@article {pmid41182881,
year = {2025},
author = {Aoki, S and Onodera, W and Takashima, A and Kawasaki, K and Imadegawa, K and Kurahashi, H and Oishi, M and Asahi, T and Soeda, Y},
title = {E3 ligase Praja1 mediates ubiquitination and degradation of microtubule-associated protein tau.},
journal = {The FEBS journal},
volume = {},
number = {},
pages = {},
doi = {10.1111/febs.70303},
pmid = {41182881},
issn = {1742-4658},
support = {JPMXS0440500024//Agency for Cultural Affairs, Government of Japan/ ; //OPTORUN Co., Ltd./ ; //Global Consolidated Research Institute for Science, Wisdom, Waseda University/ ; },
abstract = {The RING-H2 type E3 ligase Praja family is composed of E3 ubiquitin-protein ligases Praja1 and Praja2, which promote the degradation of substrates through the ubiquitin-proteasome system. Both paralogs contribute to neuronal maturation and differentiation, indicating a significant role in the nervous system. Aggregation-prone proteins associated with neurodegenerative diseases, including TAR DNA-binding protein 43 (TDP-43) and α-synuclein, are degraded and/or suppressed by Praja1. Furthermore, the expression level of the microtubule-associated protein tau (MAPT) gene, which is frequently mutated in Alzheimer's disease, is regulated by Praja2. Although the Praja family has been shown to recognize various aggregation-prone proteins as substrates, it has not been determined whether tau, a key protein that aggregates in tauopathies, is also recognized by Praja proteins. In this study, we show that Praja1, but not Praja2, recognizes tau as a candidate substrate. We observed that the tau protein level in human neuroblastoma SH-SY5Y cells decreased depending on the E3 ligase activity of Praja1. Furthermore, the in vivo/in vitro ubiquitination assay showed that Praja1 ubiquitinates tau, indicating that it is a target substrate. Next, by combining ancestral sequence reconstruction and mutational analysis, we revealed that the Praja1-tau interaction began just after the duplication of the Praja family in the common ancestor of placentals. Lastly, to test whether this interaction is disrupted under pathological conditions, P301L tau was introduced, resulting in a degradation similar to that of wild-type tau. These results reveal an unidentified mechanism of tau proteostasis by Praja1 and may provide insight into the pathogenesis of neurodegenerative diseases, including tauopathy.},
}

@article {pmid41182837,
year = {2025},
author = {Rani, S and Kaur, M and Pothal, P and Rajput, K and Khera, A and Sharma, A and Thombare, V and Sethi, A and Paul, B and Gartia, J and Yadav, VK and Patil, NA and Ranawat, P and Suresh Babu, AR and Singh, G and Barnwal, RP},
title = {Identifying Novel Spiro-Indenoquinoxaline-Pyrrolidine-Based Amyloid Beta Inhibitors in Alzheimer's Disease from In Silico to In Vitro.},
journal = {ACS chemical neuroscience},
volume = {},
number = {},
pages = {},
doi = {10.1021/acschemneuro.5c00728},
pmid = {41182837},
issn = {1948-7193},
abstract = {Alzheimer's disease (AD) is the most prevalent neurodegenerative disease characterized by memory loss and other cognitive functions. The key hallmarks of AD include extracellular beta-amyloid clumps and intracellular neurofibrillary tau tangles in the neurons. Cholinesterase inhibitors and NMDA-receptor antagonists and their combination are already approved treatments; however, these only give short-term symptom relief. Therefore, new therapeutic techniques and novel drugs are required to combat the century-old AD. This study includes the screening of nine novel small compounds (spiro-indenoquinoxaline-pyrrolidines) via in silico approaches; these compounds have been scrutinized to explore their potential as antiamyloidogenic drugs. Computational tools, including ADMET analysis, molecular docking, and molecular dynamics (MD) simulations, have been used for screening the selected compounds against monomeric peptides of Aβ (Aβ1-40 and Aβ1-42) and their oligomeric counterparts, i.e., 6Aβ9-40 and 6Aβ1-42. Among the nine molecules screened for this study, ADPR-d reflected the best drug-likeness and negligible toxicity. Further, ADPR-d has the highest binding affinity for all the peptides selected for this study. Additionally, MD simulations of Aβ peptide-ADPR-d complexes confirmed a stable complex formation. In vitro aggregation assay and cell culture studies for Aβ1-42 also support our in silico findings. The positive findings of the presented study highlight that the ADPR-d molecule may prove to be a potential therapeutic molecule against AD. However, these results would require further in vitro and in vivo analysis before proceeding to clinical settings with these compounds against AD.},
}

@article {pmid41182777,
year = {2025},
author = {Thomas, ML and Edland, SD and Duehring, J},
title = {The MMSE can yield biased and imprecise estimates of change: A novel IRT analysis of latent change scores from the A4 clinical trial.},
journal = {Psychological assessment},
volume = {},
number = {},
pages = {},
doi = {10.1037/pas0001426},
pmid = {41182777},
issn = {1939-134X},
support = {//National Institutes of Health; National Institute of Mental Health/ ; },
abstract = {The measurement precision of change scores has previously been investigated from the perspective of classical test theory. However, the measurement precision of change scores has not been thoroughly explored from an item response theory (IRT) perspective. In this study, we provide, to our knowledge, one of the first direct investigations of change score precision within an IRT framework. Specifically, using archival data from the antiamyloid treatment in asymptomatic Alzheimer's trial, we examined standard error of estimate for change scores on the mini-mental state examination, one component of the preclinical Alzheimer cognitive composite used to measure change between intervention arms. Multidimensional two-parameter IRT models were fitted to the mini-mental state examination item data with one latent dimension reflecting baseline ability and a second reflecting change in ability over time (i.e., latent change scores). Results showed that standard error depended on change magnitude and that change scores were expected to be biased toward zero when baseline performance scores were near ceiling. The results demonstrate why measures with pronounced ceiling effects should not be used to assess change in clinical trials or other longitudinal studies, and should be used cautiously in clinical settings. This study also demonstrates how IRT can be used to evaluate change score precision. (PsycInfo Database Record (c) 2025 APA, all rights reserved).},
}

@article {pmid41182424,
year = {2025},
author = {Wang, X and Zhang, L and Gao, X and Zhang, L and Yu, J and Liu, Y and Fang, M and Yan, Y and Chen, L and Du, J and Guan, H and Huang, C and Fan, S},
title = {Liu Jun Zi Decoction extends lifespan and healthspan through p16/p21 signaling in Caenorhabditis elegans.},
journal = {Biogerontology},
volume = {26},
number = {6},
pages = {201},
pmid = {41182424},
issn = {1573-6768},
support = {82073951//National Natural Science Foundation of China/ ; },
mesh = {Animals ; *Caenorhabditis elegans/drug effects/metabolism ; *Longevity/drug effects ; *Drugs, Chinese Herbal/pharmacology ; Signal Transduction/drug effects ; *Caenorhabditis elegans Proteins/metabolism/genetics ; Aging/drug effects ; },
abstract = {Age-related functional decline has emerged as a major challenge to human health and societal development. Safe and effective anti-aging interventions, particularly those involving natural products, offer promising strategies to delay aging and promote healthy longevity. In this study, we used Caenorhabditis elegans (C. elegans) models to investigate the anti-aging effects and underlying mechanisms of Liu Jun Zi Decoction (LJZD), a traditional Chinese herbal formula. The results showed that LJZD extended lifespan and enhanced stress resistance and locomotion in C. elegans. Serum pharmacochemistry, network pharmacology, and molecular docking identified key bioactive compounds that target the IIS/mTOR and p16/p21 pathways. Furthermore, we found that LJZD promoted longevity by improving mitochondrial function via the IIS-mTOR axis. Notably, LJZD also conferred neuroprotection in Aβ-/tau-expressing models. These findings provide mechanistic insights into multi-target herbal interventions for aging and neurodegeneration.},
}

Animals
*Caenorhabditis elegans/drug effects/metabolism
*Longevity/drug effects
*Drugs, Chinese Herbal/pharmacology
Signal Transduction/drug effects
*Caenorhabditis elegans Proteins/metabolism/genetics
Aging/drug effects

@article {pmid41182353,
year = {2025},
author = {Cai, Y and Huang, S and Dong, Y and Li, S and Jin, X},
title = {PIWI-Interacting RNAs in brain health and disease: biogenesis, mechanisms, and therapeutic horizons.},
journal = {Psychopharmacology},
volume = {},
number = {},
pages = {},
pmid = {41182353},
issn = {1432-2072},
support = {81971083//National Natural Science Foundation of China/ ; 25JCLZJC00190//Tianjin Natural Science Foundation Project/ ; },
abstract = {PIWI-interacting RNAs (piRNAs), a class of small non-coding RNAs originally identified for their role in transposon silencing in germ cells, have recently been recognized as pivotal regulators of gene expression in the central nervous system. Beyond their canonical functions in genome defense, emerging evidence highlights piRNAs as key modulators of neuronal development, synaptic plasticity, axonal regeneration, and neuroimmune interactions-processes central to brain function and dysfunction. This review provides a comprehensive overview of piRNA biogenesis, molecular mechanisms, and regulatory pathways relevant to neurobiology. We focus on the growing body of evidence implicating piRNA dysregulation in major neurological and neuropsychiatric disorders, including Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, stroke, glioma, autism spectrum disorder, and schizophrenia. Importantly, we discuss the neuropharmacological implications of piRNA pathways as novel targets for therapeutic intervention and their potential utility as biomarkers for early diagnosis and treatment stratification. By integrating mechanistic insights with emerging translational evidence, this review highlights piRNAs as promising molecular targets in the development of next-generation neurotherapeutics aimed at modifying disease progression and improving brain health.},
}

@article {pmid41181807,
year = {2025},
author = {Richardson, DL and Whitney, E},
title = {Deep Brain Stimulation: Overview and Applications in the Context of Neuropsychiatric Conditions.},
journal = {Cureus},
volume = {17},
number = {10},
pages = {e93661},
pmid = {41181807},
issn = {2168-8184},
abstract = {Deep brain stimulation (DBS) is a neuromodulatory therapy involving the implantation of electrodes into brain structures in order to help normalize brain activity in a variety of neurological disorders. The mechanisms of DBS operate at micro-, meso-, and macroscale levels to influence neuronal signaling, synaptic reorganization, and network-wide connectivity between brain regions. Recent advances in connectomics and sensing technologies have allowed for more precise and adaptive stimulation strategies, increasing the potential to target complex, heterogeneous neuropsychiatric conditions. DBS has already been well-explored as a treatment for obsessive-compulsive disorder. Emerging research has explored the use of DBS for other neuropsychiatric conditions as well, including autism spectrum disorder (ASD), treatment-refractory depression (TRD), and dementia associated with Alzheimer's disease (AD). DBS for ASD shows promise in reducing self-injurious behaviors and aggression by targeting the nucleus accumbens (NAc), amygdala, and posteromedial hypothalamus. In TRD, DBS to the subcallosal cingulate gyrus (SCG), medial forebrain bundle (MFB), and ventral capsule/ventral striatum (VC/VS) has demonstrated significant antidepressant effects. For dementia and AD, DBS targeting the fornix and nucleus basalis of Meynert (NBM) has shown promise in slowing cognitive decline. Despite the variety of targets, connectomic analyses reveal overlapping cortical-subcortical network dysfunctions across these disorders. These findings offer insight into shared neurobiological mechanisms of these disorders, as well as guide refinement of therapeutic targets for future study. Overall, DBS for neuropsychiatric conditions remains in its early stages, hindered by disorder heterogeneity and challenges in identifying optimal brain targets. Advances in functional neuroimaging, closed-loop stimulation, and machine learning-driven connectomic approaches can aid in target selection as well as better understanding the neuroanatomy and physiology underlying these complex conditions, which, in turn, lead to improved patient outcomes. Further research is necessary to establish standardized protocols and expand the therapeutic applications of DBS in neuropsychiatry.},
}

@article {pmid41181790,
year = {2025},
author = {Iyer, PJ and Soni, A and Waheed, N and Abboud, E and Deesawala, A and Clementina, R and Hazir, M and Chunawala, P and Jatin, CP and Vejju, S and K, V and Gedda, H and Vats, B and Devella, SG and Reddy, Y and Khan, U},
title = {Exploring Alzheimer's Awareness: A Content Quality and Reliability Assessment.},
journal = {Cureus},
volume = {17},
number = {10},
pages = {e93705},
pmid = {41181790},
issn = {2168-8184},
abstract = {Alzheimer's disease (AD) is a progressive neurodegenerative disorder with significant public health implications. Social media platforms like Instagram have emerged as influential tools for health communication, yet the quality and reliability of content remain variable. This study aimed to systematically evaluate the nature, accuracy, reliability, and overall educational quality of AD-related content disseminated on Instagram, to determine whether the information provided is evidence-based, appropriately sourced, and suitable for public health education. A cross-sectional observational study was conducted over 20 days in January 2025, analyzing posts from six popular Alzheimer's-related hashtags. A total of 600 posts were screened, of which 288 met the inclusion criteria. Posts were assessed for type, uploader category, content category, factual accuracy, Global Quality Score (GQS), and Reliability Score. Statistical comparisons were made between two groups of posts based on content accuracy and quality. Among the 288 posts analyzed, 162 (56.25%) were images and 126 (43.75%) were videos. Doctors (90, 30.94%) and researchers (82, 28.47%) were the most common uploaders. The majority of posts focused on etiology (66, 22.19%), prevention (60, 20.88%), and symptoms (60, 20.88%). Only 120 (51.9%) posts in Group A were factually accurate, compared to 22 (38.59%) in Group B (P < 0.000001). The mean GQS and Reliability Score were significantly higher in Group A (2.28 ± 1.04 and 2.29 ± 1.21) than in Group B (1.93 ± 1.10 and 1.72 ± 1.09), indicating better quality and trustworthiness of content. Instagram serves as a widely used platform for disseminating Alzheimer's-related information. However, the overall quality and reliability of content are suboptimal, with less than half of the posts being factually accurate. Healthcare professionals and researchers tend to produce more credible content, while posts from patients and non-medical users are less reliable. There is a pressing need to promote the creation and amplification of evidence-based, high-quality content to enhance public understanding and support for AD.},
}

@article {pmid41181519,
year = {2025},
author = {Shou, Q and Cen, S and Chen, NK and Ringman, JM and Kim, H and Jack, CR and Borowski, BJ and Senjem, ML and Arani, A and Wang, DJJ and , },
title = {Generative diffusion model enables quantification of calibration-free arterial spin labeling perfusion magnetic resonance imaging data in an Alzheimer's disease cohort.},
journal = {Alzheimer's & dementia (Amsterdam, Netherlands)},
volume = {17},
number = {4},
pages = {e70214},
pmid = {41181519},
issn = {2352-8729},
abstract = {INTRODUCTION: M0 images were missing in Siemens ASL data in Alzheimer's Disease Neuroimaging Initiative (ADNI) dataset, prohibiting cerebral blood flow (CBF) quantification.

METHODS: A conditional latent diffusion model was trained and evaluated on in-house datasets, then applied to the Siemens data in ADNI-3. Regional CBF differences by Alzheimer's disease (AD) stages, their accuracy for AD classification, and CBF trajectory slopes were compared between generated data (Siemens) and acquired data (General Electric).

RESULTS: The diffusion model generated M0 images with high fidelity (SSIM = 0.918 ± 0.023, PSNR = 31.361 ± 2.537) and minimal CBF bias (mean difference is 0.21 ± 1.58 mL/100 g/min). Both generated and acquired CBF showed similar spatial patterns and decreasing trends with AD progression in specific AD-related regions. Generated CBF also improved accuracy in classifying AD stages compared to qualitative perfusion images.

CONCLUSION: This study shows the potential of diffusion models for imputing missing modalities in large-scale studies exploring the use of ASL as a biomarker of AD.

HIGHLIGHTS: Using latent diffusion model, we can generate M0 image from control image in arterial spin labeling (ASL) with high fidelity.The generated M0 can be used for cerebral blood flow (CBF) quantification in Alzheimer's Disease Neuroimaging Initiative dataset.The performance of classification between Alzheimer's disease (AD) patients and cognitive normal people is better when using generated CBF maps than using non-quantitative perfusion images.ASL CBF decreases with AD progression in key AD-related brain regions.},
}

@article {pmid41181030,
year = {2025},
author = {Gray, AJ and Robinson, RE and Berghol, SA and Rosene, DL and Moore, TL and Bigio, IJ},
title = {Birefringence microscopy enables rapid, label-free quantification of myelin debris following induced cortical injury.},
journal = {Neurophotonics},
volume = {12},
number = {4},
pages = {045006},
pmid = {41181030},
issn = {2329-423X},
abstract = {SIGNIFICANCE: Myelin breakdown is prevalent in a range of neurodegenerative diseases, aging, and following various forms of trauma. Yet, current imaging techniques have limited capacity for large-scale study of myelin structural damage. A high-throughput, quantitative imaging method would greatly enhance our understanding of myelin degradation in different contexts.

AIM: We aim to establish birefringence microscopy (BRM) as a high-throughput, label-free imaging technique for large-scale, quantitative assessment of myelin pathology in post-mortem brain tissue. BRM has the capacity to provide rapid myelin imaging, which will provide information complementary to other myelin imaging techniques.

APPROACH: BRM enables label-free structural imaging of myelin with high spatial resolution. We leverage the high-throughput imaging capability of BRM to characterize the distribution of myelin pathology in a rhesus monkey model of cortical injury across the corpus callosum. This framework is applied at two different post-injury survival times (6 and 12 weeks).

RESULTS: We validate BRM for label-free structural imaging of myelin pathology across large regions of tissue (within the corpus callosum) using a fluorescent myelin stain and several immunohistochemical labels. Next, we train and validate a deep learning-based object detection network for automated identification of myelin pathology, using BRM, in the corpus callosum of monkeys with an induced cortical lesion. BRM, paired with deep learning, revealed significantly higher myelin damage through the corpus callosum, resulting from the lesion, in 6-week recovery monkeys compared with 12-week recovery and age-matched controls (P < 0.01). There was no significant difference between 12-week recovery monkeys and age-matched controls.

CONCLUSIONS: BRM enables large-scale assessment of myelin structural alterations in post-mortem brain tissue. When combined with deep-learning object detection, BRM enables rapid quantification of myelin damage in the corpus callosum after cortical injury. With proper training, this can be extended to study structural changes in other diseases and regions such as Alzheimer's disease and chronic traumatic encephalopathy as well as normal aging.},
}

@article {pmid41181014,
year = {2025},
author = {Srivastava, S and Ali, A and Kanika, and Samadder, P and Kumar, B and Mishra, AK and Khan, MR and Ali, N and Son, YO and Khan, R},
title = {Green synthesis of coconut coir-based carbon dots for efficient detection of ferric ions.},
journal = {RSC advances},
volume = {15},
number = {49},
pages = {41537-41545},
pmid = {41181014},
issn = {2046-2069},
abstract = {Iron (Fe) is an essential micronutrient for metabolic and physiological processes. Its dysregulation is associated with disorders such as Alzheimer's and hemochromatosis. Therefore, the development of cost-effective and selective probes for Fe(iii) detection is of significant clinical importance. In this study, fluorescent carbon dots derived from coconut coir (CCDs) were synthesized via a single-step hydrothermal method. The CCDs exhibited strong blue emission at 450 nm under 350 nm excitation and demonstrated selective fluorescence quenching in the presence of Fe(iii) ions, with a detection limit of 223.2 μM. HR-TEM revealed the particle size of CCDs ranged between 5.64 to 10 nm. XRD confirmed the crystalline nature. FTIR spectra indicated presence of hydroxyl and carboxyl groups contributing to dispersibility and surface passivation. Raman spectroscopy showed distinct D (1354 cm[-1]) and G (1582.61 cm[-1]) bands, characteristic of low-dimensional carbon nanostructures. Bioimaging and cytocompatibility studies in L929 fibroblast cells confirmed biocompatibility up to 500 μg mL[-1]. Collectively, these findings highlight the potential of CCDs as an effective fluorescent probe for Fe(iii) sensing and bioimaging applications in medical diagnostics. The CCDs were cytocompatible at concentrations up to 500 μg mL[-1].},
}

@article {pmid41180962,
year = {2025},
author = {Alkam, T and Tarshizi, E and Van Benschoten, AH},
title = {Red-flagging multimorbidity clusters for Alzheimer's disease risk using explainable machine learning: Evidence from a national emergency department sample.},
journal = {Journal of Alzheimer's disease reports},
volume = {9},
number = {},
pages = {25424823251392474},
pmid = {41180962},
issn = {2542-4823},
abstract = {BACKGROUND: Emergency-department (ED) visits capture diagnostic data that could flag patients at heightened risk for Alzheimer's disease (AD) long before cognitive symptoms are formally recognized.

OBJECTIVE: To examine how age and multimorbidity interact to predict AD and to test whether explainable machine learning enhances risk stratification using national ED data.

METHODS: We analyzed 554,985 ED visits (2010-2014 National Emergency Department Sample) from adults ≥ 60 y. ICD-9-CM codes identified AD and 17 chronic conditions. Logistic regression estimated odds ratios (ORs) for single and combined comorbidities across five age bands. Predictive performance of logistic regression, decision tree, random forest and XGBoost was compared; Shapley Additive exPlanations (SHAP) interpreted model output.

RESULTS: Urinary-tract infection (UTI; OR = 2.74), depression (1.93), hypothyroidism (1.68) and anemia (1.57) independently increased AD odds. Possessing all four "red-flag" conditions tripled risk (OR = 3.31), and each additional red-flag raised risk by 74%. Age showed a steep gradient: relative to 60-65 y, ORs climbed from 2.58 (66-70 y) to 25.8 (86-90 y; all p < 0.001). XGBoost performed best (AUC = 0.782; recall = 0.821), and SHAP confirmed age and red-flag multimorbidity as dominant predictors.

CONCLUSIONS: Routine ED codes reveal an age-dependent, dose-response relationship between specific multimorbidity clusters and AD. An interpretable XGBoost model accurately identifies high-risk patients, outlining a practical pathway for real-time cognitive-risk alerts in acute-care settings.},
}

@article {pmid41180961,
year = {2025},
author = {Wang, H and Mao, X and Liu, S and Zhang, J and Li, E and Song, Y and Li, H and Chang, L and Wu, Y},
title = {Effects of sleep deprivation on cognition and synaptic associated proteins in rodents: A systematic review and meta-analysis.},
journal = {Journal of Alzheimer's disease reports},
volume = {9},
number = {},
pages = {25424823251391704},
pmid = {41180961},
issn = {2542-4823},
abstract = {BACKGROUND: Sleep disorders are a significant risk factor for cognitive decline and Alzheimer's disease (AD). However, preclinical studies investigating the effects of sleep deprivation (SD) on cognition and synaptic proteins have produced inconsistent findings, hindering translational progress.

OBJECTIVE: This systematic review and meta-analysis identify key factors moderating the effects of SD on cognition and synaptic proteins in rodent models.

METHODS: Following PRISMA guidelines, we analyzed 21 eligible studies using meta-analysis, subgroup, meta-regression, and multilevel analyses to identify sources of experimental heterogeneity.

RESULTS: SD significantly reduced synaptic proteins overall. While the global effect on cognition was not significant, subgroup analyses revealed robust cognitive impairment in Wistar rats undergoing fragmented sleep, particularly when assessed by Morris water maze or novel object recognition tests. Key synaptic proteins (PSD-95, synaptophysin) were consistently reduced in the hippocampus and prefrontal cortex.

CONCLUSIONS: Our comprehensive review synthesizes diverse studies, concluding that methodological choices are the primary drivers of heterogeneity in preclinical SD research. We provide evidence-based guidance for selecting appropriate rodent models, behavioral paradigms, and biochemical indicators to investigate the molecular mechanisms linking sleep disorders and cognitive decline. This work offers a significant framework to standardize and enhance the reliability of preclinical studies. By validating models that directly connect fragmented sleep-a condition common in AD patients-to synaptic pathology in vulnerable brain regions, our research strengthens the mechanistic link between sleep disturbance and cognitive impairment in AD and encourages a greater focus on this critical relationship for the readers of the Journal of Alzheimer's Disease Reports and AD researchers.},
}

@article {pmid41180960,
year = {2025},
author = {Morales, AL and Andrade, LD and Bronberg, R and Ramallo, V and Figueroa, MI and Dipierri, JE},
title = {Geospatial and temporal disparities in Alzheimer's disease deaths in Argentina.},
journal = {Journal of Alzheimer's disease reports},
volume = {9},
number = {},
pages = {25424823251391705},
pmid = {41180960},
issn = {2542-4823},
abstract = {BACKGROUND: Alzheimer's disease (AD) and other dementias are currently among the leading causes of morbidity and mortality worldwide.

OBJECTIVE: To analyze the spatial and temporal behavior of AD mortality in Argentina.

METHODS: This is a retrospective eco-epidemiological study based on the Death Certificate between 1997-2017 provided by the Ministry of Health. The specific death rates (SDRs) related to AD were calculated per 1000 deaths (AD*1000) by gender and age at departmental, provincial, and regional levels for the entire period. The Join Point method was applied to analyze the temporal trend, and SaTScan software was used to establish geospatial disparities.

RESULTS: The highest SDRs were recorded in the departments, provinces, and regions located in the center of the country. At all administrative levels, female SDRs were almost twice as high as male SDRs. A positive secular trend in SDR was observed in all regions, with a significant increase between 1997-2002 and a less pronounced increase between 2003-2017. Clusters with the highest relative risks of AD death were located in the center of the country.

