponding to other research suggesting that cognitive domains change at relatively uniform rates over time. In separate models, total gray matter and hippocampus atrophy were salient predictors of ECog score changes. At baseline, hippocampus volume was the strongest predictor of ECog intercepts.

CONCLUSIONS: Although some caution is warranted interpreting score changes due to floor and ceiling effects, the ECog appears sensitive to underlying gray matter atrophy and change in clinical disease severity when used longitudinally. (PsycInfo Database Record (c) 2025 APA, all rights reserved).},
}

@article {pmid41129322,
year = {2025},
author = {Graves, SI and Baker, DJ},
title = {Protocol to test path integration in mice using an L-maze behavioral assay.},
journal = {STAR protocols},
volume = {6},
number = {4},
pages = {104156},
doi = {10.1016/j.xpro.2025.104156},
pmid = {41129322},
issn = {2666-1667},
abstract = {Path integration (PI) is a component of navigation whereby an organism uses self-motion cues to estimate position and move toward a goal, without relying on external landmarks. PI deficits can predict cognitive decline and Alzheimer's disease in humans. Here, we present a protocol to test PI in mice using a dry-land L-maze behavioral assay with three phases: habituation, training, and testing. This protocol may allow researchers to test for early disease in mouse models of neurodegeneration. For complete details on the use and execution of this protocol, please refer to Graves et al.[1].},
}

@article {pmid41129234,
year = {2025},
author = {Zhao, R and Sophanpanichkul, P and Chadarevian, JP and Ding, Y and Dai, H and Nayak, M and Davtyan, H and Blurton-Jones, M and Goldstein, SAN},
title = {Amyloid precursor protein and C99 are subunits in human microglial Hv1 channels that enhance current and inflammatory mediator release.},
journal = {Proceedings of the National Academy of Sciences of the United States of America},
volume = {122},
number = {43},
pages = {e2509903122},
doi = {10.1073/pnas.2509903122},
pmid = {41129234},
issn = {1091-6490},
support = {HL159711//HHS | NIH | National Heart, Lung, and Blood Institute (NHLBI)/ ; AT012544//HHS | NIH | National Center for Complementary and Integrative Health (OAM)/ ; T32 AG00096//HHS | NIH | National Institute on Aging (NIA)/ ; },
mesh = {Humans ; *Amyloid beta-Protein Precursor/metabolism/genetics ; *Microglia/metabolism ; HEK293 Cells ; *Ion Channels/metabolism/genetics ; Alzheimer Disease/metabolism/genetics/pathology ; Induced Pluripotent Stem Cells/metabolism ; *Inflammation Mediators/metabolism ; Reactive Oxygen Species/metabolism ; *Peptide Fragments/metabolism ; },
abstract = {In Alzheimer's disease (AD), hyperactivated microglia produce inflammatory mediators that contribute to neuroinflammation and neuronal damage. Amyloid precursor protein (APP), a transmembrane protein expressed in many cell types, including neurons and microglia, plays a critical role in AD pathogenesis via its secretase-mediated processing to release the C-terminal 99-residue transmembrane fragment (C99) that is further cleaved to yield amyloid-β peptides. Voltage-gated proton channels (Hv1) have been implicated in microglial activation and release of inflammatory mediators, but the potential role of these channels in human microglia and AD pathogenesis remains unclear. Here, we demonstrate that human induced pluripotent stem cell-derived microglia (iMG) express native Hv1 channels with biophysical and pharmacological attributes determined by their coassembly with APP and that APP knockdown decreases Hv1 currents, suppressing cytokine and reactive oxygen species release. In HEK293T cells, APP is shown to increase current by favoring channel opening at more negative membrane potentials. C99 is sufficient to assemble with Hv1 and alters channel function even more significantly than APP. Coimmunoprecipitation, total internal reflection fluorescence microscopy, and altered pharmacology further demonstrate that C99 forms stable complexes with Hv1 in the plasma membrane. In addition, we find that two early-onset AD mutations in APP (E682K and D694N) that reside within C99 significantly increase voltage-dependent channel activity beyond that induced by wild type C99, rationalizing their enhanced mediation of neuroinflammation.},
}

