@article {pmid40634935,
year = {2025},
author = {Wei, J and Hu, L and Xu, S and Yang, F and Liao, F and Tang, Y and Shen, X and Zhang, X and Fang, X and Li, Y and Ding, L and Chen, Z and Su, S and Cheng, J and Huang, Y and Chen, Q and Ma, D and Zhang, Q and Guo, X},
title = {Liver-specific expression of ANGPTL8 promotes Alzheimer's disease progression through activating microglial pyroptosis.},
journal = {Journal of neuroinflammation},
volume = {22},
number = {1},
pages = {177},
pmid = {40634935},
issn = {1742-2094},
support = {82471628//National Natural Science Foundation of China/ ; 82371596//National Natural Science Foundation of China/ ; },
abstract = {INTRODUCTION: Liver dysfunction contributes to Alzheimer's disease (AD) pathogenesis, and evidence suggests that the liver is involved in amyloid β (Aβ) clearance, and regulates Aβ deposition in the brain. However, the specific regulatory mechanism remains elusive.

OBJECTIVES: Angiopoietin-like protein 8 (ANGPTL8), a high expression of liver-specific secreted proinflammatory factor, crosses the blood‒brain barrier from the bloodstream to abnormally activate microglia and promote AD progression.

METHODS: The ANGPTL8[-/-] mice and 5 × FAD mice were crossed mutated and subjected to the Morris water maze test and novel object recognition test to assess cognitive ability in different cohorts. Thioflavin-S, NeuN, and Nissl staining were used to assess Aβ deposition and neuron loss. The number of phagocytic microglia was evaluated with Fitc latex beads. Adeno-associated virus 8 (AAV8) hydrodynamically injected restored the liver ANGPTL8 levels of ANGPTL8[-/-] 5 × FAD mice for further experiments. Single-cell RNA sequencing, bulk RNA sequencing and transmission electron microscopy were used to explore the role of ANGPTL8 in regulating AD progression, and drug screening was carried out to identify an effective inhibitor of ANGPTL8.

RESULTS: ANGPTL8 knockout improved cognitive function and reduced Aβ deposition by reducing microgliosis and microglial activation in 5xFAD mice. Mechanistically, ANGPTL8 crossed the blood‒brain barrier and interacted with the microglial membrane receptor PirB/LILRB2. This interaction subsequently activated the downstream NLRP3 inflammasome, leading to microglial pyroptosis and exacerbating the Aβ-induced release of inflammatory factors, thereby accelerating AD progression. Furthermore, the administration of metformin, an ANGPTL8 inhibitor, improved learning and memory deficits in 5 × FAD mice by negating microglial pyroptosis and neuroinflammation.

CONCLUSIONS: ANGPTL8 aggravates microglial pyroptosis via the PirB/NLRP3 pathway to accelerate the pathogenesis of AD. Targeting high expression of ANGPTL8 in the liver may hold potential for developing therapies for AD.},
}

@article {pmid40634792,
year = {2025},
author = {Brandt, M and Oliveira, F and Belfort, T and Nogueira, M and Baptista, MA and Lacerda, I and de Lucena, AT and Rangel, R and Dourado, MCN},
title = {The Relationship Between Facial Emotion Recognition and Executive Function Varies Depending on the Level of Cognitive Impairment.},
journal = {International journal of geriatric psychiatry},
volume = {40},
number = {7},
pages = {e70127},
doi = {10.1002/gps.70127},
pmid = {40634792},
issn = {1099-1166},
support = {//Carlos Chagas Filho Foundation/ ; //The National Council for Scientific and Technological Development/ ; },
abstract = {BACKGROUND: Cognitive domains related to attention and executive functions (a set of cognitive processes that regulate, control, and manage other cognitive abilities) seem to influence the recognition of facial expressions in people with Alzheimer's disease (AD).

PURPOSE: We examined the relationship between facial expression recognition, global cognition and executive function in people with AD according to their cognitive level.

RESEARCH DESIGN: In a cross-sectional design, we included 130 participants with AD divided into three groups based on their Mini-Mental State Examination (MMSE) scores: MMSE 1 (scores 23-28), MMSE 2 (scores 17-22), and MMSE 3 (scores 11-16). Facial expression recognition ability was analyzed using the Faces Test. Executive function was analyzed using the Trail Making Test (TMT), the Verbal Fluency Test (VFT), the Semantic Fluency Test (SFT), the Digit Span Forward (DSF) and Backward (DSB) tests, and the Clock Drawing Test (CDT).

RESULTS: In MMSE 1 group difficulties in divided attention and cognitive flexibility impacted the accuracy of facial expression recognition. In the MMSE 2 group, facial expression recognition was related to impairment in working memory. In the MMSE 3 group, the impact on facial expression recognition was directly related to visuoconstructive abilities.

CONCLUSIONS: We observed that the executive resources involved in each evaluated group differed in terms of facial recognition task performance efficacy. Interventions at stimulating executive and visuoconstructive abilities in people with AD may contribute to better preservation of facial expression recognition.},
}

@article {pmid40634788,
year = {2025},
author = {Wang, Z and Zhang, Z and Shi, J and Zhao, R},
title = {The Crosstalk Between Sepsis-Associated Encephalopathy and Alzheimer's Disease: Identifying Potential Biomarkers and Therapeutic Targets for Cognition.},
journal = {Molecular neurobiology},
volume = {},
number = {},
pages = {},
pmid = {40634788},
issn = {1559-1182},
abstract = {Patients with sepsis are at a heightened risk of long-term cognitive impairment, including neurodegenerative diseases; however, the underlying pathophysiological mechanisms remain incompletely understood. This study examines key genes associated with sepsis and Alzheimer's disease (AD), as well as their potential molecular mechanisms. We downloaded the GSE135838 dataset from the Gene Expression Omnibus (GEO) database and performed comparative analysis of differentially expressed genes (DEGs) using the AlzData database to identify co-expressed DEGs. Functional and protein-protein interaction (PPI) network analyses were used to identify hub genes and their associated molecular mechanisms. Animal experiments were conducted to validate the role of the central gene C5aR1 in the pathological processes of sepsis-related cognitive impairment, blood-brain barrier (BBB) disruption, and microglial activation. Co-culture experiments were performed to assess the protective effect of C5aR1 against inflammation-induced neuronal damage. In GSE135838, 25 DEGs exhibited consistent expression changes in the brain tissue of AD patients. Notably, LYZ, C5AR1, ZFP36, MPZL2, APOL4, CD163, SERPINA3, and CCL2 showed significant differential expression in the cortex and hippocampus of AD patients. KEGG pathway enrichment analysis revealed that among the 14 pathways meeting the criteria, the TNF signaling pathway demonstrated the highest significance. Key intersections of multiple GO enrichment terms included IL-6, ICAM1, CLEC4E, and PCK1. The top ten hub genes identified from the PPI network analysis included IL6, CCL2, ICAM1, CXCL1, CD163, C5AR1, SOCS3, CLEC4E, HSPB1, and HSPA1A. Pharmacological inhibition of the hub gene product C5aR1 using PMX205 improved cognitive and emotional dysfunction in CLP-induced septic mice and reduced BBB damage and microglial activation. Inhibition of C5aR1 also alleviated microglia-induced neuronal injury. In summary, the neuroimmune dysregulation caused by sepsis is correlated with potential pathological mechanisms in AD. This study provides additional molecular evidence for potential biomarkers and therapeutic targets for drug intervention in the risk of AD among sepsis survivors.},
}

@article {pmid40634782,
year = {2025},
author = {Oh, HS and Le Guen, Y and Rappoport, N and Urey, DY and Farinas, A and Rutledge, J and Channappa, D and Wagner, AD and Mormino, E and Brunet, A and Greicius, MD and Wyss-Coray, T},
title = {Plasma proteomics links brain and immune system aging with healthspan and longevity.},
journal = {Nature medicine},
volume = {},
number = {},
pages = {},
pmid = {40634782},
issn = {1546-170X},
support = {P50AG047366//U.S. Department of Health & Human Services | NIH | National Institute on Aging (U.S. National Institute on Aging)/ ; P30AG066515//U.S. Department of Health & Human Services | NIH | National Institute on Aging (U.S. National Institute on Aging)/ ; AG072255//U.S. Department of Health & Human Services | NIH | National Institute on Aging (U.S. National Institute on Aging)/ ; R01AG048076//U.S. Department of Health & Human Services | National Institutes of Health (NIH)/ ; R21AG058859//U.S. Department of Health & Human Services | National Institutes of Health (NIH)/ ; },
abstract = {Plasma proteins derived from specific organs can estimate organ age and mortality, but their sensitivity to environmental factors and their robustness in forecasting onset of organ diseases and mortality remain unclear. To address this gap, we estimate the biological age of 11 organs using plasma proteomics data (2,916 proteins) from 44,498 individuals in the UK Biobank. Organ age estimates were sensitive to lifestyle factors and medications and were associated with future onset (within 17 years' follow-up) of a range of diseases, including heart failure, chronic obstructive pulmonary disease, type 2 diabetes and Alzheimer's disease. Notably, having an especially aged brain posed a risk of Alzheimer's disease (hazard ratio (HR) = 3.1) that was similar to carrying one copy of APOE4, the strongest genetic risk factor for sporadic Alzheimer's disease, whereas a youthful brain (HR = 0.26) provided protection that was similar to carrying two copies of APOE2, independent of APOE genotype. Accrual of aged organs progressively increased mortality risk (2-4 aged organs, HR = 2.3; 5-7 aged organs, HR = 4.5; 8+ aged organs, HR = 8.3), whereas youthful brains and immune systems were uniquely associated with longevity (youthful brain, HR = 0.60 for mortality risk; youthful immune system, HR = 0.58; youthful both, HR = 0.44). Altogether, these findings support the use of plasma proteins for monitoring of organ health and point to the brain and immune systems as key targets for longevity interventions.},
}

@article {pmid40634770,
year = {2025},
author = {Wen, Z and Ghafouri, A and Biros, G and , },
title = {A single-snapshot inverse solver for two-species graph model of tau pathology spreading in human Alzheimer's disease.},
journal = {Brain informatics},
volume = {12},
number = {1},
pages = {18},
doi = {10.1186/s40708-025-00264-z},
pmid = {40634770},
issn = {2198-4018},
support = {OAC 22042261//NSF/ ; DE-SC0023171//U.S. Department of Energy, Office of Science, Office of Advanced Scientific Computing Research, Applied Mathematics program, Mathematical Multifaceted Integrated Capability Centers (MMICCS) program/ ; R21AG074276-01//U.S. National Institute on Aging/ ; },
abstract = {We propose a method that uses a two-species ordinary differential equation (ODE) model for subject-specific misfolded tau protein spreading in Alzheimer's disease (AD) and calibrates it from magnetic resonance imaging (MRI) and positron emission tomography (PET) scans. The ODE model is a variant of the heterodimer Fisher-Kolmogorov (HFK) model. The unknown model parameters are the initial condition (IC) for tau and three scalar parameters representing the migration, proliferation, and clearance of tau proteins. Driven by imaging data, these parameters are estimated by formulating a constrained optimization problem with a sparsity regularization for the IC. This optimization problem is solved with a projection-based quasi-Newton algorithm. We evaluate the performance of our method on both synthetic and clinical data. Subjects are from the AD Neuroimaging Initiative (ADNI) datasets: 455 cognitively normal (CN), 212 mild cognitive impairment (MCI), and 45 AD subjects. We compare the performance of our approach to the commonly used Fisher-Kolmogorov (FK) model with a fixed IC at the entorhinal cortex (EC). Our method demonstrates an average improvement of 19.6% relative error compared to the FK model on the AD dataset. HFK also achieves an R-squared score of 0.591 for fitting AD data compared with 0.256 from FK model results with IC fixing at EC. The inverted IC from our scheme indicates that the EC is the most likely initial seeding region if subcortical regions are excluded from the analysis. However, other regions also have probability to be the IC seeding regions. Furthermore, for cases that have longitudinal data, we estimate a subject-specific AD onset time.},
}

@article {pmid40634647,
year = {2025},
author = {Hammers, DB and Schulman, D and Fowler, NR and Musema, J and Brosch, JR and Summanwar, D and Swartzell, K and Higgins, C and Banks, R and Selzler, KJ and MacLeod, T and Tobyne, S and Willis, DR},
title = {Performance of Older Adults on the Digital Clock and Recall Test Compared to the Montreal Cognitive Assessment in Primary Care Settings.},
journal = {Journal of general internal medicine},
volume = {},
number = {},
pages = {},
pmid = {40634647},
issn = {1525-1497},
abstract = {BACKGROUND: Digital cognitive assessment solutions can overcome some barriers to cognitive screening in primary care by providing rapidly obtained objective insights without requiring specialty trained examiners. Real-world comparison of digital assessments to standard screenings in primary care is limited.

OBJECTIVE: Our objective was to compare performance on the Linus Health Digital Clock and Recall (DCR™) to the Montreal Cognitive Assessment (MOCA), which is a traditional "gold standard" cognitive screening test in primary care.

PARTICIPANTS: A total of 114 primary care patients ≥ 65 years old completed a DCR as part of routine primary care and scored in the "Borderline" or "Impaired" ranges, and subsequently completed a MOCA at a follow-up primary care visit.

DESIGN: Criterion and convergent validity analyses were conducted using Mann-Whitney U tests, concordance (agreement) rates, polychoric or polyserial correlations, and exploratory factor analysis.

MAIN MEASURES: DCR and MOCA Total Scores and subcomponent scores.

KEY RESULTS: DCR Total Score and select process scores successfully discriminated impairment on the MOCA using traditional cutoffs, and both agreement rates and correlations were strong between DCR and MOCA components-especially Total Scores comparisons. Exploratory factor analysis revealed a five-factor model whereby one factor was comprised of memory subtests from both the DCR and MOCA, and another was comprised of non-memory MOCA subtests and Information Processing/Spatial Reasoning subcomponents of the DCR.

CONCLUSIONS: Screening in primary care using the DCR is feasible, and shows criterion and convergent validity with a "gold standard" screening tool for detecting cognitive impairment-the MOCA. When paired with parallel advancements in detection of plasma-based biomarkers and recent FDA approvals for disease-modifying treatments for Alzheimer's disease, the DCR and similar digital cognitive assessment tools have the potential to triage patients for both Alzheimer's disease diagnostic workups and subsequent treatments beyond specialty care.},
}

@article {pmid40634605,
year = {2025},
author = {Hou, K and Ge, P and Sawaya, MR and Lutter, L and Dolinsky, JL and Yang, Y and Jiang, YX and Boyer, DR and Cheng, X and Pi, J and Zhang, J and Lu, J and Abskharon, R and Yang, S and Yu, Z and Feigon, J and Eisenberg, DS},
title = {How short peptides disassemble tau fibrils in Alzheimer's disease.},
journal = {Nature},
volume = {},
number = {},
pages = {},
pmid = {40634605},
issn = {1476-4687},
abstract = {Reducing fibrous aggregates of the protein tau is a possible strategy for halting the progression of Alzheimer's disease (AD)[1]. Previously, we found that in vitro, the D-enantiomeric peptide (D-peptide) D-TLKIVWC disassembles ultra-stable tau fibrils extracted from the autopsied brains of individuals with AD (hereafter, these tau fibrils are referred to as AD-tau) into benign segments, with no energy source other than ambient thermal agitation[2]. To consider D-peptide-mediated disassembly as a potential route to therapeutics for AD, it is essential to understand the mechanism and energy source of the disassembly action. Here, we show that the assembly of D-peptides into amyloid-like ('mock-amyloid') fibrils is essential for AD-tau disassembly. These mock-amyloid fibrils have a right-handed twist but are constrained to adopt a left-handed twist when templated in complex with AD-tau. The release of strain that accompanies the conversion of left-twisted to right-twisted, relaxed mock-amyloid produces a torque that is sufficient to break the local hydrogen bonding between tau molecules, and leads to the fragmentation of AD-tau. This strain-relief mechanism seems to operate in other examples of amyloid fibril disassembly, and could inform the development of first-in-class therapeutics for amyloid diseases.},
}

@article {pmid40634379,
year = {2025},
author = {Latif, S and Islam, NU and Uddin, Z and Cheema, KM and Ahmed, SS and Khan, MF},
title = {Deep ensemble learning with transformer models for enhanced Alzheimer's disease detection.},
journal = {Scientific reports},
volume = {15},
number = {1},
pages = {24720},
pmid = {40634379},
issn = {2045-2322},
support = {QA-APC-2025//Qassim University/ ; },
mesh = {*Alzheimer Disease/diagnosis ; Humans ; *Deep Learning ; Neural Networks, Computer ; Biomarkers ; Ensemble Learning ; },
abstract = {The progression of Alzheimer's disease is relentless, leading to a worsening of mental faculties over time. Currently, there is no remedy for this illness. Accurate detection and prompt intervention are pivotal in mitigating the progression of the disease. Recently, researchers have been developing new methods for detecting Alzheimer's at earlier stages, including genetic testing, blood tests for biomarkers, and cognitive assessments. Cognitive assessments involve a series of tests to measure memory, language, attention, and other brain functions. For disease detection, optimal performance necessitates enhanced accuracy and efficient computational capabilities. Our proposition involves the data augmentation of textual data; after this, we deploy our proposed BERT-based deep learning model to make use of its advanced capabilities for improved feature extraction and text comprehension. Our proposed model is a two-branch network. The first branch is based on the BERT encoder, which is used to encode the text data into a fixed-length vector; the BERT output is fed into the convolution layer, followed by the LSTM layer, and finally, the fully connected layer to predict whether a patient has AD or not. The second branch is based on the recurrent convolutional neural network. The recurrent convolutional neural network also takes text data as input and generates the final classification output. Finally, these branches are fused using the ensemble learning approach to give a more robust and accurate output. The proposed model is trained on a corpus of clinical notes from patients with AD and healthy control subjects. Evaluated on the Cookie Theft subset of the DementiaBank Pitt Corpus, our ensemble achieves 94.98% accuracy, 0.9523 F1-score, and 0.93 AUC. The results show that the proposed model outperforms state-of-the-art models for the early diagnosis of AD from text.},
}

*Alzheimer Disease/diagnosis
Humans
*Deep Learning
Neural Networks, Computer
Biomarkers
Ensemble Learning

@article {pmid40634156,
year = {2025},
author = {Jakabek, D and Isaacs, AM and De Strooper, B and Tuszynski, M and Lane, R and Uspenskaya, O and McDade, E and Rafii, MS and Mummery, CJ},
title = {CTAD taskforce: genetic therapies in Alzheimer's disease.},
journal = {The journal of prevention of Alzheimer's disease..},
volume = {},
number = {},
pages = {100269},
doi = {10.1016/j.tjpad.2025.100269},
pmid = {40634156},
issn = {2426-0266},
abstract = {There are an increasing number of genetic approaches to treating Alzheimer's disease and other dementias, with some promising results from early-phase trials. This prompted the convention of the first EU-US CTAD Task Force on genetic therapies in Alzheimer's disease in October 2024. Preclinical studies and clinical trials of genetic therapies in Alzheimer's disease and other dementias are presented here with key lessons for the field. Importantly, there are several challenges and opportunities unique to neurogenetic therapies which were reviewed and discussed, including means of genetic manipulation, adverse events, monitoring, timing of therapy, and the importance of patient involvement in trial design. Continued collaboration across disciplines will accelerate development of neurogenetic therapeutics.},
}

@article {pmid40634123,
year = {2025},
author = {Daudelin, D and Sama-Borbon, D and Zhang, N and Sockanathan, S},
title = {Novel roles for the GPI-anchor cleaving enzyme, GDE2, in hippocampal synaptic morphology and function.},
journal = {eNeuro},
volume = {},
number = {},
pages = {},
doi = {10.1523/ENEURO.0102-25.2025},
pmid = {40634123},
issn = {2373-2822},
abstract = {Hippocampal synaptic activity is tightly regulated to ensure appropriate synaptic function and plasticity, which are important for critical cognitive processes such as learning and memory. Altered hippocampal synaptic function can lead to cognitive and behavioral deficits observed in neurodegenerative diseases such as Alzheimer's Disease (AD), necessitating a deeper fundamental understanding of hippocampal synaptic control mechanisms. Glycerophosphodiester phosphodiesterase 2 (GDE2 or GDPD5) is a surface transmembrane enzyme that cleaves the glycosylphosphatidylinositol (GPI) anchor that tethers some proteins to the membrane. Mice lacking GDE2 (Gde2KO) display behavioral deficits in learning and memory that are hippocampal-dependent. However, roles for GDE2 in mouse hippocampal function are not known. Here, we show that GDE2 is expressed in pre- and post-synaptic compartments along apical dendrites in hippocampal CA1 cells. Gde2KO CA1 cells showed increased dendritic length and complexity and increased numbers of mushroom spines localized to the stratum radiatum Further, adult Gde2KOs displayed an increased frequency of miniature excitatory post-synaptic currents (mEPSCs), impaired paired-pulse facilitation (PPF), and disrupted N-methyl-D-aspartate (NMDAR)-mediated long-term depression (LTD). The phosphatidylinositol 3-Kinase-AKT-glycogen synthase kinase 3 (PI3K-AKT-GSK3) signaling pathway, implicated in the inhibition of NMDAR-mediated LTD, was abnormally activated in Gde2KO hippocampus, and inhibition of PI3K restored Gde2KO NMDAR-mediated LTD to WT levels. These observations identify GDE2 as an essential physiological regulator of CA1 synaptic morphology and hippocampal pre- and post-synaptic function, including the modulation of NMDAR-mediated LTD via the PI3K-AKT-GSK3 signaling axis.Significance statement Hippocampal synaptic function is critical for important cognitive functions such as learning and memory. Understanding how hippocampal synaptic activity is regulated could help clarify the basis of diseases such as Alzheimer's Disease, where these cognitive functions are impaired. This study identifies a new player that is important for regulating hippocampal synaptic morphology and function. GDE2 is essential for maintaining normal dendritic structure and synaptic activity in hippocampal CA1 cells. Loss of GDE2 leads to altered synaptic plasticity, including disrupted NMDAR-mediated long-term depression (LTD), which is due to aberrant activation of the PI3K-AKT-GSK3 signaling pathway. These results provide new insight into the molecular mechanisms underlying hippocampal synaptic regulation.},
}