CONCLUSIONS: Following the global pattern, Argentina and all its regions show an increasing trend of AD deaths, with higher rates among women and older age groups. However, notable geospatial disparities attributed to population dynamics, migrations, and regional socioeconomic characteristics were identified.},
}

@article {pmid41180959,
year = {2025},
author = {He, L and Rao, Y and Wang, J and Yang, F},
title = {Association between self-reported sensory impairments and low cognitive performance in older adults: A cross-sectional study based on National Health and Nutrition Examination Survey (NHANES).},
journal = {Journal of Alzheimer's disease reports},
volume = {9},
number = {},
pages = {25424823251392551},
pmid = {41180959},
issn = {2542-4823},
abstract = {BACKGROUND: Early identification of risk factors is vital for the control of cognitive degenerative diseases, and sensory impairments could be potential candidate indicators.

OBJECTIVE: To determine whether self-reported hearing loss (HL), olfactory dysfunction (OD), and gustatory dysfunction (GD) are associated with low cognitive performance.

METHODS: Cross-sectional data from the 2011-2012 National Health and Nutrition Examination Survey (NHANES) were used. Data on participants' subjective hearing ability, olfactory and gustatory status were obtained from corresponding questionnaire datasets. Cognitive function was measured by the Consortium to Establish a Registry for Alzheimer's Disease (CERAD), Animal Fluency Test (AFT), and Digit Symbol Substitution Test (DSST). The lowest quartile score of the four tests was used as the cutoff value to indicate low cognitive performance. Univariate and multivariate logistic regression analyses were conducted to investigate the association between sensory impairments and cognitive decline.

RESULTS: The data of 1416 adults aged ≥60 years were included. Univariate logistic regression analyses showed that the association between self-reported HL, OD, GD, and low cognitive performance was significant across all four cognition tests. Multiple models of multivariate logistic regression adjusted by covariate factors were established and showed significant association between self-reported HL, OD, GD, and low cognitive performance.

CONCLUSIONS: Self-reported hearing loss, olfactory and gustatory dysfunction demonstrated significant associations with impaired cognitive performance in older adults. Multiple sensory impairments may lead to progressively worse cognitive performance.},
}

@article {pmid41180958,
year = {2025},
author = {Libard, S and Alafuzoff, I},
title = {Tar DNA binding protein 43, a proteinopathy with preference for olfactory structures in COVID-19 subjects.},
journal = {Journal of Alzheimer's disease reports},
volume = {9},
number = {},
pages = {25424823251386016},
pmid = {41180958},
issn = {2542-4823},
abstract = {BACKGROUND: Olfactory impairment (OI) is an early symptom of neurodegenerative diseases (ND) and COVID-19 infection. Proteinopathies associated with ND include amyloid-β (Aβ), hyperphosphorylated τ (HPτ), α-synuclein (α-syn), and Tar DNA binding protein 43 (TDP43). It is unclear whether COVID-19 infection influences the listed proteinopathies in the olfactory bulb and tract (OB/OT) aggravating the OI.

OBJECTIVE: To study proteinopathies associated with ND in the brain and OB/OT in 32 subjects with COVID-19 infection and 10 age- and gender-matched controls.

METHODS: Postmortem brain tissue was assessed for various proteinopathies and the OB/OT for proteinopathies, inflammatory markers and a marker for severe acute respiratory syndrome coronavirus 2 spike protein.

RESULTS: Twenty percent of control and 16% of COVID-19 subjects lacked proteinopathies in their OB/OT. HPτ was detected in OB/OT in 80% of controls and 81% of COVID-19 subjects, Aβ in 30% of controls and 16% of COVID-19 subjects. All controls lacked TDP43 in OB/OT, 40% displayed TDP43 in their brain. TDP43 was seen in the OB/OT in 38% of COVID-19 subjects, of whom 42% lacked TDP43 in the brain. Sixty percent of controls displayed α-syn in OB/OT and the brain, whereas 34% of COVID-19 subjects displayed α-syn in the OB/OT, of whom 36% lacked it in the brain.

CONCLUSIONS: All proteinopathies associated with ND were detected in OB/OT in COVID-19 patients whereas TDP43 was lacking in controls. Our results suggest that there might be an association between COVID-19 and TDP43 and α-syn in the OB/OT, which may explain the chronic OI.},
}

@article {pmid41180957,
year = {2025},
author = {Pulukuri, SV and Spurlock, EE and Tuz-Zahra, F and Tripodis, Y and Sampani, K and Nicks, R and Meng, G and Alvarez, VE and McKee, AC and Xia, W and Mordes, DA and Subramanian, ML and Stein, TD},
title = {Vitreous STMN2 levels reflect TDP-43-associated neurodegeneration in postmortem eyes and brains.},
journal = {Journal of Alzheimer's disease reports},
volume = {9},
number = {},
pages = {25424823251392553},
pmid = {41180957},
issn = {2542-4823},
abstract = {Stathmin-2 (STMN2) levels decline in brains with transactive response DNA binding protein-43 (TDP-43) inclusions. TDP-43-related changes could extend to ocular structures, although vitreous STMN2 levels remain uncharacterized. This exploratory study analyzed 72 post-mortem brains and eyes depending on the presence or absence of TDP-43 inclusions in the brain and across neuropathological diagnostic groups (Alzheimer's disease [AD], chronic traumatic encephalopathy [CTE], AD and CTE, or neither). Results showed decreased vitreous STMN2 levels in TDP-43-positive cases but no association with diagnostic groups. Vitreous STMN2 was correlated with vitreous neurofilament light chain. Diminished vitreous STMN2 levels might indicate TDP-43-associated neurodegeneration.},
}

@article {pmid41180956,
year = {2025},
author = {Marmor, A and Meiner, Z and Kahana Merhavi, S and Vakil, E},
title = {Cognitive reserve as a predictor of cognitive decline, but not age of diagnosis in patients with possible young-onset Alzheimer's disease: An underexplored population.},
journal = {Journal of Alzheimer's disease reports},
volume = {9},
number = {},
pages = {25424823251383903},
pmid = {41180956},
issn = {2542-4823},
abstract = {BACKGROUND: The cognitive reserve (CR) theory aims to explain the disparity often observed between brain damage and its clinical manifestation.

OBJECTIVE: To explore the CR theory in young-onset Alzheimer's disease (YOAD), a population not previously investigated in this context. The goal is to assess whether, similar to late-onset Alzheimer's disease (LOAD), a high CR delays diagnosis but may accelerate cognitive decline.

METHODS: This is a retrospective study including 72 patients (ages: 46-64) who were diagnosed with possible YOAD. They were followed up for three years, using the Mini-Mental State Examination.

RESULTS: Unlike the findings with LOAD, age of diagnosis of the YOAD did not correlate significantly with CR variables, years of education or family size. However, years of education predicted greater cognitive decline in the first year, and women showed increased deterioration. Family size showed inconsistent associations, highlighting its limitations.

CONCLUSIONS: In contrast to studies among LOAD, there was no significant correlation between age of diagnosis and CR among YOAD, suggesting that other mechanisms might be more influential than CR parameters in younger individuals. However, similar to LOAD, YOAD patients with higher education experienced faster disease progression, implying that diagnoses are frequently made when brain pathology is already severe. These findings reinforce the growing perspective that YOAD and LOAD may constitute distinct forms of AD, each with unique clinical and pathological features. They also underscore the urgent need for early detection tools and cognitive interventions to ease the challenges faced by these young patients.},
}

@article {pmid41180953,
year = {2025},
author = {Nabizadeh, F},
title = {Apolipoprotein E gene allele 4 and amyloid-beta mediate tau-related network breakdown.},
journal = {Brain communications},
volume = {7},
number = {6},
pages = {fcaf404},
pmid = {41180953},
issn = {2632-1297},
abstract = {There have been reports of altered functional connectivity in Alzheimer's disease, which is associated with the buildup of pathogenic proteins in the brain, including neurofibrillary tau tangles and amyloid-beta plaques. It is believed that the tau aggregates are the main driver of functional disconnection and resulted in cognitive decline in Alzheimer's disease. Tau propagates through connected neurons, a phenomenon often described as the 'prion-like' properties of tau, which can locally result in functional connectivity disruption. Apolipoprotein E gene allele 4 status and amyloid-beta are accelerating factors for tau-related pathological changes in Alzheimer's disease. However, the potential role of apolipoprotein E gene allele 4 and amyloid-beta in mediating the tau-related functional disconnection is not clear. I aimed to investigate the mediating effect of apolipoprotein E gene allele 4 and amyloid-beta on the local association of tau spreading on functional connections. I analysed follow-up resting-state functional MRI (fMRI) (non-baseline visit) and longitudinal tau-PET data from 211 subjects from the Alzheimer's Disease Neuroimaging Initiative (ADNI) database and 138 healthy elderly individuals from the Harvard Aging Brain Study (HABS). The follow-up resting-state fMRI (non-baseline visit) was studied in order to study the time needed effect of tau pathology. The top 10 regions with the highest probability-weighted SUVR values using Gaussian mixture models were selected as individual-level tau-PET epicentres. I looked at how the relationship between functional connectivity to epicentres and individualized connectivity-related tau spreading was mediated by amyloid-beta status and the apolipoprotein E gene allele 4 genotype. Higher rates of tau aggregation accumulation were seen in areas with stronger connectedness (shorter distance-based connectivity) to the baseline-defined tau epicentres. Moreover, the association between functional connectivity to epicentres and tau spreading through functional connections was mediated by apolipoprotein E gene allele 4 and amyloid-beta status in both dataset's participants. Tau aggregates spread through functional connections and locally disrupt connectivity between tau epicentre and non-epicentre regions, which is mediated in apolipoprotein E gene allele 4 carriers and amyloid-beta-positive participants. These findings have implications for trial designs, proposing that apolipoprotein E gene allele 4 carriers and amyloid-beta-positive participants might need earlier intervention to attenuate tau spreading and tau relative functional disconnection.},
}

@article {pmid41180952,
year = {2025},
author = {Zammit, M and Price, J and Christian, B and Rafii, M and , },
title = {A comparison of multiple amyloid PET radiotracers for Down syndrome clinical trials.},
journal = {Brain communications},
volume = {7},
number = {6},
pages = {fcaf406},
pmid = {41180952},
issn = {2632-1297},
abstract = {Adults with Down syndrome carry high risk of developing Alzheimer's disease and efforts to include this population in clinical trials remain limited. A barrier to recruitment for anti-amyloid trials includes the availability of the same amyloid PET radiotracer to multiple treatment centres. The objective of the study is to compare longitudinal rates of change between different amyloid PET radiotracers, particularly Pittsburgh compound B and florbetapir, in Down syndrome and to compare the estimated age at amyloid-positivity derived from these radiotracers. Two hundred thirty-seven adults with Down syndrome from the Trial Ready Cohort-Down syndrome and Alzheimer's Biomarker Consortium-Down syndrome studies were imaged using T1-weighted MRI and using PET images of Pittsburgh compound B, florbetapir, NAV4694 or flutemetamol to screen for amyloid plaque burden. Currently, Pittsburgh compound B and florbetapir have longitudinal data from these cohorts, while NAV4694 has one individual with longitudinal scans and flutemetamol has no available longitudinal data. Pittsburgh compound B displayed a greater effect size to measure amyloid change compared to florbetapir. NAV4694 and Pittsburgh compound B, which are structurally similar compounds, displayed similar sensitivity to measure longitudinal amyloid increase. The estimated age at amyloid onset showed no significant difference between Pittsburgh compound B, florbetapir, NAV4694 or flutemetamol. The findings suggest that different amyloid PET radiotracers provide consistent estimates of amyloid onset age for adults with Down syndrome. Multicentre studies of Alzheimer's disease therapeutics can utilize multiple amyloid PET radiotracers to facilitate recruitment; however, these radiotracers have different sensitivity to detect longitudinal change.},
}

@article {pmid41180905,
year = {2025},
author = {Omar, H and Yetman, L and Tranchant, CC and Gallibois, M and Haché, JC and Faig, K and Handrigan, G and McGibbon, C and Jarrett, P},
title = {"It's About Connections": A Grounded Theory of Older Adults' Engagement in Remotely Delivered Home-Based Physical and Cognitive Exercise Interventions Aiming to Reduce the Risk of Dementia.},
journal = {Journal of patient experience},
volume = {12},
number = {},
pages = {23743735251392324},
pmid = {41180905},
issn = {2374-3735},
abstract = {Physical exercise and cognitive training have the potential to enhance cognitive function and mobility in older adults at risk of dementia. However, little is known about the experience of receiving such interventions in the home settings of older adults. Fifteen participants (mean age 70.8 years) who completed the 16-week interventions of SYNERGIC@Home feasibility trial were interviewed to understand participants' engagement in home-based physical and cognitive exercise interventions delivered one-on-one through videoconferencing. Grounded theory data analysis was completed collaboratively by qualitative researchers. Results show that participants' engagement was driven by personal connection to dementia and mediated by relationships fostered largely with individual exercise trainers. Participants were also invested in the greater good (wanting their participation to make a difference to dementia research), their own outcomes, or their family's and society at large. Overall, they reflected on their participation as a rich learning experience. We propose that the quality of interpersonal connections and personalized support are of primary importance for older adults to stay engaged in physical exercise and cognitive training programs delivered remotely. SYNERGIC@Home trial registration number: NCT04997681, https://clinicaltrials.gov/study/NCT04997681.},
}

@article {pmid41180843,
year = {2025},
author = {Ceccarelli, MC and Lai, L and Carmignani, A and Battaglini, M and Ciofani, G},
title = {Polydopamine nanoparticles as immunomodulators: inhibition of M1 microglial polarization.},
journal = {Frontiers in bioengineering and biotechnology},
volume = {13},
number = {},
pages = {1672520},
pmid = {41180843},
issn = {2296-4185},
abstract = {Neuroinflammation is a central feature of numerous neurodegenerative diseases, including Alzheimer's and Parkinson's disease, where excessive activation of microglia can contribute to neuronal damage. The pro-inflammatory M1 phenotype of microglia is characterized by increased production of reactive oxygen species (ROS), overexpression of surface markers such as CD40 and CD86, and secretion of cytokines like IL-6, IL-8, and TNF-α, all of which exacerbate oxidative stress and neurodegeneration. The development of strategies to control and tune microglial pro-inflammatory activation is therefore critical for reducing the progression of these conditions. In this study, the potential of polydopamine nanoparticles (PDNPs) as novel immunomodulatory agents for attenuating M1 microglial polarization was investigated. PDNPs were synthesized via a simple and reproducible protocol and thoroughly characterized in terms of size, morphology, hydrodynamic diameter, and surface charge, confirming their uniformity and stability. Biocompatibility assays showed that PDNPs are well tolerated by human microglial clone 3 (HMC3) cells, with minimal cytotoxicity even at relatively high concentrations. Confocal microscopy and flow cytometry analyses demonstrated efficient internalization of PDNPs by microglia, with preferential accumulation in lysosomal compartments and negligible mitochondrial localization. To mimic neuroinflammatory conditions, HMC3 cells were stimulated with interferon-gamma (IFN-γ), which significantly increased intracellular ROS levels, surface expression of CD40 and CD86, and secretion of pro-inflammatory cytokines. The co-treatment with PDNPs effectively mitigated these effects by reducing oxidative stress, suppressing the upregulation of M1 markers, and decreasing cytokine release, thereby preventing the shift toward a pro-inflammatory state. The results of this work demonstrate that PDNPs not only exhibit excellent biocompatibility and cellular uptake but also provide a robust means of counteracting IFN-induced microglial activation. These results establish PDNPs as promising nanoplatforms for modulating neuroinflammation and microglial activation. This study highlights the potential of PDNPs for future applications in the treatment of neurodegenerative diseases.},
}

@article {pmid41180815,
year = {2025},
author = {Gephine, L and Corvaisier, S and Bernay, B and Freret, T and Leger, M},
title = {LOU/c/jall rat as a model of resilience in the context of streptozotocin-induced cognitive impairment.},
journal = {Frontiers in aging neuroscience},
volume = {17},
number = {},
pages = {1666397},
pmid = {41180815},
issn = {1663-4365},
abstract = {INTRODUCTION: The concept of cognitive resilience (CR) has emerged to explain the lack of correlation between the extent of brain lesions and the severity of cognitive symptoms in Alzheimer's disease (AD), but the underlying mechanisms remain poorly understood.

METHODS: To investigate this, we developed a preclinical model of CR using a sporadic model of AD in a specific rat strain named LOU/c/jall described as a successful aging model. LOU/c/jall and Wistar control rats were bilaterally injected with streptozotocin (STZ; 3 mg/kg) or a vehicle solution into the cerebral ventricles. Cognitive performance and neuropathological examinations were evaluated 1 month after surgery.

RESULTS: Our results showed that STZ-injected Wistar exhibited greater cognitive deficits than LOU/c/jall, despite similar brain alterations, revealing for the first time CR in the LOU/c/jall strain. Proteomic analysis identified differentially expressed proteins involved in the AD pathway between the two strains.

DISCUSSION: Understanding the role of these proteins in AD could improve our understanding of the brain mechanisms underlying CR and guide the development of more targeted therapeutic strategies.},
}

@article {pmid41180813,
year = {2025},
author = {Zhu, Y and Tu, Y and Ren, C and Ke, Y and Guo, Q},
title = {Elevated gonadotropins and risk of dementia in Chinese adults aged over 80: a cross-sectional study.},
journal = {Frontiers in aging neuroscience},
volume = {17},
number = {},
pages = {1651723},
pmid = {41180813},
issn = {1663-4365},
abstract = {INTRODUCTION: Age-related elevation of gonadotropins may contribute to cognitive decline, while apolipoprotein E epsilon 4 (APOE ε4) is an established risk factor for Alzheimer's disease (AD). This study investigated the associations of follicle-stimulating hormone (FSH) and luteinizing hormone (LH) levels with global cognition and dementia in adults aged over 80.

METHODS: A total of 509 adults (440 males and 69 females) were included in this cross-sectional analysis, comprising 337 with normal cognition (NC), 97 with Alzheimer's disease-related dementia (AD-D), and 75 with vascular dementia (VD). Cognitive status was assessed using Mini-Mental State Examination (MMSE). Plasma gonadotropins and sex hormones were measured by chemiluminescence. Multivariable linear and logistic regression models, adjusted for potential confounders, were employed.

RESULTS: Follicle-stimulating hormone concentrations were significantly elevated in males with dementia and females with VD compared to NC. LH concentrations were significantly elevated in VD across sexes compared with NC. Neither estradiol nor total testosterone differed across groups. Continuous LH, rather than FSH, was significantly associated with MMSE scores in the total cohort and males after adjusting covariates (both p < 0.05). When dichotomized by median (19.9 IU/L for males; 67.1 IU/L for females), FSH was significantly associated with MMSE after further adjusting for LH (both p < 0.05). A significant interaction between high FSH and APOE ε4 carrier status on cognitive impairment was observed (p < 0.05). After multivariate adjustment including LH, elevated FSH was independently associated with higher AD-D risk both when defined by median split (total sample: OR = 3.109; males: OR = 3.597) and as a continuous variable (total: OR = 1.033; males: OR = 1.048). In contrast, higher continuous LH was linked to lower AD-D risk in the total cohort and males, regardless of FSH adjustment. Neither FSH nor LH concentrations were associated with VD risk after adjusting for covariates. The area under the receiver operating characteristic curve for FSH in predicting AD-D in males was 0.600, with an optimal cutoff value of 28.4 IU/L.

CONCLUSION: Elevated FSH and reduced LH may be associated with poorer cognition and an increased risk of AD-D in very old Chinese adults, particularly in males.},
}

@article {pmid41180709,
year = {2025},
author = {Khan, A and Asghar, T and Yumn, L and Ishtiaq, S and Saeed, M and Ansari, RA and Fatima, M and Antar, M and Haider, MZ and Laghari, MA},
title = {Trends in hypertensive heart disease-related mortality among population with Alzheimer's in the United States: a 22-year nationwide analysis.},
journal = {Annals of medicine and surgery (2012)},
volume = {87},
number = {11},
pages = {7325-7333},
pmid = {41180709},
issn = {2049-0801},
abstract = {BACKGROUND: Alzheimer's disease (AD) is a progressive neurodegenerative disorder, while hypertensive heart disease (HHD) is a major cardiovascular condition linked to chronic hypertension (HTN). HTN is common among patients with AD, significantly impacting mortality. This study explores trends in HHD-related mortality among patients with AD in the US from 1999 to 2020, utilizing the Centers for Disease Control and Prevention's Wide-ranging Online Data for Epidemiologic Research (CDC WONDER) database.

METHODS: Data from the CDC WONDER database were used to extract mortality information for individuals aged ≥65 years, with AD and HHD as the underlying or contributing causes of death. Mortality rates were analyzed by age, sex, race/ethnicity, urban-rural classification, and region. Both crude- and age-adjusted mortality rates (AAMRs) were calculated. Joinpoint regression was employed to identify significant trends and changes in mortality over time.

RESULTS: HHD-associated mortality among patients with AD showed a significant upward trend, with deaths rising from 710 in 1999 to 3263 in 2020. The AAMR increased from 2.08 per 100 000 in 1999 to 6.26 per 100 000 in 2020, a threefold increase. Female patients had higher mortality rates than males throughout the study period. The highest mortality rates were observed in the age group of 85+ years, with notable regional disparities, particularly in the South and Midwest. The COVID-19 pandemic in 2020 contributed to a marked spike in mortality.

CONCLUSION: A concerning rise in HHD-related mortality among patients with AD, particularly in the last decade is observed. Significant disparities exist across demographic groups and regions. These findings highlight the need for public health interventions and policies to address the dual burden of AD and HHD.},
}

@article {pmid41180593,
year = {2025},
author = {Civita, E and Nicolella, V and Fiorenza, M and Cosimato, V and Castaldo, G and Morra, VB and Moccia, M and Terracciano, D},
title = {Advancing Clinical Use of Neurofilament Light Chain: Translational Insights From Research to Routine Practice.},
journal = {Biomarker insights},
volume = {20},
number = {},
pages = {11772719251364018},
pmid = {41180593},
issn = {1177-2719},
abstract = {Neurofilament Light Chain (NfL) has emerged as a promising biomarker for neurological diseases. NfL, a structural component of axons, is released into cerebrospinal fluid (CSF) and blood following neuro-axonal damage. Highly sensitive immunometric assays have enabled its reliable quantification in blood, facilitating non-invasive monitoring. Several studies demonstrated strong correlations between NfL levels and the risk of developing different neurological diseases and, in individuals already living with a neurological disease, with the risk of worsening. However, interpretation is affected by factors like age, BMI, renal function, and comorbidities. NfL is already utilized as a diagnostic and prognostic biomarker in clinical practice, particularly in specialized centers and research settings, although no FDA-cleared assay is currently available for routine use. Recent research has highlighted that NfL may represent the first of a new generation of neurological biomarkers, with many more ready to come, such as glial fibrillary acidic protein (GFAP), further improving diagnostic and prognostic accuracy. Despite its promising role in the landscape of biomarkers, challenges remain to implement NfL in daily clinical practice, including standardization of assays, defining reference values, and ensuring methodological consistency. Addressing these limitations will be essential for integrating NfL into routine clinical practice, ultimately advancing precision medicine in neurology.},
}

@article {pmid41180536,
year = {2025},
author = {Zhang, S and Wu, H and Ma, L and Li, R and Zhang, L and Liu, L and He, X and Zhao, T},
title = {The exploration of using plasma biomarkers of p-tau217 and p-tau181 for screening Alzheimer's disease in very elderly people.},
journal = {Frontiers in neurology},
volume = {16},
number = {},
pages = {1668512},
pmid = {41180536},
issn = {1664-2295},
abstract = {INTRODUCTION: Blood-based biomarkers for Alzheimer's disease (AD), such as phosphorylated tau (p-tau181, p-tau217) and amyloid beta (Aβ), have the potential to serve as screening tools for probable AD in the elderly population.

METHODS: AD screening [Mini-Mental State Examination (MMSE) and Montreal Cognitive Assessment (MoCA)] was conducted among very elderly individuals residing in a nursing community and a geriatric hospital. Based on cognitive evaluation, participants were categorized into two groups: cognitively normal (n = 62) and probable AD (n = 78). Plasma concentrations of Aβ42, Aβ40, p-tau181, p-tau217, and glial fibrillary acidic protein (GFAP) were measured using the single molecule array (Simoa) platform. Group comparisons of plasma biomarker levels were performed, and receiver operating characteristic (ROC) curve analyses were conducted for each biomarker relative to AD diagnosis.

RESULTS: Significant differences were observed in plasma p-tau181, p-tau217, and GFAP levels between the cognitively normal and probable AD groups (p < 0.01). In contrast, Aβ42, Aβ40, and the Aβ42/Aβ40 ratio showed no significant differences (p > 0.01). The area under the ROC curve (AUC) was 0.886 for p-tau181, 0.655 for p-tau217, and 0.869 for GFAP.

DISCUSSION: Plasma biomarkers p-tau181, p-tau217, and GFAP demonstrate clinical utility in distinguishing AD from normal cognition, suggesting that blood-based testing may serve as a feasible screening tool for early identification of AD in very elderly populations.},
}

@article {pmid41180528,
year = {2025},
author = {Koike, T and Morita, A and Sekine, T and Sakai, T and Tsuchiya, T and Takenobu, A and Teraoka, A},
title = {SynthSR-generated 3D T1-weighted MRI from routine 2D clinical images: Validation for VSRAD analysis.},
journal = {Frontiers in neurology},
volume = {16},
number = {},
pages = {1645891},
pmid = {41180528},
issn = {1664-2295},
abstract = {BACKGROUND: The Voxel-based Specific Regional Analysis System for Alzheimer's Disease (VSRAD), a voxel-based morphometry tool quantifying medial temporal lobe atrophy as region-specific Z-scores, is widely used in clinical practice for detection of Alzheimer's disease (AD). However, it typically require high-resolution 3D T1-weighted MRI, which is often difficult to acquire in elderly or cognitively impaired patients. This study aimed to evaluate whether 3D volumes generated by SynthSR from 2D T1-weighted MRI can yield volumetric and VSRAD-derived indices that are comparable to those from standard 3D images, by assessing agreement, rank consistency, and diagnostic performance.