Humans
*Amyloid beta-Protein Precursor/metabolism/genetics
*Microglia/metabolism
HEK293 Cells
*Ion Channels/metabolism/genetics
Alzheimer Disease/metabolism/genetics/pathology
Induced Pluripotent Stem Cells/metabolism
*Inflammation Mediators/metabolism
Reactive Oxygen Species/metabolism
*Peptide Fragments/metabolism

@article {pmid41129010,
year = {2025},
author = {Carrera-Bastos, P and Muskiet, MHA and Mata-Ordoñez, F and Pruimboom, L and Lucia, A and Luque, RM and Muskiet, FAJ},
title = {Metabolic reprogramming in diabetes and other endocrine and metabolic disorders: exploring the Warburg effect, ketones, and SGLT2 inhibitors.},
journal = {Reviews in endocrine & metabolic disorders},
volume = {},
number = {},
pages = {},
pmid = {41129010},
issn = {1573-2606},
abstract = {The "Warburg effect", a metabolic adaptation observed in dividing cells, involves a shift from mitochondrial oxidative phosphorylation to cytoplasmic glucose metabolism. This metabolic process is characterized by increased cellular uptake of glucose and glutamine, elevated intracellular pH and sodium levels, enhanced protection against oxidative stress, altered autophagy, and increased lactate production. Initially identified by Otto Warburg in cancer cells, the Warburg effect is now recognized as a common feature of all dividing cells, prioritizing biomass production for cell proliferation over energy generation for specialized cellular functions. Indeed, the Warburg effect is emerging as an important feature not only in cancer but also in a range of metabolic, endocrine, and neurological chronic disorders, including type 2 diabetes, heart and kidney failure, therapy-refractory epilepsy, Alzheimer's and Parkinson's diseases, chronic fatigue syndrome, and post-viral syndromes. The prevailing notion that "dysfunctional mitochondria" are the primary cause of the "energy deficit" observed in these conditions may be misleading. Instead, this "energy deficit" can result from cells reprogramming their metabolism to support cell division. Additionally, in these disorders, senescent cells are abundant, exhibiting a Warburg-like metabolism with cell cycle arrest and enhanced anabolic activity. This review explores the multifaceted role of the Warburg effect in type 2 diabetes and other metabolic and endocrine chronic disorders and examines the therapeutic potential of different interventions such as intermittent fasting, ketogenic diets, ketone supplements, and sodium/glucose co-transporter 2 inhibitors. Through a comprehensive analysis of existing literature, we aim to shed light on the mechanisms underlying these interventions and their potential impact on disease progression and patient outcomes.},
}