@article {pmid40634107,
year = {2025},
author = {Badesso, S and Perez-Gonzalez, M and Exposito, S and Espelosin, M and Cambria, C and D'Andrea, L and Imperato, G and Moeini, P and Vales, A and Gonzalez-Aseguinolaza, G and Mitro, N and Antonucci, F and Martín, ED and Marcello, E and Cuadrado-Tejedor, M and Garcia-Osta, A},
title = {Loss of PLA2G4E compromises synaptic structure and cognitive outcomes in mice.},
journal = {Life science alliance},
volume = {8},
number = {9},
pages = {},
doi = {10.26508/lsa.202503323},
pmid = {40634107},
issn = {2575-1077},
mesh = {Animals ; Mice ; *Synapses/metabolism ; Mice, Knockout ; *Cognition/physiology ; Neuronal Plasticity/genetics/physiology ; *Group IV Phospholipases A2/genetics/metabolism ; Neurons/metabolism ; Brain/metabolism ; Alzheimer Disease/metabolism/genetics ; Dendrites/metabolism ; Male ; Mice, Inbred C57BL ; Memory Disorders/genetics ; },
abstract = {Given its potential role in supporting cognitive resilience, PLA2G4E has emerged as a compelling therapeutic target in the context of Alzheimer's disease (AD). However, its physiological functions in the central nervous system remain largely unexplored. In this study, we demonstrate that Pla2g4e expression peaks during early postnatal brain development, coinciding with the rapid formation of synapses. Loss-of-function experiments in primary neuronal cultures revealed that Pla2g4e expression is essential for proper dendritic development and neuronal maturation. In constitutive Pla2g4e knockout mice, we observed significant disruptions in the developmental profiles of cortical synaptic plasticity markers, accompanied by impairments in memory-related behaviors. Notably, the adeno-associated virus-mediated overexpression of PLA2G4E rescued memory deficits, highlighting its functional relevance in cognitive processes. Furthermore, selective deletion of Pla2g4e in excitatory neurons of the adult brain resulted in moderate memory impairments in aged animals, suggesting an ongoing role in synaptic maintenance. Together, these findings establish PLA2G4E as a key regulator of dendritic architecture, synaptic function, and cognitive performance, and highlight its potential as a gene therapy target for neurodegenerative diseases characterized by synaptic dysfunction.},
}

Animals
Mice
*Synapses/metabolism
Mice, Knockout
*Cognition/physiology
Neuronal Plasticity/genetics/physiology
*Group IV Phospholipases A2/genetics/metabolism
Neurons/metabolism
Brain/metabolism
Alzheimer Disease/metabolism/genetics
Dendrites/metabolism
Male
Mice, Inbred C57BL
Memory Disorders/genetics

@article {pmid40633621,
year = {2025},
author = {Limone, A and Di Napoli, C and De Rosa, G and Bagnoli, S and Izzo, A and Procaccini, C and Matarese, G and Nacmias, B and Lavecchia, A and Sarnataro, D},
title = {Modulation of mitochondrial quality control through autophagic pathway in familial Alzheimer's disease.},
journal = {Biochimica et biophysica acta. Molecular cell research},
volume = {},
number = {},
pages = {120019},
doi = {10.1016/j.bbamcr.2025.120019},
pmid = {40633621},
issn = {1879-2596},
abstract = {Autophagy is a highly conserved cellular catabolic process recognized as an essential pathway for the maintenance of cellular homeostasis. Growing evidence implicates autophagic dysfunction in the pathogenesis of several neurodegenerative disorders, including Alzheimer's disease (AD), thus its modulation might represent an interesting therapeutic tool. Searching for a compound that stimulates autophagic pathway, led us to identify the inhibitor of RPSA receptor, NSC47924. In this study, we show that, NSC47924 down-modulated Akt-mTOR-axis pathway, the master regulator of autophagy, which was abnormally hyperactivated in fibroblasts from genetic AD-affected patients. Consistently, by monitoring the conversion of LC3, we found that inhibition of RPSA enhanced and restored the compromised autophagic flux. Moreover, by qRT-PCR analysis we found that inhibitor treatment upregulated the expression of autophagy-linked genes. Importantly, AD-affected fibroblasts exhibited massive mitochondrial network fragmentation and mitophagy defects, which were restored through the stimulation of autophagy induced by RPSA inhibition. Consistent with an efficient elimination of dysfunctional mitochondria, we found that the turnover of both the mitophagy regulators PINK1 and Parkin and the autophagic receptors p62, NDP52, OPTN, was modulated, thus restoring a highly interconnected organelle's network. In addition, the improvement of mitochondrial morphology correlated with a functional recovery, as assessed by Seahorse analysis and mitochondrial ROS production evaluation. Collectively, our findings suggest that RPSA inhibition stimulates an autophagic pathway promoting the efficient removal of damaged mitochondria, favouring the recovery of cellular homeostasis, and counteracting crucial AD pathogenic mechanisms.},
}

@article {pmid40633584,
year = {2025},
author = {Bagheri, N and Marvelani, G and Chiang, TW and Nelson, PT and Chuang, TJ and Stamm, S},
title = {Circular RNAs from the MAPT and TARDP genes: Novel players in neurodegeneration?.},
journal = {Neurochemistry international},
volume = {},
number = {},
pages = {106019},
doi = {10.1016/j.neuint.2025.106019},
pmid = {40633584},
issn = {1872-9754},
abstract = {The microtubule associated protein tau (MAPT) and TAR DNA binding protein (TARDBP) genes play crucial roles in neurodegeneration. The tau protein encoded by MAPT is the main component of tau tangles, a pathologic hallmark of "tauopathies" such as Alzheimer's disease (AD). Cytosolic accumulations of TDP-43, encoded by TARDBP are characteristic for LATE (Limbic-predominant age-related TDP-43 encephalopathy) and other TDPopathies. In addition to the well-characterized mRNA splicing isoforms, both genes generate a multitude of circular RNAs (circRNAs). Both MAPT and TARDBP express circular RNA-specific exons characterized by suboptimal splice sites and lengths and are frequently derived from Alu-elements. Most circTau and likely all circTARDBP RNAs expressed in brain are human-specific, suggesting a possible unique contribution to human brain disease. TARDBP and MAPT circRNAs harbor open reading frames and circTau RNAs were shown to be translated into polypeptides in cells. Thus, circRNAs from the MAPT and TARDBP genes should be considered in molecular analysis of AD, LATE and other neurological diseases.},
}

@article {pmid40633469,
year = {2025},
author = {Al Shamsi, HSS and Gardener, SL and Sohrabi, HR and Taddei, K and Masters, CL and Rainey-Smith, SR and Martins, RN and Fernando, WMADB},
title = {The moderating effect of dietary patterns on the association of depression and anxiety with cognitive function.},
journal = {Clinical nutrition (Edinburgh, Scotland)},
volume = {51},
number = {},
pages = {278-286},
doi = {10.1016/j.clnu.2025.06.013},
pmid = {40633469},
issn = {1532-1983},
abstract = {BACKGROUND AND AIMS: Investigating modifiable risk factors, such as diet, is crucial in understanding their effects on the relationship between Alzheimer's disease (AD)-related cognitive decline and related conditions. This study assesses whether dietary patterns moderate the relationship between symptoms of depression, anxiety, and cognitive function in older adults. Given that biological and psychosocial differences between sexes may influence dietary behaviours, mental health symptoms, and cognitive outcomes, conducting sex-stratified analyses will allow for identification of differential associations.

METHOD: Cross-sectional data from cognitively unimpaired older adults (n = 1174, age ≥60 years) from the Australian Imaging, Biomarkers and Lifestyle (AIBL) study were included. Participants completed the Cancer Council of Victoria food frequency questionnaire, provided depression and anxiety symptom data, and underwent neuropsychological testing. Composite scores for six cognitive domains were generated from individual test scores (episodic recall, recognition, executive function, language, attention processing, and the AIBL Preclinical Alzheimer Cognitive Composite (PACC)). Dietary pattern scores were calculated for the Mediterranean diet (MeDi), Dietary Approaches to Stop Hypertension (DASH), and Western diet. Moderation analysis explored interactions between dietary patterns, depression, anxiety, and cognitive performance.

RESULTS: The MeDi was found to moderate the relationship between depressive symptoms and attention processing in males, where low to moderate MeDi adherence was linked to poorer attention with higher depressive symptoms. The Western diet moderated the relationship between anxiety and the AIBL PACC score in males, with high adherence to the Western diet associated with worse PACC performance in those with greater anxiety. No significant moderating effects were observed in females for the MeDi and Western diet, or in either sex for the DASH diet on the association of depression and anxiety with cognitive function.

CONCLUSION: These findings also emphasise the importance of sex-specific approaches in research on symptoms of depression and anxiety, cognitive health, and diet. Our results highlight the need for further investigation into sex-specific pathways using longitudinal study designs and randomised controlled trials to establish causal relationships.},
}

@article {pmid40633409,
year = {2025},
author = {Khaliq, A and Ahmad, F and Rehman, HU and Alanazi, SA and Haleem, H and Junaid, K and Andrikopoulou, E},
title = {Revolutionizing medical imaging: A cutting-edge AI framework with vision transformers and perceiver IO for multi-disease diagnosis.},
journal = {Computational biology and chemistry},
volume = {119},
number = {},
pages = {108586},
doi = {10.1016/j.compbiolchem.2025.108586},
pmid = {40633409},
issn = {1476-928X},
abstract = {The integration of artificial intelligence in medical image classification has significantly advanced disease detection. However, traditional deep learning models face persistent challenges, including poor generalizability, high false-positive rates, and difficulties in distinguishing overlapping anatomical features, limiting their clinical utility. To address these limitations, this study proposes a hybrid framework combining Vision Transformers (ViT) and Perceiver IO, designed to enhance multi-disease classification accuracy. Vision Transformers leverage self-attention mechanisms to capture global dependencies in medical images, while Perceiver IO optimizes feature extraction for computational efficiency and precision. The framework is evaluated across three critical clinical domains: neurological disorders, including Stroke (tested on the Brain Stroke Prediction CT Scan Image Dataset) and Alzheimer's (analyzed via the Best Alzheimer MRI Dataset); skin diseases, covering Tinea (trained on the Skin Diseases Dataset) and Melanoma (augmented with dermoscopic images from the HAM10000/HAM10k dataset); and lung diseases, focusing on Lung Cancer (using the Lung Cancer Image Dataset) and Pneumonia (evaluated with the Pneumonia Dataset containing bacterial, viral, and normal X-ray cases). For neurological disorders, the model achieved 0.99 accuracy, 0.99 precision, 1.00 recall, 0.99 F1-score, demonstrating robust detection of structural brain abnormalities. In skin disease classification, it attained 0.95 accuracy, 0.93 precision, 0.97 recall, 0.95 F1-score, highlighting its ability to differentiate fine-grained textural patterns in lesions. For lung diseases, the framework achieved 0.98 accuracy, 0.97 precision, 1.00 recall, 0.98 F1-score, confirming its efficacy in identifying respiratory conditions. To bridge research and clinical practice, an AI-powered chatbot was developed for real-time analysis, enabling users to upload MRI, X-ray, or skin images for automated diagnosis with confidence scores and interpretable insights. This work represents the first application of ViT and Perceiver IO for these disease categories, outperforming conventional architectures in accuracy, computational efficiency, and clinical interpretability. The framework holds significant potential for early disease detection in healthcare settings, reducing diagnostic errors, and improving treatment outcomes for clinicians, radiologists, and patients. By addressing critical limitations of traditional models, such as overlapping feature confusion and false positives, this research advances the deployment of reliable AI tools in neurology, dermatology, and pulmonology.},
}

@article {pmid40633205,
year = {2025},
author = {Metzendorf, NG and Godec, A and Petrovic, A and Chourlia, A and Napoleone, A and Syvänen, S and Rofo, F and Hultqvist, G},
title = {Somatostatin therapy, neprilysin activation, and amyloid beta reduction: A novel approach for Alzheimer's treatment.},
journal = {Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie},
volume = {189},
number = {},
pages = {118325},
doi = {10.1016/j.biopha.2025.118325},
pmid = {40633205},
issn = {1950-6007},
abstract = {INTRODUCTION: Neprilysin is the primary enzyme responsible for the degradation of amyloid beta (Aβ), with its levels regulated by the hormone somatostatin (SST).

METHODS: We have developed a novel treatment mechanism for Alzheimer's disease (AD) by combining SST with a blood-brain barrier (BBB) transporter and a Fc fragment to extend its half-life. This treatment was tested in a murine AD model overexpressing amyloid precursor protein (APP) with the Arctic mutation in Aβ (APPArcSwe).

RESULTS: Our findings demonstrate a significant increase in neprilysin levels, which correlates with a reduction in various forms of Aβ, including membrane-bound and intracellular Aβ aggregates, as well as Aβ42 in insoluble aggregates.

DISCUSSION: These results suggest that neprilysin can effectively degrade Aβ with the Arctic mutation. Additionally, this treatment strategy successfully reduces both oligomeric and larger Aβ, aggregates, a challenge for other therapeutic approaches. This novel strategy holds promise as a potential therapeutic approach for AD.},
}

@article {pmid40632863,
year = {2025},
author = {Shao, L and Zhang, Y and Yang, Z and Shi, C and Yue, X and Li, C and Liu, Y and Fu, Z and Tang, C and Zhao, X and Han, M and Zhang, J and Sun, W and Yao, Z and Xi, K and Fang, Z and Wang, Z and Feng, F and Ma, C and Zhao, K and Zhang, Y and Ni, S and Jiang, X and Chen, C},
title = {Synthetic efferocytic receptor microglia enhances anti-inflammatory clearance of amyloid-β for AD treatment in mice.},
journal = {Science advances},
volume = {11},
number = {28},
pages = {eads6613},
doi = {10.1126/sciadv.ads6613},
pmid = {40632863},
issn = {2375-2548},
mesh = {Animals ; *Amyloid beta-Peptides/metabolism ; *Microglia/metabolism ; *Alzheimer Disease/metabolism/therapy/pathology ; Mice ; Disease Models, Animal ; Phagocytosis ; Humans ; Inflammation ; Nanoparticles/chemistry ; Anti-Inflammatory Agents ; Mice, Transgenic ; },
abstract = {Monoclonal antibody immunotherapy targeting the clearance of amyloid-β (Aβ) has shown promise in Alzheimer's disease (AD). However, current antibody treatments trigger Fc receptors and induce proinflammatory responses, in turn exacerbating neuronal damage. Here, we report a synthetic efferocytic receptor (SER) integrating Aβ-targeting scFv, efferocytosis receptor backbone based on TIM4 and downstream signal for microglia (MG) reprogramming, which enabled selective elimination of Aβ without inducing an inflammatory response. Specifically, our in-house-customized MG-editing mRNA lipid nanoparticles (MERLINs) efficiently introduced SER mRNA into MG to generate Aβ-specific SER-MG in situ. SER-MG exhibited robust Aβ-specific phagocytosis and stimulated anti-inflammatory efferocytosis typical signaling in vitro. In a mouse model of AD, SER expression in the MG markedly increased the clearance of Aβ and dampened inflammation, resulting in improved behavioral outcomes along with substantially reduced synapse elimination. Our findings establish that AD-associated aberrant MG can be in situ reprogrammed with SER for Aβ clearance in an anti-inflammatory manner, with broad application in other inflammation-related diseases.},
}

Animals
*Amyloid beta-Peptides/metabolism
*Microglia/metabolism
*Alzheimer Disease/metabolism/therapy/pathology
Mice
Disease Models, Animal
Phagocytosis
Humans
Inflammation
Nanoparticles/chemistry
Anti-Inflammatory Agents
Mice, Transgenic

@article {pmid40632500,
year = {2025},
author = {Prasad, H and Rao, R},
title = {Linking Endo-lysosomal pH, Sterol and Trafficking to Neurodegenerative Disease.},
journal = {FEMS yeast research},
volume = {},
number = {},
pages = {},
doi = {10.1093/femsyr/foaf034},
pmid = {40632500},
issn = {1567-1364},
abstract = {Although endo-lysosomal abnormalities have been recognized as a pathognomonic feature of Alzheimer's disease, the lack of druggable targets has hampered the translation from bench to bedside. This article provides an overview of the insights gained from yeast research with a focus on understudied luminal acidification mechanisms and their major impact on disease progression. The yeast-to-human discovery and validation strategy identified a "druggable" triad featuring luminal pH, sterol content, and trafficking that (dys)regulate reciprocally. Endosomal Na+/H+ exchangers (eNHE), discovered in yeast and later described in mammals, provide independent support for this pathogenic model. The brain is often the most severely affected organ in patients with eNHE mutations, and a subset is causally linked to progressive and severe neurodegeneration, demonstrating that neurons heavily rely on fine-tuning of endosomal pH. We present recent advances on the role of eNHE in ageing related neurodegenerative diseases, which has implications for pathogenesis and therapy. Future studies should unravel the broader landscape of endo-lysosomal pH in neurodegenerative diseases. Given that pharmacologic correction of luminal hyper-acidification defect completely ameliorates endo-lysosomal deficits in eNHE deletion yeast, there is compelling reason to believe that efforts to target endo-lysosomal acid-base homeostasis will eventually lead to novel therapeutic approaches for neurodegenerative diseases.},
}

@article {pmid40632335,
year = {2025},
author = {Banu, Z and Das, NR},
title = {In Vitro Assessment of Cholinesterase Inhibition and Neuroprotective Effects of Elaeocarpus angustifolius Blume Against Amyloid-Beta Peptide-Induced Toxicity in SH-SY5Y and BV-2 Cells.},
journal = {Neurochemical research},
volume = {50},
number = {4},
pages = {226},
pmid = {40632335},
issn = {1573-6903},
mesh = {*Amyloid beta-Peptides/toxicity ; Humans ; *Neuroprotective Agents/pharmacology/isolation & purification ; *Cholinesterase Inhibitors/pharmacology/isolation & purification ; Animals ; *Plant Extracts/pharmacology ; Mice ; Butyrylcholinesterase/metabolism ; Cell Survival/drug effects/physiology ; *Peptide Fragments/toxicity ; Acetylcholinesterase/metabolism ; Cell Line, Tumor ; Cell Line ; Dose-Response Relationship, Drug ; },
abstract = {Alzheimer's disease (AD) is a progressive neurodegenerative disorder primarily characterized by memory impairment and cognitive decline. Pathophysiological mechanisms contributing to AD include oxidative stress, increased acetylcholinesterase activity, neuroinflammation, and the accumulation of hyperphosphorylated tau proteins and amyloid-β (Aβ) plaques in the brain. The shortcomings of existing therapeutic approaches have necessitated the exploration of alternative treatment strategies. Elaeocarpus angustifolius Blume, traditionally used for neurological disorders, has been investigated for its neuroprotective potential through its alkaloid-rich fraction. This study evaluated the acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) inhibitory activities of E. angustifolius alkaloid-rich fraction (EAF) and its protective effects against Aβ1-42-induced cytotoxicity in human neuron-like SH-SY5Y cells and murine microglial BV-2 cells using the MTT assay. The results demonstrated that for AChE and BuChE, EAF showed significant inhibition with IC50 of 145.1 ± 4.782 µg/mL and 165.8 ± 1.10 µg/mL, respectively. In the MTT assay, EAF effectively mitigated Aβ1-42-induced cytotoxicity in a dose-dependent manner, with the highest dose (100 µg/mL) restoring viability from 67.91 to 75.31% in SH-SY5Y cells and from 60.29 to 76.01% in BV-2 cells. From these results, it is apparent that EAF has anticholinesterase and neuroprotective properties. However, further research on this may help decipher underlying mechanisms before establishing EAF as an effective alternative in treating AD.},
}

*Amyloid beta-Peptides/toxicity
Humans
*Neuroprotective Agents/pharmacology/isolation & purification
*Cholinesterase Inhibitors/pharmacology/isolation & purification
Animals
*Plant Extracts/pharmacology
Mice
Butyrylcholinesterase/metabolism
Cell Survival/drug effects/physiology
*Peptide Fragments/toxicity
Acetylcholinesterase/metabolism
Cell Line, Tumor
Cell Line
Dose-Response Relationship, Drug

@article {pmid40632121,
year = {2025},
author = {Daly, T},
title = {Review of Doctored: Fraud, Arrogance and Tragedy in the Quest to Cure Alzheimer's by Charles Piller.},
journal = {AJOB neuroscience},
volume = {16},
number = {3},
pages = {W1-W2},
doi = {10.1080/21507740.2025.2519434},
pmid = {40632121},
issn = {2150-7759},
}

@article {pmid40632028,
year = {2025},
author = {Fang, S and Guan, L and Jian, H and Dai, X and Gong, L},
title = {Body weight and BMI variability linked to dementia risk: A meta-analysis.},
journal = {Biomolecules & biomedicine},
volume = {},
number = {},
pages = {},
doi = {10.17305/bb.2025.12626},
pmid = {40632028},
issn = {2831-090X},
abstract = {Emerging evidence suggests that fluctuations in body weight (BW) or body mass index (BMI), independent of average levels, may influence dementia risk. However, the association between intra-individual variability in BW or BMI and incident dementia remains unclear. This meta-analysis aimed to clarify this relationship. A systematic search of PubMed, Embase, and Web of Science was conducted through March 25, 2025, to identify longitudinal observational studies reporting dementia outcomes in relation to BW or BMI variability. Relative risks (RRs) comparing the highest versus lowest variability categories were pooled using a random-effects model. Subgroup and sensitivity analyses were performed to explore heterogeneity and assess the robustness of the results. Nine cohort studies (10 datasets; 4,232,666 participants) were included. Overall, high BW or BMI variability was associated with a significantly increased risk of dementia (RR = 1.36, 95% CI: 1.27-1.46; p < 0.001; I[2] = 84%). The association was consistent for both BW (RR = 1.45) and BMI (RR = 1.34) variability. Subgroup analyses showed stronger associations in prospective studies than in retrospective ones, and in studies that did not adjust for baseline BW/BMI compared to those that did (p for subgroup difference < 0.05). Associations remained robust in sensitivity analyses and across dementia subtypes, including Alzheimer's disease and vascular dementia. No significant publication bias was detected (Egger's test, p = 0.22). In conclusion, greater intra-individual variability in BW or BMI may be independently associated with increased dementia risk. These findings underscore the importance of maintaining weight stability in mid-to-late life as a potential preventive strategy for dementia.},
}