METHODS: In this retrospective single-center study, MRI data from 75 patients were analyzed using both standard 3D T1-weighted images and SynthSR-generated 3D volumes reconstructed from 2D T1-weighted sequences. Regional brain volumes and four key Z-score indices from VSRAD were compared using Wilcoxon signed-rank tests with Bonferroni correction, robust Bland-Altman analysis, Spearman's rank correlation, and receiver operating characteristic (ROC) curve analysis focusing on Score 1 "Severity."

RESULTS: All Z-score indices and segmented volumes showed significant absolute differences between the two methods (p < 0.0071), with SynthSR-based data generally yielding larger volume estimates. Despite these differences, Spearman's ρ remained consistently high (ρ > 0.7) for brain volume and Score 3 "Ratio," and other clinically relevant indices also demonstrated moderate correlations. ROC analysis demonstrated high value of the area under the curve (AUC) values for both standard 3D volumes (0.90) and SynthSR-generated 3D volumes (0.96), with no statistically significant difference between the two methods (Z = 0.009, p = 0.99, DeLong's test).

CONCLUSION: Although SynthSR-based images produced systematically different absolute values, they preserved rank-order correlations and maintained diagnostic performance comparable to that of standard 3D volumes in VSRAD analysis. Considering that conventional 3D acquisitions are often difficult to obtain in elderly patients undergoing dementia screening, SynthSR-based reconstruction may represent a practical alternative in routine clinical practice, particularly for Score 1 "Severity," the most clinically relevant marker of hippocampal atrophy.},
}

@article {pmid41180498,
year = {2025},
author = {Shamsi, A and Alrouji, M and AlOmeir, O and Tasqeruddin, S and Dinislam, K and Zuberi, A},
title = {CRISPR-Cas9: bridging the gap between aging mechanisms and therapeutic advances in neurodegenerative disorders.},
journal = {Frontiers in cellular neuroscience},
volume = {19},
number = {},
pages = {1681891},
pmid = {41180498},
issn = {1662-5102},
abstract = {Neurodegenerative diseases such as Alzheimer's, Parkinson's, Huntington's, ALS, and spinocerebellar ataxia are becoming more prevalent as populations age, posing major global health challenges. Despite decades of research, effective treatments that halt or reverse these conditions remain elusive. Aging is the most significant risk factor in the development of these diseases, intertwining with molecular processes like DNA damage, mitochondrial dysfunction, and protein aggregation. Recent advances in gene-editing technologies, particularly CRISPR-Cas9, are beginning to shift the therapeutic landscape. This revolutionary tool allows for precise correction of genetic mutations associated with neurodegeneration, offering the potential for disease modification rather than symptom management alone. In this review, we explore how CRISPR-Cas9 is being leveraged to target key genes implicated in various neurodegenerative conditions and how it may overcome barriers posed by aging biology. We also examine the delivery systems and safety challenges that must be addressed before clinical application. With continued progress, CRISPR-Cas9 could mark a turning point in our ability to treat or even prevent age-related neurological decline.},
}

@article {pmid41180422,
year = {2025},
author = {Gu, SC and Sun, QY and Liu, HQ and Shen, CY and Su, H and Xie, F and Ye, Q},
title = {Omics-derived biological modules reflect tau positron emission tomography in Alzheimer's disease.},
journal = {Alzheimer's & dementia (New York, N. Y.)},
volume = {11},
number = {4},
pages = {e70172},
pmid = {41180422},
issn = {2352-8737},
abstract = {BACKGROUND: Tau neurofibrillary pathology is a hallmark of Alzheimer's disease (AD) and can be quantified in vivo using tau-selective positron emission tomography (tau PET). Tau PET signal closely correlates with cognitive decline and disease stage, yet the molecular networks underpinning tau accumulation remain incompletely defined.

METHODS: We performed multi-omics integration of proteomics, transcriptomics, and tau PET standardized uptake value ratios (SUVRs), and clinical assessments data from cognitively normal and cognitively impaired individuals. Using Light Gradient Boosting Machine (LightGBM), two-way orthogonal partial least squares, and network-based approaches, we explored key tau-associated proteomic signatures and constructed protein-protein interaction (PPI) modules. Module activities were quantified by gene set variation analysis and related to tau PET and cognition.

RESULTS: Among 60 regions, 15 tau PET imaging biomarkers were selected based on group differences, LightGBM importance, and cognitive relevance. Fifty key tau-associated proteins were identified and organized into four functional modules. PPI modules 1 (metabolic-cytoskeletal) and 3 (adhesion-nutrient sensing) exhibited strong associations with elevated tau PET uptake across selected cortical and limbic regions, as well as with cognitive impairment.

CONCLUSION: Distinct modules reflected regional tau PET burden and cognitive outcomes in AD, highlighting convergent disruptions in energy metabolism, cytoskeletal stability, and intercellular signaling.

HIGHLIGHTS: Integration of proteomics, transcriptomics, tau positron emission tomography (PET) imaging, and cognition in Alzheimer's disease.Fifteen key tau PET imaging biomarkers were prioritized.Fifty key tau-associated proteins were identified.Four distinct molecular networks contribute to regional tau pathology and cognition.Modules 1 (metabolic-cytoskeletal) and 3 (adhesion-nutrient sensing) strongly associated with tau PET burden and cognitive impairment.},
}

@article {pmid41179804,
year = {2025},
author = {Yang, L and Yu, H and Chai, GS},
title = {Aβ and tau clearance through aerobic exercise: unveiling the β2-adrenergic receptor's role in regulating autophagy-lysosomal pathways.},
journal = {Autophagy reports},
volume = {4},
number = {1},
pages = {2572512},
pmid = {41179804},
issn = {2769-4127},
abstract = {The systematic dissection of molecular mechanisms through which aerobic exercise (AE) mitigates neurodegenerative pathologies remains a significant challenge. Alzheimer's disease (AD) is characterized by impaired autophagy-lysosomal flux and the accumulation of amyloid-β (Aβ) and hyperphosphorylated tau. We recently identified the β2-adrenergic receptor (β2-AR) as a key mediator of exercise-induced bene = d sought to dissect its role in regulating distinct proteostatic pathways. We revealed that AE activates β2-AR signaling to promote lysosomal acidification via upregulation of VMA21, an essential assembly factor for the vacuolar ATPase (V-ATPase) proton pump, thereby facilitating Aβ clearance. Concurrently, AE enhanced autophagosome-lysosome fusion through the β2-AR - retinoid X receptor alpha (RXRα) - charged multivesicular body protein 4B (CHMP4B) axis, promoting tau degradation. Critically, pharmacological inhibition of β2-AR fully abolished these effects. Here, we propose an integrated mechanism through which β2-AR activation by AE could coordinate dual autophagy-lysosomal recovery processes and suggest that targeting this pathway offers a promising therapeutic strategy for AD and related proteostatic disorders.},
}

@article {pmid41179212,
year = {2025},
author = {Yuan, C and Lv, S and Han, Y and Li, Y and Xian, Z and Liu, G and Xiao, S},
title = {Quercetagitrin Ameliorates Alzheimer-Like Pathologies Associated with TNFα/NFκB Pathway in APP/PS1 Mice.},
journal = {ACS omega},
volume = {10},
number = {42},
pages = {49816-49827},
pmid = {41179212},
issn = {2470-1343},
abstract = {Background: Alzheimer's disease (AD) is a neurodegenerative disease with two pathological features in the brain: amyloid β (Aβ) plaques and tau tangles. Neuroinflammation plays an important role in the development of AD, closely related to both Aβ and tau pathologies. Tumor necrosis factor α (TNFα) and nuclear factor-κB (NFκB) behave as key regulators of neuroinflammation in AD. It is pressing to develop effective AD drugs. Objective: This study aimed to explore the effects and mechanisms of quercetagitrin in AD using a combination of network pharmacology analyses and in vivo experiments. Methods: The potential target of quercetagitrin in AD was predicted by network pharmacology. The interaction between the compound and the target protein was measured by molecular docking. The in vivo effects were performed in APP/PS1 mice via mouse behavior tests, Western blotting, ThS staining, immunohistochemical staining, and immunofluorescence staining. Results: First, network pharmacology analyses were conducted to predict the primary target of the compound, which is TNFα. Then, molecular docking showed that quercetagitrin interacts with TNFα with a high affinity. Finally, the level of TNFα was reduced, and the activation of NFκB signaling was inhibited by quercetagitrin in APP/PS1 mice. Meanwhile, quercetagitrin treatment ameliorated Aβ pathology, cognitive impairments, and neuroinflammation in the AD mice. Conclusions: These findings demonstrate quercetagitrin as a potential therapeutic drug for AD.},
}

@article {pmid41179172,
year = {2025},
author = {da Silva, LRG and de Sá, CB and do Amaral, BS and Romeiro, NC and Cass, QB and Valverde, AL},
title = {Affinity Selection-Mass Spectrometry for the Identification of Ligands of Acetylcholinesterase from Topsentia ophiraphidites and Docking Studies for the Dereplicated Ligands.},
journal = {ACS omega},
volume = {10},
number = {42},
pages = {50275-50284},
pmid = {41179172},
issn = {2470-1343},
abstract = {Acetylcholinesterase (AChE) inhibition has been successful for the treatment of Alzheimer's disease and still stands as an important target in the search for novel ligands. In this context, affinity selection-mass spectrometry (AS-MS) has been acknowledged as a high-throughput screening (HTS) technique for large molecular libraries in drug discovery programs and natural product investigations. In this work, an AS-MS assay with AChE immobilized onto magnetic beads (AChE-MB) has been used to search for ligands in samples of the sponge Topsentia ophiraphidites collected in the archipelago of Fernando de Noronha, Brazil. Ligand dereplication disclosed 6-desmethyl-6-ethyl-9,10-dihydrospongosoritin A, 3,5-dibromo-O-methyltyrosine, 3-bromo-5-iodo-O-methyltyrosine, and 3,5-di-iodo-O-methyltyrosine as AChE ligands, which showed affinity ratios of 1.84, 1.34, 1.26, and 1.20, respectively, in the AS-MS assay. As a complementary approach, molecular docking analysis with human AChE has been carried out for the disclosed dereplicated ligands, in which the (R, R) stereoisomer of 6-desmethyl-6-ethyl-9,10-dihydrospongosoritin A stood out, performing important intermolecular interactions with the active sites of AChE, especially with the peripheral anionic site, at the entrance of the gorge. The results stimulate further investigations of these ligands in other pharmacological assays in order to better understand their mechanisms of action.},
}

@article {pmid41178992,
year = {2025},
author = {Chen, B and Wang, Q and Wang, Y and Liu, Q and Chen, W and Mao, H and Li, J and Liu, Q and Zhou, X},
title = {Mitochondrial quality control in neurodegenerative diseases: from molecular mechanisms to natural product therapies.},
journal = {Frontiers in physiology},
volume = {16},
number = {},
pages = {1695681},
pmid = {41178992},
issn = {1664-042X},
abstract = {BACKGROUND: Neurodegenerative diseases, such as Alzheimer's disease, Parkinson's disease, etc., are a group of complex and heterogeneous disorders characterized by progressive synaptic loss and pathological protein alterations. Mitochondria are the main source of energy produced by neurons and support the high energy consumption of the nervous system. Mitochondrial quality control, involving processes like mitophagy and mitochondrial biogenesis, is crucial for mitochondrial homeostasis, and mitochondrial dysfunction is closely related to neurodegenerative diseases pathogenesis, making targeting mitochondrial quality control a potential therapeutic strategy. Natural products offer benefits such as cost-effectiveness, fewer side effects, and other positive qualities, making them suitable choices as supplements or alternatives to traditional drugs for treating neurodegenerative diseases.

METHODS: A thorough search was conducted on many databases including Web of Science, PubMed, EMBASE, and MEDLINE to investigate the role of mitochondria in neurodegenerative diseases and the therapeutic effects of natural products.

RESULTS: By searching the relevant studies on neurodegenerative diseases and mitochondria in recent years, we observed a rise in the number of studies examining the functional characteristics and biological events of mitochondrial quality control systems in neurodegenerative diseases pathogenesis and the potential for natural products regulating mitochondrial quality control to improve neurodegenerative diseases.

CONCLUSION: This review summarizes the functional characteristics and biological events of mitochondrial quality control systems in neurodegenerative diseases pathogenesis, and comprehensively analyzes the pharmacological mechanisms by which natural products regulate mitochondrial quality control to improve neurodegenerative diseases, aiming to provide a scientific basis for further research and new clinical drug development.},
}

@article {pmid41178976,
year = {2025},
author = {Bae, HJ and Kim, SI and Kim, SY and Cho, YE and Sung, S and Lim, S and Cho, K and Park, SJ and Lim, S},
title = {Lacticaseibacillus rhamnosus CBT LR5 with skim milk alleviates scopolamine-induced cognitive impairment in mice.},
journal = {Frontiers in microbiology},
volume = {16},
number = {},
pages = {1672153},
pmid = {41178976},
issn = {1664-302X},
abstract = {INTRODUCTION: Emerging evidence highlights the gut-brain axis as a pivotal pathway linking gastrointestinal health with cognitive function, particularly in neurodegenerative conditions such as Alzheimer's disease (AD).

METHODS: This study investigated the cognitive-enhancing effects of the probiotic strain Lacticaseibacillus rhamnosus CBT LR5 (LR5), alone or in combination with skim milk, in a mouse model of scopolamine-induced cognitive impairment. The cognitive functions were evaluated using the novel object recognition test (NOR) and the passive avoidance test (PAT).

RESULTS: The results demonstrated that the oral administration of LR5, especially when combined with skim milk, significantly ameliorated scopolamine-induced cognitive deficits. Mechanistically, treatment with LR5 combined with skim milk restored the diversity and composition of the gut microbiota increased the abundance of beneficial genera, such as Muribaculaceae and enhanced intestinal barrier integrity by increasing the expression of tight junction proteins, including claudin-1, occludin, and zonula occludens-1. Additionally, this combination reduced systemic inflammation by lowering serum TNF-α and PGE2 levels and promoted increased expression of BDNF by activating the CREB-BDNF-TrkB signaling pathway in hippocampal and cortical tissues. Furthermore, correlation analyses revealed significant associations between specific gut bacterial genera, such as Lacticaseibacillus, Turicibacter, Cryptobacteroides, Ruminococcus, and Muribaculaceae, and cognitive or inflammatory biomarkers.

DISCUSSION: Collectively, these findings suggest that the synergistic effects of L. rhamnosus CBT LR5 combined with skim milk may represent an effective dietary intervention for cognitive enhancement, potentially through gut microbiota modulation, improved barrier integrity, reduced inflammation, and enhanced neurotrophic signaling.},
}

@article {pmid41178777,
year = {2025},
author = {Yigitturk, G and Cavusoglu, T},
title = {A Review of The Place of Adipose-Derived Stem Cells among Stem Cell Applications in Neurodegenerative Diseases.},
journal = {Current topics in medicinal chemistry},
volume = {},
number = {},
pages = {},
doi = {10.2174/0115680266363649250620113954},
pmid = {41178777},
issn = {1873-4294},
abstract = {Treatment of neurodegenerative diseases aims to slow disease progression, alleviate symptoms, and improve life quality. Adipose-Derived Stem Cells (ADSCs) have emerged as a promising treatment for neurodegenerative diseases that can be easily obtained from adipose tissues. Their abundance, accessibility, and potential for multilinear differentiation make them an attractive candidate for regenerative medicine. ADSCs can release neurotrophic factors, modulate neuroinflammation, and potentially differentiate into neurons, giving hope for neuronal repair and replacement. Preclinical studies have shown the efficacy of several neurodegenerative diseases, such as Alzheimer's disease, Parkinson's disease, multiple sclerosis, and spinal cord injuries. ADSC has demonstrated the potential to improve functional results, promote neurogenesis, induce tissue integrity, and reduce neuron loss. Clinical trials are still underway, but evidence of the effectiveness of ADSC in neurodegeneration is still being developed. The first clinical studies focused on safety and feasibility and achieved promising results. Optimizing cell transmission, controlling tumor growth, standardizing treatment protocols and such challenges remain. Current research is aimed at addressing these obstacles and transforming ADSC therapy into a widespread clinical practice. This review focuses on the characteristics, problems, and future approaches of ADSC in the context of neurodegenerative diseases and therapeutic processes.},
}

@article {pmid41178766,
year = {2025},
author = {Wang, Y and Hu, J and Zhu, Q and Wang, S and Yu, S},
title = {Emerging Potential of Ras-proximate-1 (Rap1) in Mediating Neurodegenerative Diseases.},
journal = {Current neuropharmacology},
volume = {},
number = {},
pages = {},
doi = {10.2174/011570159X440842251020104840},
pmid = {41178766},
issn = {1875-6190},
abstract = {Neurodegenerative diseases have posed a rising global threat to the aging population, presenting structural and functional impairments in the central nervous system. These progressive disorders, which affect the brain and spinal cord, develop due to the continuous loss of neurons and myelin sheaths. Such specific pathophysiological changes lead to neurological dysfunction in Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, and Huntington's disease, resulting in typical motor dysfunctions and cognitive disorders, as well as symptoms like behavioral abnormalities and personality changes. To date, despite various treatments attempting to manage these symptoms, patients' quality of life remains severely deteriorated. A few effective therapeutics are available to mitigate the progression of neurodegenerative injuries. Increasing attention is now focused on molecular regulatory mechanisms, particularly the association between immune regulation and the neurovascular unit. A critical component in this process is Ras-proximate-1 (Rap1), a small Guanosine Triphosphatase (GTPase). Rap1 is determined to regulate glia-mediated immunoinflammatory responses, vascular endothelial function, and neuronal activity. It also modulates synaptic plasticity and mitochondrial function via autophagy-dependent modulation, which are significantly impacted during neuronal degeneration. Additionally, signaling pathways, including PI3K/Akt and ERK, are identified as its downstream effectors. Furthermore, by mediating the permeability of the blood-brain barrier, Rap1 probably influences neuroimmune-vascular modulation throughout the development of neurological disorders. In this review, we investigate recent studies to explore the emerging therapeutic potential of Rap1 in the inflammation-related regulation within neurodegenerative diseases. We also discuss novel treatments and possible targets, including natural medicines and genetic modulation, to enhance therapeutic effects and improve prognosis.},
}

@article {pmid41178759,
year = {2025},
author = {Paitel, ER and Pettigrew, C and Callow, DD and Moghekar, A and Miller, MI and Faria, AV and Oishi, K and Albert, M and Soldan, A},
title = {Cerebellar White Matter Microstructure Is Associated With Age, Cerebrospinal Fluid Amyloid Beta Levels, and Cognition in Cognitively Unimpaired Older Adults.},
journal = {Human brain mapping},
volume = {46},
number = {16},
pages = {e70398},
doi = {10.1002/hbm.70398},
pmid = {41178759},
issn = {1097-0193},
support = {P30-AG066507/AG/NIA NIH HHS/United States ; T32-AG027668/AG/NIA NIH HHS/United States ; U19-AG033655/AG/NIA NIH HHS/United States ; U19-AG065169/AG/NIA NIH HHS/United States ; },
mesh = {Humans ; Aged ; *Amyloid beta-Peptides/cerebrospinal fluid ; Male ; Female ; *White Matter/diagnostic imaging/pathology/anatomy & histology ; Middle Aged ; Aged, 80 and over ; *Cerebellum/diagnostic imaging/pathology ; *Aging/pathology/physiology ; Magnetic Resonance Imaging ; tau Proteins/cerebrospinal fluid ; Adult ; *Cognition/physiology ; Executive Function/physiology ; Peptide Fragments/cerebrospinal fluid ; Gray Matter/diagnostic imaging/pathology ; Biomarkers/cerebrospinal fluid ; },
abstract = {Structural changes in the cerebellum contribute to cognitive decline due to aging and Alzheimer's disease (AD). However, it is unclear whether age and AD pathology are associated with structural alterations in the cerebellum among cognitively unimpaired individuals and how these alterations relate to cognition. This study examined the association of age and cerebrospinal fluid (CSF) AD biomarkers (amyloid beta [Aβ42/Aβ40], phosphorylated tau [p-tau181]) with cerebellar gray matter (GM) and white matter (WM) volumes and cerebellar WM microstructure, measured via magnetic resonance imaging (MRI) among 176 cognitively unimpaired middle-aged and older adults (mean age = 66.70, range = 34-89). Cognition was measured with executive function and visuospatial composite scores. Older age was associated with lower cerebellar GM and WM volumes (ps < 0.01) and greater mean diffusivity (MD) in the cerebellar peduncles (p < 0.01). In contrast, more abnormal Aβ levels were associated with lower MD in three regions of interest, including the middle cerebellar peduncle (MCP, p < 0.01), a composite of superior, middle, and inferior peduncles (p < 0.05), and within-cerebellar WM (p < 0.05). Patterns were similar when comparing biomarker positive versus negative groups, particularly for the MCP. Further, lower MD in the peduncles and cerebellar WM was associated with better executive function and visuospatial composite scores (ps < 0.05), whereas cerebellar volumetric measures were not related to cognition. Results suggest that older age is associated with microstructural and volumetric cerebellar GM and WM alterations. In contrast, Aβ levels are associated with WM microstructural properties in cognitively unimpaired individuals. These findings highlight the importance of cerebellar WM microstructure to cognition and are consistent with, and expand on, previous reports that have linked more abnormal amyloid levels to WM microstructure in cerebral tracts. They also suggest that cerebellar WM alterations may be markers of preclinical AD.},
}

Humans
Aged
*Amyloid beta-Peptides/cerebrospinal fluid
Male
Female
*White Matter/diagnostic imaging/pathology/anatomy & histology
Middle Aged
Aged, 80 and over
*Cerebellum/diagnostic imaging/pathology
*Aging/pathology/physiology
Magnetic Resonance Imaging
tau Proteins/cerebrospinal fluid
Adult
*Cognition/physiology
Executive Function/physiology
Peptide Fragments/cerebrospinal fluid
Gray Matter/diagnostic imaging/pathology
Biomarkers/cerebrospinal fluid

@article {pmid41178698,
year = {2025},
author = {Bangs, MC and Gadhavi, J and Carter, EK and Ping, L and Duong, DM and Dammer, EB and Wu, F and Shantaraman, A and Fox, EJ and Johnson, ECB and Lah, JJ and Levey, AI and Seyfried, NT},
title = {Proteomic subtyping of Alzheimer's disease CSF links blood-brain barrier dysfunction to reduced levels of tau and synaptic biomarkers.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21},
number = {11},
pages = {e70830},
doi = {10.1002/alz.70830},
pmid = {41178698},
issn = {1552-5279},
support = {U01AG061357/AG/NIA NIH HHS/United States ; R01AG070937/AG/NIA NIH HHS/United States ; P30AG066511/AG/NIA NIH HHS/United States ; T32AG087922/AG/NIA NIH HHS/United States ; //Foundation for the National Institutes of Health/ ; A2024029F//BrightFocus Foundation/ ; },
mesh = {Humans ; *Alzheimer Disease/cerebrospinal fluid/classification ; *tau Proteins/cerebrospinal fluid ; *Proteomics ; Biomarkers/cerebrospinal fluid ; Male ; Female ; *Blood-Brain Barrier/physiopathology/metabolism ; Aged ; Black or African American ; Middle Aged ; Aged, 80 and over ; Synapses/metabolism ; White ; },
abstract = {INTRODUCTION: Alzheimer's disease (AD) shows clinical and molecular heterogeneity shaped by demographic and genetic factors.

METHODS: To resolve this heterogeneity, we performed a network-based proteomic analysis of cerebrospinal fluid (CSF) from 431 individuals, including 111 African Americans, to identify protein co-expression modules and define AD subtypes.

RESULTS: Ten co-expression modules reflecting diverse pathways and cell types were identified, many linked to demographics and AD biomarkers. One subtype, enriched in African Americans and males, showed low CSF tau, elevated plasma proteins, and reduced synaptic proteins, features consistent with blood-brain barrier (BBB) dysfunction. This subtype also showed the highest levels of thrombin activity, capable of cleaving tau. Introducing plasma into CSF ex vivo recapitulated the BBB subtype signature, supporting a causal role for plasma proteases in tau and synaptic protein depletion.

CONCLUSION: These findings link BBB dysfunction and plasma proteases to CSF tau loss and highlight the need for diversity in AD-biomarker research.

HIGHLIGHTS: Race and sex correlate with key AD proteomic network modules. We identify six proteomic subtypes with distinct demographic and AD biomarker profiles. Subtype 3 demonstrates an A+/T- phenotype and a profile suggestive of BBB dysfunction. Low CSF tau and neuronal proteins may stem from infiltrating plasma protease cleavage. Plasma spike-in experiments show decreased endogenous CSF tau and neuronal proteins.},
}

Humans
*Alzheimer Disease/cerebrospinal fluid/classification
*tau Proteins/cerebrospinal fluid
*Proteomics
Biomarkers/cerebrospinal fluid
Male
Female
*Blood-Brain Barrier/physiopathology/metabolism
Aged
Black or African American
Middle Aged
Aged, 80 and over
Synapses/metabolism
White

@article {pmid41178581,
year = {2025},
author = {Şen, İ and Yeşildal, TK and Abdulqadir, AH and Yaman, İ and Tosun, SN and Zengin, G and Cakmak, YS},
title = {Comprehensive evaluation of Onosma rostellatum: antioxidant, enzyme inhibitory and anticancer properties of root and leaf extracts.},
journal = {Journal of the science of food and agriculture},
volume = {},
number = {},
pages = {},
doi = {10.1002/jsfa.70284},
pmid = {41178581},
issn = {1097-0010},
support = {//Türkiye Bilimsel ve Teknolojik Araştırma Kurumu/ ; },
abstract = {BACKGROUND: The incidence and mortality of diseases such as cancer, Alzheimer's, and diabetes have increased in recent years. Along with limited treatment success, severe side effects of synthetic drugs are a major concern. Therefore, natural bioactive compounds are gaining attention as alternative therapeutic agents due to their efficacy and lower toxicity. This study investigated the protective and therapeutic potential of extracts of different parts of Onosma rostellatum, a plant used in traditional medicine, in terms of their antioxidant, enzyme inhibitory and anticancer activities.