@article {pmid41128923,
year = {2025},
author = {Buck, SA and Malankhanova, T and Strader, S and Ma, EB and Yim, S and Pratt, HW and Ervin, J and Lee, EB and Wang, SJ and Cohen, TJ and West, AB and Sanders, LH},
title = {LRRK2 kinase-mediated accumulation of lysosome-associated phospho-Rabs in tauopathies and synucleinopathies.},
journal = {Acta neuropathologica},
volume = {150},
number = {1},
pages = {44},
pmid = {41128923},
issn = {1432-0533},
support = {PF-PRF-1244721//Parkinson's Foundation/ ; P30AG072979/NH/NIH HHS/United States ; P30AG072958/NH/NIH HHS/United States ; R21AG084216/NH/NIH HHS/United States ; R01NS064934/NH/NIH HHS/United States ; R01NS119528/NH/NIH HHS/United States ; },
mesh = {*Leucine-Rich Repeat Serine-Threonine Protein Kinase-2/metabolism/genetics ; Humans ; *rab GTP-Binding Proteins/metabolism ; Phosphorylation ; *Tauopathies/pathology/metabolism/genetics ; *Lysosomes/metabolism/pathology ; Animals ; tau Proteins/metabolism ; Male ; Aged ; Female ; alpha-Synuclein/metabolism ; *Synucleinopathies/pathology/metabolism/genetics ; Mice ; Brain/pathology/metabolism ; Mice, Transgenic ; Aged, 80 and over ; Mutation/genetics ; Middle Aged ; Parkinson Disease/pathology/metabolism ; Neurons/metabolism/pathology ; },
abstract = {Parkinson's disease (PD) pathogenic mutations in leucine-rich repeat kinase 2 (LRRK2) are associated with endolysosomal dysfunction across cell types, and carriers of LRRK2 mutations variably present with phosphorylated tau and α-synuclein deposits in post-mortem analysis. LRRK2 mutations increase the phosphorylation of Rab substrates including Rab12 and Rab10. Rab12 and Rab10 are expressed in neuronal and non-neuronal cells with localization to membranes in the endolysosomal compartment, and lysosomal stress activates LRRK2 phosphorylation of Rabs. In this study, using antibodies directed to the LRRK2-mediated phosphorylation sites on Rab12 at amino acid Ser106 (pS106-Rab12) and Rab10 at amino acid Thr73 (pT73-Rab10), we test whether aberrant LRRK2 phosphorylation is associated with tau and/or α-synuclein pathology across clinically distinct neurodegenerative diseases. Analysis of brain tissue lysates and immunohistochemistry of pathology-susceptible brain regions demonstrate that pS106-Rab12 levels are increased in Alzheimer's disease (AD) and Lewy body disease (LBD), including PD with and without G2019S LRRK2 mutation. At early pathological stages, phosphorylated Rab12 localizes to granulovacuolar degeneration bodies (GVBs), which are thought to be active lysosomal-like structures, in neurons. pS106-Rab12-positive GVBs accumulate with pathological tau across brain tissues in AD and LBD, and in G2019S LRRK2 mutation carriers. In a mouse model of tauopathy, pS106-Rab12 localizes to GVBs during early tau deposition in an age-dependent manner. While GVBs are largely absent in neurons with mature protein pathology, subsets of both tau and α-synuclein inclusions appear to incorporate pS106-Rab12 at later pathological stages. Further, pS106-Rab12 labels GVBs in neurons and shows co-pathology with tau inclusions in primary tauopathies including Pick's disease, progressive supranuclear palsy, and corticobasal degeneration. Finally, pT73-Rab10 is elevated and localizes to GVBs, but not tau and α-synuclein inclusions, in AD and LBD, including G2019S LRRK2 mutation carriers. These results implicate LRRK2 kinase activity and Rab phosphorylation in endolysosomal dysfunction in tau- and α-synuclein-associated neurodegenerative diseases.},
}

*Leucine-Rich Repeat Serine-Threonine Protein Kinase-2/metabolism/genetics
Humans
*rab GTP-Binding Proteins/metabolism
Phosphorylation
*Tauopathies/pathology/metabolism/genetics
*Lysosomes/metabolism/pathology
Animals
tau Proteins/metabolism
Male
Aged
Female
alpha-Synuclein/metabolism
*Synucleinopathies/pathology/metabolism/genetics
Mice
Brain/pathology/metabolism
Mice, Transgenic
Aged, 80 and over
Mutation/genetics
Middle Aged
Parkinson Disease/pathology/metabolism
Neurons/metabolism/pathology

@article {pmid41128902,
year = {2025},
author = {Pilipenko, V and Lieknina, I and Skrastina, D and Aktas, S and Revina, BL and Upite, J and Jansone, B and Tars, K},
title = {Active immunization with bacteriophage AP205 VLPs results in reduced amyloid load and microgliosis in 5xFAD female mice.},
journal = {Naunyn-Schmiedeberg's archives of pharmacology},
volume = {},
number = {},
pages = {},
pmid = {41128902},
issn = {1432-1912},
support = {VPP-EM-BIOMEDICĪNA-2022/1-0001//State Research Programme/ ; },
abstract = {Alzheimer's disease (AD) is the leading cause of dementia worldwide and the accumulation of amyloid β (Aβ) oligomers in the brain parenchyma is one of the main characteristics of AD. Pyroglutamate-modified amyloid β (pE3Aβ) forms are highly pathogenic components of Aβ plaques and are viable targets for disease-modifying strategies. Active immunization using virus-like particles (VLPs) represents a promising therapeutic approach to combating AD. Using RNA bacteriophage-based VLPs, we developed and tested a vaccine targeting pE3Aβ in 5xFAD female mice. This study utilized the bacteriophage AP205 VLP platform to generate candidate compounds for active immunization. AP205 VLPs were modified to display short pE3Aβ peptides. At 2 months of age, 5xFAD female mice received four immunizations with either pE3Aβ VLPs or AP205 VLPs. Blood titers were assessed biweekly for the first 45 days and then every 2 months using ELISA. Behavioral tests, including open field, spontaneous alternation, Morris water maze, and elevated zero maze (EZM), were performed at 6 and 8 months of age. Immunohistochemical analyses evaluated levels of Aβ42, pE3Aβ, glial fibrillary acidic protein (GFAP), and ionized calcium-binding adapter molecule-1 (Iba-1). pE3Aβ VLPs and AP205 VLPs did not alter cognitive or locomotor performance in 5xFAD mice. The working memory of 8-month-old pE3Aβ VLP-treated mice was better than it was at 6-months of age. A moderate reduction in Aβ42 pathology and microglial activation was observed in both vaccinated groups. VLP-based vaccine administration showed no behavioral improvements in 5xFAD mice but demonstrated modest effects on Aβ42 load and microgliosis.},
}