@article {pmid40631882,
year = {2025},
author = {Anand, C and Abdelnour, F and Sipes, B and Ma, D and Maia, PD and Torok, J and Raj, A},
title = {Selective vulnerability and resilience to Alzheimer's disease tauopathy as a function of genes and the connectome.},
journal = {Brain : a journal of neurology},
volume = {},
number = {},
pages = {},
doi = {10.1093/brain/awaf179},
pmid = {40631882},
issn = {1460-2156},
support = {R01NS092802/GF/NIH HHS/United States ; RF1AG062196/GF/NIH HHS/United States ; R01AG072753/GF/NIH HHS/United States ; },
abstract = {Brain regions in Alzheimer's disease exhibit distinct vulnerability to its hallmark pathology with the entorhinal cortex and hippocampus succumbing early to tau tangles while others like the primary sensory cortices remain resilient. The quest to understand how local/regional genetic factors, pathogenesis and network-mediated pathology spread, together govern this selective vulnerability (SV) or resilience (SR) is ongoing. Although many Alzheimer's risk genes are known from gene association and transgenic studies, it is still unclear whether and how their baseline expression confers SV/SR to pathology. Prior analyses have yielded conflicting results, pointing to a disconnect between the location of genetic risk factors and downstream tau pathology. The spatial distribution of vulnerability doesn't always align with genetic factors, suggesting a role for non-cell-autonomous mechanisms like transneuronal tau transmission. We hypothesize that a full accounting of the role of genes in mediating SV/SR would require modelling of network-based vulnerability, whereby tau misfolds, aggregates and propagates along fibre projections. We employed an extended network diffusion model (eNDM) and fitted it on tau PET data from 196 patients from the Alzheimer's Disease Neuroimaging Initiative. The fitted eNDM then becomes a reference from which to assess the role of innate genetic factors. Using the residual (observed - model-predicted) tau as a novel target outcome, we obtained its association with 100 Alzheimer's risk genes, whose baseline spatial transcriptional profiles were obtained from the Allen Human Brain Atlas. Our eNDM was successful in capturing tau pathology distribution in patients. After regressing out the model, we found that while many risk genes have spatial expression patterns that correlate with regional tau, many others showed a stronger association with residual tau. This suggests that direct vulnerability aligned with the network, as well as network-independent vulnerability, are conferred by risk genes. We report four classes of risk genes: network-aligned SV (SV-NA), network-independent SV (SV-NI), network-aligned SR (SR-NA) and network-independent SR (SR-NI), each with a distinct spatial signature and associated vulnerability to tau. Remarkably, using gene ontology analysis, we found that the identified gene classes have distinct and sometimes surprising functional enrichment patterns. Network-aligned genes broadly participate in cell death, stress response and metabolic processing; network-independent genes in amyloid-β processing and immune response. These previously unreported segregated roles point to multiple distinct pathways by which risk genes confer vulnerability or resilience in Alzheimer's disease. Our findings offer new insights into vulnerability signatures in Alzheimer's disease and may prove helpful in identifying potential intervention targets.},
}

@article {pmid40631789,
year = {2025},
author = {Zhao, F and Yang, H and Liu, H and Yu, H and Zhao, Y},
title = {FGF21 restores metabolic function in Alzheimer's disease via activation of PI3K/Akt signaling.},
journal = {Neurological research},
volume = {},
number = {},
pages = {1-16},
doi = {10.1080/01616412.2025.2521721},
pmid = {40631789},
issn = {1743-1328},
abstract = {BACKGROUND AND OBJECTIVE: Alzheimer's disease (AD) is a neurodegenerative disorder characterized by cognitive decline, oxidative stress, and mitochondrial dysfunction. Fibroblast growth factor 21 (FGF21) has demonstrated neuroprotective effects, though its role in AD pathogenesis remains unclear. The present study aims to discover neuroprotective effects of FGF21 in AD by examining its influence on energy metabolism and neuronal survival through the PI3K/Akt signaling pathways.

METHODS: In vivo experiments were performed using 5×FAD transgenic mice, while in vitro assays utilized amyloid beta 1-42 (Aβ1-42)-treated SH-SY5Y cells and a co-culture system of primary rat astrocytes with SH-SY5Y cells. To evaluate the effects of FGF21 modulation, we performed both gain- and loss-of-function experiments and assessed outcomes using behavioral testing, histopathological and ultrastructural analyses, oxidative stress and mitochondrial function assays, and Western blotting. The involvement of the PI3K/Akt/mTOR pathway was explored using the PI3K inhibitor LY294002.

RESULTS: Both in vivo and in vitro AD models exhibited reduced FGF21 expression. FGF21 downregulation impaired PI3K/Akt signaling, induced neuronal apoptosis, and disrupted metabolic homeostasis. Loss of FGF21 resulted in cognitive and metabolic dysfunction in AD mice. Conversely, FGF21 overexpression activated PI3K/Akt signaling, suppressed neuronal apoptosis, and restored metabolic functions in AD models.

CONCLUSION: FGF21 alleviates AD-related cognitive impairment and restores metabolic function by activating the PI3K/Akt pathway.},
}

@article {pmid40631777,
year = {2025},
author = {LaBarge, B and Lorenz, FJ and Gniady, JP},
title = {Association of Laryngeal Dystonia With Common Neurologic Disorders.},
journal = {The Laryngoscope},
volume = {},
number = {},
pages = {},
doi = {10.1002/lary.32407},
pmid = {40631777},
issn = {1531-4995},
support = {UL1 TR002014/TR/NCATS NIH HHS/United States ; },
abstract = {OBJECTIVE: Laryngeal dystonia is a heterogenous disorder consisting of involuntary spasms of laryngeal muscles. There are multiple forms including adductor, abductor, and mixed phenotypes. The disorder is thought to be multifactorial, with various reported associations with family history of dystonia or movement disorders. The relationship between laryngeal dystonia and various neurologic disorders is not well defined in the literature.

METHODS: We utilized the TriNetX de-identified electronic medical record database system spanning 2010-2023 to assess the prevalence of laryngeal dystonia with common neurologic disorders, compared to an age-sex matched control population. We included patients with the laryngeal spasm J38.5 ICD-10 code and 64617 CPT code, in order to categorize laryngeal dystonia patients undergoing chemodenervation.

RESULTS: The patient cohort consisted of approximately 4000 patients. 75% were female, 71% were white, and the mean age was 61 years. The laryngeal dystonia population had an elevated relative risk of Parkinson's disease (RR = 2.7, 1.8-3.9, 95% CI). In contrast, the relative risk of Alzheimer's disease was decreased in the laryngeal dystonia population (RR = 0.28, 0.16-0.48, 95% CI). There were no differences between the laryngeal dystonia and control populations for multiple sclerosis, amyotrophic lateral sclerosis, epilepsy, migraine, muscular dystrophy, or cerebral palsy.

CONCLUSION: Laryngeal dystonia patients have a significantly greater association with Parkinson's disease and less association with Alzheimer's disease compared to the control population. There were no meaningful associations with the remainder of the neurologic conditions included in the study.},
}

@article {pmid40631607,
year = {2025},
author = {Gavriel, Y and Voinsky, I and Klin, H and Squassina, A and Gurwitz, D},
title = {Reduced Taurine Transporter Expression in Lymphoblastoid Cell Lines From Alzheimer's Disease Patients Compared With Age-Matched Controls: Therapeutic Implications?.},
journal = {Drug development research},
volume = {86},
number = {5},
pages = {e70124},
doi = {10.1002/ddr.70124},
pmid = {40631607},
issn = {1098-2299},
support = {//The authors received no specific funding for this work./ ; },
mesh = {Humans ; *Alzheimer Disease/metabolism/genetics ; *Membrane Transport Proteins/genetics/metabolism ; Aged ; *Taurine/metabolism ; Male ; Female ; Cell Line ; RNA, Messenger/metabolism ; *Membrane Glycoproteins/genetics/metabolism ; Aged, 80 and over ; Glutathione Peroxidase/genetics/metabolism ; *Lymphocytes/metabolism ; Case-Control Studies ; },
abstract = {Taurine is an atypical amino acid that cannot form peptide bonds and thus does not take place in building proteins. Yet, taurine takes part in regulating many cell functions, including cell osmolarity and volume, mitochondrial function, membrane ion channels and neuronal activity, and cell survival. Taurine is synthesized by the liver, and available from consumption of meat and fish, but not plants. It has millimolar concentrations in the brain, skeletal muscle, blood, heart, retina, and other tissues. Taurine is transported from the liver (following synthesis) or the intestine (following consumption) to blood by the taurine transporter, encoded in humans by SLC6A6. A recent study reported that blood taurine declines dramatically in aged individuals. Several studies indicated that dietary taurine slows cognitive decline in Alzheimer's disease (AD) model mice. We therefore measured SLC6A6 mRNA expression in human lymphoblastoid cell lines (LCLs) from AD patients and age-matched controls and observed 2.8-fold lower expression in AD LCLs (p = 0.0005). Additionally, glutathione peroxidase 1 (GPX1), a key free-radical scavenging selenoenzyme, had reduced mRNA expression in LCLs from AD patients compared with controls. Our observations suggest that reduced taurine transporter expression may contribute to AD pathogenesis and that dietary taurine might be beneficial for slowing disease progression in early-stage AD. Clinical trials with dietary taurine supplementation of individuals with mild cognitive impairment (MCI) or early-stage AD are required to assess its tentative therapeutic potential.},
}

Humans
*Alzheimer Disease/metabolism/genetics
*Membrane Transport Proteins/genetics/metabolism
Aged
*Taurine/metabolism
Male
Female
Cell Line
RNA, Messenger/metabolism
*Membrane Glycoproteins/genetics/metabolism
Aged, 80 and over
Glutathione Peroxidase/genetics/metabolism
*Lymphocytes/metabolism
Case-Control Studies

@article {pmid40631452,
year = {2025},
author = {Gupta, AK and Martin, W and Pieper, AA and Wang, Y and Saykin, AJ and Cheng, F},
title = {Comprehensive characterization of the RNA editing landscape in the human aging brains with Alzheimer's disease.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21},
number = {7},
pages = {e70452},
doi = {10.1002/alz.70452},
pmid = {40631452},
issn = {1552-5279},
support = {U01AG073323//National Institute on Aging (NIA)/ ; R01AG066707//National Institute on Aging (NIA)/ ; R01AG076448//National Institute on Aging (NIA)/ ; R01AG082118//National Institute on Aging (NIA)/ ; R01AG084250//National Institute on Aging (NIA)/ ; R01AG092462//National Institute on Aging (NIA)/ ; R01AG092591//National Institute on Aging (NIA)/ ; RF1AG082211//National Institute on Aging (NIA)/ ; R21AG083003//National Institute on Aging (NIA)/ ; RF1NS133812//National Institute of Neurological Disorders and Stroke (NINDS)/ ; },
mesh = {Humans ; *Alzheimer Disease/genetics/pathology ; *RNA Editing/genetics ; Male ; *Brain/metabolism/pathology ; Female ; Genome-Wide Association Study ; *Aging/genetics ; Aged ; Aged, 80 and over ; },
abstract = {INTRODUCTION: While RNA editing has been linked to Alzheimer's disease (AD), its specific impact on the transcriptomic landscape in human AD brains remains under explored.

METHODS: We conducted a comprehensive analysis of RNA editing across nine human brain regions affected by AD, utilizing RNA-seq data and matched whole-genome sequencing data from three human brain biobanks, adjusting for age, post mortem interval, sex, and apolipoprotein E4 (APOE4) status.

RESULTS: RNA-editing events were identified in both AD and healthy control aging brains, highlighting 127 genes with significant RNA editing loci. AD exhibited elevated RNA editing in the parahippocampal gyrus and cerebellar cortex. We also discovered 147 colocalized genome-wide association studies (GWAS) and cis-edQTL (± 1 MB) signals in 48 likely causal genes encompassing CLU, BIN1, and GRIN3B, primarily allied to amyloid and tau pathology, and neuroinflammation.

DISCUSSION: Our findings delineate RNA editing regulatory signatures in human AD, providing novel insights into AD pathophysiology and potential biomarkers and therapeutic targets.

HIGHLIGHTS: ·We discovered genome-wide landscape of RNA editing signals from 4208 (1364 Alzheimer's disease [AD] cases vs. 742 healthy controls) RNA-seq data across nine human brain regions from three large brain biobanks (Mount Sinai Brain Bank [MSBB], Mayo Clinic [MAYO] Religious Order Study and Memory and Aging Project [ROSMAP]) tied with AD, including in sex-specific and apolipoprotein E4 (APOE4) -specific manner adjusting for age, post mortem interval (PMI), sex, and APOE4 status. ·We emphasize 127 genes, including SYT11, KCNIP4, NRG3, ANKS1B, and RALYL, exhibiting significant RNA editing loci shared by multiple brain tissues, mainly implicated in synaptic plasticity, signaling and transmission, neuronal development, and morphogenesis. ·Brain-wide tissue-specific cis-regulatory variants (cis-edQTLs) were inspected using matched genotyping data from 3627 samples from all brain biobanks. We revealed 147 colocalized AD-GWAS and cis-edQTLs signals pertaining to 48 likely causal genes comprising CLU (rs7982, rs1532278), BIN1 (rs2276582, rs3768863), GRIN3B (rs10417824, rs1058603), NYAP1 (rs12539172), DGKQ (rs4690197, rs3733347), CLPTM1 (rs204468), etc. ·Colocalized signals show affiliations to tau protein binding, amyloid-β regulation, cellular morphogenesis, and immune response pathway suggesting possible roles of epitranscriptomic mechanisms in shaping the AD risk.},
}

Humans
*Alzheimer Disease/genetics/pathology
*RNA Editing/genetics
Male
*Brain/metabolism/pathology
Female
Genome-Wide Association Study
*Aging/genetics
Aged
Aged, 80 and over

@article {pmid40631443,
year = {2025},
author = {Daskoulidou, N and Shaw, B and Zelek, WM and Morgan, BP},
title = {The Alzheimer's disease-associated complement receptor 1 variant confers risk by impacting glial phagocytosis.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21},
number = {7},
pages = {e70458},
doi = {10.1002/alz.70458},
pmid = {40631443},
issn = {1552-5279},
support = {DRI-3002//UK Dementia Research Institute/ ; },
mesh = {*Phagocytosis/genetics/physiology ; Humans ; *Alzheimer Disease/genetics ; *Receptors, Complement 3b/genetics/metabolism ; Induced Pluripotent Stem Cells ; *Microglia/metabolism ; *Neuroglia/metabolism ; *Astrocytes/metabolism ; Genetic Predisposition to Disease ; Amyloid beta-Peptides/metabolism ; },
abstract = {INTRODUCTION: Genome-wide association studies have implicated complement in Alzheimer's disease (AD). The CR1*2 variant of complement receptor 1 (CR1; CD35), confers increased AD risk. We confirmed CR1 expression on glial cells; however, how CR1 variants influence AD risk remains unclear.

METHODS: Induced pluripotent stem cell-derived microglia and astrocytes were generated from donors homozygous for the common CR1 variants (CR1*1/CR1*1;CR1*2/CR1*2). CR1 expression was quantified and phagocytic activity assessed using diverse targets (Escherichia coli bioparticles, amyloid β aggregates, and synaptoneurosomes), with or without serum opsonization.

RESULTS: Expression of CR1*1 was significantly higher than CR1*2 on glial lines. Phagocytosis for all targets was markedly enhanced following serum opsonization, attenuated by Factor I-depletion, demonstrating CR1 requirement for C3b processing. CR1*2-expressing glia showed significantly enhanced phagocytosis of all opsonized targets compared to CR1*1-expressing cells.

DISCUSSION: CR1 is critical for glial phagocytosis of opsonized targets. CR1*2, despite lower expression, enhances glial phagocytosis, providing mechanistic explanation of increased AD risk.

HIGHLIGHTS: Induced pluripotent stem cell (iPSC)-derived glia from individuals expressing the Alzheimer's disease (AD) risk variant complement receptor (CR) 1*2 exhibit lower CR1 expression compared to those from donors expressing the non-risk form CR1*1. The iPSC-derived glia from individuals expressing the AD risk variant CR1*2 exhibit enhanced phagocytic activity for opsonized bacterial particles, amyloid-β aggregates and human synaptoneurosomes compared to those from donors expressing the non-risk form CR1*1. We suggest that expression of the CR1*2 variant confers risk of AD by enhancing the phagocytic capacity of glia for opsonized targets.},
}

*Phagocytosis/genetics/physiology
Humans
*Alzheimer Disease/genetics
*Receptors, Complement 3b/genetics/metabolism
Induced Pluripotent Stem Cells
*Microglia/metabolism
*Neuroglia/metabolism
*Astrocytes/metabolism
Genetic Predisposition to Disease
Amyloid beta-Peptides/metabolism

@article {pmid40631440,
year = {2025},
author = {Gogola, A and Zeng, X and Williams, LA and Chapple-McGruder, T and Saeed, A and Lopresti, BJ and Snitz, B and Tudorascu, D and Minhas, D and Ikonomovic, MD and Kofler, J and Matan, C and Pascoal, TA and Aizenstein, H and Zetterberg, H and Blennow, K and Lopez, O and Villemagne, VL and Karikari, TK and Cohen, AD},
title = {Impact of racialization on neuroimaging and plasma biomarkers of Alzheimer's disease.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21},
number = {7},
pages = {e70463},
doi = {10.1002/alz.70463},
pmid = {40631440},
issn = {1552-5279},
support = {P30 AG066468/AG/NIA NIH HHS/United States ; P50 AG005133/AG/NIA NIH HHS/United States ; RF1 AG025516/AG/NIA NIH HHS/United States ; R01 AG052446/AG/NIA NIH HHS/United States ; R01 AG052521/AG/NIA NIH HHS/United States ; P01 AG025204/AG/NIA NIH HHS/United States ; R01 AG063752/AG/NIA NIH HHS/United States ; R01 AG083874/AG/NIA NIH HHS/United States ; R01AG083874/NH/NIH HHS/United States ; U24AG082930/NH/NIH HHS/United States ; P30AG066468/NH/NIH HHS/United States ; RF1AG052525/NH/NIH HHS/United States ; R01AG053952/NH/NIH HHS/United States ; R37AG023651/NH/NIH HHS/United States ; RF1AG025516/NH/NIH HHS/United States ; R01AG073267/NH/NIH HHS/United States ; R01AG075336/NH/NIH HHS/United States ; R01AG072641/NH/NIH HHS/United States ; P01AG025204/NH/NIH HHS/United States ; #2023-00356//Swedish Research Council/ ; #2022-01018//Swedish Research Council/ ; and #2019-02397//Swedish Research Council/ ; 101053962//the European Union's Horizon Europe research and innovation programme/ ; #ALFGBG-71320//Swedish State/ ; #AF-930351//the Swedish Alzheimer Foundation/ ; #AF-939721//the Swedish Alzheimer Foundation/ ; #AF-968270//the Swedish Alzheimer Foundation/ ; and #AF-994551//the Swedish Alzheimer Foundation/ ; #ALZ2022-0006//Hjärnfonden, Sweden/ ; #FO2024-0048-TK-130//Hjärnfonden, Sweden/ ; and FO2024-0048-HK-24//Hjärnfonden, Sweden/ ; #ALFGBG-965240//Swedish government and the County Councils/ ; #ALFGBG-1006418//Swedish government and the County Councils/ ; JPND2019-466-236//the European Union Joint Program for Neurodegenerative Disorders/ ; ZEN-21-848495//Alzheimer's Association 2021 Zenith Award/ ; SG-23-1038904 QC//Alzheimer's Association 2022-2025 Grant/ ; },
mesh = {Humans ; *Alzheimer Disease/blood/diagnostic imaging/ethnology ; *Biomarkers/blood ; Male ; Aged ; Female ; Amyloid beta-Peptides/blood ; tau Proteins/blood ; Positron-Emission Tomography ; Magnetic Resonance Imaging ; *Neuroimaging ; Middle Aged ; Black or African American ; Aged, 80 and over ; White People ; Neurofilament Proteins/blood ; Brain/diagnostic imaging ; White ; },
abstract = {INTRODUCTION: Given the predominance of imaging and plasma biomarkers in Alzheimer's disease observational studies and clinical trials, it is critical to understand the differences between these biomarkers across racialized groups.

METHODS: A total of 260 older adults without dementia racialized as Black and/or African American (AA) and non-Hispanic white (NHW), ranging in age from 50 to 90 years (68.8 ± 9.1 years), were evaluated for differences in plasma amyloid-β (Aβ) 42/Aβ40, p-tau181, p-tau217, p-tau231, neurofilament light chain (NfL), and glial fibrillary acidic protein (GFAP) as well as Aβ positron emission tomography (PET) and magnetic resonance (MR) imaging-derived cortical thickness using Mann-Whitney U tests and analysis of covariance (ANCOVA).

RESULTS: Both Mann-Whitney tests and ANCOVA found significant differences between groups racialized as AA or NWH with respect to global [11][C]-Pittsburgh Compound B (PiB) standardized uptake value ratio (SUVR), cortical thickness values, p-tau181, and p-tau231 values (p < 0.05).

DISCUSSION: Racialization should be given more consideration in AD clinical research, particularly when biomarker results are used for inclusion or exclusion criteria for clinical trials and qualification in clinical practice.