RESULTS: Antioxidant, enzyme inhibition, anticancer activities and phenolic composition of the extracts were evaluated. Methanol leaf extract showed the strongest activity in antioxidant assays, with the highest 2,2-diphenyl-1-picrylhydrazyl (46.59 ± 0.03 g Trolox equivalents (TE) kg[-1]) and ferric reducing antioxidant power (90.74 ± 0.59 g TE kg[-1]) activities, while the root methanol extract exhibited the strongest 2,2'-azino-bis(3-ethylbenzothiazoline-6-sulfonic acid radical scavenging activity (453.86 ± 2.20 g TE kg[-1]) and the highest cupric reducing antioxidant capacity value (243.64 ± 0.49 g TE kg[-1]). The aqueous leaf extract demonstrated superior metal-chelating ability (32.59 ± 0.13 g ethylenediaminetetraacetic acid kg[-1]). Leaf extracts displayed the highest copper ion reducing capacity (94.64 ± 0.23 g TE kg[-1]). Ethyl acetate leaf extracts showed the most significant inhibition against α-amylase and α-glucosidase. High-performance liquid chromatographic analysis revealed rosmarinic acid and quercetin as major phenolic constituents. In cell culture experiments, the ethyl acetate leaf extract demonstrated the most potent anticancer effect, with an IC50 value of 167.2 ± 0.32 μg mL[-1] after 72 h.

CONCLUSION: Onosma rostellatum extracts possess strong antioxidant, enzyme inhibitory and anticancer activities, largely associated with their phenolic components. These findings highlight the potential of this plant as a natural source of therapeutic agents. © 2025 Society of Chemical Industry.},
}

@article {pmid41178353,
year = {2025},
author = {Raket, LL and Pichet Binette, A and Mattsson-Carlgren, N and Janelidze, S and Zetterberg, H and Ashton, NJ and Blennow, K and Stomrud, E and Palmqvist, S and Hansson, O},
title = {Estimating the time course of biomarker changes in Alzheimer's disease.},
journal = {Brain : a journal of neurology},
volume = {},
number = {},
pages = {},
doi = {10.1093/brain/awaf413},
pmid = {41178353},
issn = {1460-2156},
abstract = {Recent advancements in biomarkers have transformed Alzheimer's disease (AD) diagnosis from being purely symptom-based to include biological criteria. With new treatments targeting AD's core biology, understanding the timeline of biological changes is crucial as the disease progresses over decades. Longitudinal data from amyloid-beta (Aβ) PET and cognitive tests (MMSE and ADAS-cog) from the Alzheimer's Disease Neuroimaging Initiative (n=1,448) and BioFINDER (n=2,088) were used to stage patients against an estimated continuous disease timeline (predicted time since Aβ-PET positivity). The estimated timeline was validated by comparing correlations with unseen biomarkers and cognitive measures against alternative staging approaches. Trajectories for plasma, CSF, MRI, and PET biomarkers, measuring Aβ, tau, and neurodegeneration, were mapped along this AD continuum. The proposed staging approach was found to produce stronger correlations with unseen cognitive measures and biomarkers compared to alternative staging methods, including amyloid and tau PET clocks (all pairwise p<0.05). Findings related to biomarker trajectories were highly consistent across cohorts. The period from Aβ-PET positivity to end-stage AD dementia (MMSE = 0) was estimated at 20-25 years, with a presymptomatic phase of 7-11 years. CSF Aβ42/40 became abnormal about a year before Aβ-PET positivity, CSF p-tau231, p-tau217, and plasma p/np-tau217 1-3 years after, and tau-PET about 8 years after. Neurodegenerative biomarkers, such as hippocampal volume, became clearly abnormal in early dementia stages, 14-16 years after Aβ-PET positivity. The progression from initial biomarker abnormality to severe AD spans two decades. Disease progression modeling elucidates the evolution of AD biomarkers and cognition, highlighting the relative timing of biomarker abnormalities. These models can determine disease stages, aiding prognosis and evaluation for disease-modifying treatments.},
}

@article {pmid41178220,
year = {2025},
author = {Jang, YJ and Kim, H and Jung, JH and Han, K and Jeon, HJ},
title = {Changes in Smoking Status in Depressed Patients and the Risk of Dementia.},
journal = {The Journal of nervous and mental disease},
volume = {},
number = {},
pages = {},
doi = {10.1097/NMD.0000000000001849},
pmid = {41178220},
issn = {1539-736X},
support = {SMO1161491//Samsung Medical Center/ ; },
abstract = {INTRODUCTION: Smoking is a known risk factor for dementia, but the effects of changes in smoking behavior after a depression diagnosis remain unclear.

METHODS: We conducted a nationwide cohort study of 1,290,530 individuals newly diagnosed with depression in South Korea between 2009 and 2012. Participants were categorized by smoking status before and after diagnosis. Incident dementia, including Alzheimer disease (AD) and vascular dementia (VD), was tracked through 2018. Adjusted hazard ratios (HRs) were estimated using Cox models.

RESULTS: Continued smoking showed the highest dementia risk (HR 1.338 for all-cause; 1.323 for AD; and 1.524 for VD). Quitting reduced risk but remained higher than in persistent non-smokers. Middle age was a key risk period for AD. For VD, men had consistently higher risk, while women had increased risk only in the cessation group.

CONCLUSIONS: Changes in smoking behavior after depression diagnosis influence dementia risk, underscoring the need for cessation strategies.},
}

@article {pmid41178159,
year = {2025},
author = {Mosna, S and Dormann, D},
title = {TDP-43 Phosphorylation: Pathological Modification or Protective Factor Antagonizing TDP-43 Aggregation in Neurodegenerative Diseases?.},
journal = {BioEssays : news and reviews in molecular, cellular and developmental biology},
volume = {},
number = {},
pages = {e70084},
doi = {10.1002/bies.70084},
pmid = {41178159},
issn = {1521-1878},
support = {//Deutsche Forschungsgemeinschaft (DFG)/ ; //VERUM Foundation/ ; },
abstract = {TDP-43 is a ubiquitously expressed RNA-binding protein that aggregates in the brains of patients suffering from neurodegenerative diseases, such as amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD) and Alzheimer's disease. Aggregated TDP-43 in these diseases is hyperphosphorylated in its C-terminal intrinsically disordered region, while physiological TDP-43 is normally unphosphorylated. Whether TDP-43 phosphorylation is a pathological driver, or rather a protective antagonist of TDP-43 aggregation and consequently neurodegeneration, is still debated and a matter of ongoing research. Here, we review current knowledge about TDP-43 phosphorylation in disease and the kinases and phosphatases that regulate this post-translational modification. We discuss how TDP-43 phosphorylation is thought to shape TDP-43's phase separation, aggregation and toxicity in neurodegenerative diseases. We highlight recent research that provides evidence that hyperphosphorylation antagonizes TDP-43 phase separation and aggregation, and speculate about a potential role of condensates in TDP-43 phosphorylation.},
}

@article {pmid41178110,
year = {2025},
author = {Polk, S and Rassaeikashuk, M and Thilagavathi, R and Selvam, C},
title = {Targeting Poly (ADP-Ribose) Polymerase-1 for the Treatment of Neurodegenerative Diseases.},
journal = {Chemical biology & drug design},
volume = {106},
number = {5},
pages = {e70189},
doi = {10.1111/cbdd.70189},
pmid = {41178110},
issn = {1747-0285},
mesh = {Humans ; *Neurodegenerative Diseases/drug therapy/metabolism/pathology/enzymology ; *Poly (ADP-Ribose) Polymerase-1/metabolism/antagonists & inhibitors ; alpha-Synuclein/metabolism ; Animals ; *Poly(ADP-ribose) Polymerase Inhibitors/therapeutic use/chemistry/pharmacology ; tau Proteins/metabolism ; Amyloid beta-Peptides/metabolism ; },
abstract = {Poly (ADP-ribose) Polymerase 1 (PARP1) has many functions that intertwine with the pathology of many diseases. Because of PARP1's function in DNA repair and cell death, neurodegeneration research is another pathology that PARP1 included. By PARylation, PARP1 acts as a direct and indirect modulator of amyloid β, α-Synuclein (α-syn), tau protein, and other proteins indicated in neurodegenerative diseases. PARylation influences the function, activation, and localization of these proteins. This review paper overviews neurodegeneration and the significant diseases resulting from neurodegeneration and compiles mechanisms and functions Poly (ADP-ribose) Polymerase-1 has in neurodegenerative diseases.},
}

Humans
*Neurodegenerative Diseases/drug therapy/metabolism/pathology/enzymology
*Poly (ADP-Ribose) Polymerase-1/metabolism/antagonists & inhibitors
alpha-Synuclein/metabolism
Animals
*Poly(ADP-ribose) Polymerase Inhibitors/therapeutic use/chemistry/pharmacology
tau Proteins/metabolism
Amyloid beta-Peptides/metabolism

@article {pmid41177994,
year = {2025},
author = {Hyde, Z and Flicker, L and Douglas, R and Rind, S and Rind, N and LoGiudice, D and Smith, K},
title = {Development of a Memory Clinic at an Aboriginal Community-Controlled Health Service: Profile of the First Patients.},
journal = {Australasian journal on ageing},
volume = {44},
number = {4},
pages = {e70106},
doi = {10.1111/ajag.70106},
pmid = {41177994},
issn = {1741-6612},
support = {//National Health and Medical Research Council/ ; //Medical Research Future Fund/ ; },
mesh = {Humans ; Female ; Male ; Aged ; Middle Aged ; Aged, 80 and over ; Adult ; *Health Services, Indigenous/organization & administration ; Western Australia/epidemiology ; *Cognitive Dysfunction/diagnosis/ethnology/therapy/psychology ; *Dementia/diagnosis/ethnology/therapy/psychology ; *Community Health Services/organization & administration ; *Memory ; },
abstract = {OBJECTIVES: Dementia is the leading cause of burden of disease in older Australians. Older Aboriginal and Torres Strait Islander people experience an increased risk of cognitive impairment and dementia. This article describes the clinical profile of the first patients seen at a memory clinic established in an Aboriginal community-controlled health service (ACCHS) in metropolitan Perth, Western Australia.

METHODS: This was an audit of 64 patients attending a memory clinic between March 2020 and February 2023 (inclusive).

RESULTS: The median age of patients was 67.7 years (range 35-95 years; interquartile range [IQR] 13.4 years) and 34 (53%) were female. The majority (94%) were living independently. Thirty-four patients (53%; 95% confidence interval 41%-65%) were diagnosed with cognitive impairment. A further six (9%) were diagnosed with depression without cognitive impairment. The most common diagnoses in cognitively impaired patients were cognitive impairment not dementia (CIND; 27%); mild neurocognitive disorder (21%); dementia due to Alzheimer's disease (15%); Alzheimer's disease dementia, mixed type (9%); and other mixed dementias (9%). Women were slightly more likely than men to have cognitive impairment (56% vs. 52%), although this was not statistically significant (p = 0.74). The number of Aboriginal people seen in the clinic's first 3 years of operation was over 12 times that seen at a nearby hospital-based service during the same period.

CONCLUSIONS: A memory clinic located within an ACCHS was well-attended and fulfilled a need not met by mainstream services. The successful model described in this article could be adopted by other Aboriginal health services.},
}

Humans
Female
Male
Aged
Middle Aged
Aged, 80 and over
Adult
*Health Services, Indigenous/organization & administration
Western Australia/epidemiology
*Cognitive Dysfunction/diagnosis/ethnology/therapy/psychology
*Dementia/diagnosis/ethnology/therapy/psychology
*Community Health Services/organization & administration
*Memory

@article {pmid41177895,
year = {2025},
author = {Au, R and Bose, N and Imam, F and Kolachalama, VB},
title = {Technological advances enabling an enhanced understanding of early Alzheimer's disease.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21},
number = {11},
pages = {e70883},
doi = {10.1002/alz.70883},
pmid = {41177895},
issn = {1552-5279},
support = {RDADB-202104-2021750//Alzheimer's Drug Discovery Foundation/ ; 20SFRN35360180//American Heart Association/ ; AG083735/AG/NIA NIH HHS/United States ; AG072654/AG/NIA NIH HHS/United States ; AG062109/AG/NIA NIH HHS/United States ; AG083735/AG/NIA NIH HHS/United States ; },
mesh = {Humans ; *Alzheimer Disease/diagnosis ; *Early Diagnosis ; Brain ; Precision Medicine ; },
abstract = {The aspirations of Alzheimer's disease (AD) precision medicine and precision brain health are not fully realized despite significant advances in early pathological detection. Hampering progress is the difficult challenge of the accurate detection of behavioral symptoms that can help differentiate those at high risk specific to AD versus those with more AD and related dementias (ADRD), who may have AD along with other types of dementia, as well as those who will and will not progress to clinically expressed disease. Technological advances in hardware, software, and analytics are paving the way to opportunities to overcome these long-standing barriers to early clinical symptom detection, when recent and emerging interventions might be most effective. It is important to note that these innovations must not exist in isolation. Integration of data from both AD/ADRD related studies and non-AD related studies is needed whenever brain-related measures are collected to fully realize the scientific opportunities. We envision a near future of harmonized participant data sharing, encompassing standardized multimodal data alongside emerging digital streams, to deliver an invaluable resource for the global research community. HIGHLIGHTS: Technology is overcoming barriers to accurate early detection of behavioral symptoms of AD/ADRD. The National Alzheimer's Coordinating Center is paving the way for the integration of technological advances into AD/ADRD research. A technologically-enabled framework provides a solution for open science on a global scale.},
}

Humans
*Alzheimer Disease/diagnosis
*Early Diagnosis
Brain
Precision Medicine

@article {pmid41177791,
year = {2025},
author = {Bolshakova, OI and Golomidov, IM and Latypova, EM and Ryabova, EV and Sarantseva, SV},
title = {Role of Oxidative Stress in Human Neurodegenerative Pathologies: Lessons from the Drosophila Model.},
journal = {Current topics in medicinal chemistry},
volume = {},
number = {},
pages = {},
doi = {10.2174/0115680266356916250729040245},
pmid = {41177791},
issn = {1873-4294},
abstract = {Oxidative stress plays a critical role in many diseases, making it essential to study its impact on disease progression. However, clinical trials have many limitations and, in some cases, may not be possible at all. In this case, the development of in vivo models is highly anticipated. This is especially relevant for neurodegenerative diseases. Drosophila melanogaster models have a number of advantages over many other animal models, including the availability and costeffectiveness of breeding, the accumulated knowledge of the Drosophila genome, and the ability to manipulate a large number of individuals. The latter allows for rapid screening and in-depth studies of potential therapeutic agents, including natural compounds with antioxidant activity. This review describes genetic models of such pathologies as Parkinson's disease, Huntington's disease, Alzheimer's disease and hereditary spastic paraplegia created on Drosophila melanogaster. Studies conducted on such models are presented with an emphasis on the role of oxidative stress analysis. Oxidative stress is proven to be a link between neurodegenerative and metabolic diseases. In addition, studies on Drosophila melanogaster have been analyzed, in which the prospects of natural compounds as therapeutic agents for neurodegenerative and metabolic diseases have been demonstrated.},
}

@article {pmid41177743,
year = {2025},
author = {Pereira da Silva, AM and de Deus, O and Ribeiro, FV and Tudella, GCN and Cabeça, LS and Silva, LL and Han, ML and Franco, JO and Costa, JGP and Santos do Nascimento, MDV and Andrade Fernandes, JV and Franco, ES and de Sousa Maia, MB},
title = {Efficacy and Safety of Lithium for Behavioral and Cognitive Symptoms in Alzheimer's Disease Dementia: A Systematic Review With Frequentist and Bayesian Meta-Analysis.},
journal = {The American journal of geriatric psychiatry : official journal of the American Association for Geriatric Psychiatry},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.jagp.2025.10.001},
pmid = {41177743},
issn = {1545-7214},
abstract = {BACKGROUND: Alzheimer's disease (AD) dementia is the leading cause of cognitive decline in late life, yet treatment options remain limited. Lithium, widely used in bipolar disorder, has been suggested to exert neuroprotective effects through inhibition of GSK-3β and modulation of amyloid and tau pathology. We aimed to evaluate the efficacy and safety of lithium in AD dementia.

METHODS: This systematic review and meta-analysis was prospectively registered in PROSPERO and conducted following PRISMA guidelines. We searched PubMed, Embase, and Cochrane Library through April 2025 for randomized controlled trials (RCTs) comparing lithium with placebo or standard therapy in patients with AD dementia or amnestic mild cognitive impairment. Outcomes included cognition (MMSE, ADAS-Cog, memory tasks), function (CDR-SB, conversion to AD), neuropsychiatric symptoms (NPI), CSF biomarkers, and safety (adverse events [AEs], serious AEs [SAEs]). Random-effects meta-analyses were complemented by Bayesian methods and trial sequential analyses.

RESULTS: Six RCTs involving 394 participants (196 lithium, 198 placebo) met inclusion criteria. Lithium did not significantly improve global cognition (MMSE: MD -1.61, 95% CI -4.11 to 0.88; ADAS-Cog: MD -1.82, -3.05 to -0.60; both with high heterogeneity). Memory outcomes were mixed, with possible benefit for figure recall but not delayed verbal recall. No consistent benefits were observed for episodic memory, functional outcomes (CDR-SB), neuropsychiatric symptoms, or CSF biomarkers. Safety analyses showed no increased risk of SAEs; drug-related AEs were more frequent but heterogeneous across trials.

CONCLUSIONS: Lithium demonstrated an acceptable safety profile within the dosing regimens studied. However, current evidence does not support consistent cognitive or functional benefits in AD dementia. Larger, well-designed RCTs are warranted to clarify its potential therapeutic role.},
}

@article {pmid41177554,
year = {2025},
author = {Novau-Ferré, N and Mateu-Fabregat, J and Papagiannopoulos, CK and Chalitsios, CV and Panisello, L and Markozannes, G and Tsilidis, KK and Bulló, M and Papandreou, C},
title = {Glycemic index, glycemic load, and risk of dementia: a prospective analysis within the UK Biobank cohort.},
journal = {International journal of epidemiology},
volume = {54},
number = {6},
pages = {},
doi = {10.1093/ije/dyaf182},
pmid = {41177554},
issn = {1464-3685},
support = {/ALZ/Alzheimer's Association/United States ; //Spanish Ministry of Health/ ; PI19/00854//European Union/ ; PI22/001139//European Union/ ; },
mesh = {Humans ; Male ; Female ; Prospective Studies ; United Kingdom/epidemiology ; *Glycemic Index ; Aged ; *Dementia/epidemiology ; *Glycemic Load ; Middle Aged ; Proportional Hazards Models ; Risk Factors ; Biological Specimen Banks ; Incidence ; Diet ; Alzheimer Disease/epidemiology ; Dementia, Vascular/epidemiology ; *Dietary Carbohydrates ; UK Biobank ; },
abstract = {BACKGROUND: Dementia risk is influenced by metabolic and lifestyle factors, including hyperinsulinemia, chronic inflammation, and type 2 diabetes. Glycemic index (GI) and glycemic load (GL) reflect the quality and quantity of dietary carbohydrates and their impact on glucose metabolism and systemic health. However, their associations with the risk of dementia subtypes remain unclear. This study examined the associations between dietary GI and GL and the risk of all-cause and different dementia subtypes, such as Alzheimer's disease (AD), vascular dementia (VD), and frontotemporal dementia.

METHODS: A prospective analysis was conducted by using data from 202 302 dementia-free participants in the UK Biobank cohort. Dietary GI and GL were estimated by using the Oxford WebQ 24-hour web-based dietary questionnaire. Cox proportional hazards regressions with restricted cubic splines were used to evaluate nonlinear relationships. Two-piece Cox models were used to identify inflection points, which served as reference values to estimate hazard ratios (HRs).

RESULTS: Dementia incidence was 0.89 per 1000 person-years. GI (mean±SD: 48.71 ± 7.68) showed an inverse J-shaped association with dementia risk, while GL (121.49 ± 39.00) showed a J-shaped pattern, with inflection points at 49.30 and 111.01, respectively. After adjusting for potential confounders, GI values of <49.30 were inversely associated with dementia risk [HR, 0.838; 95% confidence interval (CI), 0.758-0.926], while GL values of >111.01 were associated with higher dementia risk (HR, 1.145; 95% CI, 1.048-1.251). Similar findings were observed for AD and VD.

CONCLUSION: Low-GI diets may offer protective effects against all-cause dementia, AD, and VD, whereas high-GL diets may increase the risk. These findings underscore the importance of considering both carbohydrate quality and quantity in dementia prevention and management strategies.},
}

Humans
Male
Female
Prospective Studies
United Kingdom/epidemiology
*Glycemic Index
Aged
*Dementia/epidemiology
*Glycemic Load
Middle Aged
Proportional Hazards Models
Risk Factors
Biological Specimen Banks
Incidence
Diet
Alzheimer Disease/epidemiology
Dementia, Vascular/epidemiology
*Dietary Carbohydrates
UK Biobank

@article {pmid41177416,
year = {2025},
author = {Bashir, B and Gulati, M and Vishwas, S and Hussain, MS and Gupta, G and Kumar, P and Negi, P and Mittal, N and Dua, K and Singh, SK},
title = {Bridging the gap in the management of Alzheimer's disease using fecal microbiota transplantation.},
journal = {Molecular and cellular neurosciences},
volume = {},
number = {},
pages = {104052},
doi = {10.1016/j.mcn.2025.104052},
pmid = {41177416},
issn = {1095-9327},
abstract = {Alzheimer's disease (AD) is a neurodegenerative disease that greatly impairs the health status of human beings and creates significant burdens on individuals, families, and society. AD is characterized by the buildup of pathological proteins and glial cell dysregulated activity. Additional hallmark features include oxidative stress, neuroinflammation, impaired autophagy, cellular senescence, mitochondrial dysfunction, epigenetic alterations, reduced neurogenesis, increased blood-brain barrier permeability, and age-inappropriate intestinal dysbiosis. There is significant evidence that shows that microbiota in the gut affects the development and progression of AD. As a result, gut microbiota modulation has been identified as a new method of clinical management of AD, and more and more efforts have been devoted to identifying new methodologies for its prevention and treatment. This paper will discuss the role of gut microbiome in the etiopathogenesis of AD and consider the possibilities of fecal microbiota extract (FME) supplementation, commonly referred to as fecal microbiota transplantation (FMT). It is both a prophylactic and curative approach. The FMT therapy is grounded on the premise that anti-inflammatory effects, modifications of amyloid β, improved synaptic plasticity, short-chain fatty acids, and histone acetylation are the principles behind the enhancement of AD. The current review will present an overview of the linkage between FMT and AD as well. It further examines and evaluates the effects of FMT on aging-based mechanisms that support the development of AD. It also provides a broad description of the recent clinical and preclinical evidence on the application of FMT to AD.},
}

@article {pmid41177383,
year = {2025},
author = {Gu, T and Ma, S and Liu, W and Wang, L},
title = {Pregnane X receptor activation regulate amyloid transport to improve cognition functions in Alzheimer's disease.},
journal = {European journal of pharmacology},
volume = {1007},
number = {},
pages = {178310},
doi = {10.1016/j.ejphar.2025.178310},
pmid = {41177383},
issn = {1879-0712},
abstract = {OBJECTIVES: To explore the concept about nuclear receptor pregnane X receptor (PXR) activation could be beneficial for the Alzheimer's disease (AD) treatment, as well as the underlying mechanism.

METHODS: For in vitro experiments, human brain microvascular endothelial cells (hCMEC/D3) were exposed to Aβ42 and hyperforin (HPF), a human PXR agonist followed by measurement of P-glycoprotein(P-gp)and low-density lipoprotein receptor-related protein 1 (LRP1) expression. Further, 7 months old 5 × FAD mice were used for in vivo experiments. Due to the species-difference characteristics of PXR, these mice were treated with pregnenolone carbonitrile (PCN, a rodent PXR agonist) rather than hPXR agonist, or corn oil for 28 days. Meanwhile, untreated C57BL/6 mice were used as the control group. The improvements of animal behavior were evaluated by Morris water maze and novel arm exploration test. The pathological profiles were assessed by immunohistochemistry and transmission electron microscopy. The cerebral blood flow (CBF) and Aβ transporters were analyzed by speckle contrast imaging and Western blot respectively.

RESULTS: In vitro experiments showed that the P-gp and LRP1 levels in hCMEC/D3 were reduced due to exposure of Aβ42, while HPF can restore their expression levels. 5 × FAD mice treated with the PCN improved cognitive functions and cerebral blood flow. These functional improvements were associated with a reduction in amyloid plaques, cerebral amyloid angiopathy, neuroinflammation and a recovery of blood-brain barrier transport function. The underlying mechanisms could be that PXR activation up-regulates the expression of P-gp and LRP1 and inhibits inflammation via STAT3, and increases the clearance of Aβ42 in the brain.