@article {pmid41128826,
year = {2025},
author = {Hoveizi, E and Bijavi, G and Parsa, H},
title = {Advancing Cell Therapy to Enhance Passive Avoidance Memory: Integrative Approaches Combining Neural-Like Cells and Rosmarinic Acid Through Behavioral, Molecular, and Histological Analyses.},
journal = {Neurochemical research},
volume = {50},
number = {6},
pages = {334},
pmid = {41128826},
issn = {1573-6903},
mesh = {Animals ; Rosmarinic Acid ; *Depsides/pharmacology/therapeutic use ; *Cinnamates/pharmacology/therapeutic use ; Male ; *Alzheimer Disease/therapy/metabolism/pathology ; Rats ; *Avoidance Learning/physiology/drug effects ; *Cell- and Tissue-Based Therapy/methods ; *Memory/physiology/drug effects ; Mesenchymal Stem Cells/cytology ; Rats, Sprague-Dawley ; *Neurons/drug effects/metabolism ; Cell Differentiation/physiology/drug effects ; Dental Pulp/cytology ; Oxidative Stress/drug effects ; },
abstract = {Alzheimer's disease (AD) is characterized by progressive neurodegeneration, synaptic dysfunction, and cognitive decline. Regenerative strategies aim to replace lost neurons and modulate the inflammatory milieu to restore neural networks. This study examined the effects of neural-like cells (NLCs) derived from dental pulp mesenchymal stem cells (DPSCs) on a chitosan scaffold using rosmarinic acid (RA) in AD rats. In this study, DPSCs were extracted from teeth, characterized and differentiated, induced an AD model by destroying the Meynert nucleus, conducted passive avoidance tests, analyzed histology and immunohistochemistry, and measured inflammatory and oxidative stress markers. The extraction and differentiation of DPSCs were successful. Differentiated DPSCs into neural progenitors showed increased expression of Tuj-1, Map2, Nestin, and NF (RT-PCR, p < 0.001). Behavioral tests confirmed the AD model after seven days, and histology showed neuronal loss and gliosis following Meynert destruction. Histomorphology revealed improved brain tissue and significantly increased choline acetyltransferase (ChAT) expression in the treatment groups. Notable behavioral improvements were observed in the Y‑maze and shuttle box for treated rats compared with the AD group. Biochemical analyses showed a significant decrease in inflammatory markers IL‑1β, IL‑6, and TNF‑α, along with increases in superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GPX) in the RA-treated groups. The results provide reliable evidence that DPSCs, in combination with RA, exert a promising therapeutic effect and represent a meaningful advance toward the clinical application of combination therapies for patients with AD.},
}

Animals
Rosmarinic Acid
*Depsides/pharmacology/therapeutic use
*Cinnamates/pharmacology/therapeutic use
Male
*Alzheimer Disease/therapy/metabolism/pathology
Rats
*Avoidance Learning/physiology/drug effects
*Cell- and Tissue-Based Therapy/methods
*Memory/physiology/drug effects
Mesenchymal Stem Cells/cytology
Rats, Sprague-Dawley
*Neurons/drug effects/metabolism
Cell Differentiation/physiology/drug effects
Dental Pulp/cytology
Oxidative Stress/drug effects