HIGHLIGHTS: Global [11][C]-Pittsburgh compound B (PiB) standardized uptake value ratio (SUVR), cortical thickness, p-tau181, and p-tau231 differed between groups Differences were unaffected by age, sex, apolipoprotein E *4 (APOE*4), education, and Mini-Mental State Examination (MMSE) score Racialization needs more consideration in Alzheimer's disease clinical research Additional work is needed to understand the sources of biomarker differences.},
}

Humans
*Alzheimer Disease/blood/diagnostic imaging/ethnology
*Biomarkers/blood
Male
Aged
Female
Amyloid beta-Peptides/blood
tau Proteins/blood
Positron-Emission Tomography
Magnetic Resonance Imaging
*Neuroimaging
Middle Aged
Black or African American
Aged, 80 and over
White People
Neurofilament Proteins/blood
Brain/diagnostic imaging
White

@article {pmid40631430,
year = {2025},
author = {Knopman, DS and Weigand, SD and Wiste, HJ and Graff-Radford, J and Graff-Radford, NR and Petersen, RC and Boeve, BF and Jr, CRJ and Lowe, VJ and Machulda, MM and Fields, JA and Ramanan, VK and Botha, H and McCarter, SJ and Jones, DT and Neth, BJ and Day, GS and Kantarci, K and Algeciras-Schimnich, A and Bornhorst, JA and Johnson, DR and , },
title = {Discrepancies between CSF biomarker and PET determinations of elevated brain amyloid and their prognostic significance.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21},
number = {7},
pages = {e70468},
doi = {10.1002/alz.70468},
pmid = {40631430},
issn = {1552-5279},
support = {U19AG024904/NH/NIH HHS/United States ; U01 AG006786/AG/NIA NIH HHS/United States ; },
mesh = {Humans ; *Positron-Emission Tomography ; Male ; Female ; *Cognitive Dysfunction/cerebrospinal fluid/diagnostic imaging ; Biomarkers/cerebrospinal fluid ; *Amyloid beta-Peptides/cerebrospinal fluid/metabolism ; Aged ; *Brain/diagnostic imaging/metabolism ; Prognosis ; *Alzheimer Disease/cerebrospinal fluid/diagnostic imaging ; Longitudinal Studies ; Aged, 80 and over ; },
abstract = {INTRODUCTION: When cerebrospinal fluid (CSF) and positron emission tomography (PET) measurements for amyloid-beta-peptide (Aβ) related pathology are discordant, therapeutic decision-making becomes uncertain.

METHODS: Using data from patients with mild cognitive impairment (n = 541) from the Alzheimer's Disease Neuroimaging Initiative, we examined baseline characteristics and longitudinal clinical outcomes in persons grouped according to normal/abnormal Aβ via concurrent CSF and PET determinations using standard cutpoints.

RESULTS: Discordant groups for brain Aβ status (CSF+/PET- and CSF-/PET+) each represented about 5% of the mild cognitive impairment (MCI) population. Longitudinally, neither discordant group declined more than the CSF-/PET- group on either a memory measure or the Clinical Dementia Rating Sum of Boxes scores over a median 4 years of observation, while the CSF+/PET+ group exhibited worsening on both measures.

DISCUSSION: In contrast to the clinical decline observed in the CSF+/PET+ group, persons with MCI and CSF+/PET- or CSF-/PET+ brain amyloid patterns did not exhibit incipient decline.

HIGHLIGHTS: Discrepant abnormal cerebrospinal fluid (CSF) and positron emission tomography (PET) brain amyloid indicators are uncommon in mild cognitive impairment (MCI). CSF-PET discrepant persons with MCI tend to have less abnormal values initially. CSF-PET discrepant persons with MCI have a benign prognosis at 4 years.},
}

Humans
*Positron-Emission Tomography
Male
Female
*Cognitive Dysfunction/cerebrospinal fluid/diagnostic imaging
Biomarkers/cerebrospinal fluid
*Amyloid beta-Peptides/cerebrospinal fluid/metabolism
Aged
*Brain/diagnostic imaging/metabolism
Prognosis
*Alzheimer Disease/cerebrospinal fluid/diagnostic imaging
Longitudinal Studies
Aged, 80 and over

@article {pmid40631427,
year = {2025},
author = {Hu, S and Zhu, P and Gao, S and Wu, S and He, Y and Liu, F and Wang, K and Liu, G},
title = {Self-Report Alzheimer's Disease Statuses in UK Biobank Distort Downstream Analyses.},
journal = {Journal of neurochemistry},
volume = {169},
number = {7},
pages = {e70151},
doi = {10.1111/jnc.70151},
pmid = {40631427},
issn = {1471-4159},
support = {JQ21022//Beijing Municipal Natural Science Foundation/ ; 82471449//National Natural Science Foundation of China/ ; 2023YFC3605200//National Key Research and Development Program of China/ ; 2023YFC3605202//National Key Research and Development Program of China/ ; },
mesh = {Humans ; *Alzheimer Disease/genetics/diagnosis/epidemiology ; United Kingdom/epidemiology ; Genome-Wide Association Study/methods ; *Biological Specimen Banks ; Mendelian Randomization Analysis/methods ; Male ; *Self Report/standards ; Female ; Aged ; Middle Aged ; Polymorphism, Single Nucleotide ; UK Biobank ; },
abstract = {Genetic studies have identified Alzheimer's disease (AD)-linked variants through genome-wide association studies (GWAS) and proxy-based GWAS (GWAX), yet inconsistent causal inferences still persist. Here, we systematically evaluated how self-reported AD diagnoses in the UK Biobank (UKB) distort Mendelian randomization (MR) analyses. Using seven AD datasets (four GWAS and three GWAX, including IGAP, N = 63 926; FinnGen R10, N = 191 061; UKB G30, N = 420 531; UKB2024, N = 434 286, and GWAX2017, N = 74 366; GWAX2018, N = 548 955; GWAX2021, N = 408 691) and six education subtypes (including years of schooling, N = 1 131 881; hardest math class completed, N = 430 445; self-reported math ability, N = 564 698; college completion, N = 280 007; cognition test performance, N = 257 841; and non-cognitive skills, N = 257 841). We also assessed the heterogeneity and pleiotropy across these datasets. We found opposing causal directions between GWAS and GWAX cohorts. In GWAS datasets, genetic variations related to education were causally linked to a lower risk of AD (OR < 1, p < 0.05), with years of schooling showing the strongest protective effects (OR = 0.71 in IGAP, p < 0.05). Conversely, UKB-based GWAX analyses paradoxically linked education-related traits to increased AD risk (OR > 1, p < 0.05), directly conflicting with the protective associations in clinical AD GWAS results. Genetic heterogeneity was observed in both AD GWAS and GWAX datasets. Pleiotropy was noted in AD outcomes, but MR estimates remained stable after outlier adjustments. Our findings reveal that self-reported AD statuses in UKB distorted genetic effect estimates, particularly for education subtypes requiring validation. The research urges caution in interpreting MR results from GWAX studies that use self-reported endpoints and highlights the need for rigorous phenotyping in biobank studies.},
}

Humans
*Alzheimer Disease/genetics/diagnosis/epidemiology
United Kingdom/epidemiology
Genome-Wide Association Study/methods
*Biological Specimen Banks
Mendelian Randomization Analysis/methods
Male
*Self Report/standards
Female
Aged
Middle Aged
Polymorphism, Single Nucleotide
UK Biobank

@article {pmid40631426,
year = {2025},
author = {Behera, DK and Rahut, DB and Tripathy, S},
title = {Alzheimer's disease and dementia in Japan: Epidemiological trends, regional disparities, and future projections.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21},
number = {7},
pages = {e70444},
doi = {10.1002/alz.70444},
pmid = {40631426},
issn = {1552-5279},
mesh = {Humans ; Japan/epidemiology ; *Alzheimer Disease/epidemiology ; Risk Factors ; Aged ; *Dementia/epidemiology ; Prevalence ; Female ; Forecasting ; Incidence ; Male ; Aged, 80 and over ; Disability-Adjusted Life Years ; Global Burden of Disease/trends ; Life Expectancy ; },
abstract = {INTRODUCTION: Alzheimer's disease and other dementias (ADOD) are a growing public health concern in Japan. This study examines historical ADOD burden trends, identifies contributing risk factors, and forecasts future projections using time-series modeling.

METHODS: This study uses the Global Burden of Disease (GBD) study 2021 data to analyze ADOD trends in Japan, and assess incidence, mortality, and Disability-adjusted life years (DALYs). Regression analysis identifies risk factors, and an Autoregressive Integrated Moving Average (ARIMA) model is employed to forecasts the burden from 2021 to 2030.

RESULTS: ADOD cases have steadily increased, with projections indicating continued growth by 2030. Aging and life expectancy are major contributors, with urban areas like Kantō and Kansai region experiencing higher prevalence than Tōhoku and Kyūshū. High fasting plasma glucose, obesity, and smoking are significant modifiable risk factors. The ARIMA model forecasts an ongoing upward trend, highlighting a rising public health challenge.

DISCUSSION: Targeted policies, early interventions, and equitable health care access are vital to mitigating Japan's growing ADOD burden.

HIGHLIGHTS: Alzheimer's disease and other dementias (ADOD) are rising in Japan due to an aging population. Key risk factors include high fasting plasma glucose, obesity, and smoking. Kantō and Kansai region have higher ADOD prevalence than other region ARIMA modeling predicts a continuous increase in ADOD cases through 2030. Targeted health care policies and preventive measures are crucial to mitigate the burden.},
}

Humans
Japan/epidemiology
*Alzheimer Disease/epidemiology
Risk Factors
Aged
*Dementia/epidemiology
Prevalence
Female
Forecasting
Incidence
Male
Aged, 80 and over
Disability-Adjusted Life Years
Global Burden of Disease/trends
Life Expectancy

@article {pmid40631359,
year = {2025},
author = {Omole, JG and Okon, IA and Udom, GJ and Aziakpono, OM and Agbana, RD and Aturamu, A and Niwamanya, N and Oritsemuelebi, B and Etukudo, EM and Yemitan, OK},
title = {Neurophysiological mechanisms underlying cardiovascular adaptations to exercise: A narrative review.},
journal = {Physiological reports},
volume = {13},
number = {13},
pages = {e70439},
doi = {10.14814/phy2.70439},
pmid = {40631359},
issn = {2051-817X},
mesh = {Humans ; *Exercise/physiology ; *Adaptation, Physiological/physiology ; *Brain/physiology/metabolism ; Animals ; *Cardiovascular System/metabolism ; Neuronal Plasticity ; Brain-Derived Neurotrophic Factor/metabolism ; Neurovascular Coupling ; *Cardiovascular Physiological Phenomena ; *Heart/physiology ; },
abstract = {The brain-heart connection, particularly during physical activity, plays a crucial role in health and disease management. This review examined the neurophysiological mechanisms driving cardiovascular adaptations to exercise, focusing on the bidirectional relationship between the brain and heart. Key mediators such as central autonomic networks, brain-derived neurotrophic factors (BDNF), and vascular endothelial growth factor (VEGF) enhance neural plasticity and vascular health. Regular structured exercise (e.g., high-intensity interval training, moderate and resistance exercise) moderates autonomic responses, increases BDNF, and supports neurovascular coupling, improving both cognitive and cardiovascular resilience through molecular pathways such as PGC-1α and TrkB signaling. Exercise enhances cerebral perfusion, reduces oxidative stress, and protects brain-heart health. It mitigates risks linked to neurodegenerative diseases, such as Alzheimer's and Parkinson's, by promoting neuroplasticity and vascular integrity. This review highlights the importance of incorporating exercise-based interventions in clinical practice and public health policies to optimize cognitive and cardiovascular health. Future studies should explore exercise-induced neurovascular coupling to further elucidate the mechanisms connecting brain and cardiovascular health.},
}

Humans
*Exercise/physiology
*Adaptation, Physiological/physiology
*Brain/physiology/metabolism
Animals
*Cardiovascular System/metabolism
Neuronal Plasticity
Brain-Derived Neurotrophic Factor/metabolism
Neurovascular Coupling
*Cardiovascular Physiological Phenomena
*Heart/physiology

@article {pmid40631275,
year = {2025},
author = {Tutrow, KD and Harkin, J and Varghese, L and Hernandez, M and Huang, KC and Fang, Y and Wilcox, P and Bedford, L and Lin, TY and Zhang, C and Gomes, C and Puntambekar, S and Bissel, S and Lamb, BT and Meyer, JS},
title = {Human induced pluripotent stem cell-derived microglia with a CX3CR1-V249I genetic variant exhibit dysfunctional phenotypes and modulate neuronal growth and function.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.1101/2025.07.01.662163},
pmid = {40631275},
issn = {2692-8205},
abstract = {The involvement of microglia in neurodegenerative diseases has drawn increasing attention, as many genetic risk factors are preferentially expressed in microglia. Microglial fractalkine receptor (CX3CR1) signaling regulates many key microglial functions, and the CX3CR1-V249I single nucleotide polymorphism (SNP) has been associated with increased risk for multiple neurodegenerative conditions, including Alzheimer's disease, yet its functional consequences in human microglia remain unexplored. In this study, we generated iPSC-derived human microglia-like cells (hMGLs) and found that the CX3CR1-V249I variant increased susceptibility to starvation-induced cell death, reduced amyloid-beta uptake, altered microglial morphology, and impaired migration, with more pronounced effects in homozygous cells. Co-culture with neurons demonstrated that hMGLs with the CX3CR1-V249I variant misregulated neuronal properties, including abnormal neuronal growth as well as an induction of neuronal hyperexcitability. These findings highlight the critical role of CX3CR1 in regulating microglial function and implicate the V249I variant in driving pathogenic microglial states relevant to neurodegeneration.},
}

@article {pmid40631238,
year = {2025},
author = {Brisendine, MH and Nieves-Esparcia, DQ and Willoughby, OS and Brown, JR and Braxton, DS and Henry, SN and McCoin, C and Thyfault, JP and Morris, JK and Poelzing, S and Grange, RW and Najt, CP and Drake, JC},
title = {Age-dependent remodeling of the sciatic proteome in 5xFAD mice can be attenuated by exercise or donepezil treatment to maintain neuromuscular function.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.1101/2025.07.01.662603},
pmid = {40631238},
issn = {2692-8205},
abstract = {UNLABELLED: Background: Alzheimer's disease (AD) progresses along a continuum for years to possibly decades prior to cognitive decline and clinical diagnosis. Preclinical AD is associated with neuromuscular dysfunction. We previously characterized early neuromuscular impairment prior to cognitive decline at 4 months of age in the 5xFAD mouse model of AD. However, the underlying cause(s) for peripheral nerve dysfunction leading to impaired skeletal muscle torque production are not understood, therefore limiting interventional capacity. We hypothesized that either voluntary wheel running or donepezil treatment, begun prior to neuromuscular decline, would delay manifestation of neuromuscular impairment in 5xFAD mice. Methods: Sciatic nerves from 5xFAD and wild-type (WT) mice were analyzed by tandem mass tag (TMT)-labeled proteomics at 3, 4, and 7 months to investigate proteome remodeling. Separate cohorts, using 3-month-old 5xFAD mice and WT littermates given voluntary wheel access for 4 weeks or treated with the acetylcholinesterase inhibitor donepezil to test if neuromuscular dysfunction could be attenuated. Afterwards, we assessed tibial nerve stimulated plantar flexion torque and sciatic nerve compound (motor) neuron action potential (CNAP) in-vivo at 4 months. Additionally, we performed TMT-labeled proteomics to ascertain the effect of exercise and donepezil treatments on sciatic proteome. Results: Sciatic nerves in 5xFAD mice exhibited proteomic remodeling from 3 to 4 months, particularly in pathways linked to mitochondrial turnover, calcium handling, lipid metabolism, and inflammation, coinciding with onset of neuromuscular dysfunction. Both exercise and donepezil attenuated in nerve-stimulated muscle torque and CNAP dysfunction. Both exercise and donepezil attenuated proteomic remodeling of the sciatic nerve involving mitochondrial-centric processes through both shared and independent mechanisms. Conclusions: Declines in neuromuscular function may be pre-clinical identifiers for AD that share pathway similarities with noted central effects of the pathology on the brain. Our findings highlight the importance of a systemic approach to AD pathology and importance of disease state in interventional efficacy.

GRAPHICAL ABSTRACT: Created in Biorender.},
}

@article {pmid40631232,
year = {2025},
author = {Yousofvand, R and Handy, G and Tithof, J},
title = {Boundary Homogenization and Numerical Modeling of Solute Transport Across the Blood-Brain Barrier.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.1101/2025.07.01.662658},
pmid = {40631232},
issn = {2692-8205},
abstract = {Effective clearance of amyloid-β (Aβ) from the brain is essential for preventing neurodegenerative diseases such as Alzheimer's. A significant portion of this clearance occurs through the blood-brain barrier (BBB) via receptor-mediated transport. However, current models fail to capture the complex kinetics and spatial heterogeneity of receptors at the BBB. In this study, we derive a novel boundary condition that accounts for finite receptor kinetics, receptor density, and bidirectional transport across the BBB. Specifically, we develop a nonlinear homogenized boundary condition that ensures mass conservation and incorporates receptor-mediated Michaelis-Menten kinetics. We then implement this boundary condition in a cylindrical geometry representing a capillary surrounded by brain tissue. After verifying that the model matches an analytical steady state solution that we derive and that it yields realistic blood Aβ concentrations, we explore how realistic variations in parameter values drive changes in both steady state Aβ concentration and transient dynamics. Simulations and analytical results reveal that Aβ concentrations in the brain are sensitive to receptor number ratios, while concentrations in the blood are primarily affected by the blood clearance rate. Additionally, we use the model to investigate Aβ clearance during sequential sleep cycles and due to a pathological phenomenon, spreading depolarization. This work presents the first biophysically consistent boundary condition for Aβ transport across the BBB, offering a powerful tool for studying brain waste clearance under both physiological and pathological conditions.},
}

@article {pmid40631204,
year = {2025},
author = {O'Toole, HJ and James, A and Nasim, N and Hadley, DJ and Hale, EJ and He, Q and Bein, KJ and Valenzuela, AE and Rojalin, T and Dugger, BN and Wexler, AS and Lein, PJ and Carney, RP},
title = {Spatial and spectral mapping of traffic-related air pollution (TRAP) nanoparticles in relation to plaques and inflammatory markers in an Alzheimer disease model.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.1101/2025.07.01.662638},
pmid = {40631204},
issn = {2692-8205},
abstract = {Chronic exposure to traffic-related air pollution (TRAP) is linked to increased risk of neurodegenerative diseases, including Alzheimer disease (AD). Ultrafine particulate matter (UFPM) is a suspected driver of TRAP neurotoxicity, but its spatial interactions with AD pathology remain poorly defined. We investigated the distribution, composition, and pathological context of TRAP-derived UFPM in the hippocampus of TgF344-AD rats chronically exposed to TRAP or filtered air (FA) for 14 months. Using a multimodal imaging workflow that combines enhanced darkfield hyperspectral imaging (EDF-HSI) with confocal immunofluorescence for microglia (CD68/Iba1) and amyloid beta (Aβ) plaques (Thioflavin S), we mapped the localization and spectral properties of UFPM in situ. UFPM accumulation was elevated in TRAP-exposed females, suggesting sex-specific vulnerability in blood-brain barrier (BBB) permeability or particle retention. Particles near plaques showed red-shifted spectral signatures, consistent with biochemical transformation. Dimension reduction revealed clustering of particle spectra by TRAP exposure and plaque proximity. However, UFPM was rarely found within plaques or microglia, implying indirect neuroimmune modulation. These findings highlight a novel spatial and spectral imaging approach for characterizing environmental nanoparticle interactions in the brain and suggest that chronic TRAP exposure may influence AD-related inflammation and pathology in a sex- and region-dependent manner.},
}

@article {pmid40631171,
year = {2025},
author = {Genner, RM and Meredith, M and Moller, A and Weller, C and Daida, K and Ayuketah, A and Jerez, PA and Akeson, S and Malik, L and Baker, B and Kouam, C and Paquette, K and Marenco, S and Auluck, P and Mandal, A and Paten, B and Reed, X and Jain, M and Cookson, MR and Singleton, AB and Nalls, M and Blauwendraat, C and Billingsley, KJ},
title = {Haplotype-Resolved DNA Methylation at the APOE Locus identifies Allele-Specific Epigenetic Signatures Relevant to Alzheimer's Disease Risk.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.1101/2025.07.01.662592},
pmid = {40631171},
issn = {2692-8205},
abstract = {The APOE gene encodes a key lipid transport protein and plays a central role in Alzheimer's disease (AD) pathogenesis. Three common APOE alleles, ε2 (rs7412(C>T), ε3 (reference), and ε4 (rs429358(T>C)), arise from two coding variants in exon 4 and confer distinct AD risk profiles, with ε4 increasing risk and ε2 providing protection. The ε3-linked APOE variant rs769455[T] has also been associated with elevated AD risk in individuals of African ancestry carrying both rs769455[T] and ε4 alleles. These single nucleotide variants (SNVs) reside in a cytosine-phosphate-guanine (CpG) island, which is a region with a higher frequency of CpG sites compared to the rest of the genome. CpG sites are subject to 5-methylcytosine (5mC) methylation by DNA methyltransferases which add a methyl group to the fifth carbon on the cytosine residue of a CpG site. The presence of SNVs can disrupt this process, making these regions prime targets for differential methylation; however, allele-specific methylation patterns in APOE remain poorly resolved due to technical limitations of conventional bisulfite and methylation array based methods, including degraded DNA quality, sparse CpG coverage, and lack of haplotype phasing. Here, we leverage high-accuracy long-read sequencing data to generate haplotype-resolved methylation profiles of the APOE locus in 332 postmortem brain samples from two ancestrally different cohorts. This includes 201 individuals of European ancestry from the North American Brain Expression Consortium (NABEC), comprising 402 haplotypes (48 ε2 and 58 ε4 alleles), and 131 individuals of African and African admixed ancestry from the Human Brain Core Collection (HBCC), comprising 262 haplotypes (25 ε2, 64 ε4, and 7 rs769455 alleles). A linear regression analysis identified 18 novel differentially methylated CpG sites (DMCs) associated with APOE ε2, ε4, and rs769455 within a gene cluster spanning TOMM40, APOE, APOC1, and APOC4-APOC2 . This represents the most comprehensive haplotype-resolved methylation study of APOE in human brain tissue to date. Our results uncover distinct allele-specific methylation signatures and demonstrate the power of long-read sequencing for resolving epigenetic variation relevant to AD risk.},
}

@article {pmid40630924,
year = {2025},
author = {Li, J and Xu, Y and Balboni, G and Xia, Y},
title = {A new pathway for neuroprotection against tau hyperphosphorylation via δ-opioid receptor initiated inhibition of CDK5 and AMPK signaling.},
journal = {Frontiers in aging neuroscience},
volume = {17},
number = {},
pages = {1587219},
pmid = {40630924},
issn = {1663-4365},
abstract = {INTRODUCTION: Alzheimer's disease (AD) is a progressive neurodegenerative disease characterized by decreased memory and cognitive impairment. Abnormal tau hyperphosphorylation ultimately forms neurofibrillary tangles, which is one of the most important pathological features of AD. Since we have previously shown that the δ-opioid receptor (DOR) is neuroprotective in the brain, we asked if DOR plays any role in the control of tauopathy.