CONCLUSIONS: These results demonstrate the beneficial impact of PXR activation on cognitive functions, parenchymal amyloid plagues and cerebral angiopathy, and highlights the therapeutic potential of PXR agonists for treatment of AD patients.},
}

@article {pmid41177382,
year = {2025},
author = {Maisto, N and Dashtiani, S and Forte, J and Ammendolia, MG and Triaca, V and Rinaldi, F and Mango, D},
title = {Ellagic acid-loaded nanovesicles rescue LTP impairment and neuroinflammation in an AD ex-vivo model.},
journal = {European journal of pharmacology},
volume = {},
number = {},
pages = {178317},
doi = {10.1016/j.ejphar.2025.178317},
pmid = {41177382},
issn = {1879-0712},
abstract = {Neurodegenerative diseases, such as Alzheimer's disease (AD), cause progressive neurological decline and major healthcare challenges. AD is marked by deterioration in learning, memory, and cognition, leading to dementia. Early-stage AD brains show accumulation of amyloid-beta (Aβ) protofibrils and plaques, particularly in the hippocampus, associated with chronic neuroinflammation and impaired synaptic plasticity that drive cognitive decline. Current AD treatments primarily relieve symptoms without slowing disease progression, and existing monoclonal antibodies targeting Aβ plaques have controversial side effects. This has driven interest in natural compounds like polyphenols for their broad biological activities. Ellagic acid (EA), a natural polyphenol, exhibits antioxidant, anti-inflammatory, and neuroprotective properties. Experimental models of neurodegenerative diseases have shown EA's potential to improve memory and cognition by modulating synaptic plasticity. This study has evaluated EA's impact on hippocampal synaptic plasticity and its neuroprotective effects against Aβ1-42-mediated impairments using electrophysiological recordings and immunofluorescence analysis, evaluating microglial morphological normalization as well as interleukins expression. It has been found that, in ex vivo brain slices, EA modulated synaptic plasticity at high concentration, while at the dose that per se does not alter neurotransmission it rescued LTP and basal neurotransmission impairment Aβ1-42 mediated, and normalized neuroinflammation by reducing interleukins expression released by activated microglia. However, EA's poor water solubility and extensive first-pass metabolism limit its clinical use. Here, EA has been encapsulated in non-ionic surfactant vesicles (NSVs), and the formulation (EA-NSVs) has demonstrated a neuroprotective effect at a lower dose compared to free EA, effectively rescuing synaptic impairment induced by Aβ1-42.},
}

@article {pmid41176993,
year = {2025},
author = {Xue, P and Yu, H and Zhu, Y and Liu, F},
title = {Quantitative perfusion assessment with arterial spin labeling magnetic resonance imaging for predicting cognitive decline in Alzheimer's disease: A systematic review and meta-analysis.},
journal = {Journal of clinical neuroscience : official journal of the Neurosurgical Society of Australasia},
volume = {143},
number = {},
pages = {111711},
doi = {10.1016/j.jocn.2025.111711},
pmid = {41176993},
issn = {1532-2653},
abstract = {BACKGROUND: Arterial spin labeling (ASL) magnetic resonance imaging (MRI) is a potential tool for diagnosis and prediction of Alzheimer's disease (AD). This study evaluates effectiveness of ASL in differentiating AD patients or individuals with mild cognitive impairment (MCI) from healthy individuals with normal cognition (HC).

METHODS: After conducting literature search in electronic databases (Google Scholar, PubMed, and Science Direct), studies were selected by following precise eligibility criteria. Meta-analyses of standardized mean difference (SMDs) were performed to examine differences in cerebral blood flow (CBF) between individuals with AD, MCI, and HC. Meta-analyses of correlation coefficients were performed to achieve pooled correlation between CBF and cognitive performance measures.

RESULTS: Fifteen studies (671 HC, 539 MCI, and 463 CE individuals) were included. The ages of these individuals were: 70.6 [95 %CI: 66.6, 74.7], 71.9 [95 %CI: 67.8, 76.1], and 73.2 [95 %CI: 69.2, 77.3] years for HC, MCI, and AD individuals respectively. The percentages of women in HC, MCI and AD groups in these studies were 58 % [95 %CI: 52, 63], 54 % [95 %CI: 49, 60], and 54 % [95 %CI: 48, 61]. As a composite measure for multiple brain regions, CBF was significantly lower in AD patients compared to HC (SMD - 0.70 [95 %CI: -0.92, -0.49]; I[2] = 0 %; p < 0.0001) or individuals with MCI (SMD - 0.62 [95 %CI: -0.86, -0.37]; I[2] = 0 %; p < 0.0001). However, composite CBF was not significantly lower in individuals with MCI in comparison with HC (SMD - 0.17 [95 %CI: -0.42, 0.08]; I[2] = 11.7 %; p = 0.190). In various parts of the brain including the cerebellum, cingulate, deep gray matter, limbic system, and cortices, CBF was significantly lower in AD patients in comparison with HC or MCI individuals. However, CBF was not significantly different in individuals with MCI in comparison with HC in some parts including deep gray matter, limbic system, and frontal lobe. Pooled correlation coefficients between CBF and any cognitive assessment test score were - 0.005 [95 %CI: -0.066, 0.057] (p = 0.878) for HC, -0.114 [95 %CI: -0.236, 0.009] (p = 0.070) for MCI, and 0.297 [95 %CI: 0.213, 0.381] (p < 0.0001) for AD groups.

CONCLUSIONS: ASL is a promising MRI method that can provide an alternative to nuclear methods for the diagnosis of AD. However, more studies are required to evaluate its detecting and predicting role in individuals with MCI.},
}

@article {pmid41176929,
year = {2025},
author = {Akan, T and Akan, S and Alp, S and Ledbetter, CR and Tafti, AP and Arevalo, O and Bhuiyan, MAN},
title = {Deep Learning in neuroimaging for neurodegenerative diseases: State-of-the art, Challenges, and Opportunities.},
journal = {Journal of the neurological sciences},
volume = {478},
number = {},
pages = {123735},
doi = {10.1016/j.jns.2025.123735},
pmid = {41176929},
issn = {1878-5883},
abstract = {Neuroimaging is commonly used to diagnose neurodegenerative diseases (NDDs), providing crucial insights into brain changes before clinical symptoms manifest. Deep learning (DL) for neuroimaging can improve early diagnosis and disease monitoring. Clinical implementation of DL faces challenges in accurately representing real-world data. Recent models, particularly those focused on diagnostic categorization, have achieved high accuracy, but their applicability to patients is limited. Conflicting inferences have been reported, with findings from small cohorts generalizing conclusions without considering inter-scanner, intra- and inter-site variations. A theoretically feasible method involves gathering a comprehensive dataset that encompasses all patient demographics, but this presents practical challenges including harmonization, data incompleteness, class imbalance, and substantial costs. Existing research has also mostly focused on common NDDs like Alzheimer's Disease (AD) and Parkinson's Disease (PD). This contribution expands the literature by looking at a wider range of NDDs, exploring the latest advancements in applying deep learning algorithms to neuroimaging analysis for the diagnosis and monitoring of NDDs, including AD, Frontotemporal Dementia (FTD), Lewy Body Dementia, PD, Huntington's Disease, Amyotrophic Lateral Sclerosis, and Multiple Sclerosis. We emphasize how these approaches are handling spatial/temporal information available in brain volume imaging data. We conclude by discussing the challenges associated with the use of voxel-based, patch-based, ROI-based, and slice-based approaches in brain volume imaging. These challenges are further compounded by issues such as inter-site and inter-scanner variability, class imbalances in medical datasets, and the scarcity of accurately annotated data, all of which impact the performance and generalizability of deep learning models.},
}

@article {pmid41176545,
year = {2025},
author = {El Hajj, W and Pujo-Menjouet, L and Tine, LM and Volpert, V},
title = {Modelling of anti-inflammatory treatment in the Alzheimer disease: optimal regimen and outcome.},
journal = {Bulletin of mathematical biology},
volume = {87},
number = {12},
pages = {171},
pmid = {41176545},
issn = {1522-9602},
support = {Project-ANR-21-CE15-0011//PrionDiff/ ; },
mesh = {*Alzheimer Disease/drug therapy/immunology ; Humans ; *Anti-Inflammatory Agents, Non-Steroidal/administration & dosage/therapeutic use ; Mathematical Concepts ; Cytokines/metabolism ; *Models, Biological ; Treatment Outcome ; Computer Simulation ; Microglia/drug effects ; Disease Progression ; Inflammation Mediators/metabolism/antagonists & inhibitors ; },
abstract = {The application of non-steroidal anti-inflammatory drugs (NSAIDs) for Alzheimer's disease is considered to be a promising therapeutic approach. Epidemiological studies suggest potential benefits of NSAIDs; however, these findings are not consistently supported by clinical trials. This long-standing discrepancy has persisted for decades and remains a significant barrier to developing effective treatment strategies. To assess the efficacy of NSAIDs in Alzheimer's disease, we have developed a mathematical model based on a system of ordinary differential equations. The model captures the dynamics of key players in disease progression, including A β -monomers, oligomers, pro-inflammatory mediators (M1 microglial cells and pro-inflammatory cytokines), and anti-inflammatory mediators (M2 microglial cells and anti-inflammatory cytokines). The effects of NSAIDs are modeled through a reduction in the production rate of inflammatory cytokines (IC). While a single NSAID administration temporarily reduces IC levels, their concentration eventually returns to baseline due to drug elimination. The return time depends on the drug dose, resulting in a patient-specific return time function. By analyzing this function, we propose an optimal treatment regimen and identify conditions under which NSAID treatment is most effective in reducing IC levels. Our results suggest that NSAID efficacy in Alzheimer's disease is influenced by the stage of the disease (with earlier intervention being more effective), patient-specific parameters, and the treatment regimen. The approach developed here can also be generalized to evaluate the efficacy of anti-inflammatory treatments for other diseases.},
}

*Alzheimer Disease/drug therapy/immunology
Humans
*Anti-Inflammatory Agents, Non-Steroidal/administration & dosage/therapeutic use
Mathematical Concepts
Cytokines/metabolism
*Models, Biological
Treatment Outcome
Computer Simulation
Microglia/drug effects
Disease Progression
Inflammation Mediators/metabolism/antagonists & inhibitors

@article {pmid41176298,
year = {2025},
author = {Pishgahzadeh, E and Bozorgchami, N and Talebi, M and Masoudifar, R and Ahmadi, M and Ghorbani-Bidkorpeh, F},
title = {Different strategies to make biobetters: physicochemical, pharmacodynamics, and pharmacokinetic aspects came into focus.},
journal = {International journal of pharmaceutics},
volume = {},
number = {},
pages = {126319},
doi = {10.1016/j.ijpharm.2025.126319},
pmid = {41176298},
issn = {1873-3476},
abstract = {Technological advancements in the discovery/development of biological products have led to significant improvements in both products and processes, resulting in more effective medications. Biological medications, or biopharmaceuticals, whose patents have expired, present a substantial opportunity for the development of biosimilars, biobetters, and subsequent iterations of biological drugs. Interest in biological drugs has surged, primarily because of their potential to address diseases that conventional synthetic drugs inadequately manage. These pathological conditions includecancer, diabetes, ophthalmic disorders, arthritis, Alzheimer's disease, hemophilia, and diseases related to the immune system. Biobetters represent a new category of biopharmaceutical molecules developed through modifications to their molecular profiles. These modifications can be achieved through molecular, chemical, or functional changes. As a result, these enhanced biologics can exhibit significant ameliorations, such as extended half-life, reduced toxicity and adverse effects, mitigated immunogenetic responses, and improved pharmacodynamic properties. The Quality by Design (QbD) approach plays a crucial role in developing biobetters and improved versions of existing protein-based therapeutics. By employing QbD principles, the design of biobetters can be optimized to enhance characteristics such as target epitope affinity, selectivity, and stability against degradation. Given the importance of this topic, this comprehensive review article aims to provide an in-depth examination of various approaches for developing biobetters, with a primary focus on pharmacodynamics and pharmacokinetics. The article begins by clarifying the concepts of biologics, biosimilars, and biobetters before delving into the diverse strategies used in creating biobetters.},
}

@article {pmid41176285,
year = {2025},
author = {Glaubitz, E and Wang, XH and Xi, K and Feiz, F and Pahlajani, S and Maloney, T and Tanzi, E and Hojjati, H and Zhou, L and Glodzik, L and Chiang, G and Li, Y and Razlighi, R and de Leon, M and Butler, T},
title = {PET-measured tau deposition in emotion-related brain regions is differentially associated with depressive symptoms in individuals with versus without Alzheimer's disease pathology.},
journal = {Behavioural brain research},
volume = {},
number = {},
pages = {115889},
doi = {10.1016/j.bbr.2025.115889},
pmid = {41176285},
issn = {1872-7549},
abstract = {Depressive symptoms are common in patients diagnosed with Alzheimer's Disease (AD) and can also precede AD as a risk factor and/or prodrome. Brain deposition of hyper-phosphorylated tau is a hallmark pathology of AD. Tau deposition in brain regions involved in emotional processing is likely to be pathophysiologically relevant to these links between AD and depression. We used 18F-MK6240 PET to measure tau in amygdala, hippocampus, and nucleus accumbens-regions implicated in depression-in 141 participants with and without AD. In addition to tau PET, participants underwent amyloid-beta (Aβ) PET, MRI, and cognitive evaluation. Depressive symptoms were assessed with the Beck Depression Inventory (BDI). Multiple regression analyzed contributions of tau and Aβ status (positive vs. negative), depression (BDI > 13), cognition (impaired vs. normal), age and sex to tau burden in the three regions. A significant interaction between tau status and depression prompted subgroup analyses of tau-positive (n=34) and tau-negative (n=107) participants. Among tau-positive participants, depression was associated with greater tau in the nucleus accumbens, a region critical for reward processing and motivation. This finding suggests that tau-mediated accumbens dysfunction may contribute to anhedonia, a key symptom of depression that is particularly common in AD-related depression. In tau-negative participants, greater depression was associated with less tau in the medial temporal lobe. This unexpected finding requires confirmation through further research, but could reflect impaired neurogenesis in depression without AD pathology.},
}

@article {pmid41176079,
year = {2025},
author = {Wnuk, HK and Van Orden, KA and Wang, KH},
title = {Bridging Social Isolation, Loneliness, and Brain Aging: A Narrative Review of Mechanisms and Translational Interventions.},
journal = {Neuroscience and biobehavioral reviews},
volume = {},
number = {},
pages = {106451},
doi = {10.1016/j.neubiorev.2025.106451},
pmid = {41176079},
issn = {1873-7528},
abstract = {Social isolation and loneliness (SIL) are increasingly recognized as potent determinants of cognitive decline in aging and Alzheimer's disease-related dementias (ADRD). Yet, despite their prevalence, the neurobiological pathways through which SIL accelerates brain aging remain incompletely understood, and effective interventions are scarce. This narrative review synthesizes human and animal research to present a translational framework linking SIL to brain aging across cognitive-affective, socio-behavioral, physiological, and neural domains. Converging evidence indicates that SIL and cognitive impairment constitute a self-reinforcing loop: isolation amplifies age-related deficits in cognitive control, emotional regulation, and stress resilience, while these impairments heighten social threat sensitivity and blunt social reward, perpetuating isolation. Cross-species findings implicate interconnected neural networks, including the prefrontal and insular cortices, hippocampus, and associated reward and stress-regulatory systems, as critical hubs mediating this loop. Large-scale human neuroimaging consortia reveal convergent neural signatures of SIL within these networks, supported by mechanistic findings from animal models that identify shared molecular cascades involving neuroinflammation, glucocorticoid imbalance, myelin disruption, and dysregulated oxytocin and dopaminergic signaling. Importantly, evidence from animal resocialization paradigms and human multimodal interventions demonstrates that SIL-related neural and behavioral alterations are partially reversible, highlighting enduring plasticity in the aging brain. Together, these findings define SIL and cognitive decline as a dynamic, mutually reinforcing cycle that accelerates brain aging through convergent molecular and circuit mechanisms. Targeting these pathways, by enhancing cognitive control, modulating reward systems, reducing stress reactivity, and strengthening social connectedness, offers a promising translational route to preserve resilience and cognitive vitality across the lifespan.},
}

@article {pmid41175989,
year = {2025},
author = {Andraini, T and Fauré, L and Mouledous, L and Gauzin, S and Ghasemi, Z and Lejards, C and Florian, C and Belenguer, P and Miquel, MC and Rampon, C},
title = {Targeting adult-born neurons to correct early deficits in pattern separation in the Tg2576 mouse model of Alzheimer's disease.},
journal = {Neurobiology of disease},
volume = {},
number = {},
pages = {107158},
doi = {10.1016/j.nbd.2025.107158},
pmid = {41175989},
issn = {1095-953X},
abstract = {Hippocampal adult neurogenesis in mammals generates a unique population of immature granule neurons that play a crucial role in memory, learning and spatial processing. In both Alzheimer's disease (AD) patients and mouse models, this neurogenic capacity of the dentate gyrus is reduced. Mouse models of AD have shown that hippocampal adult neurogenesis is altered early in the course of the disease, contributing to hippocampal-dependent memory impairments. Early stages of AD are also associated with mitochondrial dysfunction in adult-born neurons. While mitochondria have emerged as key regulators of adult neurogenesis, they have been found to be dysfunctional in AD context and to contribute to neurodegenerative diseases. In this study, we investigated the timing and nature of memory deficits in Tg2576 mice, a model of AD, focusing on tasks that depend on hippocampal neurons born in adulthood. We found that Tg2576 mice exhibit early deficits in pattern separation tasks. Notably, adult-born neurons in Tg2576 mice show reduced connectivity and mitochondrial content along with the first memory deficits. To mitigate these defects, we used NeuroD1, a potent neuronal transcription factor, to enhance the development of adult-born neurons in Tg2576 mice. Overexpression of NeuroD1 restored both mitochondrial content and spine density in these neurons to levels comparable to those in control mice. In addition, this intervention restored pattern separation performance in Tg2576 mice, highlighting the potential of strategies targeting mitochondria to correct adult neurogenesis-related memory deficits in the early stages of AD.},
}

@article {pmid41175945,
year = {2025},
author = {Fujii, K and Takeuchi, T and Fujino, Y and Tanaka, N and Fujino, N and Takeda, A and Minakawa, EN and Nagai, Y},
title = {Oral administration of arginine suppresses Aβ pathology in animal models of Alzheimer's disease.},
journal = {Neurochemistry international},
volume = {191},
number = {},
pages = {106082},
doi = {10.1016/j.neuint.2025.106082},
pmid = {41175945},
issn = {1872-9754},
abstract = {Although amyloid β (Aβ)-targeting antibody therapies for Alzheimer's disease (AD) have recently been developed, their clinical efficacy remains limited, and issues such as high cost and adverse effects have been raised. Therefore, there is an urgent need for the establishment of safe and cost-effective therapeutic approaches that inhibit Aβ aggregation or prevent its accumulation in the brain. In this study, we report that arginine, a clinically approved and safe chemical chaperone, suppresses Aβ aggregation both in vitro and in vivo. We demonstrated using an in vitro assay that arginine inhibits the aggregation formation of the Aβ42 peptide in a concentration-dependent manner. In a Drosophila model of AD expressing the Aβ42 peptide with an Arctic mutation E22G, the oral administration of arginine dose-dependently reduced Aβ42 accumulation and rescued Aβ42-mediated toxicity. In an App[NL-G-F] knockin mouse model harboring human APP familial mutations, the oral administration of arginine suppressed Aβ plaque deposition and reduced the level of insoluble Aβ42 in the brain. The arginine-treated App[NL-G-F] knockin mice also showed the improvement of behavioral abnormalities and the reduced expression of the neuroinflammation-associated cytokine genes. These results indicate that the oral administration of arginine not only reduced Aβ deposition, but also ameliorated Aβ-mediated neurological phenotypes in animal models of AD. These findings identify arginine as a safe and cost-effective drug candidate that suppresses Aβ aggregation, and highlight its repositioning potential for rapid clinical translation for AD treatment. Arginine is also potentially applicable to a wide range of neurodegenerative diseases caused by protein misfolding and aggregation.},
}

@article {pmid41175916,
year = {2025},
author = {Vanya, and Kumari, S and Bagri, K and Deshmukh, R},
title = {Tangles and Plaques: A deep dive into the pathological hallmarks of Alzheimer's disease.},
journal = {Neuroscience},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.neuroscience.2025.10.050},
pmid = {41175916},
issn = {1873-7544},
abstract = {Alzheimer's disease (AD) is the most prevalent neurodegenerative disorder. In AD, there is a gradual impairment of memory and cognitive function that interferes with daily living. The pathophysiology of AD revolves around complex interactions between amyloid-β (Aβ) overproduction and accumulation, followed by tau hyperphosphorylation, which together promote a cascade of neuronal dysfunction and degeneration. AD has two forms, sporadic and familial, with genetic variants such as triggering receptor expressed on myeloid cells-2 (TREM2). Various other variants also lead to impaired amyloid clearance and altered immune responses. Along with these genetic factors, aging remains the primary risk factor, and environmental as well as lifestyle factors can act synergistically to accelerate disease onset and progression. Although significant advances have been made in the last five decades, there has been only limited progress in the treatment because of a poor understanding of the molecular basis of AD. This makes current treatments largely focus on symptomatic management. This narrative review provides an updated synthesis of Alzheimer's disease pathophysiology, focusing on Aβ and tau pathology, glial activation, neuroinflammatory cascades, disrupted neurogenesis, and blood-brain barrier dysfunction. A focus and deeper understanding can help to develop new strategies that might work beyond the present conventional treatment. Due to the increasing global prevalence of AD, it is important to continue research into these mechanisms for the development of more effective interventions and improved patient outcomes.},
}

@article {pmid41175892,
year = {2025},
author = {Prajapati, P and Desai, A and Shah, P and Pulusu, V and Haque, A and Kalam, MA and Shah, S},
title = {Comparative in-vivo and in-vitro characterization of Donepezil loaded Lactoferrin linked PEG coated and uncoated nanocarriers as intranasal drug delivery system.},
journal = {Journal of liposome research},
volume = {},
number = {},
pages = {1-17},
doi = {10.1080/08982104.2025.2573681},
pmid = {41175892},
issn = {1532-2394},
abstract = {Alzheimer's disease treatment faces challenges with conventional oral formulations of donepezil (DNP). This study aims to develop and characterize DNP-loaded Lactoferrin (LCF)-linked PEG-coated nano-carriers for intranasal delivery. The formulation was developed using a Quality by Design (QbD) approach integrated with molecular docking. A novel micelle-enhanced spectrofluorimetric method was developed and validated for in-vitro and in-vivo characterization of the nano-carriers. The method was optimized using Analytical Quality by Design (AQbD) principles. In-vivo pharmacokinetic and bio-distribution studies were conducted in rats to compare the developed formulation with uncoated NLCs and conventional dosage forms. The LCF-PEG-coated NLCs showed improved brain targeting efficiency compared to uncoated NLCs and conventional formulations. The spectrofluorimetric method demonstrated high sensitivity and reliability for both in-vitro and in-vivo analyses. The developed DNP-loaded LCF-PEG-coated NLCs show promise as an effective intranasal delivery system for Alzheimer's disease treatment. The novel spectrofluorimetric method offers a sustainable and efficient alternative to conventional LC-MS/MS techniques for characterizing DNP formulations.},
}

@article {pmid41175871,
year = {2025},
author = {Zhu, B and Wangzhou, A and Yu, D and Li, T and Schmidt, R and De Florencio, SL and Chao, L and Thurber, AL and Zhou, M and Msheik, Z and Perez, Y and Grinberg, LT and Spina, S and Ransohoff, RM and Kriegstein, AR and Seeley, WW and Nowakowski, T and Piao, X},
title = {G-protein-coupled receptor ADGRG1 drives a protective microglial state in Alzheimer's disease through MYC activation.},
journal = {Neuron},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.neuron.2025.10.029},
pmid = {41175871},
issn = {1097-4199},
}

@article {pmid41175793,
year = {2025},
author = {Torrealba-Acosta, G and Yang, S and Calvo-Marín, J and Moghekar, AR and Kamalian, A and Lutz, MW and , },
title = {Identifying a proteomics signature of cognitive impairment and dementia in blood and cerebrospinal fluid through a mediation analysis framework.},
journal = {Neurobiology of aging},
volume = {157},
number = {},
pages = {79-88},
doi = {10.1016/j.neurobiolaging.2025.10.004},
pmid = {41175793},
issn = {1558-1497},
abstract = {This study aimed to identify CSF and plasma proteins that mediate the association between age and mild cognitive impairment (MCI) and Alzheimer's disease using mediation analysis. By focusing on proteins significantly associated in both CSF and plasma, we sought to identify biomarkers accessible for clinical applications. Proteomic measurements were obtained from CSF and plasma from a cohort of cognitively normal and MCI patients at the Johns Hopkins Alzheimer's Disease Research Center using Olink Proximity Extension Assay technology. Mediation effects were estimated using single- and multiple-mediator models and validated in three independent datasets: Duke (CSF), ADNI (CSF), and UK Biobank (plasma). Over 3000 proteins in 86 patients were analyzed. Three candidates, leiomodin-1 (LMOD1), glial fibrillary acidic protein (GFAP), and elastin (ELN), met the criteria for mediation in both CSF and plasma. Multiple mediator models demonstrated a significant combined mediation effect on MCI in CSF (OR: 1.122, 95 % CI: 1.026-1.439) and plasma (OR: 1.142, 95 % CI: 1.058-1.410). Across validation cohorts, GFAP consistently showed significant mediation effects (Duke CSF: OR: 1.114, 95 % CI: 1.069-1.206; ADNI: OR: 1.004, 95 % CI: 1.000-1.009; UK Biobank: OR: 1.030, 95 % CI: 1.026-1.034). In contrast, ELN and LMOD1 demonstrated mediation effects in the discovery dataset but were not consistently reproduced in external cohorts. Our findings highlight GFAP as a robust mediator of age-related risk of cognitive impairment across CSF and plasma, supporting its utility as a practical biomarker. ELN and LMOD1 may represent exploratory candidates reflecting extracellular matrix and vascular processes requiring further validation.},
}

@article {pmid41175714,
year = {2025},
author = {Kovac, D and Novakova, L and Mekyska, J and Novotny, K and Brabenec, L and Klobusiakova, P and Rektorova, I},
title = {Digital speech biomarkers for assessing cognitive decline across neurodegenerative conditions.},
journal = {Computers in biology and medicine},
volume = {198},
number = {Pt B},
pages = {111251},
doi = {10.1016/j.compbiomed.2025.111251},
pmid = {41175714},
issn = {1879-0534},
abstract = {This study investigates speech impairments in individuals with mild cognitive impairment due to Alzheimer's disease (MCI-AD), mild cognitive impairment with Lewy bodies (MCI-LB), and Parkinson's disease with mild cognitive impairment (PD-MCI), compared to healthy controls (HC), aiming to identify linguistic and acoustic digital biomarkers that differentiate these groups. Monologue recordings were collected from 68 HC, 42 MCI-AD, 50 MCI-LB, and 47 PD-MCI participants (ON state). Participants were instructed to speak spontaneously for one and a half minutes. Speech was automatically transcribed, manually corrected, and analyzed using natural language processing to extract eight linguistic (lexical/syntactic) and four acoustic (prosodic) biomarkers. Group differences were assessed using the Mann-Whitney U test, with Spearman's correlation used to examine associations with clinical and MRI measures (FDR-corrected). Machine learning models (XGBoost) were applied to evaluate the classificatory and predictive potential of speech features. Distinct speech patterns were observed across groups: MCI-AD participants exhibited reduced use of function words, resulting in increased content density, PD-MCI participants used shorter sentences and fewer coordinating conjunctions with longer pauses, and MCI-LB participants exhibited greater lexical repetition than MCI-AD. Altered speech features correlated with structural brain changes but not with global cognition (MoCA) or depressive symptoms (GDS). Sentence structure and pausing features showed strong interrelationships. Machine learning models showed that adding speech biomarkers improved classification performance compared to using clinical scores alone. In regression analyses, the models predicted MoCA with a normalized error of 10%, performing similarly on automatic and manually corrected transcripts. These findings suggest that speech biomarkers and traditional clinical assessments may offer complementary information about cognitive status and brain health, supporting their use in scalable, non-invasive cognitive monitoring.},
}

@article {pmid41175671,
year = {2025},
author = {Träuble, J and Hiscox, LV and Johnson, CL and Aviles-Rivero, A and Schönlieb, CB and Kaminski Schierle, GS},
title = {Brain age prediction and early neurodegeneration detection using contrastive learning on brain biomechanics: a retrospective, multicentre study.},
journal = {EBioMedicine},
volume = {121},
number = {},
pages = {105996},
doi = {10.1016/j.ebiom.2025.105996},
pmid = {41175671},
issn = {2352-3964},
abstract = {BACKGROUND: One of the main reasons why drugs for neurodegenerative diseases often fail is that treatment typically begins only after symptoms have appeared-by which point significant, and possibly irreversible, damage may have already occurred. Non-invasive imaging techniques, such as Magnetic Resonance Imaging (MRI), have previously been explored for presymptomatic diagnosis, but with limited success. More recently, Magnetic Resonance Elastography (MRE)-a technique capable of mapping the brain's biomechanical properties, including stiffness and damping ratio-has shown promise in detecting early changes. However, current studies have been limited by small sample sizes, and a lack of robust algorithms capable of accurately interpreting data under such constraints.