@article {pmid41128636,
year = {2025},
author = {Abdulazeez, Y and Utami, RN and Al-Jamal, KT and Mok, ZH},
title = {Effects of Ghrelin Hormone on Alzheimer's and Parkinson's Disease: A Systematic Review of the Existing Literature.},
journal = {ACS chemical neuroscience},
volume = {},
number = {},
pages = {},
doi = {10.1021/acschemneuro.5c00683},
pmid = {41128636},
issn = {1948-7193},
abstract = {Ghrelin is an orexigenic hormone secreted mainly in the stomach and small intestine. It has many functions, including appetite stimulation, growth hormone release triggering, and maintaining glucose and energy homeostasis. It has also been linked to many neuroregenerative and neuroprotective activities via its activity on the growth hormone secretagogue receptor 1a (GHS-R1a). In brain tissues, it has been revealed that only the acylated ghrelin (AG) but not the unacylated ghrelin (UAG) has the affinity to GHS-R1a. In addition, AG has been shown to undergo fast enzymatic conversion into the inactive UAG form in the serum. Many experimental trials were conducted to study ghrelin's effect on Alzheimer's disease (AD) and Parkinson's disease (PD), but there have not been systematic reviews made to date. This systematic review highlighted the findings from preclinical trials between 2010 and July 2023, in which ghrelin and/or one of its agonists have been investigated for their effects in treating AD and PD. The search databases used were Embase, Cochrane, and Medline. All articles reviewed were animal studies as there were no clinical trials. The findings on AD showed that AG has demonstrated improved outcomes histopathologically and symptomatically. Meanwhile for PD, AG was found to have neuroprotective effects, especially in the early stage of the disease. This systematic review paves the way for more studies to be done to ensure the applicability of ghrelin and/or its agonists in treating and/or slowing the progression of AD, and early prevention and diagnosis of PD.},
}

@article {pmid41128446,
year = {2025},
author = {Graff, RE and Chen, DM and Swinnerton, KN and Ackley, SF and Ospina-Romero, M and Zimmerman, SC and Wang, J and Buto, P and Nierenberg, JL and Elahi, FM and Lu, KP and Witte, JS and Glymour, MM},
title = {Evaluation of Polygenic Risk Scores for a Possible Genetic Basis of the Inverse Association Between Cancer and Cognitive Decline.},
journal = {Alzheimer disease and associated disorders},
volume = {},
number = {},
pages = {},
doi = {10.1097/WAD.0000000000000696},
pmid = {41128446},
issn = {1546-4156},
abstract = {BACKGROUND: Accumulating evidence suggests that the incidence of cancer and dementia are inversely associated. Bias does not appear to fully account for the relationship, but causal explanations have not been adequately investigated. We thus considered a possible inverse shared genetic basis.

METHODS: We constructed polygenic risk scores for cancer (PRScancer) and Alzheimer disease (PRSAD) in European ancestry UK Biobank (UKB) and Health and Retirement Study (HRS) participants aged 60 years or older. Linear mixed-effects models evaluated associations of PRScancer with cognition, and logistic regression evaluated associations of PRSAD with cancer.

RESULTS: In UKB, PRScancer was nominally associated with improved fluid intelligence (β: 0.12, 95% CI: 0.01-0.22). Twelve variants in PRScancer, including 7 in the human leukocyte antigen (HLA) complex, were positively associated with fluid intelligence, and 7 were inversely associated (P<5.8×10-5). PRScancer and its contributing variants were not associated with cognitive outcomes in HRS. PRSAD was not associated with cancer risk in either study cohort.

DISCUSSION: Though not conclusive, the direction of the association between PRScancer and fluid intelligence was consistent with our a priori hypothesis that cancer risk variants would decrease cognitive decline. The association pattern with HLA-related variants suggests potential relevance of immune surveillance for the inverse association between dementia and cancer.},
}