METHODS: In the PC12 cell model with okadaic acid-induced tau hyperphosphorylation, cell viability and cytotoxicity were evaluated by using CCK8 assay kit and lactate dehydrogenase cytotoxicity assay kit. The techniques of western blot and immunofluorescence were used to investigate the effect of DOR on tau hyperphosphorylation.

RESULTS: We found that DOR activation inhibited okadaic acid-induced tau hyperphosphorylation in PC12 cells and attenuated the cell cycle reactivation and apoptosis. The DOR effect was blocked by Naltrindole, a DOR antagonist. Furthermore, the mechanistic studies showed that the DOR displayed its effect by reducing the expression of cyclin-dependent kinase (CDK) 5 and AMP-activated protein kinase (AMPK) in the model of tauopathy.

DISCUSSION: Our novel findings suggest that DOR signaling may protect neurons from AD injury by inhibiting tau hyperphosphorylation.},
}

@article {pmid40630923,
year = {2025},
author = {Pascuzzo, R and Palesi, F and Wan, YM and Cazzaniga, FA},
title = {Editorial: A comprehensive look at biomarkers in neurodegenerative diseases: from early diagnosis to treatment response assessment.},
journal = {Frontiers in aging neuroscience},
volume = {17},
number = {},
pages = {1642793},
pmid = {40630923},
issn = {1663-4365},
}

@article {pmid40630916,
year = {2025},
author = {Huang, X and Ji, Q and Tong, T and Cai, L and Elmadhoun, O and Zeng, Y and Geng, X and Ding, Y},
title = {Evaluating the safety and feasibility of remote ischemic conditioning for slowing cognitive decline in mild Alzheimer's dementia.},
journal = {Frontiers in neurology},
volume = {16},
number = {},
pages = {1592829},
pmid = {40630916},
issn = {1664-2295},
abstract = {OBJECTIVE: Alzheimer's disease (AD) is characterized by complex pathological mechanisms involving neuroinflammation, oxidative stress, and vascular dysfunction. Remote Ischemic Conditioning (RIC) has shown potential in addressing these pathways by improving cerebral blood flow, reducing oxidative stress, and modulating inflammatory responses. This protocol focuses on evaluating the safety, feasibility, and preliminary efficacy of RIC as a multi-target intervention for delaying cognitive decline in patients with mild Alzheimer's dementia, aiming to improve cognitive outcomes and overall quality of life.

METHODS AND EXPECTED RESULTS: This study is a randomized, controlled, single-center, prospective clinical trial designed to evaluate the safety, feasibility, and preliminary efficacy of RIC in patients with mild Alzheimer's dementia. Eligible participants will be recruited and randomly assigned to either the RIC group or a control group receiving sham RIC, with 20 patients in each group. Participants will receive either RIC or sham RIC once daily over a 3-month period. Outcome measures will assess cognitive function, psychological well-being, and inflammatory and neurodegenerative biomarkers. Psychiatric adverse events will be monitored throughout the treatment using the Hamilton Anxiety Rating Scale (HAMA) and the Hamilton Depression Rating Scale (HAMD-17). Cognitive function and daily living abilities will be evaluated at baseline, 3 months, 6 months, and 12 months post-treatment using the Mini-Mental State Examination (MMSE), Montreal Cognitive Assessment (MoCA), Clinical Dementia Rating (CDR), and the Activities of Daily Living (ADL) scales. In addition, blood samples will be collected at each time point to measure plasma biomarkers of β-amyloid species and serum inflammatory cytokines to assess potential changes in cognitive decline, disease progression, and inflammation. The primary endpoint is safety, with the expectation that RIC will not increase psychiatric adverse events as reflected in HAMA and HAMD-17 scores. Primary efficacy endpoints include improvements in MMSE, MoCA, CDR, and ADL scores, indicating potential cognitive benefits and enhanced daily functioning. Secondary endpoints will analyze biomarkers to evaluate disease progression and inflammation levels before and after treatment.

CONCLUSION: This trial aims to determine the safety, feasibility, and potential effectiveness of RIC as a multi-target intervention for mild Alzheimer's dementia by integrating cognitive and neuropsychological assessments with biological markers, providing a foundation for future studies.},
}

@article {pmid40630682,
year = {2025},
author = {Chen, X and Chen, S and Chen, L and Zheng, H and Nie, J and Yang, L and Li, X and Ju, K},
title = {Profiling characteristics of plasma exosomal miRNAs across cognitive stages: from normalcy to mild cognitive impairment and Alzheimer's disease.},
journal = {RSC advances},
volume = {15},
number = {29},
pages = {23670-23680},
pmid = {40630682},
issn = {2046-2069},
abstract = {The rising global prevalence of Alzheimer's disease (AD) and mild cognitive impairment (MCI) underscores the urgent need to elucidate their underlying pathogenic mechanisms. This study investigated the dynamic alterations of plasma-derived exosomal miRNAs across the cognitive spectrum from normal cognition (NC) through MCI to AD, and their potential pathogenetic implications. Here, we enrolled 10 AD patients, 9 MCI patients, and 10 normal cognitive (NC) patients rigorously diagnosed using amyloid PET imaging, cerebrospinal fluid biomarkers, and standardized neuropsychological assessments. Serum exosomes were isolated and identified, then small RNA sequencing was performed. The results revealed distinct exosomal miRNA expression profiles across disease stages, with 10 conserved miRNAs showing progressive dysregulation along the NC-MCI-AD continuum. Target gene prediction formed numerous miRNA-mRNA pairs. GO and KEGG enrichment indicated that exosomal miRNAs might affect cognitive decline by regulating neurodevelopment and cell senescence. Strikingly, ROC analysis demonstrated superior diagnostic performance for miR-151a-3p and miR-210-3p in distinguishing disease states. Our findings not only characterize stage-specific exosomal miRNA signatures during AD progression but also identify novel circulating biomarkers with diagnostic potential. This work provides mechanistic insights into exosome-mediated pathological processes and advances the development of liquid biopsy approaches for early detection and therapeutic monitoring in neurodegenerative diseases.},
}

@article {pmid40630648,
year = {2025},
author = {Eagle, SR and Puccio, A and Svirsky, S and Mountz, J and Laymon, C and Borasso, A and Henry, L and Okonkwo, DO},
title = {Identifying a Biological Signature of Trauma-Related Neurodegeneration Following Repeated Traumatic Brain Injuries Compared with Healthy Controls.},
journal = {Neurotrauma reports},
volume = {6},
number = {1},
pages = {560-568},
pmid = {40630648},
issn = {2689-288X},
abstract = {The objective of this study was to compare participants at-risk for trauma-related neurodegeneration to a healthy control group on outcomes associated with Alzheimer's disease (AD), such as subjective symptoms, neurocognitive performance, plasma biomarkers, volumetrics, amyloid-beta (Aβ) positron emission tomography (PET), and tau PET. Participants completed a comprehensive assessment protocol for neurodegenerative disease, including magnetic resonance imaging (MRI), PET scans for tau and Aβ, blood draw, subjective symptom reports related to neurodegenerative disease, and objective neurocognitive assessment. Surveys included the Neurobehavioral Symptom Inventory (NSI), Insomnia Severity Index (ISI), Epworth Sleepiness Severity (ESS), PTSD Checklist for DSM-5 (PCL-5), Brief Symptom Inventory-18 (BSI-18), Satisfaction with Life Scale (SWLS), Barratt Impulsivity Scale (BIS), and Buss Perry Aggression Questionnaire (BPAQ). PET scans were read by a neuroradiologist and rated positive or negative based upon established cutoffs. General linear models compared participants with TBI history with controls on outcomes. Age, years of education, military status, biological sex, race/ethnicity, and total self-reported TBIs were included as covariates in all models with Bonferroni corrections. Forward stepwise linear regression models were built to associate neuroimaging outcomes with symptom domains; inclusion in the linear regression required a p value <0.1. The average age for both groups was ∼40 years. The TBI group reported an average of five TBIs; the control group reported an average of one TBI. Across seven regions of interest, only one TBI participant met established PET cutoffs for neuropathology in one cortical region. After controlling for age, sex, race/ethnicity, years of education, military status, and TBI history, there were no statistically significant differences between groups in any neurocognitive outcome (p = 0.06-0.95), Aβ or tau PET (p = 0.05-0.70), MRI volumetrics (p = 0.06-0.98), or plasma biomarkers (p = 0.06-0.85). The TBI group had higher NSI, PCL-5, BSI-18, BPAQ, ESS, and ISI scores compared with the controls (p < 0.001-0.042). Within the TBI group, amygdala normative percentile and/or amygdala asymmetry index were included in the final models for NSI, SWLS, PCL5, BIS, BPAQ, and ISI. Only two models included a statistically significant PET outcome in the final model. In this sample with a mean age of 40 and a history of 5+ TBIs, core diagnostic biomarkers for AD were not different from controls despite significantly higher symptom burden. Volumetrics in critical brain regions were associated with several symptom domains in the TBI group, indicating that cortical volumetrics (especially in the amygdala) may be a more viable early biomarker of chronic symptom burden in this population than PET scans.},
}

@article {pmid40630563,
year = {2025},
author = {Dobrushina, M and Chandni, S and Dietrich, L and Glanz, W and Butryn, M and Hämmerer, D and Penalba-Sánchez, L},
title = {Conducting MRI trials in Alzheimer's patients: Challenges and Guidelines.},
journal = {medRxiv : the preprint server for health sciences},
volume = {},
number = {},
pages = {},
doi = {10.1101/2025.07.02.25330723},
pmid = {40630563},
abstract = {Combining pharmaceutical interventions with neuroimaging in Alzheimer's disease (AD) research presents logistical and methodological challenges. This perspective paper outlines early-phase experiences from a 7-tesla (7T) fMRI clinical trial involving individuals with mild cognitive impairment (MCI) and mild AD, highlighting recruitment hurdles and practical recommendations. From a pool of 1,000 patients, 475 had MCI or AD clinically diagnosed; following pre-selection and screening, only 6% met all inclusion criteria. Major barriers included exclusion due to comorbidities, difficulties with blood draws, miscommunication about study procedures, and unreported medical conditions discovered during MRI. Effective communication, often requiring caregiver involvement, was essential for obtaining accurate medical histories and improving adherence. Internally, clear team coordination helped manage scheduling and protocol compliance. While strict eligibility criteria enhance data quality, they significantly impede recruitment and feasibility in high-field MRI drug studies. We offer recommendations to optimize recruitment and screening, improve protocol execution, and better balance scientific rigor with real-world clinical constraints.},
}

@article {pmid40630497,
year = {2025},
author = {Stites, SD and Schumann, R and Kuz, C and Harkins, K and Largent, E and Krieger, A and Sankar, P and Zuelsdorff, M},
title = {Are Knowledge and Interpersonal Contact Cures for Alzheimer's Stigma? Data From Caregivers Offer Clues.},
journal = {Stigma and health},
volume = {10},
number = {2},
pages = {199-213},
pmid = {40630497},
issn = {2376-6972},
abstract = {Research on caregivers suggests interpersonal contact with persons with Alzheimer's disease (AD) and higher disease-oriented knowledge may heighten AD stigma, though these same mechanisms are often employed in anti-stigma campaigns. If we better understand associations among caregiver experience, interpersonal contact, AD knowledge and AD stigma, we can develop improved ways of reducing stigma and avoid unintended consequences. In a factorial design experiment, 2,371 participants read a vignette describing a fictional person; the vignette varied on clinical symptom stage, AD biomarker result, and treatment availability. Multivariable analyses assessed effects of caregiver experience, interpersonal contact, and different domains of disease-oriented knowledge on modified Family Stigma in Alzheimer's Disease Scale (FS-ADS) outcomes. Interaction analyses tested how clinical features may modify those associations. AD caregiver experience was associated with higher reactions on 6 of 7 FS-ADS domains. Disease-oriented knowledge, independent of content domain, did not substantially affect those associations. However, knowledge of caregiving, treatment, and life impact associated with lower FS-ADS scores, and knowledge about disease course and risk factors associated with higher reactions on FS-ADS domains. Knowledge of treatment modified reactions to symptoms and treatment availability. Knowledge of disease course modified reactions to a biomarker result. AD caregiver experience and interpersonal contact did not modify associations between clinical characteristics and FS-ADS domains. Distinct associations among different domains of AD knowledge and stigma outcomes should be considered when developing anti-stigma campaigns. Failure to do so risks worsening rather than alleviating AD stigma.},
}

@article {pmid40630407,
year = {2025},
author = {Wang, Y and Liu, D and Wang, H and Wang, M and Ruan, W and Han, Y and Han, Y},
title = {The role of physical activity in preventing cognitive decline among U.S. older adults with diabetes and prediabetes: a cross-sectional study.},
journal = {Frontiers in public health},
volume = {13},
number = {},
pages = {1603627},
pmid = {40630407},
issn = {2296-2565},
mesh = {Humans ; Cross-Sectional Studies ; Female ; Male ; *Prediabetic State/epidemiology ; Aged ; *Exercise/physiology ; *Cognitive Dysfunction/prevention & control ; United States/epidemiology ; Middle Aged ; Nutrition Surveys ; *Diabetes Mellitus/epidemiology ; Aged, 80 and over ; },
abstract = {BACKGROUND: Physical activity (PA) has been widely recognized as a key strategy to slow age-related cognitive decline. However, its specific effects on older adults with diabetes or prediabetes remain poorly understood. Therefore, we investigated the association between different levels of PA and cognitive function among older Americans with diabetes and prediabetes.

METHODS: This cross-sectional study used data from the 2011-2014 National Health and Nutrition Examination Survey (NHANES) and included a total of 1,299 older adults aged ≥60 years. The PA levels were determined by calculating the weekly metabolic equivalent of task time (MET-min/week). The participants' cognitive abilities were assessed using the Consortium to Establish a Registry for Alzheimer's disease (CERAD) Word Learning Test, Animal Fluency Test (AFT), and Digit Symbol Substitution Test (DSST). Multivariable logistic regression models were used to analyze the association between different PA levels and cognitive function in patients with diabetes and prediabetes. The study utilized the restricted cubic spline (RCS) models to explore the nonlinear correlation of PA with cognitive function.

RESULTS: Upon controlling for confounders, DSST scores were still significantly associated with moderate-level PA (OR: 0.457, 95% CI: 0.244, 0.853, p = 0.020) and high-level PA (OR: 0.478, 95% CI: 0.240, 0.955, p = 0.039). According to the RCS models, PA showed a significant nonlinear correlation with cognitive function, and the risk of cognitive decline decreased with the increase of PA levels.

CONCLUSION: In older adults with diabetes and prediabetes, moderate and high levels of physical activity are associated with a lower risk of cognitive decline. Clinicians should encourage patients to participate actively in exercise to maximize the benefits of PA.},
}

Humans
Cross-Sectional Studies
Female
Male
*Prediabetic State/epidemiology
Aged
*Exercise/physiology
*Cognitive Dysfunction/prevention & control
United States/epidemiology
Middle Aged
Nutrition Surveys
*Diabetes Mellitus/epidemiology
Aged, 80 and over

@article {pmid40630177,
year = {2025},
author = {Stapley, S and Pentecost, C and Hillman, A and Jones, IR and Morris, R and Quinn, C and Ravi, M and Thom, J and Clare, L},
title = {Continuity, change and 'living well' for older people with dementia: longitudinal qualitative findings from the IDEAL cohort study.},
journal = {Ageing and society},
volume = {},
number = {},
pages = {1-20},
pmid = {40630177},
issn = {0144-686X},
abstract = {'Living well' is an important concept across national dementia strategies, where qualitative research has contributed to understandings of living well for people with dementia. Longitudinal, qualitative approaches are fewer but can explore potential changes in accounts of living well, psychological coping and adaptation to dementia, and if or how people with dementia maintain continuity in their lives. The aim of this longitudinal qualitative study was to gauge what is important for 'living well' with mild-to-moderate dementia and whether this changes over time in a group of older people with mild-to-moderate dementia living at home. Semi-structured, qualitative interviews with 20 people with dementia from the IDEAL cohort study were conducted in 2017 and again one year later and analysed using longitudinal thematic analyses. The overarching narrative was largely that of continuity and adaptation, with incremental not disruptive change. Continuing participation and meaningful occupation were important to maintain living well over time, where individuals pursued new as well as previous interests. As a key psychological coping strategy to support continuity in their lives, individuals emphasised their capabilities to maintain activities in spite of dementia, compartmentalising specific areas which had become more challenging. Maintaining social networks and accommodating changes in social relationships were also central to living well over time including managing the psychological impacts of changes in spousal relationships. People in the earlier stages of dementia emphasise continuity and their capabilities, reporting change over time only in certain aspects of their lives. However, small, incremental changes in their social relationships and opportunities for meaningful occupation may still afford key areas for supporting capability to 'live well'.},
}

@article {pmid40629981,
year = {2025},
author = {Shaaban, AE and Ali, AR and Ayyad, SN and Badria, FA},
title = {Novel Purine-Based Natural Products as Inhibitors of Cholinesterases and Monoamine Oxidases Presenting Potential Multitarget Therapeutics Tackling Alzheimer's Disease.},
journal = {Archiv der Pharmazie},
volume = {358},
number = {7},
pages = {e70035},
doi = {10.1002/ardp.70035},
pmid = {40629981},
issn = {1521-4184},
support = {//This study is partly funded by Research Unit, Mansoura University (project code: MU-Phra-23-27). The authors would like to acknowledge the STDF (Science, Technology & Innovation Funding Authority) financial fund from grant within the framework of the German Egyptian Research Fund (GERF), Project ID: 33601./ ; },
mesh = {*Cholinesterase Inhibitors/pharmacology/chemistry/chemical synthesis ; *Alzheimer Disease/drug therapy ; *Monoamine Oxidase Inhibitors/pharmacology/chemistry/chemical synthesis ; *Biological Products/pharmacology/chemistry/chemical synthesis ; *Purines/pharmacology/chemistry/chemical synthesis ; Humans ; Structure-Activity Relationship ; Molecular Docking Simulation ; *Monoamine Oxidase/metabolism ; Molecular Structure ; Acetylcholinesterase/metabolism ; Dose-Response Relationship, Drug ; Antioxidants/pharmacology/chemical synthesis/chemistry ; Butyrylcholinesterase/metabolism ; Molecular Dynamics Simulation ; Animals ; },
abstract = {Alzheimer's disease (AD) is a complex neurological disorder that arises from multiple factors. The innovative multitarget-directed ligand (MTDL) approach, which incorporates multiple pharmacophores into one molecule, enhances the development of effective therapeutics for AD. Eighteen novel natural product-based purine MTDLs were synthesized. These hybrids were evaluated In Vitro for their inhibitory effects on AChE, BChE, MAO-A, and MAO-B. The findings revealed that most hybrids effectively and selectively inhibited AChE. Hybrid 9b demonstrated the highest inhibitory potency against AChE, BChE, MAO-A, and MAO-B, exhibiting IC50 values of 5.52, 11.64, 25.99, and 34.78 µM, respectively. In addition, hybrid 9b exhibited interesting antioxidant activity, with an IC50 of 6.69 µM. The mechanism of action and the binding modes of hybrid 9b were analyzed through molecular docking studies. Molecular dynamics simulation revealed that hybrid 9b is stable within the AChE active site. In Silico assessments of physicochemical properties for hybrid 9b indicate that it is well absorbed following oral administration and can penetrate brain tissue. Finally, hybrid 9b stability studies in simulated gastric and intestinal conditions suggested that it could be absorbed into the bloodstream without significant degradation. Consequently, these findings reinforce the potential therapeutic applications of hybrid 9b as a multifunctional therapeutic candidate for addressing AD.},
}

*Cholinesterase Inhibitors/pharmacology/chemistry/chemical synthesis
*Alzheimer Disease/drug therapy
*Monoamine Oxidase Inhibitors/pharmacology/chemistry/chemical synthesis
*Biological Products/pharmacology/chemistry/chemical synthesis
*Purines/pharmacology/chemistry/chemical synthesis
Humans
Structure-Activity Relationship
Molecular Docking Simulation
*Monoamine Oxidase/metabolism
Molecular Structure
Acetylcholinesterase/metabolism
Dose-Response Relationship, Drug
Antioxidants/pharmacology/chemical synthesis/chemistry
Butyrylcholinesterase/metabolism
Molecular Dynamics Simulation
Animals

@article {pmid40629914,
year = {2025},
author = {Devara, D and Sharma, B and Goyal, G and Rodarte, D and Kulkarni, A and Tinu, N and Pai, A and Kumar, S},
title = {MiRNA-501-3p and MiRNA-502-3p: A promising biomarker panel for Alzheimer's disease.},
journal = {Clinical and translational medicine},
volume = {15},
number = {7},
pages = {e70389},
doi = {10.1002/ctm2.70389},
pmid = {40629914},
issn = {2001-1326},
support = {K99AG065645//National Institute on Aging, NIH/ ; R00AG065645//National Institute on Aging, NIH/ ; R00AG065645-04S1//National Institute on Aging, NIH/ ; //The Edward N. & Margaret G. Marsh Foundation/ ; //TTUHSC EP MTM Startup Funds/ ; },
mesh = {*Alzheimer Disease/genetics/diagnosis/cerebrospinal fluid/blood ; *MicroRNAs/blood/analysis/genetics ; Humans ; Biomarkers/blood/analysis ; Male ; Female ; Aged ; Middle Aged ; Exosomes/metabolism ; },
abstract = {INTRODUCTION: Alzheimer's disease (AD) lacks a less invasive and early detectable biomarker. Here, we investigated the biomarker potential of miR-501-3p and miR-502-3p using different AD sources.