METHODS: We developed a self-supervised contrastive regression framework trained on 3D MRE-derived stiffness and damping ratio maps from 311 healthy individuals (aged 14-90) and evaluated its performance against structural 3D T1-weighted MRI. Brain age predictions were used to compute brain age gaps (BAGs), quantifying deviations from normative ageing trajectories. We applied the models to Alzheimer's disease (AD, n = 11) and mild cognitive impairment (MCI, n = 20) cohorts, and analysed whole-brain and region-specific predictions using occlusion-based saliency maps and subcortical segmentation.

FINDINGS: Self-supervised models using MRE achieved a mean absolute error (MAE) of 3.51 years in brain age prediction-significantly outperforming MRI (MAE: 4.79 years, p < 0.05) under matched conditions. The greater age sensitivity of MRE translated into improved differentiation of Alzheimer's disease (AD) and mild cognitive impairment (MCI) from healthy individuals. Stiffness was the dominant ageing biomarker in AD (BAG increase: +9.2 years, p < 0.05), whereas damping ratio revealed early MCI-related changes (BAG increase: +6.3 years, p < 0.05). Region-wise analysis identified the caudate (stiffness) and thalamus (damping ratio) as key markers for AD and MCI, respectively. Notably, some cognitively normal individuals exhibited biomechanical profiles resembling patients with MCI or AD, suggesting that these individuals may share some biomechanical characteristics with clinical populations.

INTERPRETATION: In our controlled experimental setting, MRE combined with contrastive learning provides a sensitive, non-invasive biomarker of brain ageing and neurodegeneration, outperforming MRI and differentiating disease stage-specific biomechanical signatures. Regional BAG profiling may have the potential to identify at-risk, cognitively normal individuals, which could facilitate timely intervention trials in the future, pending longitudinal validation.

FUNDING: Gates Cambridge Trust; Cambridge Centre for Data-Driven Discovery (Schmidt Sciences); Wellcome Trust; NIH (R01-AG058853, U01-NS112120); UK EPSRC; UK MRC; Alzheimer's Research UK; Michael J. Fox Foundation; Infinitus China Ltd.},
}

@article {pmid41175634,
year = {2025},
author = {Wu, P and Chen, D and Wang, F and Lu, K and Sigurdsson, EM and Jin, C},
title = {Corrigendum to "Formaldehyde induces and promotes Alzheimer's disease pathologies in a 3D human neural cell culture model" [Food Chem. Toxicol. (2025 Dec) 206 115777].},
journal = {Food and chemical toxicology : an international journal published for the British Industrial Biological Research Association},
volume = {207},
number = {},
pages = {115824},
doi = {10.1016/j.fct.2025.115824},
pmid = {41175634},
issn = {1873-6351},
}

@article {pmid41175591,
year = {2025},
author = {Xu, Z and Huang, F and Wu, Z and Xu, K and Huang, L},
title = {Syringin attenuates Alzheimer's disease-associated neuroinflammation by inhibiting NLRP3 inflammasome activation.},
journal = {Phytomedicine : international journal of phytotherapy and phytopharmacology},
volume = {148},
number = {},
pages = {157454},
doi = {10.1016/j.phymed.2025.157454},
pmid = {41175591},
issn = {1618-095X},
abstract = {BACKGROUND: NLRP3 inflammasome‑driven neuroinflammation contributes to Alzheimer's disease (AD), with the SWELL1 channel acting as a critical upstream signal. Syringin improved behavioral deficits in AD models, but its link to NLRP3 inhibition via SWELL1 remains unclear.

PURPOSE: This study aimed to investigate how syringin ameliorates AD pathology by modulating microglial NLRP3 inflammasome activation and regulating the SWELL1 channel.

STUDY DESIGN AND METHODS: APP/PS1 mice (5 months) received daily syringin (20 or 60 mg/kg) or vehicle for 7 months. Morris water maze (MWM) and NLRP3 inflammasome markers were evaluated. BV2 microglial cells were used to assess syringin's effects on ATP‑induced activation, including inflammatory cytokine, NLRP3 inflammasome components, microglial phenotypes, and pyroptosis. Conditioned BV2 media were applied to HT22 neurons to assess neuroprotection. Interactions among inflammasome components, ASC oligomerization, and SWELL1 channel activity were further assessed. Molecular dynamics (MD) simulations were performed to predict syringin-SWELL1 protein binding.

RESULTS: In the MWM, syringin reduced escape latency. It also reduced inflammatory mRNA levels and decreased NLRP3, ASC, pro-caspase-1, and GSDMD-N protein levels. During activation, syringin suppressed cleaved caspase-1/IL-1β secretion, Iba-1 protein, transcription of microglial activation markers, LDH release, and GSDMD-N expression. Conditioned medium improved HT22 viability and reduced cleaved‑Caspase‑3. Syringin disrupted ASC-pro‑Caspase‑1 but not ASC-NLRP3 interaction, lowered ASC monomer/dimer, suppressed ROS, and restored mitochondrial potential. It inhibited SWELL1 currents. MD simulations suggested binding at key residues Tyr99 and Asp100.

CONCLUSION: Syringin may inhibit SWELL1 channel in microglia, thereby limiting NLRP3 inflammasome activation and reducing neuroinflammation in AD.},
}

@article {pmid41175361,
year = {2025},
author = {Dawood, M and Saqib, HW},
title = {Donanemab in Alzheimer's disease: Promise, limitations, and implementation challenges in Australia.},
journal = {Australasian psychiatry : bulletin of Royal Australian and New Zealand College of Psychiatrists},
volume = {},
number = {},
pages = {10398562251393775},
doi = {10.1177/10398562251393775},
pmid = {41175361},
issn = {1440-1665},
}

@article {pmid41175292,
year = {2025},
author = {Pennington, B and Davis, S and Cranmer, H},
title = {Caring for and Caring about in Economic Evaluation: Modelling the Family and Caregiving Effects.},
journal = {PharmacoEconomics},
volume = {},
number = {},
pages = {},
pmid = {41175292},
issn = {1179-2027},
support = {NIHR300160//NIHR/ ; },
abstract = {Current methods for modelling spillover effects on carers in economic evaluation include four main methods: (absolute) utilities, disutilities, increments and multipliers. Each of these approaches assumes that the spillover effect is one-dimensional. We aimed to develop a new approach that better reflects the complexity of caring and the nuances of how a new treatment may impact the caregiver. We propose a new method based on the established concepts of the 'family effect' (or caring about someone) and the 'caregiving effect' (providing care for someone). These effects can be disentangled through analysis of carer-patient dyads or using patient and carer (dis)utilities and estimates from the literature. We consider case studies in Duchenne Muscular Dystrophy, Spinal Muscular Atrophy and Alzheimer's Disease. Our approach models a small carer health-related quality of life (HRQoL) gain for each intervention, whereas the utility approach consistently models a substantial carer HRQoL gain, and the disutility approach models a carer HRQoL loss in two case studies. Our method allows explicit consideration of the benefits to carers of extending patient survival or improving patient health, with the negative HRQoL impact of increased caregiving burden. We propose that our method can be used with published data at present, and further research should analyse the family and caregiving effects in different conditions.},
}

@article {pmid41175186,
year = {2025},
author = {Yildiz, Y and Durmuş, NŞ and Bütün, VK and Inan, BD and Numanoğlu, BK and Çelenk, ME and Kaya, ED and Yilmaz, ZB and Alkaç, Ç and Can, B and Tufan, A and Bahat, G},
title = {Potentially inappropriate medication use by TIME criteria in nursing home residents and its relationship with common geriatric syndromes.},
journal = {European geriatric medicine},
volume = {},
number = {},
pages = {},
pmid = {41175186},
issn = {1878-7649},
abstract = {OBJECTIVE: To assess potentially inappropriate medication use (IMU), including both potentially inappropriate prescribing (PIP) and potential prescribing omissions (PPOs) according to the Turkish Inappropriate Medication Use in oldEr adults (TIME) criteria in older nursing home residents and to investigate its association with common geriatric syndromes.

METHODS: This multi-center cross-sectional observational study was conducted from December 2023 to June 2024 across three nursing homes in Istanbul. Two geriatricians performed comprehensive geriatric assessments and used TIME criteria to identify IMU. The link between prevalent geriatric syndromes and IMU was examined.

RESULTS: We included 165 residents with a mean age of 84.6 ± 7.9 years, 71.5% of whom were female. Of the participants, 81.6% (n = 134) had dementia. Respectively, 93% (n = 154) and 51% (n = 85) of the participants had polypharmacy and hyperpolypharmacy. The top three PIPs according to TIME-to-STOP criteria were tight blood pressure control with antihypertensives (51.5%), use of neuroleptics as hypnotics(50.3%), and proton pump inhibitors (PPIs) for multiple drug use indication (47.3%).Based on the TIME-to-START criteria, the three most common PPOs were the omission of acetylcholinesterase inhibitors for mild-moderate Alzheimer's disease and memantine for moderate-severe Alzheimer's disease and failure to initiate oral nutritional supplements in malnourished or at-risk individuals(47.9%).TIME-to-STOP PIPs were significantly associated with polypharmacy (p < 0.001) in univariate analysis. In the logistic regression analyses of variables associated with TIME-to-START PPO, significant associations were observed with age (odds ratio (OR) = 1.14; 95% confidence interval (CI): 1.02-1.27; p = 0.015) and frailty (OR: 2.95; 95% CI: 1.209-7.201; p = 0.017), the latter conferring a roughly threefold increased risk.

CONCLUSION: Polypharmacy and IMU were highly prevalent among nursing home residents, and national/international prescribing tools like the TIME criteria are valuable in detecting both PIPs and PPOs. Frailty was significantly associated with prescribing omissions as identified by the TIME-to-START criteria, underscoring the need for targeted interventions in this vulnerable population.},
}

@article {pmid41174936,
year = {2025},
author = {Borda, MG and Venegas-Sanabria, LC and Canevelli, M and Landi, F and Páez-García, S and O'Hara-Veintimilla, K and Wallace, L and Rockwood, K and Cederholm, T and Duque, G and Pérez-Zepeda, MU and Aarsland, D},
title = {Frailty and Health Outcomes in People 65 Years or Older Living With Dementia: A Systematic Review of the Literature.},
journal = {Journal of the American Geriatrics Society},
volume = {},
number = {},
pages = {},
doi = {10.1111/jgs.70190},
pmid = {41174936},
issn = {1532-5415},
support = {354885//EU Joint Programme Neurodegenerative Disease Research/ ; //Helse Vest (Western Norway Regional Health Authority)/ ; },
abstract = {INTRODUCTION: Although frailty is considered a potentially modifiable risk factor for dementia, its influence on health outcomes in individuals with established dementia remains unclear. This study aims to systematize the current evidence to understand the impact of frailty on the development of adverse outcomes in older adults with dementia.

METHODOLOGY: We conducted a systematic review to investigate which adverse outcomes in 65 years or older adults with dementia are influenced by frailty. A comprehensive search was conducted across three databases-MEDLINE, EMBASE, and Cochrane-to identify relevant studies addressing this research question as of November 2024. Studies were considered for inclusion if they were observational studies or clinical trials involving individuals with dementia, assessed frailty within this population, and documented adverse health outcomes. Two independent and blinded researchers performed screening, data extraction, and risk of bias assessment. PROSPERO register CRD42024543327.

RESULTS: Our search identified 5891 articles, from which 12 were included after screening and eligibility assessment (n = 172,025 participants). Alzheimer's disease was the most studied type of dementia, and the prevalence of frailty ranged from 8% to 65.9%. The reported adverse outcomes associated with frailty in patients suffering from dementia were mortality, institutionalization, functional and cognitive decline, neuropsychiatric symptoms, reduced quality of life, caregiver burden, and hospitalization.

DISCUSSION: Understanding frailty in older adults with dementia may inform improved care strategies. Our findings suggest that higher levels of frailty are associated with an increased risk of adverse health outcomes.},
}

@article {pmid41174898,
year = {2025},
author = {Wang, C and Guo, R and Wang, X and Li, H and Zhong, T},
title = {Post-Translational Modifications of Tubulin in Oocyte Maturation and Female Infertility.},
journal = {Cytoskeleton (Hoboken, N.J.)},
volume = {},
number = {},
pages = {},
doi = {10.1002/cm.70062},
pmid = {41174898},
issn = {1949-3592},
support = {82101864//National Natural Science Foundation of China/ ; ZR2025MS508//Natural Science Foundation of Shandong Province/ ; 2023KJ262//Shandong Provincial Youth Innovation Technology Support Program/ ; 2023YXNS228//Key R&D Plan of Jining City/ ; 2023-1-43//Ji'nan Municipal Health Commission Science and Technology Plan Project/ ; 202412//High-Level Talents in the Medical and Health Industry in Ji'nan/ ; },
abstract = {Microtubules are critical components of the cytoskeleton that are extensively involved in various cellular and biological processes. The execution of these functions is intricately linked to post-translational modifications of tubulin. Post-translational modifications of tubulin include acetylation, tyrosination, de-tyrosination, glutamylation, SUMOylation, and so on. These modifications are closely associated with a wide range of biological processes. Accumulating evidence indicates that aberrant microtubule modifications are implicated in various diseases, including cancer, Alzheimer's disease, neurodevelopmental disorders, cardiac atrial hypertrophy, and even infertility. Aneuploid oocytes are a common cause of infertility, spontaneous abortion, trisomy syndrome, and other congenital abnormalities. The occurrence of aneuploidy is often closely associated with defects in spindle assembly, which are influenced by a series of tubulin modifications. In this review, we aimed to summarize the factors that affect tubulin modification and explore the key mechanisms underlying aneuploidy in human oocytes, thereby providing new insights and strategies for the treatment of infertility and prevention of congenital defects in newborns.},
}

@article {pmid41174814,
year = {2025},
author = {Choi, J and Hwang, J and Kim, D and Jang, E and Jang, G and Cho, HH and Kim, BC and Jeong, HS and Jang, S},
title = {Inhibition of miR-4284 could reduce apoptosis and neuroinflammation by targeting APBA1/JAK1/STAT3 signaling in Alzheimer's disease.},
journal = {Cell & bioscience},
volume = {15},
number = {1},
pages = {151},
pmid = {41174814},
issn = {2045-3701},
support = {RS-2020-KH088567//Korea Health Industry Development Institute/Republic of Korea ; RS-2025-24536036//Korea Health Industry Development Institute/Republic of Korea ; RS-2024-00442775//National Research Foundation of Korea/ ; },
abstract = {BACKGROUND: microRNA-4284 is associated with various diseases, but its role in Alzheimer's disease remains unclear. This study explores the therapeutic potential of miR-4284 inhibition by targeting the APBA1 and the JAK/STAT3 pathways in AD models.

RESULTS: miR-4284 expression was analyzed in Aβ-treated SH-SY5Y cells and 5xFAD mice. Luciferase assays identified APBA1 as a direct target of miR-4284. Apoptosis, inflammation, and neuronal survival were assessed using qPCR, western blotting analysis, FACS, and immunohistochemistry. The Morris water maze test evaluated cognitive function, while western blotting analysis examined the JAK/STAT3 pathway. miR-4284 was upregulated in AD models. Its inhibition increased APBA1 expression, reduced Aβ accumulation, suppressed apoptosis and inflammation, and enhanced neuronal survival and cognitive function, correlating with JAK/STAT3 activation.

CONCLUSIONS: miR-4284 inhibition confers neuroprotection by modulating APBA1 and JAK/STAT3 signaling, suggesting its potential as a therapeutic target for AD.},
}

@article {pmid41174156,
year = {2025},
author = {Zattoni, M and Bernegger, S and Weinbender, S and Altendorfer, B and Mrowetz, H and Benedetti, A and Poupardin, R and Unger, MS and Aigner, L},
title = {The involvement of microglia and the CXCL16-CXCR6 axis in the recruitment of CD8[+] T cells to an amyloidogenic mouse brain.},
journal = {Scientific reports},
volume = {15},
number = {1},
pages = {38221},
pmid = {41174156},
issn = {2045-2322},
support = {P 35417-B//Austrian Science Fund/ ; P 35417-B//Austrian Science Fund/ ; P 35417-B//Austrian Science Fund/ ; P 35417-B//Austrian Science Fund/ ; P 35417-B//Austrian Science Fund/ ; E-20/32/169-UNG//PMU Research Fund (PMU-FFF) Stand-Alone-Project/ ; E-20/32/169-UNG//PMU Research Fund (PMU-FFF) Stand-Alone-Project/ ; },
mesh = {Animals ; *Chemokine CXCL16/metabolism/genetics ; *Receptors, CXCR6/metabolism/genetics ; *Microglia/metabolism/immunology ; *CD8-Positive T-Lymphocytes/metabolism/immunology ; Mice ; *Brain/metabolism/pathology/immunology ; *Alzheimer Disease/pathology/metabolism/immunology/genetics ; Mice, Transgenic ; Disease Models, Animal ; Humans ; Organic Chemicals ; },
abstract = {Alzheimer's disease (AD) progression has been associated with the presence of brain-resident CD8[+] T cells, and recent studies suggest a potential role of the CXCL16-CXCR6 axis in their recruitment to the brain. Here, we examined publicly available single-cell RNA sequencing datasets revealing that in the mouse brain, the receptor Cxcr6 is mainly expressed by CD8[+] T cells, while the expression of its ligand Cxcl16 is predominantly observed in microglial cells. We found higher levels of Cxcl16 and Cxcr6 expression in APP/PS1 compared to wild-type mice. Furthermore, in vitro experiments using immortalized and primary murine cells suggested that Cxcl16 expression is driven by Aβ pathology. In contrast to our expectations, no changes in the number of Cxcr6[+]CD8[+] cells was evident in the brains of microglia-depleted APP/PS1 mice, treated with the CSF1R antagonist PLX5622. This was related to an increased compensatory Cxcl16 expression by depletion-resistant microglia or by other brain-resident myeloid cells. Although we demonstrated a strong association between microglial Cxcl16 and AD pathology, PLX5622-sensitive microglia are dispensable in the recruitment of Cxcr6[+]CD8[+] T cells to the brain of APP/PS1 mice. Future in vivo analysis will help to dissect the mechanism of CD8[+] T cell recruitment to the brain.},
}

Animals
*Chemokine CXCL16/metabolism/genetics
*Receptors, CXCR6/metabolism/genetics
*Microglia/metabolism/immunology
*CD8-Positive T-Lymphocytes/metabolism/immunology
Mice
*Brain/metabolism/pathology/immunology
*Alzheimer Disease/pathology/metabolism/immunology/genetics
Mice, Transgenic
Disease Models, Animal
Humans
Organic Chemicals

@article {pmid41174069,
year = {2025},
author = {Sakurai, R and Suzuki, H and Fujiwara, Y and Uchida, K and Fujita, K and Nakamura, A and Sakurai, T and Arai, H},
title = {Elevated plasma GFAP levels in MCI link APOE ε4 allele with impaired gait speed.},
journal = {GeroScience},
volume = {},
number = {},
pages = {},
pmid = {41174069},
issn = {2509-2723},
support = {JP19de0107002//Japan Agency for Medical Research and Development/ ; },
abstract = {The presence of at least one copy of the apolipoprotein ε4 allele (APOE ε4) is a known predictor of gait impairment risk among older adults. However, the mechanisms by which APOE ε4 affects gait performance remain unclear. This cross-sectional study aimed to reveal underlying pathological mechanisms linking APOE ε4 carriage to slow gait. This secondary analysis used baseline assessments from the J-MINT multicenter intervention trial, focusing on older adults with mild cognitive impairment. Gait speed was measured at baseline, with slow gait (SG) defined as speeds one standard deviation below the age- and sex-specific mean. APOE phenotype and plasma biomarkers related to Alzheimer's disease (AD), including amyloid-β composite biomarker, phosphorylated Tau 181, neurofilament light, and glial fibrillary acidic protein (GFAP), were also measured. The analysis included 236 non-APOE ε4 carriers and 84 carriers of at least one APOE ε4. APOE ε4 carriers exhibited significantly slower gait speed than non-carriers (1.20 m/s [SD = 0.22] vs 1.26 m/s [SD = 0.23], p = 0.042). Significant interaction between APOE ε4 carriage and SG was observed only in plasma GFAP levels (F1, 312 = 7.17, p = 0.008), indicating that individuals with APOE ε4 and SG had significantly higher plasma GFAP levels. Elevated plasma GFAP levels fully mediated the association between APOE ε4 carriage and gait speed (partially standardized indirect effect = -0.059: -0.12 to -0.013]). No other AD-related biomarkers mediated this association. Our results suggest that APOE ε4-related gait changes may reflect AD pathology, as indicated by elevated GFAP levels, and could potentially accelerate dementia symptoms.},
}

@article {pmid41174000,
year = {2025},
author = {Zhao, Q and Gou, C and Luo, G and Dai, S and Wang, D and Zhang, S and Wang, F and Xu, H and Han, Y and Wang, S},
title = {Combined multi-omics and brain pathology reveal novel biomarkers for alzheimer's disease.},
journal = {Scientific reports},
volume = {15},
number = {1},
pages = {38239},
pmid = {41174000},
issn = {2045-2322},
support = {81260199, 81660228, and 82160261//National Natural Science Foundation of China/ ; L-2019019//Yunnan Province Talent Training Program/ ; RLMY20200005//Yunnan High-Level Talent Training Support Program Famous Doctor Special Project/ ; 202303AC100026//Yunnan Province Key Research and Development Program/ ; 202401AY070001-008//Kunming Medical University Joint Special Key Project/ ; },
mesh = {*Alzheimer Disease/pathology/metabolism/genetics ; Animals ; *Biomarkers/metabolism ; Mice ; Proteomics/methods ; Protein Interaction Maps ; *Hippocampus/metabolism/pathology ; Transcriptome ; Gene Expression Profiling ; *Brain/pathology/metabolism ; Disease Models, Animal ; Mice, Transgenic ; Amyloid beta-Protein Precursor/genetics/metabolism ; Multiomics ; },
abstract = {Alzheimer's disease (AD) is a complex disorder with significant genetic contributions, yet only a limited number of risk loci have been conclusively identified. This research aimed to discover novel potential biomarkers for AD through multi-omics and brain pathology analysis. In this study, we investigated hippocampal molecular alterations in APP/PS1 mouse using transcriptomics and data-independent acquisition (DIA) proteomics. To further validate the involvement of differentially expressed genes (DEGs) and differentially expressed proteins (DEPs) in AD pathology and potential drug treatment, we performed an integrative analysis incorporating pathological data and protein-protein interaction networks. We identified 263 DEGs and 448 DEPs. Integrative transcriptomic and proteomic analyses revealed five co-upregulated DEGs/DEPs and one co-downregulated DEG/DEP. Comparison of KEGG pathway enrichment between the two datasets showed significant involvement in the complement and coagulation cascade, as well as neurodegeneration-multiple diseases. Furthermore, mRNA levels of LY86, CD180, and C1QB were strongly associated with amyloid-β plaque load in the AD mouse hippocampus. Protein-protein interaction analysis suggested that APP, LY86, CD180, and C1QB could serve as potential therapeutic targets for AD. The study identified three novel AD loci (EGFL8, ERMN, and CD180), with CD180 showing association with AD at both the expression and pathological levels, highlighting their potential roles in disease progression and therapeutic intervention.},
}