@article {pmid41128402,
year = {2025},
author = {Joshy, M and Liu, L and Dassanayake, P and Aiello, M and Di Cecca, A and Cavaliere, C and Anazodo, U and Finger, E and St Lawrence, K},
title = {Disrupted Coupling Between Cerebral Glucose Metabolism and Intrinsic Functional Connectivity: A Hybrid PET/fMRI Study on Frontotemporal Dementia.},
journal = {Human brain mapping},
volume = {46},
number = {15},
pages = {e70388},
doi = {10.1002/hbm.70388},
pmid = {41128402},
issn = {1097-0193},
support = {PJT-180306/CAPMC/CIHR/Canada ; R3592A14//Alzheimer Foundation London and Middlesex/ ; RR182074//Weston Brain Institute/ ; PE0000006//National Recovery and Resilience Plan/ ; },
mesh = {Humans ; *Frontotemporal Dementia/diagnostic imaging/metabolism/physiopathology ; Positron-Emission Tomography ; Female ; Male ; Magnetic Resonance Imaging ; Middle Aged ; *Glucose/metabolism ; *Nerve Net/diagnostic imaging/metabolism/physiopathology ; Aged ; *Connectome ; Fluorodeoxyglucose F18 ; Multimodal Imaging ; *Cerebral Cortex/diagnostic imaging/metabolism/physiopathology ; },
abstract = {It is increasingly established that the organization of the brain into functional resting-state networks allows efficient integration and processing of information. Functional hubs anchoring such networks are characterized by a high degree of communication, which relies on efficient utilization of glucose. Alzheimer's disease (AD) disrupts the balance between glucose metabolism and intrinsic functional connectivity (FC). We hypothesized that this critical coupling would also be weakened in frontotemporal dementia (FTD), particularly within the salience network, given its association with the disease. Towards this goal, behavioral variant FTD (bvFTD) patients (n = 21) and healthy participants (n = 18) underwent simultaneous FDG-PET and functional MRI imaging in a hybrid PET/MR system, with an additional cohort completing the MRI component only. PET images were converted into standardized uptake value ratios (SUVr), and local FC was quantified using regional homogeneity (ReHo) and fractional amplitude of low-frequency fluctuations (fALFF), two metrics that have been demonstrated to be related to FDG-PET uptake. The interplay between FC and glucose metabolism was investigated within the salience and default mode networks. The bvFTD group showed network-level functional breakdown and significantly weakened metabolism/FC coupling, especially in the dorsal anterior insula and posterior cingulate cortex. Importantly, reduced coupling in the posterior cingulate cortex was associated with cognitive and behavioral symptoms in patients. Though significant, the reduction in whole-brain metabolic/FC coupling in bvFTD was not as strong as reported previously for AD. These results highlight the vulnerability of functional hubs to neurodegenerative disease. Aberrant regional disruptions in the coupling between metabolism and neuronal activity may drive network-level dysfunction and contribute to functional impairments characteristic of the disease.},
}

Humans
*Frontotemporal Dementia/diagnostic imaging/metabolism/physiopathology
Positron-Emission Tomography
Female
Male
Magnetic Resonance Imaging
Middle Aged
*Glucose/metabolism
*Nerve Net/diagnostic imaging/metabolism/physiopathology
Aged
*Connectome
Fluorodeoxyglucose F18
Multimodal Imaging
*Cerebral Cortex/diagnostic imaging/metabolism/physiopathology

@article {pmid41127459,
year = {2025},
author = {Saiz-Vazquez, O and Ubillos-Landa, S and Puente-Martínez, A},
title = {Meta meta-analysis of cardiovascular risk factors in Alzheimer's disease.},
journal = {eNeurologicalSci},
volume = {41},
number = {},
pages = {100590},
pmid = {41127459},
issn = {2405-6502},
abstract = {BACKGROUND: Alzheimer's disease (AD) is the most common cause of dementia in the elderly. Identifying some of the cardiovascular risk factors for AD could be crucial for primary prevention and help reduce the incidence of AD. Objective: We aimed to perform a meta-meta-analysis of 3 studies to assess the effect of cholesterol, blood pressure and stroke on diagnosis of AD.

METHODS: The search was restricted to meta-analyses in the last three years assessing cholesterol, blood pressure, stroke and Alzheimer's disease. We applied the PRISMA guidelines.

RESULTS: The total effect of cholesterol on risk of AD was significant and heterogeneous. Subgroup analysis shows that LDL-C levels influence the development of AD. High SBP is associated with AD. The exploration of parameters (sex, age, study design, region, and BP measurements) shows that only region significantly moderates the relationship between BP and AD. Results report significant association between ischemic stroke (IS), hemorrhagic stroke (HS) and microinfarcts (MI) with the risk of AD.