METHODS: MiR-501-3p and miR-502-3p expressions were evaluated in AD cerebrospinal fluid (CSF) exosomes, serum exosomes, familial and sporadic AD fibroblasts and B-lymphocytes by qRT-PCR analysis. Further, miR-501-3p and miR-502-3p expressions were analysed in APP, Tau plasmid transfected cells media exosomes and in different brain cell types.

RESULTS: MiR-501-3p and miR-502-3p expressions were significantly up-regulated in AD CSF exosomes relative to controls. MiRNA levels were high in accordance with amyloid plaque and NFT density in multiple brain regions. Similarly, both miRNAs were elevated in AD and MCI serum exosomes compared with controls. MiR-502-3p expression was high in familial AD and sporadic AD B-lymphocytes. MiR-501-3p and miR-502-3p expression were elevated intracellularly and secreted extracellularly in response to APP and Tau pathology. Finally, neurons and astrocytes displayed high expression of these miRNAs.

DISCUSSION: These results suggest that miR-501-3p and miR-502-3p could be promising biomarkers for AD.

KEY POINTS: MiR-501-3p and miR-502-3p expression is elevated in AD CSF exosomes, AD serum exosomes, AD B-lymphocytes and Aβ- and Tau-treated cells. MiR-501-3p and miR-502-3p are correlated with amyloid plaque and NFT tangle density in specific brain regions. MiR-501-3p and miR-502-3p are highly expressed in neurons and astrocytes, suggesting that these cells are the source of miRNA secretion. MiR-501-3p and miR-502-3p could be a promising biomarker panel for AD.},
}

*Alzheimer Disease/genetics/diagnosis/cerebrospinal fluid/blood
*MicroRNAs/blood/analysis/genetics
Humans
Biomarkers/blood/analysis
Male
Female
Aged
Middle Aged
Exosomes/metabolism

@article {pmid40629890,
year = {2025},
author = {Loring, DW and Hermann, BP and Meador, KJ and Lah, JJ and Goldstein, FC and Bilder, RM},
title = {Would a rose by any other name smell as sweet? Complexity, context, and consequences of neuropsychology performance labels.},
journal = {The Clinical neuropsychologist},
volume = {},
number = {},
pages = {1-9},
doi = {10.1080/13854046.2025.2529530},
pmid = {40629890},
issn = {1744-4144},
abstract = {Objective: The American Academy of Clinical Neuropsychology (AACN) has proposed standardized performance labels to enhance consistency in neuropsychological reporting. While valuable in forensic and medicolegal contexts, these guidelines may limit interpretive flexibility and clinical relevance in diverse practice settings. This manuscript examines the contextual appropriateness of AACN labels across diverse clinical and research settings, highlighting the need for diagnostic flexibility over rigid adherence to normative descriptors. Methods: We reviewed the historical and conceptual underpinnings of neuropsychological assessment, focusing on Ward Halstead's distinction between "biological" and "psychometric" intelligence. This framework was used to explore how interpretive models shape clinical reasoning and test interpretation. Special attention was given to the implications of score labeling in multidisciplinary team settings (e.g. dementia diagnosis, epilepsy surgery and within large-scale research initiatives, including Alzheimer's Disease Research Centers (ADRCs). Conclusions: Although AACN performance labels support greater transparency and consistency in select contexts, their universal implementation may obscure meaningful cognitive patterns and diminish diagnostic precision. Labels such as "below average" may fail to capture clinically meaningful decline in high-functioning individuals or obscure clinically relevant cognitive patterns critical for diagnosis and treatment planning. We argue for a context-sensitive approach to score interpretation that allows flexible, informed use of descriptors aligned with specific referral questions and clinical goals. Neuropsychological assessment is most effective when guided by integrative clinical reasoning rather than uncritical application of standardized labeling conventions.},
}

@article {pmid40629712,
year = {2025},
author = {Rosbergen, MT and van der Veere, P and Claus, JJ and Evans, TE and Venkatraghavan, V and Barkhof, F and van Harten, AC and Ikram, MA and van der Flier, WM and Vernooij, MW and Wolters, FJ},
title = {Subcortical gray matter volumes and 5-year dementia risk in individuals with subjective cognitive decline or mild cognitive impairment: A multi-cohort analysis.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21},
number = {7},
pages = {e70413},
doi = {10.1002/alz.70413},
pmid = {40629712},
issn = {1552-5279},
support = {//Medical Delta Society/ ; //Ministerie van Onderwijs, Cultuur en Wetenschap/ ; //European Commission (DG XII)/ ; //gemeente Rotterdam/ ; //Ministerie van Volksgezondheid, Welzijn en Sport/ ; //Netherlands Genomics Initiative/ ; //Research Institute for Diseases in the Elderly (RIDE),/ ; //Erasmus Medisch Centrum/ ; //Erasmus Universiteit Rotterdam/ ; AARF-22-924982/ALZ/Alzheimer's Association/United States ; //Vereniging Trustfonds Erasmus Universiteit Rotterdam/ ; //Alzheimer Nederland/ ; //Health Holland/ ; 10510032120003/ZONMW_/ZonMw/Netherlands ; //The Netherlands Organisation for Scientific Research/ ; },
mesh = {Humans ; *Cognitive Dysfunction/pathology/diagnostic imaging ; Female ; Male ; Aged ; *Gray Matter/pathology/diagnostic imaging ; Magnetic Resonance Imaging ; *Dementia/pathology/diagnostic imaging/epidemiology ; *Hippocampus/pathology/diagnostic imaging ; *Amygdala/pathology/diagnostic imaging ; Cohort Studies ; Risk Factors ; Longitudinal Studies ; Prognosis ; },
abstract = {INTRODUCTION: The prognostic value of subcortical gray matter structures for dementia beyond the hippocampus remains unclear.

METHODS: We included participants with subjective cognitive decline or mild cognitive impairment from two memory clinic-based cohorts (Amsterdam Dementia Cohort and National Alzheimer's Coordinating Center) and one population-based cohort (Rotterdam Study). We assessed volumes of subcortical structures on magnetic resonance imaging and determined 5-year dementia risk using Cox models.

RESULTS: Of 7076 participants (mean age: 66-69 years, 58.8%-61.0% women; NSCC = 5425, NMCI = 1661), 622 developed dementia within 5 years. Smaller volumes of the hippocampus and amygdala were consistently associated with increased dementia risk, independent of other subcortical structures. Smaller hippocampal volume was predominantly associated with the clinical diagnosis of Alzheimer's disease, but the prognostic value did not differ by amyloid status.

DISCUSSION: Hippocampal and amygdalar volume are consistently associated with dementia risk in individuals with subjective cognitive decline or mild cognitive impairment, which may hold potential for personalized prognosis.

HIGHLIGHTS: Seven thousand seventy-six participants from three large longitudinal cohorts were followed for a maximum of 5 years. Hippocampal volume is associated with 5-year risk of dementia in subjective cognitive decline (SCD) or mild cognitive impairment (MCI). Amygdalar volume is associated with a 5-year risk of dementia in SCD or MCI. Stratifying by SCD and MCI revealed no consistent major differences.},
}

Humans
*Cognitive Dysfunction/pathology/diagnostic imaging
Female
Male
Aged
*Gray Matter/pathology/diagnostic imaging
Magnetic Resonance Imaging
*Dementia/pathology/diagnostic imaging/epidemiology
*Hippocampus/pathology/diagnostic imaging
*Amygdala/pathology/diagnostic imaging
Cohort Studies
Risk Factors
Longitudinal Studies
Prognosis

@article {pmid40629696,
year = {2025},
author = {Singleton, EH and Mattsson-Carlgren, N and Pichet Binette, A and Stomrud, E and Strandberg, O and Palmqvist, S and Ossenkoppele, R and Hansson, O},
title = {Longitudinal tau aggregation, atrophy, and cognitive decline in Alzheimer's disease.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21},
number = {7},
pages = {e70435},
doi = {10.1002/alz.70435},
pmid = {40629696},
issn = {1552-5279},
support = {ADG-101096455/ERC_/European Research Council/International ; //GHR Foundation/ ; 2022-00775//Swedish Research Council/ ; 2021-02219//Swedish Research Council/ ; 2018-02052//Swedish Research Council/ ; ERAPERMED2021-184//ERA PerMed/ ; 2022-0231//Knut and Alice Wallenberg foundation/ ; //Lund University/ ; AF-980907//Swedish Alzheimer Foundation/ ; AF-994229//Swedish Alzheimer Foundation/ ; FO2021-0293//Swedish Brain Foundation/ ; FO2023-0163//Swedish Brain Foundation/ ; 1412/22//Parkinson foundation of Sweden/ ; FRS-0003//Familjen Rönnströms Stiftelse/ ; 2020-O000028//Skåne University Hospital Foundation/ ; 2022-1259//Regionalt Forskningsstöd/ ; SG-23-1061717/ALZ/Alzheimer's Association/United States ; ZEN24-1069572/ALZ/Alzheimer's Association/United States ; WASP/DDLS22-066//WASP and DDLS Joint call for research projects/ ; 2022-Projekt0080//Cure Alzheimer's fund, Berg Family Foundation, Konung Gustaf V:s och Drottning Victorias Frimurarestiftelse, Swedish federal government under the ALF agreement/ ; 2022-Projekt0107//Cure Alzheimer's fund, Berg Family Foundation, Konung Gustaf V:s och Drottning Victorias Frimurarestiftelse, Swedish federal government under the ALF agreement/ ; //GE Healthcare and Roche/ ; },
mesh = {Humans ; *Alzheimer Disease/pathology/diagnostic imaging/metabolism ; *tau Proteins/metabolism ; Male ; Positron-Emission Tomography ; Female ; *Cognitive Dysfunction/diagnostic imaging/pathology/metabolism ; Magnetic Resonance Imaging ; Aged ; Atrophy/pathology ; Longitudinal Studies ; *Brain/pathology/diagnostic imaging/metabolism ; Sweden ; },
abstract = {INTRODUCTION: The independent contributions of baseline and longitudinal tau positron emission tomography (PET) and magnetic resonance imaging (MRI) to cognitive decline remain unclear.

METHODS: We included n = 761 amyloid-positive individuals from the Swedish BioFINDER-2 study with [[18]F]RO948-tau-PET, 3-Tesla structural-MRI, and cognition (n = 322 with longitudinal imaging data). Linear-mixed-models with random-intercepts and -slopes or linear-regressions were adjusted for age, sex, education, diagnosis, and other-imaging-modality.

RESULTS: Tau-PET showed stronger associations with cognitive decline than MRI, showing the strongest associations in a neocortical-composite-region with a cognitive composite (β = -0.25 ± 0.02, p < 0.001) for baseline and longitudinal tau-PET (β = -0.62 ± 0.05, p < 0.001). Baseline tau-PET explained the largest proportion of cognitive decline (54.0%-94.0%), with modest mediation effects for longitudinal tau-PET or MRI pathways (2.0%-15.0%). Simulated reductions of tau-PET-slopes (up to 100%) were associated with marginally altered cognitive trajectories.

DISCUSSION: The strong associations between baseline tau-PET and longitudinal cognition, with marginal contributions of longitudinal tau-PET and MRI, emphasize the importance of baseline tau aggregates for prognostics and treatments in Alzheimer's disease (AD).

HIGHLIGHTS: Baseline and longitudinal regional tau-PET uptake were more closely associated than structural MRI with longitudinal cognitive decline. Baseline tau-PET was a stronger determinant of longitudinal cognitive decline than longitudinal tau-PET. Simulated reductions of tau-PET accumulation showed limited alterations of cognitive trajectories, with potential implications for tau-targeting therapies.},
}

Humans
*Alzheimer Disease/pathology/diagnostic imaging/metabolism
*tau Proteins/metabolism
Male
Positron-Emission Tomography
Female
*Cognitive Dysfunction/diagnostic imaging/pathology/metabolism
Magnetic Resonance Imaging
Aged
Atrophy/pathology
Longitudinal Studies
*Brain/pathology/diagnostic imaging/metabolism
Sweden

@article {pmid40629423,
year = {2025},
author = {Chen, C and Zhou, Y and Li, Y and Xu, J and Li, D and Wang, L},
title = {MRDDA: a multi-relational graph neural network for drug-disease association prediction.},
journal = {Journal of translational medicine},
volume = {23},
number = {1},
pages = {753},
pmid = {40629423},
issn = {1479-5876},
support = {4252021//Natural Science Foundation of Beijing Municipality/ ; 2023-NHLHCRF-YYPPLC-TJ-01//National High Level Hospital Clinical Research Funding/ ; 62376017//National Natural Science Foundation of China/ ; buctrc202221//Fundamental Research Funds for the Central Universities/ ; buctrc202403//Fundamental Research Funds for the Central Universities/ ; },
mesh = {*Drug Repositioning ; *Neural Networks, Computer ; Humans ; *Disease ; Graph Neural Networks ; },
abstract = {BACKGROUND: Drug repositioning offers a promising avenue for accelerating drug development and reducing costs. Recently, computational repositioning approaches have gained attraction for identifying potential drug-disease associations (DDAs). Biological entities such as drugs, genes, proteins, RNA, and diseases interact within a complex network. How to adequately extract the intrinsic relationships among them and accurately predict the drug-disease associations remains a challenge.

METHODS: In this study, we introduce MRDDA, a novel graph neural network model that utilizes multiple relations, for drug repositioning. First, we design a hybrid graph convolutional framework to capture both local and global representations of drugs and diseases. Subsequently, a meta-path-based approach is employed to capture high-order topological representations from these entities. Finally, we present a layer-wise attention mechanism to integrate embeddings from various layers.

RESULTS: The MRDDA model demonstrated superior performance in predicting drug-disease associations compared to existing methods, achieving higher results during the 10-fold cross-validation on three benchmark datasets. Notably, in our case studies focusing on Alzheimer's disease and breast cancer, MRDDA effectively identified several promising drug candidates that were previously unrecognized for these conditions. Additionally, molecular docking experiments reinforced our results by confirming the binding affinities and interactions between selected drugs and their target diseases, suggesting a solid basis for further experimental studies.

CONCLUSION: MRDDA offers an innovative framework for drug repositioning by effectively modeling and predicting drug-disease associations through advanced graph neural network techniques. The model's ability to integrate multi-relational data with greater accuracy paves the way for more efficient identification of potential therapeutic uses for existing drugs, ultimately contributing to the acceleration of drug development and reduced costs in the pharmaceutical industry.},
}

*Drug Repositioning
*Neural Networks, Computer
Humans
*Disease
Graph Neural Networks

@article {pmid40629407,
year = {2025},
author = {Choi, Y and Chung, WS},
title = {Glial phagocytosis for synapse and toxic proteins in neurodegenerative diseases.},
journal = {Molecular neurodegeneration},
volume = {20},
number = {1},
pages = {81},
pmid = {40629407},
issn = {1750-1326},
support = {2020M3E5D9079912//Ministry of Science and ICT, South Korea/ ; 2021R1A2C3005704//Ministry of Science and ICT, South Korea/ ; 2022M3E5E8081188//Ministry of Science and ICT, South Korea/ ; IBS-R025-A1//Institute for Basic Science/ ; },
abstract = {Glia, as resident immune and supportive cells of the central nervous system, play a critical role in maintaining brain homeostasis. One of their key homeostatic functions is phagocytic capacity in pruning synapses and removing cellular debris/protein aggregates, a process vital for synaptic plasticity and brain maintenance. However, these phagocytic functions are often dysregulated with aging and in neurodegenerative diseases (NDs), such as Alzheimer's disease, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, and frontotemporal dementia. This review aims to examine the phagocytic roles of glia under both physiological and pathological conditions, with a special focus on their interactions with misfolded protein aggregates, including amyloid beta, tau, alpha synuclein, prion, huntingtin, and TAR DNA-binding protein 43. We also explore the fate of ingested molecules after being phagocytosed by glia-whether they are degraded, accumulate intracellularly, or are transferred between cells-and their implications for disease progression. Finally, we review current therapeutic strategies and the potential approaches for modulating glial phagocytosis to mitigate several NDs. We believe that understanding the exact mechanisms of glial phagocytosis and clearance will serve as key elements in developing future treatments for NDs.},
}

@article {pmid40629315,
year = {2025},
author = {Wei, X and Peng, J and Chang, R and Liu, Q},
title = {Prevalence and influencing factors of cognitive frailty in Chinese maintenance hemodialysis patients: a systematic review and meta-analysis.},
journal = {BMC nephrology},
volume = {26},
number = {1},
pages = {365},
pmid = {40629315},
issn = {1471-2369},
abstract = {OBJECTIVE: Chronic kidney disease (CKD) has become a major challenge in global public health, and China has one of the heaviest burdens of CKD in the world, approximately 89.5% of patients require hemodialysis. Cognitive frailty (CF) is a condition characterized by physical frailty and cognitive impairment while excluding Alzheimer's disease and other dementias. CF is associated with adverse clinical outcomes, including hospitalization, disability, and increased mortality. The purpose of this study was to explore the prevalence and influencing factors of CF in Chinese maintenance hemodialysis (MHD) patients through systematic review and meta-analysis.

METHODS: We searched PubMed, Cochrane Library, Web of Science, EMBASE, China National Knowledge Infrastructure (CNKI), Wanfang Database, Chinese Scientific Journal Database (VIP) and Chinese Biomedical Database (CBM) for epidemiological data on CF in Chinese patients undergoing MHD from inception to December 2024. A random-effects model was used to estimate the overall prevalence of CF in Chinese patients undergoing MHD. Odds ratios (OR) and 95% confidence intervals (CI) were used to estimate factors associated with CF in Chinese patients undergoing MHD. Stata 15.0 software was used to conduct systematic review and meta-analysis of the prevalence and influencing factors of CF in Chinese patients undergoing MHD.

RESULTS: A total of 16 studies with 5690 Chinese patients undergoing MHD were included. The results of this meta-analysis showed that the prevalence of CF in Chinese patients undergoing MHD was 25%. The results of subgroup analyses showed that the frailty assessment tool (TFI) and education level (≥ College) may be sources of heterogeneity in the prevalence of CF in Chinese patients undergoing MHD. The meta-analysis results indicate that age (> 60, > 75), female, depression (HADS scale), malnutrition, triglycerides, waist circumference, stroke history, fall history, complications, CCI, comorbidities and dialysis age were risk factors for CF. High education level, calf circumference and serum creatinine level were protective factors for CF.

CONCLUSIONS: The prevalence of CF in Chinese patients undergoing MHD is high (25%). Therefore, this patient population necessitates early screening and targeted interventions with influencing factors.

CRD42023493122CRD42023475424.},
}

@article {pmid40629265,
year = {2025},
author = {Wang, J and Liu, C and Dai, Y and Mei, C and Wang, G and Wang, Y and Huang, T and Zhan, J and Cheng, J},
title = {Efficacy of music therapy as a non-pharmacological measure to support alzheimer's disease patients: a systematic review.},
journal = {BMC geriatrics},
volume = {25},
number = {1},
pages = {508},
pmid = {40629265},
issn = {1471-2318},
support = {S202410488180X,202310488043X//Key Laboratory Open Fund of Ministry of Education College Student Innovation and Entrepreneurship Project/ ; OHIC2024G07, OHIC2024Z04//Occupational Hazard Identification and control Key laboratory of Hubei Province open fund/ ; 2023KF002//Ministry of Education/ ; WJ2023M107//Health Commission of Hubei Province scientific research project/ ; },
abstract = {BACKGROUND: Alzheimer's disease (AD) is a degenerative disease of the central nervous system characterized by progressive memory degradation and language and behavior disorders. Apart from curative pharmacological therapies, music therapy (MT) has been diffusely used as an efficient and economical non-pharmacological treatment for AD patients in recent years.

METHODS: Three databases (PubMed, Web of Science and PsycINFO) were searched to analyse the efficacy of MT in patients with AD. Keywords included "Alzheimer's disease", "AD", "Mild Cognitive Impairment", "MCI", "music" and "music therapy".

RESULTS: Literatures between January 2013 and January 2023 were selected, with 42 literatures included in the study, which highlights the beneficial impact of MT on cognition (memory, attention, language), behavioural and psychological symptoms (anxiety, depression and agitation), quality of life, self-esteem and physical pain in AD patients.

CONCLUSION: MT is a promising non-pharmacological treatment approach for individuals living with AD. However, further evidences from prospective, randomised, blinded, uniform, and rigorous method-logical investigations in this field are required to conclusively validate MT's impact on this disease. PROSPERO REGISTRATION NUMBER: CRD420251034039.},
}

@article {pmid40629207,
year = {2025},
author = {Park, BN and Kim, SM and An, YS},
title = {Combining Dopamine Transporter and Amyloid PET Tracer: A Preclinical Study on Dual-Target Imaging.},
journal = {Molecular imaging and biology},
volume = {},
number = {},
pages = {},
pmid = {40629207},
issn = {1860-2002},
support = {NRF-2022R1A2C1003039//National Research Foundation of Korea/ ; },
abstract = {PURPOSE: This study aimed to evaluate the feasibility and diagnostic utility of a dual-target positron emission tomography (PET) imaging approach using a cocktail of N-3-[[18]F]fluoropropyl-2β-carbomethoxy-3β-(4-iodophenyl) nortropane ([[18]F]FP-CIT) and [[18]F]florbetaben (FBB) for the simultaneous assessment of dopaminergic and amyloid changes in a preclinical setting.

PROCEDURES: We utilized both Parkinson's disease (PD) and Alzheimer's disease (AD) mouse models, as well as a control group, to investigate the uptake of [[18]F]FP-CIT and [[18]F]FBB individually and in combination. PET imaging was conducted, and standardized uptake value ratios (SUVRs) were analyzed for each model across the striatal and cortical regions. Comparisons were made between single and cocktail PET scans to assess potential cross-interference of the tracers.

RESULTS: In both PD and AD models, no statistically significant differences were observed in the SUVRs between single-tracer and cocktail PET scans in the striatum and cortex (p > 0.4 for striatal comparisons, p > 0.8 for cortical comparisons). Bland-Altman analysis showed no significant bias, supporting the interchangeability of SUVRs between single and cocktail PET scans.