*Alzheimer Disease/pathology/metabolism/genetics
Animals
*Biomarkers/metabolism
Mice
Proteomics/methods
Protein Interaction Maps
*Hippocampus/metabolism/pathology
Transcriptome
Gene Expression Profiling
*Brain/pathology/metabolism
Disease Models, Animal
Mice, Transgenic
Amyloid beta-Protein Precursor/genetics/metabolism
Multiomics

@article {pmid41173884,
year = {2025},
author = {Schmidt, V and Ziemlinska, E and Obrebski, T and Gomes, JP and Zurawska-Plaksej, E and Cendrowski, J and Palmfeldt, J and Hempstead, BL and Willnow, TE and Malik, AR},
title = {Astrocytes distress triggers brain pathology through induction of δ secretase in a murine model of Alzheimer's disease.},
journal = {Nature communications},
volume = {16},
number = {1},
pages = {9653},
pmid = {41173884},
issn = {2041-1723},
support = {18OC0033928//Novo Nordisk Fonden (Novo Nordisk Foundation)/ ; 23001R//Alzheimer Forschung Initiative (Alzheimer Forschung Initiative e.V.)/ ; 2020/37/B/NZ3/00761//Narodowe Centrum Nauki (National Science Centre)/ ; I.3.4 Action of the Excellence Initiative//Uniwersytet Warszawski (University of Warsaw)/ ; },
mesh = {Animals ; *Astrocytes/metabolism/pathology ; *Alzheimer Disease/pathology/metabolism/genetics ; Disease Models, Animal ; Mice ; Amyloid beta-Peptides/metabolism ; *Amyloid Precursor Protein Secretases/metabolism/genetics ; *Brain/pathology/metabolism ; tau Proteins/metabolism ; Humans ; Mice, Transgenic ; Male ; Mice, Inbred C57BL ; },
abstract = {The importance of astrocytes for Alzheimer's disease (AD) pathology is increasingly appreciated, yet the mechanisms whereby this cell type impacts neurodegenerative processes remain elusive. Here we show that, in a genetic mouse model with diminished astrocyte stress response, even low levels of amyloid-β trigger astrocyte reactivity, resulting in brain inflammation and massive amyloid and tau pathologies. This dysfunctional response of astrocytes to amyloid-β acts through activation of δ secretase, a stress-induced protease implicated in both amyloid and tau-related proteolytic processing. Our findings identify a failed astrocyte stress response to amyloid-β as an early inducer of amyloid and tau co-morbidity, a noxious process in AD acting through a non-canonical secretase pathway.},
}

Animals
*Astrocytes/metabolism/pathology
*Alzheimer Disease/pathology/metabolism/genetics
Disease Models, Animal
Mice
Amyloid beta-Peptides/metabolism
*Amyloid Precursor Protein Secretases/metabolism/genetics
*Brain/pathology/metabolism
tau Proteins/metabolism
Humans
Mice, Transgenic
Male
Mice, Inbred C57BL

@article {pmid41173868,
year = {2025},
author = {Nabi, F and Ahmad, O and Ajmal, MR and Amir, M and Parveen, I and Almutairi, FM and Khan, RH},
title = {Baicalein inhibits amyloid beta42 aggregation through disruption of the Asp23-Lys28 salt bridge.},
journal = {Scientific reports},
volume = {15},
number = {1},
pages = {38237},
pmid = {41173868},
issn = {2045-2322},
mesh = {*Amyloid beta-Peptides/chemistry/metabolism ; *Flavanones/pharmacology/chemistry ; Molecular Dynamics Simulation ; Humans ; *Peptide Fragments/chemistry/metabolism ; *Protein Aggregates/drug effects ; Protein Aggregation, Pathological ; Circular Dichroism ; Lysine/chemistry/metabolism ; Alzheimer Disease/metabolism/drug therapy ; },
abstract = {The aggregation of amyloid beta-42 (Aβ42) into β-sheet-rich fibrillar structures is a critical pathogenic feature of Alzheimer's disease (AD). Baicalein (BCN), a natural flavonoid, has been shown to inhibit aggregation in amyloidogenic proteins, including human islet amyloid polypeptide (hIAPP), which shares structural similarities with Aβ42. This study investigates the inhibitory and disaggregation effects of BCN on Aβ42 using biophysical assays and atomistic molecular dynamics (AT-MD) simulations. Thioflavin-T (ThT) fluorescence, circular dichroism (CD) spectroscopy, and fluorescence microscopy reveal that BCN significantly reduces fibril formation and induces disaggregation of preformed Aβ42 fibrils in a concentration-dependent manner. Dynamic light scattering (DLS) analysis further confirms that BCN stabilizes Aβ42 in its monomeric form, preventing the formation of larger aggregates. AT-MD simulations show that BCN interacts with the aggregation-prone region of Aβ42, specifically disrupting the Asp23-Lys28 salt bridge, which is crucial for β-sheet formation. The simulations also reveal that BCN promotes the formation of α-helical structures, reducing β-sheet content and hindering aggregation. Secondary structure analysis via DSSP plots confirms that BCN shifts Aβ42 towards less aggregation-prone conformational states. These results highlight BCN's dual function in inhibiting both the formation and disaggregation of Aβ42 fibrils. This study provides mechanistic insights into BCN's therapeutic potential for amyloid-related diseases, suggesting that it can effectively target the β-sheet spine structures common to multiple amyloidogenic proteins, offering a promising approach for mitigating AD progression.},
}

*Amyloid beta-Peptides/chemistry/metabolism
*Flavanones/pharmacology/chemistry
Molecular Dynamics Simulation
Humans
*Peptide Fragments/chemistry/metabolism
*Protein Aggregates/drug effects
Protein Aggregation, Pathological
Circular Dichroism
Lysine/chemistry/metabolism
Alzheimer Disease/metabolism/drug therapy

@article {pmid41173863,
year = {2025},
author = {Mueller, RL and Combs, B and Kanaan, NM},
title = {Seeding Alzheimer's disease-associated tau pathology in MAPT knock-in primary neurons causes early axonopathy and synaptic dysfunction.},
journal = {Scientific reports},
volume = {15},
number = {1},
pages = {38140},
pmid = {41173863},
issn = {2045-2322},
support = {F31 AG074521/AG/NIA NIH HHS/United States ; R01 AG067762/AG/NIA NIH HHS/United States ; T32 GM142521/GM/NIGMS NIH HHS/United States ; R01 NS082730/NS/NINDS NIH HHS/United States ; },
mesh = {*tau Proteins/metabolism/genetics ; *Alzheimer Disease/pathology/metabolism/genetics ; Animals ; Humans ; *Neurons/metabolism/pathology ; Mice ; *Synapses/pathology/metabolism ; *Axons/pathology/metabolism ; Gene Knock-In Techniques ; Cells, Cultured ; Mice, Transgenic ; Tauopathies/pathology/metabolism ; Phosphorylation ; Disease Models, Animal ; },
abstract = {The progressive accumulation of pathological tau is a hallmark of Alzheimer's disease (AD). The bulk of existing in vitro and in vivo evidence suggests that pathological tau forms can seed further aggregation of the protein. However, many of the subsequent functional consequences following the formation of pathogenic tau aggregates are not yet fully understood. Here, we utilized the tau seeding phenomenon to induce the formation of pathogenic tau and identify intracellular consequences in a neuron culture model of AD-associated tauopathy. Primary neurons from human tau knock-in (MAPT-KI) mice were seeded with human AD brain-derived insoluble tau (AD-tau). Microscopy and biochemical assays were used to characterize the pathological tau species formed, as well as the extent of neuronal, axonal and synaptic degeneration in seeded MAPT-KI neurons. In addition, high-density microelectrode arrays were used to assess synaptic functionality in seeded MAPT-KI neuron cultures. Human-derived AD-tau seeded intracellular endogenous tau inclusions that contained AD-associated modifications (i.e. phosphorylation at the PHF1, AT8, and pS422 antibody epitopes) and adopted multiple pathogenic conformations (i.e. oligomers and exposure of an N-terminal phosphatase activating domain; PAD). Tau inclusions, containing pS422 + and PAD-exposed tau, colocalized with active glycogen synthase kinase 3β (the kinase involved in PAD-mediated axonal transport impairment) and accumulations of axonal transport cargo proteins (i.e. synaptophysin and amyloid precursor protein) in dystrophic axons. While there was no overt axonal degeneration or cell loss, intact excitatory synapses were reduced in the AD-tau neurons. Neuron cultures treated with AD-tau exhibited an N-methyl-D-aspartate receptor-dependent increase in network burst frequency when activated with glutamate as measured through high-density microelectrode arrays. Together, the data demonstrate that the AD-tau seeded MAPT-KI neuron model exhibits features associated with neuronal dysfunction resembling those that occur early in human disease (i.e. axonal pathology and dystrophy, hyperexcitability and hypersynchrony), without causing overt neurodegeneration.},
}

*tau Proteins/metabolism/genetics
*Alzheimer Disease/pathology/metabolism/genetics
Animals
Humans
*Neurons/metabolism/pathology
Mice
*Synapses/pathology/metabolism
*Axons/pathology/metabolism
Gene Knock-In Techniques
Cells, Cultured
Mice, Transgenic
Tauopathies/pathology/metabolism
Phosphorylation
Disease Models, Animal

@article {pmid41173857,
year = {2025},
author = {Chen, CY and Maner-Smith, K and Khadka, M and Ahn, J and Gulbin, XL and Ivanova, AA and Dammer, EB and Seyfried, NT and Bennett, DA and Hajjar, IM and Ortlund, EA},
title = {Integrative brain omics approach highlights sn-1 lysophosphatidylethanolamine in Alzheimer's dementia.},
journal = {Nature communications},
volume = {16},
number = {1},
pages = {9627},
pmid = {41173857},
issn = {2041-1723},
support = {RF1AG057470//U.S. Department of Health & Human Services | NIH | National Institute on Aging (U.S. National Institute on Aging)/ ; RF1AG057470//U.S. Department of Health & Human Services | NIH | National Institute on Aging (U.S. National Institute on Aging)/ ; RF1AG057470//U.S. Department of Health & Human Services | NIH | National Institute on Aging (U.S. National Institute on Aging)/ ; },
mesh = {Humans ; *Alzheimer Disease/metabolism/pathology ; Male ; Aged ; Female ; Lipidomics/methods ; *Brain/metabolism/pathology ; *Lysophospholipids/metabolism ; Aged, 80 and over ; Proteomics/methods ; Lysophosphatidylcholines/metabolism ; Biomarkers/metabolism ; },
abstract = {The biology of individual lipid species and their relevance in Alzheimer's disease (AD) remains incompletely understood. To explore the lipidomic biomarkers associated with cognition function and neuropathological changes in AD, we utilize non-targeted mass spectrometry on 316 post-mortem brains from participants in the Religious Orders Study (ROS) or Rush Memory and Aging Project (MAP) cohorts classified as control, asymptomatic AD (AAD), or symptomatic AD (SAD), and integrate the lipidomics data with untargeted proteomics from the same individuals. We find that lysophosphatidylethanolamine (LPE) and lysophosphatidylcholine (LPC) species are significantly lower in SAD than controls or AAD. Lipid-protein network analyses reveal that LPE/LPC modules are significantly associated with protein modules involved in MAPK/metabolism, post-synaptic density, and cell-ECM interaction pathways, and correlate with better antemortem cognition and reduced AD neuropathology. Particularly, LPE 22:6 [sn-1] is significantly decreased SAD and exerts a pronounced influence on protein changes relevant to neurotransmitter-driven post synaptic changes and plasticity compared to other lysophospholipids species. These findings suggest LPE 22:6 as a potential lipid signature and therapeutic target for AD.},
}

Humans
*Alzheimer Disease/metabolism/pathology
Male
Aged
Female
Lipidomics/methods
*Brain/metabolism/pathology
*Lysophospholipids/metabolism
Aged, 80 and over
Proteomics/methods
Lysophosphatidylcholines/metabolism
Biomarkers/metabolism

@article {pmid41173821,
year = {2025},
author = {Amin, N and Liu, J and Sproviero, W and Arnold, M and Batra, R and Bonnechere, B and Chiou, YJ and Fernandes, M and Krumsiek, J and Newby, D and Nho, K and Kim, JP and Saykin, AJ and Shi, L and Winchester, LM and Yang, Y and Nevado-Holgado, AJ and Kastenmüller, G and Kaddurah-Daouk, R and van Duijn, CM},
title = {Interplay between age, APOE Ɛ4 and the metabolome in plasma and brain in Alzheimer's disease.},
journal = {Translational psychiatry},
volume = {15},
number = {1},
pages = {460},
pmid = {41173821},
issn = {2158-3188},
mesh = {Humans ; *Alzheimer Disease/metabolism/genetics/blood ; Aged ; *Apolipoprotein E4/genetics/metabolism ; Male ; Female ; Middle Aged ; *Brain/metabolism ; *Metabolome/genetics ; Adult ; *3-Hydroxybutyric Acid/blood/metabolism ; *Amino Acids, Branched-Chain/metabolism/blood ; *Aging/metabolism/genetics ; Age Factors ; Aged, 80 and over ; Proteomics ; Metabolomics ; },
abstract = {Age and the ε4 variant of the apolipoprotein E gene (APOE ε4) are two major drivers of Alzheimer's disease (AD). APOE is also the major determinant of longevity. How age and APOE interact in the development of AD is largely unknown. In this study we integrate metabolomics (N = 274,259) and proteomics (N = 54,219) data in plasma from the UK Biobank with the metabolomics (N = 514) and proteomics (N = 618) data in brain from the Religious Orders Study and the Rush Memory and Aging Project (ROSMAP) to understand the interplay of age, APOE ε4 and metabolome in the development of AD. We find that levels of β-hydroxybutyrate (BHBA) and branch-chained amino acids (BCAAs) are dysregulated in plasma and brains of AD patients. APOE ε4 carriers manifest significantly higher plasma concentration of BHBA that is detectable as early as 37 years of age and remains high throughout the studied age range of 37-73 whereas the plasma concentrations of BCAAs decline in APOE ε44 carriers after the age of 58 years. Proteomic signatures of APOE ε4, BHBA and BCAAs suggest downregulation of lysosome, immune and insulin-like growth factor (IGF1) transport/uptake pathways in plasma, and downregulation of the tricarboxylic acid (TCA) cycle, neurexins/neuroligins and clathrin-mediated endocytosis pathways in brain. Our data identifies two major shifts in metabolism occurring decades apart over the age course in AD in APOE ε4 carriers. These include early ketogenesis that manifests around late 30 s and gluconeogenesis, which manifests around the age of 60 years.},
}

Humans
*Alzheimer Disease/metabolism/genetics/blood
Aged
*Apolipoprotein E4/genetics/metabolism
Male
Female
Middle Aged
*Brain/metabolism
*Metabolome/genetics
Adult
*3-Hydroxybutyric Acid/blood/metabolism
*Amino Acids, Branched-Chain/metabolism/blood
*Aging/metabolism/genetics
Age Factors
Aged, 80 and over
Proteomics
Metabolomics

@article {pmid41173390,
year = {2025},
author = {Ambareen, N and Gharami, K and Mondal, A and Sarkar, UA and Biswas, SC},
title = {Sertad1 is elevated and plays a necessary role in neuron loss and cognitive impairment in a mouse model of Alzheimer's disease.},
journal = {The Journal of biological chemistry},
volume = {},
number = {},
pages = {110875},
doi = {10.1016/j.jbc.2025.110875},
pmid = {41173390},
issn = {1083-351X},
abstract = {Aberrant activation of autophagy contributes to neuronal cell death and plays a pivotal role in the pathogenesis of Alzheimer's disease (AD). To study this further, we assessed autophagy-related proteins in 5xFAD mice at different ages and found a progressive inappropriate elevation of autophagic proteins in these mice. We identified a transcriptional coregulator, Sertad1 which plays a necessary role in neuron death, as a key regulator of aberrant autophagy in AD. We found a progressive elevation in Sertad1 levels in 5xFAD mice with age compared to wild-type (WT) mice. Sertad1 knockdown in 5xFAD mice brain lowered levels of autophagy-related proteins and lysosomal proteins, suggesting its role in the regulation of the autophagy-lysosomal pathway. We found that Sertad1 knockdown restored Akt activity which is inhibited in AD and blocked the activation of its target, FoxO3a which is translocated to the nucleus in absence of active Akt and mediates neuron death by apoptosis and autophagy. Further, we showed that lentivirus mediated RNAi targeting of Sertad1 in 5xFAD mice led to better performance in behavioural experiments compared to 5xFAD mice treated with non-targeting shRNA, accompanied by significant restoration of synaptic integrity. Overall, our results demonstrated that autophagy is robustly induced with disease progression but autophagy-related proteins accumulate in the brain due to their impaired clearance; Sertad1 knockdown restored synaptic failure and improved cognition in 5xFAD mice by enhancing clearance of autophagy-related proteins and neuronal survival. Hence, Sertad1 could be an excellent target for therapeutic intervention to combat the multifaceted pathologies of AD.},
}

@article {pmid41173323,
year = {2025},
author = {Morrow, CB and Sah, E and Onyike, CU},
title = {Examining neuropsychiatric symptoms and functional decline in behavioral variant frontotemporal dementia.},
journal = {International review of psychiatry (Abingdon, England)},
volume = {},
number = {},
pages = {1-9},
doi = {10.1080/09540261.2025.2571072},
pmid = {41173323},
issn = {1369-1627},
abstract = {AIM: Neuropsychiatric symptoms (NPS) are core features of behavioral variant frontotemporal dementia (bvFTD), but their association with functional decline is incompletely understood.

METHODS: Participants (N = 219) were individuals enrolled in Alzheimer's Disease Research Centers between 2005 and 2024 with early-stage bvFTD (CDR ≤ 0.5). Functional status was coded as a binary variable based on the Functional Activities Questionnaire. Behavioral data were derived from the Neuropsychiatric Inventory Questionnaire and Clinician Judgement of Symptoms. Descriptive statistics and Cox proportional hazard analyses were used to characterize functional impairments and their association with NPS.

RESULTS: Impairments in transactions (47%) and verbal communication (44%) were common at baseline, while impairments in self-care and incontinence (<10%) were rare. Apathy (65%), disinhibition (55%), depression, anxiety, irritability, and agitation were common at baseline (>40%). Psychosis was rare at baseline (<10%). By visit 4, impairments in transactions (81%), meal-preparation (65%), self-care (55%) and verbal communication (61%) were common. Emergence of apathy, disinhibition, depression, anxiety, and irritability were associated with an increased hazard of impairments in ambulation, meal preparation, self-care, and transactions.

CONCLUSION: NPS in bvFTD are frequent, occur early, and are associated with functional decline. Timely recognition and treatment of NPS may mitigate their impact on function.},
}

@article {pmid41173224,
year = {2025},
author = {Zheng, M and Zhang, Q and Siebert, HC and Loers, G and Wen, M and Wang, Q and Zhang, R and Han, J and Zhang, N},
title = {Semaglutide attenuates Alzheimer's disease model progression by targeting microglial NLRP3 inflammasome-mediated neuroinflammation and ferroptosis.},
journal = {Experimental neurology},
volume = {},
number = {},
pages = {115537},
doi = {10.1016/j.expneurol.2025.115537},
pmid = {41173224},
issn = {1090-2430},
abstract = {Microglial activation driven by NOD-, LRR- and pyrin domain-containing protein 3 (NLRP3) inflammasome signaling exacerbates Alzheimer's disease (AD) pathology through enhanced neuroinflammation and amyloid beta (Aβ) accumulation. Semaglutide (SEM) has attracted growing attention for its potential therapeutic effects in AD, while its underlying mechanisms remain unclear. In this study, we investigated the neuroprotective effects of SEM in both APP/PS1 transgenic mice and LPS + ATP-stimulated BV2 microglia. Our results demonstrate that SEM treatment rescued APP/PS1 mice from cognitive impairment and suppressed Aβ aggregation and tau hyper-phosphorylation in the hippocampus of APP/PS1 mice. Furthermore, we found that SEM inhibited microglial NLRP3 activation, promoted microglial M2 polarization and alleviated ferroptosis via NLRP3/nuclear factor kappa B (NF-κB) and nuclear factor erythroid 2-related factor 2 (Nrf2)/heme oxygenase 1 (HO-1)/ cystine/glutamate antiporter SLC7A11 (xCT)/glutathione peroxidase 4 (GPX4) pathways in APP/PS1 mice and LPS + ATP-stimulated BV2 microglia. These findings were further corroborated by microglia-specific NLRP3 knockdown, which reduced Aβ deposition, promotied M2 polarization, attenuated neuroinflammation, and suppressed ferroptosis. Our findings provide further theoretical support for the clinical application of SEM in AD treatment, while also establishing a scientific foundation for AD therapeutic strategies targeting the microglial NLRP3 pathway.},
}

@article {pmid41173152,
year = {2025},
author = {Sun, ZX and Xie, F and Zhao, Y and Wang, X and Sun, ZW and Qian, LJ and Feng, H},
title = {Exercise and the blood-brain barrier: Mechanistic insights and therapeutic implications.},
journal = {Neurobiology of disease},
volume = {217},
number = {},
pages = {107166},
doi = {10.1016/j.nbd.2025.107166},
pmid = {41173152},
issn = {1095-953X},
abstract = {The blood-brain barrier (BBB) is a critical structure for maintaining homeostasis in the central nervous system, and its dysfunction is widely implicated in the pathogenesis and progression of various neurological disorders. In recent years, exercise, as a low-cost and low-side-effect non-pharmacological intervention, has demonstrated significant potential in modulating the structure and function of the BBB. In this article, we comprehensively review the key mechanisms regulating BBB permeability under physiological and pathological conditions, with a focus on three core pathways: oxidative stress-inflammation-mediated disruption, vascular endothelial growth factor-mediated bidirectional repair, and Wnt/Sonic hedgehog/transcription factor-dependent homeostasis maintenance. Furthermore, we compare the effects of different exercise modalities, including aerobic exercise, high-intensity interval training, and resistance training, on the BBB and discuss their differential impacts across distinct brain regions, populations, and disease states. Additionally, this review integrates rodent and human evidence supporting the therapeutic potential of exercise interventions for patients with typical neurological disorders (e.g., Alzheimer's disease, multiple sclerosis, stroke, and depression) as well as non-disease risk conditions such as obesity and aging that profoundly affect BBB integrity, highlighting its multi-pathway and multi-target mechanisms in maintaining BBB dynamic homeostasis. Overall, the collected evidences support that moderate and regular exercise may protect BBB function through multidimensional mechanisms, offering novel insights and theoretical foundations for non-pharmacological therapies for neurological disorders.},
}

@article {pmid41173000,
year = {2025},
author = {Ziegler, KC and Askarova, A and Gergian, C and Yaa, RM and van Dalen, JD and Transfeld, JL and Zoppi, F and Du, J and Clode, D and Rahbar, F and Graham, RE and Sargurupremraj, M and Debette, S and Gonda, DD and Levy, ML and Chandran, S and Falk, S and Karow, M and Matthews, PM and Coufal, NG and Nott, A},
title = {The brain neurovascular epigenome and its association with dementia.},
journal = {Neuron},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.neuron.2025.10.001},
pmid = {41173000},
issn = {1097-4199},
abstract = {Cerebral small vessel disease (SVD) is frequently comorbid with Alzheimer's disease (AD), and brain endothelial cells (BECs) express genes associated with AD genetic risk. However, the epigenome of neurovascular cells and its intersection with genetic risk remain unexplored. Here, we generated gene regulomes for human BECs, mural cells, and other brain cell types and showed that AD heritability is primarily immune related, with a modest BEC enrichment. On the other hand, SVD heritability is enriched across the neurovascular unit, including astrocytes. Enhancer-to-gene interactomes implicated disease-distinct putative risk genes associated with amyloid and phospholipid processes in AD and senescence-associated pathways in SVD. Motifs for putative partners of lineage-determining transcription factors (TFs) in microglia and BECs were enriched for AD and SVD variants linked to disease-associated genes. In silico screening of compounds implicated vitamin D receptor agonists, mammalian target of rapamycin (mTOR), histone deacetylase (HDAC), and vascular endothelial growth factor receptor (VEGFR) inhibitors for AD. Our findings highlight regulatory mechanisms and therapeutic targets within the neurovascular system.},
}

@article {pmid41172986,
year = {2025},
author = {Zhang, Y and Zhang, Z},
title = {Structural basis of VAChT inhibition by spiroindolines and alkylsulfones.},
journal = {Structure (London, England : 1993)},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.str.2025.10.005},
pmid = {41172986},
issn = {1878-4186},
abstract = {Cholinergic signaling relies on the vesicular acetylcholine transporter (VAChT) to package acetylcholine (ACh) into synaptic vesicles. VAChT dysfunction is implicated in neurological and neuromuscular disorders, including Alzheimer's disease and myasthenia gravis, yet current inhibitors such as vesamicol suffer from off-target effects. Here, we present cryo-EM structures of human VAChT bound to two inhibitors, spiroindoline and alkylsulfone, revealing their divergent binding modes that converge in occupying the central substrate pocket. Mutagenesis studies identify conserved residues critical for inhibitor binding. These findings elucidate the molecular mechanisms by which VAChT binds structurally distinct inhibitors, providing a blueprint for designing optimized therapeutics. Furthermore, species-specific structural variations identified here suggest opportunities to develop selective insecticides through ortholog-targeted inhibition. Taken together, this work bridges mechanistic insights with therapeutic and agricultural applications, advancing precision tools for modulating the cholinergic system.},
}

@article {pmid41172923,
year = {2025},
author = {Karakose, S and Terracciano, A and Luchetti, M and Stephan, Y and Sutin, AR},
title = {Meaning in life and Parkinson's disease: Evidence from a 17-year study across 14 countries.},
journal = {Archives of gerontology and geriatrics},
volume = {141},
number = {},
pages = {106062},
doi = {10.1016/j.archger.2025.106062},
pmid = {41172923},
issn = {1872-6976},
abstract = {BACKGROUND: Meaning in life is associated consistently with a reduced risk of incident Alzheimer's disease and related dementias. It also changes across the disease continuum. Less work has examined the association between meaning in life and Parkinson's disease and the natural history of meaning with onset of Parkinson's disease has yet to be evaluated. This study examines the prospective association between meaning in life and incident Parkinson's disease and evaluates changes in meaning in life prior and after onset of Parkinson's disease.