CONCLUSIONS: These results strengthen the evidence that the risk factors related to cardiovascular diseases increase risk for AD. Moreover, moderator analysis supports the robustness of our results. Therefore, future studies should use other uncontrolled factors, such as diabetes, to explain the relationship between these variables.},
}

@article {pmid41127441,
year = {2025},
author = {Sanjuan-Ruiz, I and Serneels, L and Craessaerts, K and Goate, A and Annaert, W and Chávez-Gutiérrez, L and Shi, Y and Sheikh-Bahaei, N and Jen, JC and Ramos, EM and Campan, M and Ward, PM and Magaki, S and Bartlone, K and Vinters, HV and , and Craig, DW and Ringman, JM and De Strooper, B},
title = {The curious case of a heterozygous loss-of-function PSEN1 variant associated with early-onset Alzheimer's disease.},
journal = {Molecular neurodegeneration advances},
volume = {1},
number = {1},
pages = {4},
pmid = {41127441},
issn = {3059-4944},
abstract = {BACKGROUND: Over 300 mutations in PSEN1 have been identified as causes of early-onset Alzheimer's disease (EOAD). While these include missense mutations and a few insertions, deletions, or duplications, none result in open reading frame shifts, and all alter γ-secretase function to increase the long/short Aβ ratio.

METHODS: We identified a novel heterozygous PSEN1 nonsense variant, c.325A > T, in a patient and his father, both presenting with EOAD, resulting in the substitution of lysine 109 with a premature stop codon at position (p.K109*). This produces a truncated 109 amino acid (aa) N-terminal PSEN1 fragment. Functional characterization was performed using overexpression models and a heterozygous mouse model (Psen1[K109*/+]).

RESULTS: In overexpression models, downstream ATGs serve as alternative starting codons, generating a > 37 kDa and a > 27 kDa PSEN1 C-terminal fragment (PSEN1-CTFA and PSEN1-CTFB, respectively) that retain the two catalytic aspartates of γ-secretase. Heterozygous Psen1[K109*/+] mice exhibited subtle phenotypic defects, including reduced Pen2 expression and mild APP-CTF accumulation. Notably, aged mice demonstrated significantly increased Psen2 protein expression, potentially contributing to an elevated Aβ42/Aβ38 ratio.

CONCLUSIONS: These findings indicate that PSEN1 c.325A > T (p.K109*) is not a complete loss-of-function mutation. However, to what extent and by what mechanism it contributes to EOAD pathogenesis remains unclear.

SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s44477-025-00004-x.},
}

@article {pmid41127252,
year = {2025},
author = {Salih, AM and Salatzki, J and Wang, Y and Akilu, T and Maldonado, C and Husain, M and Neubauer, S and Topiwala, A and Altmann, A and Raisi-Estabragh, Z},
title = {Genetic associations of plasma proteomics with dementia subtypes and neuroimaging markers.},
journal = {Alzheimer's & dementia (Amsterdam, Netherlands)},
volume = {17},
number = {4},
pages = {e70202},
pmid = {41127252},
issn = {2352-8729},
abstract = {INTRODUCTION: Dementia is a rising global health challenge. Advances in large-scale proteomics and genetic databases have enabled high-throughput screening approaches to uncover novel mechanistic pathways and therapeutic targets.

METHODS: This study used a Mendelian randomization framework to examine genetic associations of 2172 plasma proteins (UK Biobank, n = 54,219) with: (1) dementia subtypes (FinnGen, n = 429,209), including Alzheimer's disease (n = 12,348), vascular dementia (n = 2667), and Parkinson's disease dementia (n = 589); and (2) global neuroimaging markers (UK Biobank), including white matter hyperintensities (n = 42,310), fractional anisotropy (n = 17,663), and mean diffusivity (n = 17,467).

RESULT: Multiple potential causal protein-outcome relationships were identified, corroborating known associations (e.g., apolipoprotein E, synaptosomal-associated protein 25) and uncovering more novel proteins (e.g., butyrophilin subfamily 3 member A2, granzyme A, contactin-2, and trefoil factor 3) potentially involved in dementia disease processes.

DISCUSSION: The identified proteins have diverse functions spanning immune regulation, cellular proliferation, neuronal stability, and neuroinflammation. The findings increase our understanding of disease processes governing cognitive health and highlight candidate proteins with potential as new disease biomarkers or therapeutic targets.

HIGHLIGHTS: We used Mendelian randomization to link 2172 plasma proteins to dementia and brain imaging traits.Apolipoprotein E, triggering receptor expressed on myeloid cells 2, and Fc receptor-like 3 showed protective associations across dementia subtypes.Butyrophilin subfamily 3 member A2, granzyme A, contactin-2, and trefoil factor 3 were uncovered as novel dementia-associated proteins.Immune, metabolic, and vascular pathways were implicated in the etiology of dementia.},
}