CONCLUSIONS: This preclinical study suggests that [[18]F]FP-CIT and [[18]F]FBB PET imaging is a viable dual-target imaging approach for neurodegenerative disease evaluation. The method could streamline diagnostic workflows and improve patient convenience. Further clinical studies are warranted to validate the efficacy and safety of this approach in human populations.},
}

@article {pmid40628936,
year = {2025},
author = {Kaub, L and Milz, S and Barapatre, N and Büttner, A and Michalke, B and Schmitz, C and Gilder, SA},
title = {Magnetic iron-oxide nanoparticles in the brain connected to alcohol-associated liver disease.},
journal = {Scientific reports},
volume = {15},
number = {1},
pages = {24505},
pmid = {40628936},
issn = {2045-2322},
mesh = {Humans ; *Magnetic Iron Oxide Nanoparticles/chemistry ; *Liver Diseases, Alcoholic/metabolism/pathology ; Male ; *Brain/metabolism/pathology ; Iron/metabolism ; Middle Aged ; *Brain Stem/metabolism/pathology ; Aged ; Female ; },
abstract = {Magnetic iron-oxide nanoparticles in the form of magnetite (Fe3O4) are present in the human brain. They have been hypothesized to biomineralize in situ, as a result of dysfunctional iron homeostasis related to Alzheimer's disease, or to enter the brain as airborne pollution particles. Regardless of their origin, magnetic iron-oxides pose a potential hazard to human health due to their high redox activity and surface charge. Here we report measurements on four post-mortem human brainstems, with one brainstem showing approximately 100 times higher magnetite concentrations than the other cases. This brainstem came from a subject with alcohol-associated liver disease (ALD) that manifested in liver cirrhosis and massive hepatic iron overload. Laser ablation - inductively coupled plasma - mass spectrometry showed the highest levels of trace metals (iron, copper and manganese) in the ALD brainstem. It is well established that a dysfunctional liver can result in the accumulation of trace metals in the brain. Our data indicate a similar pathway for magnetite particles, yet liver pathology has not been linked to magnetite occurrence in the brain so far. It may prove to be a crucial factor in understanding the high variation of magnetite concentrations found in human brains.},
}

Humans
*Magnetic Iron Oxide Nanoparticles/chemistry
*Liver Diseases, Alcoholic/metabolism/pathology
Male
*Brain/metabolism/pathology
Iron/metabolism
Middle Aged
*Brain Stem/metabolism/pathology
Aged
Female

@article {pmid40628933,
year = {2025},
author = {Wu, S and Liu, C and Li, Y and Zhang, X and Han, Q and Zhao, H and Zhao, K and Dang, Y and Wang, R and Song, S},
title = {Inhibitory mechanisms of amentoflavone on amyloid-β peptide aggregation revealed by replica exchange molecular dynamics.},
journal = {Scientific reports},
volume = {15},
number = {1},
pages = {24352},
pmid = {40628933},
issn = {2045-2322},
support = {QN2025083//Science Research Project of Hebei Education Department/ ; QN2025083//Science Research Project of Hebei Education Department/ ; QN2025083//Science Research Project of Hebei Education Department/ ; },
mesh = {*Amyloid beta-Peptides/chemistry/metabolism ; *Molecular Dynamics Simulation ; *Biflavonoids/pharmacology/chemistry/metabolism ; *Protein Aggregates/drug effects ; Humans ; Hydrophobic and Hydrophilic Interactions ; Protein Binding ; Protein Aggregation, Pathological/drug therapy ; },
abstract = {Amyloid-β (Aβ) aggregation is a central pathological hallmark of Alzheimer's disease, with soluble trimers recognized as particularly neurotoxic species. Amentoflavone (AMF), a natural biflavonoid compound, has shown strong inhibitory effects on Aβ aggregation. However, its underlying molecular mechanism remains poorly understood. In this study, we employed replica exchange molecular dynamics (REMD) and molecular mechanics/Poisson-Boltzmann surface area (MM/PBSA) method to elucidate the interaction between AMF and Aβ peptides. Our results reveal that AMF preferentially binds to the [16]KLVFFAEDV[24] segment, a hydrophobic core that plays a critical role in the initiation of aggregation. It disrupts b-sheet formation through hydrophobic interactions with Leu-17, Phe-20, and Val-24. This binding stabilizes disordered coil conformations and prevents the conformational transitions required for fibril formation. Based on these findings, we performed structure-based virtual screening and identified two natural product-derived candidates with higher predicted affinity. These insights provide an atomic-level understanding of AMF's inhibitory mechanism and support the rational design of natural product-inspired inhibitors that target Aβ aggregation.},
}

*Amyloid beta-Peptides/chemistry/metabolism
*Molecular Dynamics Simulation
*Biflavonoids/pharmacology/chemistry/metabolism
*Protein Aggregates/drug effects
Humans
Hydrophobic and Hydrophilic Interactions
Protein Binding
Protein Aggregation, Pathological/drug therapy

@article {pmid40628716,
year = {2025},
author = {Chen, Y and Jin, H and Chen, J and Li, J and Găman, MA and Zou, Z},
title = {The multifaceted roles of apolipoprotein E4 in Alzheimer's disease pathology and potential therapeutic strategies.},
journal = {Cell death discovery},
volume = {11},
number = {1},
pages = {312},
pmid = {40628716},
issn = {2058-7716},
abstract = {Alzheimer's disease (AD), the most common dementia in the elderly, is marked by progressive cognitive decline and neurodegeneration. Core pathological hallmarks include amyloid-beta (Aβ) plaques, hyperphosphorylated tau aggregates, neuroinflammation, and metabolic dysfunction (e.g., impaired glucose utilization, mitochondrial deficits). Apolipoprotein E4 (ApoE4), the strongest genetic risk factor for AD, interacts with these processes, yet its precise pathogenic mechanisms remain unclear. This review examines ApoE4's multifaceted contributions to AD pathogenesis, focusing on its roles in Aβ accumulation, tau hyperphosphorylation, neuroinflammatory activation, and metabolic dysregulation. We further evaluate emerging therapeutic strategies targeting these pathways, including ApoE4 modulation, anti-amyloid/tau interventions, and metabolic rescue approaches. Elucidating the molecular interplay between ApoE4 and AD pathology is critical for developing targeted therapies to modify disease progression and mitigate cognitive decline in patients.},
}

@article {pmid40628712,
year = {2025},
author = {Huang, LY and Tan, CC and Xu, W and Tan, L and , },
title = {Relationships of PGRN with sTREM2 in AD continuum and non-AD pathophysiology and their reciprocal roles in modulating amyloid pathology: two population-based study.},
journal = {Translational psychiatry},
volume = {15},
number = {1},
pages = {233},
pmid = {40628712},
issn = {2158-3188},
support = {NO.tsqn202211375//Taishan Scholar Foundation of Shandong Province/ ; },
mesh = {Humans ; *Progranulins/cerebrospinal fluid ; Male ; Female ; Aged ; *Membrane Glycoproteins/cerebrospinal fluid ; *Amyloid beta-Peptides/cerebrospinal fluid ; Middle Aged ; *Alzheimer Disease/cerebrospinal fluid/physiopathology/pathology ; *Receptors, Immunologic ; Biomarkers/cerebrospinal fluid ; *Peptide Fragments/cerebrospinal fluid ; Aged, 80 and over ; Cohort Studies ; },
abstract = {Progranulin (PGRN) and soluble triggering receptor expressed on myeloid cells-2 (sTREM2) are emerging biomarkers of Alzheimer's disease (AD). This study explores the roles of their interplay in modulating amyloid pathology. We analyzed data from 905 participants (mean age = 62.0) in the CABLE cohort and 973 participants (mean age = 73.1) in the ADNI, classified using the A/T/N biomarker framework. One-way ANOVA was used to assess whether cerebrospinal fluid (CSF) PGRN and sTREM2 differed across biomarker profiles and clinical stages. Multiple linear regression models and linear mixed-effects models were used to test the relationships among PGRN, sTREM2, and CSF Aβ1-42 levels. Mediation analysis was used to explore the reciprocal relationships between sTREM2 and PGRN in influencing amyloid pathology. CSF proteomic and bioinformatic analyses were finally used to investigate the underlying biological mechanisms. In both cohorts, PGRN and sTREM2 were higher in individuals within the TN+ profile irrespective of the A status, and followed similar trajectory across different clinical and biomarker stage. CSF PGRN was associated with higher sTREM2 across AD continuum and non-AD pathophysiology. Bidirectional mediation was observed between PGRN (14.6% in CABLE, 15.6% in ADNI) and sTREM2 (29.7% in CABLE, 33.5% in ADNI) in modulating Aβ pathology (p < 0.0001). Proteomic analysis identified 1539 CSF proteins (Bonferroni-corrected p < 7.13 × 10[-6]) simultaneously associated with PGRN, sTREM2, and Aβ1-42. These proteins are mainly enriched in immune processes and neural plasticity. These findings suggest that the interplay between lysosome function and microglia-related neuroinflammation plays key roles in amyloid metabolism.},
}

Humans
*Progranulins/cerebrospinal fluid
Male
Female
Aged
*Membrane Glycoproteins/cerebrospinal fluid
*Amyloid beta-Peptides/cerebrospinal fluid
Middle Aged
*Alzheimer Disease/cerebrospinal fluid/physiopathology/pathology
*Receptors, Immunologic
Biomarkers/cerebrospinal fluid
*Peptide Fragments/cerebrospinal fluid
Aged, 80 and over
Cohort Studies

@article {pmid40628581,
year = {2025},
author = {Amano, T and Inoue, M and Dixit, S and Tarafder, A},
title = {Ethnoracial Disparities in Advance Care Planning Among People With Alzheimer's Disease and Related Dementias.},
journal = {The American journal of geriatric psychiatry : official journal of the American Association for Geriatric Psychiatry},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.jagp.2025.06.006},
pmid = {40628581},
issn = {1545-7214},
abstract = {OBJECTIVES: This study aims to investigate racial/ethnic variations in advance care planning (ACP) among people with Alzheimer's disease and related dementias (ADRD) and identify race/ethnicity-specific correlates of ACP.

METHODS: The study used data from four waves of the Health and Retirement Study (HRS, 2012-2018). We included 5,420 observations with dementia, which was estimated using the machine-learning based Gianattasio-Power algorithm. Five types of engagement in ACP were measured: durable power of attorney, living will, future treatment discussion, limiting medical treatment, and number of ACP engaged. Besides ethnoracial identity, potential correlates of ACP were selected based on the literature. Regression analyses with subgroup analyses by race/ethnicity were performed.

RESULTS: Ethnoracial identity was significantly associated with the likelihood of ACP engagement. The association between ethnoracial identity and the number of ACP engagement was significant after adjusting for covariates. Non-Hispanic Black (Risk Ratio [RR] = 0.670, 95% Confidence Interval [CI] = [0.607, 0.740]) and Hispanic (RR= 0.597, 95% CI = [0.518, 0.688]) individuals with ADRD engaged in fewer ACP than non-Hispanic White counterparts. Factors such as gender, marital status, household wealth and income, number of ADL difficulty, number of health conditions, self-rated health, and nursing home residency were differentially associated with the number of ACP engagement among three ethnoracial groups.

CONCLUSIONS: The prevalence of engagement in ACP varies across ethnoracial groups. Non-Hispanic Black and Hispanic individuals are less likely to engage in various aspects of ACP than their non-Hispanic white counterparts. Race/ethnicity-specific correlates of ACP should be considered to develop equitable strategies that promote ACP among diverse populations.},
}

@article {pmid40628253,
year = {2025},
author = {Arslan-Sarimehmetoğlu, E and Bazancir-Apaydin, Z},
title = {Comparison of Swallowing Dysfunction, Endurance, and Dysphagia Symptom Severity in Early-Stage Alzheimer's Disease and Age-Matched Controls.},
journal = {Folia phoniatrica et logopaedica : official organ of the International Association of Logopedics and Phoniatrics (IALP)},
volume = {},
number = {},
pages = {1-15},
doi = {10.1159/000547270},
pmid = {40628253},
issn = {1421-9972},
abstract = {AIM: The aim of this study is to compare swallowing dysfunction, swallowing endurance, and dysphagia symptom severity in early-stage Alzheimer's disease (AD) and age-matched healthy controls (HCs).

METHODS: The case-control study included twenty-five individuals diagnosed with AD and fifteen age-matched elderly participants. Demographic data, including body mass index (BMI), disease history, comorbidities, and food habits, were obtained from first-degree relatives or patient records. Swallowing dysfunction was assessed using standardized dysphagia tests, including the 10-mL and 100-mL water swallowing tests. Swallowing endurance was assessed using the Repetitive Saliva Swallowing Test (RSST), and dysphagia symptom severity was evaluated with the Eating Assessment Tool-10 (EAT-10).

RESULTS: The duration of the 10 ml water swallow test was significantly longer in individuals with AD compared to HCs [4.1 (3.1-5.5), %95 confidence interval (CI) of 3.2 to 5.5 versus 3 (2.4-3.5), %95 CI of 2.4 to 3.5; effect size = 0.325, p = 0.019]. The groups were similar in terms of EAT-10 score (p = 0.400), 100-ml water swallowing test duration (p = 0.197) and RSST (p = 0.319) results. EAT-10 score was correlated with disease duration (r = 0.451, p = 0.031) and total number of snacks (r = -0.404, p = 0.045) in AD group. Additionally, the 100-ml water swallowing test duration was correlated with BMI (r = -0.559, p = 0.004) in individuals with AD.

CONCLUSIONS: It has been determined that swallowing difficulties in individuals with AD are associated with disease duration, BMI and snack consumption. Swallowing dysfunction is common in individuals with early-stage AD and they exhibit a longer duration in the 10 ml water swallowing test compared to HCs. This test may be an indicator of dysphagia. Early screening for dysphagia in these individuals is essential to prevent potential complications and enable timely interventions.},
}

@article {pmid40628129,
year = {2025},
author = {Chauhan, P and Wadhwa, K and Singh, G},
title = {Unravelling the Alzheimer's pathogenesis: Molecular and cellular pathways to neurodegeneration and therapeutic targets.},
journal = {Pathology, research and practice},
volume = {272},
number = {},
pages = {156109},
doi = {10.1016/j.prp.2025.156109},
pmid = {40628129},
issn = {1618-0631},
abstract = {Alzheimer's disease (AD) is indeed a overwhelming neurodegenerative disorder whose intricated pathogenesis still remains exclusive and requires to be completely elucidated. This review undertakes a comprehensive analysis of the multifactorial signaling mechanism implicated in AD, such as AKT/MAPK, Wnt, Leptin, mTOR, ubiquitin, Sirt1, and insulin, exploring their pivotal individual and/or synergistic contribution in the dysregulation of diverse cellular processes accountable for neuronal health. Furthermore, it also delves into the molecular and cellular mechanism underlying oxidative stress, neuroinflammation, apoptosis, metal ion dyshomeostasis, and viral reactivation in the pathogenesis of AD, along with accentuating the interconnection between the intracellular signalling cascades and the alterations within the synaptic transmission, blood-brain barrier, and gut microbiota. Nevertheless, due to the enormous complexity of the brain, the application of these several signaling pathways as feasible targets for drug development against AD is minimal. This review also explores the numerous drug candidates, both synthetic and natural, currently being investigated for their anti-AD potential via targeting diverse pathological hallmark of AD and their associated signalling mechanisms. Ultimately, this review seeks to stimulate further research into these promising "anti-AD pathways" and to accelerate the expansion of disease-modifying therapies.},
}

@article {pmid40628039,
year = {2025},
author = {Ma, Y and Bresson, P and Zhou, L and Zhao, M and Marchioni, E and Julien-David, D},
title = {Separation of acetylcholinesterase inhibitors using high-temperature liquid chromatography: A method development approach.},
journal = {Journal of chromatography. A},
volume = {1758},
number = {},
pages = {466184},
doi = {10.1016/j.chroma.2025.466184},
pmid = {40628039},
issn = {1873-3778},
abstract = {Alzheimer's disease (AD) is a chronic and progressive brain disorder and acetylcholinesterase (AChE) inhibitor is an important way of treating AD. High-temperature liquid chromatography (HTLC) is a green analytical tool that can be applied to achieve rapid separation of compounds with fewer organic solvents. In this study, a method to separate AChE inhibitors based on HTLC was established. AChE inhibitors were rapidly separated in 7.50 min with 10 % EtOH solvent by utilizing a combination of gradient temperature and gradient flow rate. The method showed satisfactory linearity (R[2] > 0.990). For the three selected inhibitors, limits of detection (LOD) ranged from 0.20 to 1.35 μg/mL, and limits of quantification (LOQ) from 0.78 to 4.51 μg/mL. Stability tests showed no significant degradation over 30 days at 4 °C, with variations in peak areas within ±5 %. Precision studies yielded intra-day and inter-day RSDs below 2 %. No significant change was observed between 70 and 200 °C, confirming no thermal degradation during HTLC analysis. These results demonstrate the effectiveness and reliability of the method as a tool for scientific research. It highlights the effectiveness in separating AChE inhibitors, while also contributing to the advancement of green chemistry methodologies.},
}

@article {pmid40628019,
year = {2025},
author = {Hattiholi, A and Hegde, H and Shetty, SK},
title = {Tauopathies: Emerging discoveries on tau protein, with a special focus on Alzheimer's disease.},
journal = {Neuropeptides},
volume = {112},
number = {},
pages = {102536},
doi = {10.1016/j.npep.2025.102536},
pmid = {40628019},
issn = {1532-2785},
abstract = {Tauopathies encompass a group of neurodegenerative disorders (NDDs) driven by the abnormal accumulation of mutated tau protein, leading to hyperphosphorylation, neuronal damage, and neuroinflammation. The protein plays essential roles in brain function but undergoes hyperphosphorylation and aggregation into toxic oligomers in NDDs. Recent research emphasizes the need to understand tau's post-translational modifications (PTMs) and their role in pathological states. Insights into tau's structure, isoform-specific properties, and aggregation mechanisms are critical for elucidating its propagation in neurodegeneration. Moreover, tau's potential as a biomarker and the development of targeted therapies to mitigate tauopathies, particularly in AD, remain promising avenues. However, many strategies targeted at tau have repeatedly failed, which continues the search for better alternatives. This review focuses on recent advances in tau research, highlighting its structural and functional characteristics, and roles in disease, that may be critical to understanding their implications for new therapeutic strategies. PTMs are important for the stable structure and physiological functions of a protein. However, dysfunctional PTMs are the leading causes of tau protein aggregation. The recent shift on tau hyperphosphorylation has resulted in many discoveries related to their functions in AD. Therapeutic strategies targeting phosphorylated tau are being extensively studied worldwide. This paper gives a comprehensive view on these aspects.},
}

@article {pmid40627621,
year = {2025},
author = {Elovsson, G and Klingstedt, T and Nilsson, KPR and Brorsson, AC},
title = {Diversity of Aβ aggregates produced in a gut-based Drosophila model of Alzheimer's disease.},
journal = {PloS one},
volume = {20},
number = {7},
pages = {e0314832},
doi = {10.1371/journal.pone.0314832},
pmid = {40627621},
issn = {1932-6203},
}

@article {pmid40627435,
year = {2025},
author = {Tran, E and Cabán, M and Meng, A and Wetmore, JB and Ottman, R and Siegel, K},
title = {Knowledge and Beliefs About Medical and Non-Medical Interventions to Control Alzheimer's Disease Among Latinos in New York City.},
journal = {International journal of geriatric psychiatry},
volume = {40},
number = {7},
pages = {e70128},
doi = {10.1002/gps.70128},
pmid = {40627435},
issn = {1099-1166},
support = {R01AG062528/NH/NIH HHS/United States ; UL1TR001873/NH/NIH HHS/United States ; },
mesh = {Humans ; *Hispanic or Latino/psychology ; Middle Aged ; Female ; New York City ; *Alzheimer Disease/therapy/ethnology/psychology ; Male ; *Health Knowledge, Attitudes, Practice/ethnology ; Adult ; Qualitative Research ; Interviews as Topic ; White ; },
abstract = {OBJECTIVES: Latinos experience significant health disparities for Alzheimer's disease (AD) with an increased likelihood in developing the disease relative to non-Latino Whites. Our study sought to examine Latinos' beliefs about controlling the symptoms and progression of AD to identify gaps in community knowledge and improve understanding of culturally based perceptions of health and illness.

METHODS: We conducted in-depth, semi-structured interviews in English or Spanish with 216 Latinos aged 40-60 years (average age 53 years) living in the neighborhoods of northern Manhattan. We asked them whether they believed there were interventions that could help control AD. The data was analyzed using content analysis.

RESULTS: Most participants viewed medications as important in the management of AD, though they had limited specific knowledge about existing medications for AD. Some participants thought herbal and nutritional supplements could have some benefits. Many believed activities for mental stimulation could help enhance cognitive functioning. A few suggested that a healthy diet and exercise could help slow the progression of AD. Some participants believed that emotional wellness and degree of support influenced AD progression.

CONCLUSIONS: Limited knowledge of available medications and evidence-based non-medical approaches to control AD may adversely impact help-seeking behavior and use of effective management strategies among those with AD. Future interventions should strive to expand knowledge about ways to effectively manage and treat AD in Latino communities.