METHODS: This prospective cohort study used assessments of meaning in life and incident Parkinson's disease from 2004 to 2022 in the Survey of Health, Ageing and Retirement in Europe. Meaning in life was measured with a single-item measure from the Control, Autonomy, Self-realization and Pleasure scale. Parkinson's disease was self/proxy-reported doctor diagnosis up to 2022.

RESULTS: Accounting for age, sex, and education, greater meaning in life was associated with lower risk of developing incident Parkinson's disease over up to 17 years follow-up. This association was accounted for behavioral, clinical, and psychological factors. Accounting for demographic differences and normative changes that occur in meaning, meaning in life did not decline significantly before the onset of Parkinson's disease but showed a significant and accelerated decline following disease onset.

CONCLUSIONS: Behavioral, clinical, and psychological risk factors accounted for the association between meaning in life and risk of Parkinson's disease. Meaning in life levels remained stable before Parkinson's disease's onset but declined significantly afterward, paralleling the worsening of psychological outcomes in Parkinson's disease.},
}

@article {pmid41172802,
year = {2025},
author = {Kui, X and Dai, Y and Zou, B and Zhu, C and Li, Y and Ji, Z and Chen, L and Bordallo López, M},
title = {Alzheimer's disease classification based on multimodal consistent distribution and trusted fusion.},
journal = {Neural networks : the official journal of the International Neural Network Society},
volume = {195},
number = {},
pages = {108245},
doi = {10.1016/j.neunet.2025.108245},
pmid = {41172802},
issn = {1879-2782},
abstract = {Multimodal data fusion has the potential to improve Alzheimer's disease (AD) classification by capturing diverse disease manifestations. However, existing methods often fail to address the heterogeneity and reliability differences across modalities, limiting their effectiveness. This paper proposes a novel AD classification framework based on multimodal consistent distribution and trusted fusion. Our approach projects structural magnetic resonance imaging (sMRI), fluorodeoxyglucose positron emission tomography (PET), and mini-mental state examination (MMSE) scores into a unified latent feature space, aligning heterogeneous multimodal features into a consistent distribution. This alleviates inconsistent interference during multimodal fusion. To address reliability differences, we estimate the belief and uncertainty inherent in the class prediction probabilities of each modality using a Dirichlet distribution-based mechanism, providing interpretability for subsequent classification decisions. Furthermore, we design a novel fusion strategy that integrates the belief and uncertainty from different modalities, enhancing the reliability of the final classification results. Evaluated on the ADNI and AIBL datasets across four AD-related classification tasks, our method achieves promising performance, demonstrating its effectiveness in addressing multimodal heterogeneity and reliability for robust AD classification.},
}

@article {pmid41172789,
year = {2025},
author = {Kjaergaard, D and Simonsen, AH and Stomrud, E and Bali, D and Janelidze, S and Hansson, O and Waldemar, G and Nielsen, TR},
title = {Combining plasma p-tau217 and cross-cultural cognitive tests to identify Alzheimer's Disease in an ethnically diverse mixed memory clinic cohort.},
journal = {Journal of the neurological sciences},
volume = {478},
number = {},
pages = {123739},
doi = {10.1016/j.jns.2025.123739},
pmid = {41172789},
issn = {1878-5883},
abstract = {OBJECTIVE: To determine whether combining routine cross-cultural cognitive assessments with plasma phosphorylated tau217 (p-tau217) increases diagnostic accuracy in identifying Alzheimer's disease (AD) in a consecutive mixed memory clinic cohort of ethnically diverse patients.

METHODS: We included 201 memory clinic patients originating from 42 different countries. Patients were examined with the Multicultural Cognitive Examination (MCE) as part of their routine cognitive assessment. Plasma p-tau217 levels were analyzed blinded to the results of the clinical evaluation. Repeated cross-validated models assessed the added diagnostic value of plasma p-tau217 through change in accuracy metrics, including sensitivity, specificity, predictive values, and likelihood ratios. The primary outcome was clinically established AD. In subgroup analyses, accuracy metrics were evaluated for differentiating AD from other dementia disorders and patients with and without AD pathology determined by cerebrospinal fluid biomarkers or Amyloid-β PET.

RESULTS: Routine cognitive assessment with the MCE alone demonstrated high diagnostic accuracy for identifying AD (AUC: 0.80-0.81). However, combining the MCE with plasma p-tau217 significantly increased diagnostic accuracy (AUC: 0.91-0.93), which mainly reflected an increased ability to rule-out AD. When differentiating AD from other dementia disorders, the MCE alone was less accurate (AUC: 0.64-0.65), and accuracies increased by including plasma p-tau217 (AUC: 0.85-0.89).

CONCLUSIONS: Combining routine cross-cultural cognitive tests with an accurate plasma biomarker increased the accuracy of identifying AD in a diverse mixed memory clinic cohort. These results demonstrate the value of using appropriate diagnostic tools in culturally, linguistically, and ethnically diverse patients, who are known to face barriers in their clinical evaluation.},
}

@article {pmid41172319,
year = {2025},
author = {Avdeenko, TA and Guseinova, NM and Dzhafarzade, FY and Zagorul'ko, AA},
title = {[Modern therapeutic strategies for the treatment of Alzheimer's disease (literature review).].},
journal = {Advances in gerontology = Uspekhi gerontologii},
volume = {38},
number = {3},
pages = {441-449},
pmid = {41172319},
issn = {1561-9125},
mesh = {*Alzheimer Disease/therapy/drug therapy/metabolism ; Humans ; *Cholinesterase Inhibitors/therapeutic use ; Amyloid beta-Peptides/metabolism ; *Diabetes Mellitus, Type 2/complications/drug therapy/metabolism ; Immunotherapy/methods ; tau Proteins/metabolism ; Calcium Channel Blockers/therapeutic use ; Receptors, N-Methyl-D-Aspartate/antagonists & inhibitors ; },
abstract = {The article analyzes contemporary literature data on standard and alternative therapeutic methods for Alzheimer's disease (AD). The main approaches currently include the use of cholinesterase inhibitors and NMDA receptor antagonists, which help slow disease progression and improve patients' quality of life. Due to their insufficient effectiveness, there is a search for new treatment methods based on the connection between AD and other conditions. This article will examine the cross-mechanisms of pathogenesis linking type 2 diabetes and AD, as well as analyze new therapeutic approaches, including intranasal insulin administration and the use of insulin sensitizers. Neurodegenerative processes, including AD, are based on a violation of intracellular calcium metabolism, which suggested the potential efficiency of calcium channel blocker drugs currently used in the treatment of arterial hypertension. Key hypotheses regarding the pathogenesis of AD include the amyloid hypothesis, based on the accumulation of beta-amyloid, and the tau hypothesis, related to hyperphosphorylated tau protein aggregation. Alternative mechanisms such as neuroinflammation are also discussed. In this context, an innovative method for treating AD is immunotherapy, aimed at eliminating beta-amyloid that causes neurodegeneration. Thus, the necessity for integrating various hypotheses for a more comprehensive understanding of pathology and developing effective therapeutic strategies is emphasized. The article highlights the importance of further research in this field.},
}

*Alzheimer Disease/therapy/drug therapy/metabolism
Humans
*Cholinesterase Inhibitors/therapeutic use
Amyloid beta-Peptides/metabolism
*Diabetes Mellitus, Type 2/complications/drug therapy/metabolism
Immunotherapy/methods
tau Proteins/metabolism
Calcium Channel Blockers/therapeutic use
Receptors, N-Methyl-D-Aspartate/antagonists & inhibitors

@article {pmid41172131,
year = {2025},
author = {Martín-Fuentes, I and Fernandez-Gamez, B and Vidal-Almela, S and Caro-Rus, A and Solis-Urra, P and Sánchez-Aranda, L and Fernández-Ortega, J and Sanchez-Martinez, J and Coca-Pulido, A and Olvera-Rojas, M and Barranco-Moreno, EJ and Marin-Alvarez, JD and Bakker, EA and Toval, A and Bellón, D and Sclafani, A and Karikari, TK and Erickson, KI and Gómez-Río, M and Ortega, FB and Esteban-Cornejo, I},
title = {Understanding Cerebral Blood Flow Dynamics for Alzheimer's Disease Prevention Through Acute Exercise (flADex): Protocol for a Randomized Crossover Trial.},
journal = {Brain and behavior},
volume = {15},
number = {11},
pages = {e70636},
pmid = {41172131},
issn = {2162-3279},
support = {//MCIN/AEI/10.13039/501100011033/ PID2022-137399OB-I00, CNS2024-154835, RTI2018-095284-J-I00/ ; //MCIN/AEI/10.13039/501100011033/ RYC2019-027287-I/ ; },
mesh = {Humans ; *Alzheimer Disease/prevention & control/physiopathology/blood ; Aged ; Cross-Over Studies ; *Cerebrovascular Circulation/physiology ; Aged, 80 and over ; Male ; Female ; *Exercise/physiology ; Amyloid beta-Peptides/blood ; Biomarkers/blood ; Brain/metabolism/blood supply ; Magnetic Resonance Imaging ; Brain-Derived Neurotrophic Factor/blood ; *Exercise Therapy/methods ; tau Proteins/blood ; Randomized Controlled Trials as Topic ; },
abstract = {INTRODUCTION: Alzheimer's disease (AD) is a leading cause of disability worldwide. Alterations in cerebral blood flow (CBF) and AD blood biomarkers are fundamental at early stages of AD. Exercise shows promise in delaying physiological changes, but its mechanisms for enhancing brain health remain unclear. flADex aims to examine the acute effects of different exercise types on CBF and blood biomarkers in older adults. This protocol describes the methodology and rationale of flADex.

METHODS: flADex is a counterbalanced crossover trial in 20 older adults, aged 68-83 years old, with negative brain amyloid status (< 12 centiloid) who are APOEε4 noncarriers. Participants will complete a 30-min session of each condition in a randomized order: (i) moderate-intensity aerobic exercise (60%-70% age-predicted maximal heart rate), (ii) moderate-intensity resistance exercise (rating of perceived exertion: 4-6 points out of 10), and (iii) resting condition. Changes in CBF are the primary outcome and will be assessed by magnetic resonance imaging using pseudo-continuous arterial spin labeling at pre- and at 3 timepoints post-condition (starting at 20, 27, 34 min). Secondary outcomes are biomarkers of AD pathology and neurodegeneration (Aβ42, Aβ40, p-tau217, p-tau181, BD-tau, GFAP, NfL) and growth factors (BDNF, IGF-1), measured through blood samples collected at pre- and post-condition (at 3, 50, 70 min). Moreover, cognitive outcomes and mood status will be measured pre- and post-condition.

CONCLUSION: flADex will highlight the acute effects of different exercise types on CBF and biomarkers before beta-amyloid accumulation. Acute effects on CBF dynamics and blood biomarkers are expected to be greater with aerobic than resistance exercise when compared to resting. CBF is expected to vary by brain region, and biomarkers to fluctuate dynamically postexercise. This will provide critical insights into exercise's impact on vascular and molecular pathways associated with AD pathology and potential recommendations for standardized blood sampling to enhance diagnostic accuracy.},
}

Humans
*Alzheimer Disease/prevention & control/physiopathology/blood
Aged
Cross-Over Studies
*Cerebrovascular Circulation/physiology
Aged, 80 and over
Male
Female
*Exercise/physiology
Amyloid beta-Peptides/blood
Biomarkers/blood
Brain/metabolism/blood supply
Magnetic Resonance Imaging
Brain-Derived Neurotrophic Factor/blood
*Exercise Therapy/methods
tau Proteins/blood
Randomized Controlled Trials as Topic

@article {pmid41172052,
year = {2025},
author = {Laursen, TM and Nilsson, SF and Pedersen, CB and Waldemar, G and Janbek, J},
title = {Dementia in Denmark: Uncovering the causes of death and life years lost in a nationwide, register-based cohort study.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877251389963},
doi = {10.1177/13872877251389963},
pmid = {41172052},
issn = {1875-8908},
abstract = {BackgroundDementia is associated with increased mortality, yet limited data exist on cause-specific life years lost (LYL) in large national populations.ObjectiveTo quantify excess all-cause and cause-specific mortality, including life years lost, among older adults with dementia in Denmark using nationwide data.MethodsWe conducted a register-based cohort study of over 2.3 million individuals aged 65+, including 191,038 individuals diagnosed with dementia. Using state-of-the-art LYL methodology, we compared mortality rate ratios (MRRs) and LYL between people with and without dementia, stratified by age and sex, with follow-up covering 22.6 million person-years.ResultsFemales and males with dementia had adjusted all-cause MRRs of 2.88 (95% CI: 2.86-2.90) and 3.15 (95% CI: 3.12-3.17), respectively, compared to those without. The average cause-specific LYL among individuals with dementia was 3.73 years (95% CI: 3.71-3.76) for females and 3.96 years (95% CI: 3.93-3.98) for males. Dementia as the underlying cause of death accounted for the majority of life years lost among individuals with dementia, while other major causes of death, such as cancer and heart disease, were associated with fewer lost years compared to the general population.ConclusionsThe findings underscore the substantial mortality burden associated with dementia among older adults in Denmark. Recognizing dementia as a life-threatening condition highlights the urgent need for targeted public health and policy responses. Including LYL in prognostic considerations may also improve clinical care planning and support services following diagnosis.},
}

@article {pmid41171995,
year = {2025},
author = {Angelidou, IA and Ntova, T and Karar, E and Tsatali, M and Teichmann, B},
title = {Measuring dementia knowledge and attitudes among the German Deaf community: Adaptation and validation of the Knowledge Assessment Scale, the Dementia Attitude Scale, and the Confidence in Dementia Scale in German Sign Language.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877251390842},
doi = {10.1177/13872877251390842},
pmid = {41171995},
issn = {1875-8908},
abstract = {BackgroundDeaf individuals face barriers in accessing healthcare for dementia and Alzheimer's disease and are often overlooked in research. Deaf-friendly scales in German Sign Language (DGS) are urgently needed to ensure inclusive and equitable dementia care for Deaf individuals.ObjectiveThe aim of the study is the linguistic and cultural adaptation/validation of the Dementia Knowledge Assessment Scale (DKAS-D), the Dementia Attitude Scale (DAS-D), and the Confidence in Dementia Care Scale (CODE-D) into DGS.MethodThe three scales were adapted into DGS using a collaborative translation process involving Deaf and hearing bilingual signers. A convenience sample of 205 Deaf participants answered the DKAS-DGS and DAS-DGS; a subsample answered the CODE-DGS (n = 160) online via Google Forms or as a pencil-and-paper version in person. Psychometric validation included internal consistency, structural and construct validity. For the DKAS-DGS an item analysis was conducted.ResultsInternal consistency was acceptable to good for all scales. The removal of five items from the DKAS-DGS and four from the DAS-DGS led to improvements in structural validity for both. The CODE-DGS one-factor structure showed good model fit. Construct validity was confirmed, with participants with practical or professional experience with people living with dementia scoring higher on all scales. Item analysis of the DKAS-DGS revealed challenges in translation, as well as the need for accessible, tailored dementia education for the Deaf community.ConclusionsThe three scales are valuable tools for measuring dementia knowledge, attitudes, and confidence in care among DGS-signers and may be used in future research settings.},
}

@article {pmid41171994,
year = {2025},
author = {Arshad, F and Pinto, JM and Yaffe, K and Brenowitz, WD},
title = {Racial and ethnic differences in the associations of sensory impairments with cognition in older United States adults.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877251387115},
doi = {10.1177/13872877251387115},
pmid = {41171994},
issn = {1875-8908},
abstract = {BackgroundSensory impairments are associated with cognitive decline and Alzheimer's disease risk.ObjectiveWe studied how sensory function and cognitive change varied by race/ethnicity in Hispanic, non-Hispanic Black (NHB), and non-Hispanic White (NHW) older US adults.MethodsWe studied 2799 individuals, 57-85 years-old, in the National Social Life, Health, and Aging Project with baseline sensory and follow-up Montreal Cognitive Assessment (MoCA) information from 2005-2016. Hearing was interviewer-rated; vision, smell, taste, and touch were objectively measured. Senses were categorized (poor, moderate, normal); number of poor senses (impairment) was summed. Multivariable linear regressions evaluated the association between sensory impairments and cognition, adjusting for demographic and clinical variables. We tested for differences by race/ethnicity using interaction terms.ResultsHispanic (n = 180) and NHB (n = 509) older adults had higher prevalence of ≥1 sensory impairments and lower cognition scores versus NHW respondents (n = 2110). Having multiple impairments significantly interacted with race/ethnicity such that estimates for the association with cognition was significantly lower for NHB versus NHW respondents (beta = -3.08, 95% CI: -5.14, -1.02; p = 0.004). Interactions were borderline significant for smell, where estimated difference in cognition associated with moderate (β=-0.91, 95% CI: -1.91, 0.10, p = 0.077) and poor (β=-1.33, 95% CI: -2.77, 0.11, p = 0.071) smell was lower for NHB versus NHW participants.ConclusionsOur findings suggest racial/ethnic differences in how strongly sensory impairments predict cognition, especially for number of impairments and possibly smell. Further insight may reduce disparities in cognitive aging.},
}

@article {pmid41171961,
year = {2025},
author = {Dybala, A and Pils, M and Bannach, O and Tamgüney, G and Riesner, D},
title = {Analysis of Single Particles of Amyloid Beta and α-Synuclein With Seeded Amplification for the Diagnosis of Alzheimer's and Parkinson's Disease.},
journal = {Biotechnology and applied biochemistry},
volume = {},
number = {},
pages = {},
doi = {10.1002/bab.70083},
pmid = {41171961},
issn = {1470-8744},
abstract = {Neurodegenerative diseases, including Alzheimer's disease (AD) and Parkinson's disease (PD), are characterized by the pathological aggregation of specific proteins such as amyloid beta (Aβ) and α-synuclein, respectively. Early detection of these protein aggregates in biological fluids could facilitate timely diagnosis and therapeutic intervention. This study explores an aggregate amplification approach using the surface-based fluorescence intensity distribution analysis (sFIDA) method to enhance the detection sensitivity of Aβ and α-synuclein seeds. Two amplification strategies were investigated: surface-bound and solution-phase amplification. In the case of Aβ, surface-bound amplification using immobilized Aβ-specific antibodies was tested with synthetic Aβ1-42 seeds and monomeric Aβ1-42 as the substrate. Despite observable aggregation, self-aggregation of the monomeric substrate interfered with seed-dependent amplification, rendering the approach ineffective at physiologically relevant concentrations. Attempts to suppress self-aggregation using blocking peptides, bovine serum albumin, and truncated Aβ11-42 substrates were unsuccessful. Solution-phase amplification followed by surface detection also failed to reliably differentiate seeded aggregation from self-aggregation, indicating that Aβ amplification is unsuitable for diagnostic applications. In contrast, α-synuclein exhibited significantly lower self-aggregation, allowing for more effective seeded amplification. Surface-bound α-synuclein amplification successfully detected synthetic seeds at nanomolar concentrations, while solution-phase amplification further improved sensitivity, enabling detection down to the picomolar range. The method was successfully applied to brain homogenates from transgenic PD model mice, demonstrating the potential for detecting α-synuclein seeds in biological samples. These findings highlight the limitations of Aβ amplification for diagnostic purposes while supporting the feasibility of α-synuclein amplification for PD detection. Future work will focus on optimizing this approach for clinical applications.},
}

@article {pmid41171934,
year = {2025},
author = {},
title = {Correction to "Baseline Impaired Insight Predicts Longitudinal Brain Atrophy in Alzheimer's Disease and Related Cognitive States: A 30-Month Cohort Study From the ADNI Dataset".},
journal = {Brain and behavior},
volume = {15},
number = {11},
pages = {e71028},
doi = {10.1002/brb3.71028},
pmid = {41171934},
issn = {2162-3279},
}

@article {pmid41171782,
year = {2025},
author = {Heuer, S and Besser, LM and Dominguez, B and Huynh, S and Le, BN and Nguyen, BS and Pham, J and Vu, U and Meyer, OL},
title = {'See something, say something': a qualitative study of neighborhood perceptions and brain health.},
journal = {Aging & mental health},
volume = {},
number = {},
pages = {1-11},
doi = {10.1080/13607863.2025.2573073},
pmid = {41171782},
issn = {1364-6915},
abstract = {OBJECTIVES: Studies have shown the importance of neighborhood factors, such as residential segregation and green space, in associations with older adult brain health. In this qualitative study, we examine older adults' perceptions of their neighborhood, with a particular focus on residential diversity and segregation.

METHOD: We recruited participants from the longitudinal cohort at the UC Davis Alzheimer's Disease Research Center to participate in semi-structured interviews. Participants were interviewed and asked to describe features and perceptions of their neighborhood. Individual interviews lasted twenty-three minutes on average and were audio-taped, transcribed verbatim, and analyzed for recurring themes.

RESULTS: A total of twenty-six participants were interviewed: 61.5% female, 50.0% non-Hispanic White and 50.0% Black/African American, mean age= 81.12, SD = 6.93 years.The most prominent themes were (1) Importance of public stores and similar third spaces; (2) Accessibility to green space, including parks and trees; (3) Staying active in the community, both physically and socially; (4) Neighborhood awareness and cohesion; and (5) Stereotypes, discrimination, and segregation.

CONCLUSION: These findings highlight the social and built environment factors that are important to older adults and that may potentially affect brain health. Future research should examine how salient themes might differ depending on older adults' cognition.},
}

@article {pmid41171329,
year = {2025},
author = {Zyuz'kov, GN and Zhdanov, VV and Miroshnichenko, LA and Polyakova, TY and Chaykovskyi, AV and Agafonov, VI},
title = {Psychopharmacological and Neuroregenerative Properties of Protein Kinase A Inhibitor in Alzheimer's Disease Model.},
journal = {Bulletin of experimental biology and medicine},
volume = {},
number = {},
pages = {},
pmid = {41171329},
issn = {1573-8221},
abstract = {We studied the effect of a protein kinase A (PKA) inhibitor and the content of different types of progenitor cells in the subventricular zone of the brain of 16-month-old male C57BL/6 mice (characterized by pathological endogenous amyloid formation in the brain) and on the mental status of these mice. The pharmacological agent ameliorated disorders of orientation and exploratory behavior and conditioned response performance in experimental animals. At the same time, an increase in the content of resident neural stem cells and committed neuronal precursors in the nervous tissue was found.},
}

@article {pmid41170936,
year = {2025},
author = {Haggerty, KL and Reuben, DB and Stoeckle, R and Bass, D and Boustani, M and Clevenger, C and Kremer, I and Lee, DR and Johnson, M and Minyo, MJ and Possin, KL and Samus, QM and Spragens, L and Jennings, LA and Epstein-Lubow, G},
title = {GUIDE and Beyond: Strategies for Comprehensive Dementia Care Integration.},
journal = {Journal of the American Geriatrics Society},
volume = {},
number = {},
pages = {},
doi = {10.1111/jgs.70107},
pmid = {41170936},
issn = {1532-5415},
support = {2023-0347//The John A. Hartford Foundation/ ; 1K01AG076992-01A1/NH/NIH HHS/United States ; },
abstract = {The Centers for Medicare & Medicaid Services' (CMS) Guiding an Improved Dementia Experience (GUIDE) Model represents a landmark opportunity to improve outcomes for persons with dementia and their caregivers and scale comprehensive dementia care through a structured service delivery and alternative payment approach. The National Dementia Care Collaborative (NDCC), a coalition of scientific and clinical leaders in evidence-based dementia care, works to promote comprehensive dementia care. Drawing from the experiences of six previously tested programs-Aging Brain Care, Alzheimer's and Dementia Care, BRI Care Consultation, Care Ecosystem, Integrated Memory Care, and MIND at Home-we describe a four-step approach to enable successful adoption and implementation: identifying key leaders and partners, preparing a tailored value proposition, initiating program start-up, and ensuring sustainable implementation. Our guidance also emphasizes leveraging existing community assets, aligning efforts with organizational priorities, and using both storytelling and data to make the case for change. We highlight practical tools and resources to address operational challenges, including electronic health record integration, reimbursement strategies, and staff training. By focusing on evidence-based models, health systems and other providers can accelerate implementation, reduce costly emergency and institutional care, and deliver high-quality, person-centered support. This approach can help to empower GUIDE participants and others to build effective, durable, scalable comprehensive dementia care systems, ultimately advancing the goal of establishing such care as a permanent Medicare benefit.},
}