TRIAL REGISTRATION: The ClinicalTrials.gov ID is NCT04471779. The date registered was July 15, 2020.},
}

Humans
*Hispanic or Latino/psychology
Middle Aged
Female
New York City
*Alzheimer Disease/therapy/ethnology/psychology
Male
*Health Knowledge, Attitudes, Practice/ethnology
Adult
Qualitative Research
Interviews as Topic
White

@article {pmid40627123,
year = {2025},
author = {Rowsthorn, E and Sim, MA and O'Brien, WT and McDonald, SJ and Franks, K and Sinclair, B and Chong, TT and Yiallourou, S and Cavuoto, M and Vivash, L and O'Brien, TJ and Shao, X and Wang, DJJ and Law, M and Harding, IH and Pase, MP},
title = {Factor analysis of multimodal MRI, biofluid, and vascular biomarkers reveals latent constructs of brain health.},
journal = {GeroScience},
volume = {},
number = {},
pages = {},
pmid = {40627123},
issn = {2509-2723},
abstract = {Individual imaging and fluid biomarkers provide insights into specific components of brain health, but integrated multimodal approaches are necessary to capture the complex, interrelated biological systems that contribute to brain homeostasis and neurodegenerative disease. Using data from the Brain and Cognitive Health (BACH) cohort study (N = 127; mean age = 67 years, 68% women), we performed an exploratory factor analysis to identify latent constructs of brain health. We included multimodal neurovascular imaging markers, brain atrophy metrics, plasma Alzheimer's disease (AD) biomarkers, and cardiovascular risk factors. Five constructs emerged: "Brain & Vascular Health" (greater hippocampal volume, basal ganglia enlarged perivascular spaces (ePVS), cerebral blood flow, and HDL cholesterol; lower ventricle volume and BMI), "Structural Integrity" (greater cortical thickness, fractional anisotropy, and basal ganglia ePVS), "White Matter (WM) Fluid Dysregulation" (greater WM ePVS and Free Water), "AD Biomarkers" (higher phosphorylated tau [pTau]181 and pTau217; lower amyloid-beta 42/40 ratio), and "Neuronal Injury" (higher glial fibrillary acidic protein and neurofilament light chain). All constructs were associated with age (β = - 0.70-0.39, p ≤ 0.014), except for WM Fluid Dysregulation (p > 0.05). Brain and Vascular Health and Structural Integrity (partial r = 0.305, p < 0.001) and AD biomarkers and neuronal injury (partial r = 0.248, p = 0.005) were positively correlated. Only Brain and Vascular Health was associated with global cognition (β = 0.27, SE = 0.13, p = 0.043). These findings provide a data-driven framework for examining distinct constructs underlying vascular health, fluid regulation, and neurodegenerative pathology. We demonstrate the utility of using multiple biomarkers to probe these biological systems, paving the way for future research to explore how these systems change across diverse neurodegenerative conditions.},
}

@article {pmid40627107,
year = {2025},
author = {Mushtaq, T and Hameed, H and Cláudia Paiva-Santos, A and Tariq, U and Hameed, A},
title = {Exosome-Mediated Delivery of Amyloid Beta Modulators: A Potential Therapeutic Strategy for Alzheimer's Disease.},
journal = {Molecular neurobiology},
volume = {},
number = {},
pages = {},
pmid = {40627107},
issn = {1559-1182},
abstract = {Alzheimer's disease (AD) is a neurodegenerative disorder characterized by the deposition of amyloid-beta (Aβ) plaques and tau protein abnormalities, disrupting synaptic function and causing progressive cognitive decline. However, significant efforts in research are still hampered by current treatments, which are limited by poor penetration of the BBB and non-specific effects. Recent developments in nanotechnology and drug delivery have found exosomes as innovative carriers targeting Aβ. They have identified a novel approach to treating the underlying pathology of AD. Exosomes are naturally occurring extracellular vesicles with several unique advantages. They are biocompatible, can cross the BBB, and can be engineered to deliver therapeutic agents with precision. These agents range from small interfering RNA (siRNA), peptides, or drugs designed to either inhibit Aβ aggregation, enhance its clearance, or regulate the genes involved in its production. Among these agents, neural-derived exosomes offer great promise as they naturally attract neuronal tissue and, therefore, increase the specificity of the treatment. In preclinical studies, such therapies have proven encouraging by demonstrating reduced Aβ accumulation, a decrease in neuroinflammation, and cognitive improvement in models of AD. However, translation into clinical application faces some challenges, such as development of scalable methods of exosome production, drug loading efficiency, stability, and safety upon administration. The present review takes an outlook toward the growing area of targeting Aβ pathology via exosomes with potential benefits, recent breakthroughs, and open challenges. Harnessed therapy from exosomes can create groundbreaking-therapies in treating AD that hope for millions to come out from this devastator disease.},
}

@article {pmid40627000,
year = {2025},
author = {Shrestha, J and Blanchard, J and Tadesse, S},
title = {Cyclin-dependent Kinase 11: Cellular Functions and Potential Therapeutic Applications.},
journal = {ChemMedChem},
volume = {},
number = {},
pages = {e202500305},
doi = {10.1002/cmdc.202500305},
pmid = {40627000},
issn = {1860-7187},
abstract = {Cyclin-dependent kinase 11 (CDK11) is a multifunctional serine/threonine protein kinase that plays a pivotal role in transcription and pre-mRNA splicing. It phosphorylates serine 2 of RNA polymerase II C-terminal domain, thereby promoting transcriptional elongation and 3'-end processing of replication-dependent histone genes, as well as contributing to proper chromosome segregation during mitosis. CDK11 is essential for global pre-mRNA splicing by phosphorylating Splicing Factor 3B Subunit 1, a core U2 small nuclear ribonucleoprotein component, thereby activating the spliceosome. Since splicing is closely linked to optimal transcription and cell proliferation, inhibition of CDK11 is hypothesized to indirectly disrupt general transcription and cell cycle progression. CDK11 drives cancer cell proliferation, promotes HIV-1 mRNA 3'-end processing to enhance viral replication, and contributes to tau phosphorylation in Alzheimer's disease. Given its integral role in key cellular processes and its dysregulation in various diseases, CDK11 has emerged as a compelling therapeutic target. This review provides a comprehensive overview of the biological functions and regulatory mechanisms of CDK11, discusses its role in cancer, viral and neurodegenerative diseases, and highlights advances in the discovery and development of CDK11 inhibitors, including OTS964, which has expanded our understanding of the biological functions of CDK11 and its prospects as a cancer-specific vulnerability.},
}

@article {pmid40626901,
year = {2025},
author = {},
title = {RETRACTION: Aggravation of Alzheimer's Disease due to the COX-2-Mediated Reciprocal Regulation of IL-1β and Aβ Between Glial and Neuron Cells.},
journal = {Aging cell},
volume = {},
number = {},
pages = {e70158},
doi = {10.1111/acel.70158},
pmid = {40626901},
issn = {1474-9726},
}

@article {pmid40626545,
year = {2025},
author = {Wang, W and Huang, X and Xu, Z and Yu, C},
title = {The Interaction between Oligodendrocytes and Aβ in Alzheimer's Disease.},
journal = {Current Alzheimer research},
volume = {},
number = {},
pages = {},
doi = {10.2174/0115672050401966250625171338},
pmid = {40626545},
issn = {1875-5828},
abstract = {Oligodendrocytes (OLs) are the primary myelinating cells in the central nervous system (CNS), responsible for maintaining the rapid conduction of nerve signals and ensuring neuronal stability through metabolic and nutritional support. Recent studies have reported that OLs are also involved in the development and progression of Alzheimer's disease (AD), particularly in the production and clearance of amyloid-beta (Aβ), exhibiting complex and critical regulatory functions. While traditional research has predominantly focused on the roles of neurons and microglia in Aβ metabolism, recent evidence indicates that OLs engage in a complex bidirectional interaction with Aβ in AD. On the one hand, OLs can produce Aβ, frequently generating aggregated and highly toxic Aβ42, which contributes to plaque expansion and disease progression. On the other hand, neuronderived Aβ exerts a concentration-dependent dual effect on OLs. At high concentrations, it induces oxidative stress and cell apoptosis, while at low concentrations, it promotes their differentiation and myelin repair functions. Therefore, OLs serve as both a "source" and a "target" of Aβ production and response, making them a key factor in AD pathogenesis. This review discusses the interaction between OLs and Aβ in AD, aiming to provide new perspectives on targeting OLs for AD therapy. Given the dual role of OLs in Aβ metabolism, targeting OLs dysfunction and the regulatory mechanisms underlying Aβ production and clearance could provide novel therapeutic strategies for AD. Future research should investigate the roles of specific OL populations (including oligodendrocyte precursor cells (OPCs), pre-myelinating OLs, and mature OLs) in Aβ generation and metabolism, focusing on the signaling pathways involved. Additionally, the molecular mechanisms by which OLs regulate other glial cells, such as astrocytes and microglia, through intercellular signaling to facilitate Aβ clearance and maintain neuroglial homeostasis warrant further exploration.},
}

@article {pmid40626458,
year = {2025},
author = {Lee, D and Choi, Y and Jeong, E and Eun Park, J and Kim, HS},
title = {Relationship between cerebrovascular risk factors and oxygen metabolic stress in a cognitively impaired population: Dynamic susceptibility contrast-derived oxygen parametric analysis.},
journal = {Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism},
volume = {},
number = {},
pages = {271678X251355742},
doi = {10.1177/0271678X251355742},
pmid = {40626458},
issn = {1559-7016},
abstract = {Cerebrovascular risk factors contribute to cognitive decline via mechanisms such as small vessel disease and chronic ischemia. Advanced MRI parameters, including maximum oxygen extraction fraction (OEF[max]) and cerebral metabolic rate of oxygen (CMRO2), provide insights into cerebral oxygenation and cognition. This retrospective study evaluated the relationships between oxygen metabolic stress, cerebrovascular risk factors, and cognitive function in 226 adults undergoing dynamic susceptibility contrast (DSC)-MRI. White matter hyperintensity (WMH) volumes, OEF[max], and CMRO2 were quantified and analyzed against cerebrovascular risk factors (e.g., age, smoking, hypertension), MMSE scores, clinical diagnoses, and history of cerebrovascular disease. A history of smoking was linked to a higher OEF[max] (P = 0.015). An older age correlated with a larger WMH volume (P < 0.001), higher OEF[max] (P < 0.001), and lower CMRO2 (P = 0.001). Patients with history of infarcts exhibited larger WMH volumes (P < 0.001) and lower CMRO2 (P < 0.001). Multivariable regression showed WMH volume (P = 0.03) and OEF[max] (P = 0.018) were negatively associated with MMSE scores, while CMRO2 had no significant association (P = 0.52). Patients with vascular dementia exhibited lower CMRO2 than those with Alzheimer's or mild cognitive impairment (P = 0.001). These findings suggest that DSC-derived OEF[max] and CMRO2 could provide insights into the relationship between cerebrovascular risk factors and cognitive decline, emphasizing their role as key indicators of brain oxygenation.},
}

@article {pmid40626445,
year = {2025},
author = {Yang, Y and Lane, B and Ravndal, D and Sorkpor, SK},
title = {Educational Attainment and Alzheimer's Disease and Related Dementias (ADRD) Risk Among Black Adults: A Comparative Analysis of U.S.-Born and Non-U.S.-born Populations in the All of Us Research Program.},
journal = {Journal of applied gerontology : the official journal of the Southern Gerontological Society},
volume = {},
number = {},
pages = {7334648251359005},
doi = {10.1177/07334648251359005},
pmid = {40626445},
issn = {1552-4523},
abstract = {Objective: To examine the association between educational attainment and Alzheimer's disease and related dementias (ADRD) risk among U.S.-born and non-U.S.-born Black adults. Methods: We conducted a retrospective cohort study using survey and electronic health record data from the All of Us Research Program. ADRD cases were identified using ICD-9/10 codes. Propensity score matching was applied to balance demographic and socioeconomic factors between U.S.-born and non-U.S.-born Black adults aged 65 and older (n = 1412 per group). Results: After matching, ADRD prevalence was higher among non-U.S.-born Black adults (8.1%) than U.S.-born Black adults (7.2%). Among non-U.S.-born Black individuals, higher education was associated with lower ADRD prevalence (7.4% with college + vs. 10.7% with high school or less). Conclusion: Educational attainment may confer differential protective effects against ADRD by nativity. Findings highlight the need to consider nativity, educational context, and early-life structural factors to reduce disparities in cognitive aging and guide targeted ADRD prevention.},
}

@article {pmid40626372,
year = {2025},
author = {Storti, B and Stanziano, M and Marinoni, G and Mazzè, A and Francia, A and Zacarias, E and Strazzabosco, C and De Toma, C and Rifino, N and Boncoraglio, G and Di Fede, G and Pollaci, G and Gatti, L and Canavero, I and Bersano, A},
title = {Hippocampal Subfields Volume: Another Hint of the Continuum Between CAA and AD?.},
journal = {European journal of neurology},
volume = {32},
number = {7},
pages = {e70284},
doi = {10.1111/ene.70284},
pmid = {40626372},
issn = {1468-1331},
support = {//Ministero della Salute/ ; },
mesh = {Humans ; *Alzheimer Disease/cerebrospinal fluid/pathology/diagnostic imaging ; Male ; Female ; Aged ; *Hippocampus/pathology/diagnostic imaging ; Magnetic Resonance Imaging ; Middle Aged ; *Cerebral Amyloid Angiopathy/cerebrospinal fluid/pathology/diagnostic imaging ; Aged, 80 and over ; Amyloid beta-Peptides/cerebrospinal fluid ; tau Proteins/cerebrospinal fluid ; Amygdala/pathology/diagnostic imaging ; Organ Size ; },
abstract = {OBJECTIVE: This study investigates whether cerebral amyloid angiopathy (CAA) patients with Alzheimer's disease (AD)-like CSF profile exhibit radiological features characteristic of AD, specifically reduced hippocampal and amygdala volumes.

METHODS: From a database of 162 probable CAA cases (Boston 2.0 criteria) at the Fondazione IRCCS Istituto Neurologico Carlo Besta, 44 patients underwent CSF analysis (Aβ42, Aβ40, and p-Tau181) and brain MRI with volumetric T1 sequences. Participants with CSF levels of Aβ42 < 640 pg/mL and p-Tau181 > 56.5 pg/mL were classified as CAA/AD+; otherwise, as CAA/AD-. Hippocampal and amygdala volumes were assessed using volBrain software, and statistical analyses included t-tests and Mann-Whitney U tests.

RESULTS: CAA/AD+ patients (n = 22) were older than CAA/AD- (median age: 73 vs. 67 years, p = 0.006). No significant differences were observed in total hippocampal or amygdala volumes. However, Cornu Ammonis 2-3 (CA2-CA3) hippocampal subfield volume and its ratio to total intracranial volume were significantly lower in CAA/AD+ patients (0.29 vs. 0.35, p = 0.015; 0.02 vs. 0.03, p = 0.011).

DISCUSSION: We found that CA2-CA3 atrophy, potentially linked to tau pathology, was a distinctive feature in our CAA/AD+ cohort. While total hippocampal and amygdala volumes did not differentiate these groups, CA2-CA3 volume may serve as a radiological marker for identifying biological overlaps between CAA and AD. Future studies should validate these findings and explore their implications for neurodegenerative diseases.

TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT04204642.},
}

Humans
*Alzheimer Disease/cerebrospinal fluid/pathology/diagnostic imaging
Male
Female
Aged
*Hippocampus/pathology/diagnostic imaging
Magnetic Resonance Imaging
Middle Aged
*Cerebral Amyloid Angiopathy/cerebrospinal fluid/pathology/diagnostic imaging
Aged, 80 and over
Amyloid beta-Peptides/cerebrospinal fluid
tau Proteins/cerebrospinal fluid
Amygdala/pathology/diagnostic imaging
Organ Size

@article {pmid40626308,
year = {2025},
author = {Aktary, N and Jeong, Y and Oh, S and Shin, Y and Sung, Y and Rahman, M and Ramos Santiago, L and Choi, J and Song, HG and Nurkolis, F and Ribeiro, RIMA and Park, MN and Kim, B},
title = {Unveiling the therapeutic potential of natural products in Alzheimer's disease: insights from in vitro, in vivo, and clinical studies.},
journal = {Frontiers in pharmacology},
volume = {16},
number = {},
pages = {1601712},
pmid = {40626308},
issn = {1663-9812},
abstract = {Alzheimer's disease (AD) is a multifactorial neurodegenerative disorder described as progressive cognitive decline and neuronal dysfunction, affecting millions globally. While current pharmacological treatments provide symptomatic relief and modestly slow disease progression, they fail to address the underlying pathophysiology and are often accompanied by severe adverse effects. This underscores the urgent need for innovative, multi-target therapeutic strategies that can effectively step in AD's complex pathogenesis. Emerging evidence highlights the therapeutic potential of natural products, particularly herbal medicines, as versatile modulators of key pathogenic processes in AD. These compounds exert neuroprotective effects by mitigating oxidative stress, suppressing neuroinflammation, inhibiting tau hyperphosphorylation, and reducing amyloid-beta aggregation. Additionally, they strengthen synaptic plasticity and stabilize mitochondrial function, offering a holistic approach to disease control. This comprehensive review synthesizes findings from network pharmacology, in vitro and in vivo studies, and clinical trials to evaluate the role of natural products in AD treatment. Advances in bioinformatics and systems biology facilitate the mapping of intricate protein-protein interactions, the identification of potential biomarkers, and the clarification of molecular mechanisms underlying AD progression. Integrating phytochemicals with conventional AD medications may improve therapeutic efficacy through synergistic mechanisms; however, pharmacokinetic interactions and safety considerations must be rigorously assessed. Notably, clinical trials investigating compounds such as curcumin, resveratrol, and ginsenosides suggest promising adjunctive benefits when incorporated into established treatment regimens. Furthermore, the convergence of herbal therapeutics with modern pharmacology presents an avenue for customized and integrative AD management. This review also emphasizes advancements in experimental models, including brain organoids and transgenic animals, which serve as crucial platforms for mechanistic studies and therapeutic validation. Ongoing trials on plant-derived compounds continue to pave the way for translational applications, reinforcing the viability of natural product-based interventions. By advocating a multidisciplinary framework that merges traditional medicine, modern pharmacology, and precision medicine, this work contributes to reshaping the AD landscape of therapy. It provides a roadmap for future research, fostering novel treatment paradigms that prioritize efficacy, safety, and sustainability in combating this disastrous disorder.},
}

@article {pmid40626303,
year = {2025},
author = {Li, K and Chen, Y and Xu, Y and Pang, Y and Bao, Y and Zhang, S and Shi, X and Ran, J and Qiao, Y and Xu, Y and Wang, Y and Di, B and Xu, P},
title = {Age-specific effects of synthetic cannabinoids on cognitive function and hippocampal gene expression in mice: insights from behavioral and molecular correlates.},
journal = {Frontiers in pharmacology},
volume = {16},
number = {},
pages = {1618929},
pmid = {40626303},
issn = {1663-9812},
abstract = {The increasing use of Synthetic cannabinoids (SCs) in adolescents and young adults poses significant medical and psychiatric risks, and previous reports have been dominated by single-age animal studies. Here, we first investigated the effects of a single exposure of the fourth-generation synthetic cannabinoid 4F-ABUTINACA on cognitive behaviors in adolescent (PND 28-35 days) and adult (PND 49-56 days) male mice in an animal model, followed by an age-specific systematic study by conducting a whole-gene transcriptomics study of hippocampal tissue in the brain. Behavioral results showed that 4F-ABUTINACA impaired recognition memory, fear memory extraction, and spatial navigation memory in adolescent mice, as well as spatial navigation memory in adult mice. The transcriptomics results revealed different alterations in age-enriched signaling pathways affected by 4F-ABUTINACA, such as Alzheimer's disease, Parkinson's disease, and neurodegenerative diseases. In addition, 4F-ABUTINACA causes selective downregulation of transcription of genes involved in stress response and mitochondrial expression in adolescent mice, whereas no significant differences were observed in adult mice. This study provides an innovative resource on the behavioral and molecular landscape of age-specific changes in cognitive function by synthetic cannabinoids and offers new opportunities for follow-up studies to target age-specific functional significance and related molecular mechanisms to be mined.},
}

@article {pmid40626228,
year = {2025},
author = {Li, Y and Wang, X and Yu, M and Wang, F and Song, D and Liu, M and Liang, X and Liu, H and Liu, J and Fu, S and Liu, X},
title = {The relationship between vitamin D levels and Alzheimer's disease risk: insights from a centenarian study of Chinese women.},
journal = {Frontiers in nutrition},
volume = {12},
number = {},
pages = {1628732},
pmid = {40626228},
issn = {2296-861X},
abstract = {BACKGROUND: While vitamin D3 (VD3) has been implicated in Alzheimer's disease (AD) prevention, limited evidence exists among centenarians-particularly women-who exhibit unique cognitive aging trajectories. This study aimed to examine the association between serum 25-hydroxyvitamin D [25(OH)D] levels and AD risk in Chinese female centenarians.

METHODS: We included 514 female participants aged ≥100 years from the China Healthy Longevity Multicenter Study (CHLMS). AD was diagnosed using education-adjusted MMSE thresholds and clinical exclusion of non-AD dementias. Serum 25(OH)D and biochemical markers were measured using standardized laboratory protocols. Logistic regression models (unadjusted and progressively adjusted) assessed associations between 25(OH)D and AD. Restricted cubic spline (RCS) and piecewise regressions evaluated non-linear and threshold effects, while subgroup analyses explored effect modification.

RESULTS: Higher serum 25(OH)D levels were independently associated with lower odds of AD (adjusted OR per 1 ng/mL: 0.95; 95% CI: 0.90-1.00; p = 0.037). Compared to the lowest quartile, participants in the highest quartile had an 87% reduced risk (OR = 0.13; 95% CI: 0.03-0.50; p = 0.007). RCS analysis revealed a significant inverse dose-response relationship, with a potential threshold effect observed at 29.3 ng/mL. Piecewise regression confirmed that the protective association was strongest below this threshold. Subgroup analyses across smoking, hypertension, and early-life indicators showed consistent effects with no significant interactions.

CONCLUSION: Among Chinese female centenarians, serum vitamin D₃ levels are inversely associated with AD risk in a dose-dependent manner, particularly below 29.3 ng/mL. These findings highlight the relevance of vitamin D₃ as a potentially modifiable factor in cognitive aging and support further interventional studies in the oldest-old population.},
}

@article {pmid40626100,
year = {2025},
author = {Amaliah, S and Aulifa, DL and Gazzali, AM and Budiman, A},
title = {Ternary Solid Dispersions as an Alternative Approach to Enhance Pharmacological Activity.},
journal = {Drug design, development and therapy},
volume = {19},
number = {},
pages = {5663-5684},
pmid = {40626100},
issn = {1177-8881},
mesh = {Humans ; Solubility ; Biological Availability ; Animals ; Pharmaceutical Preparations/chemistry/administration & dosage ; Drug Compounding ; Drug Liberation ; Administration, Oral ; },
abstract = {Poor solubility and limited bioavailability remain significant challenges in developing oral drugs, affecting the clinical efficacy of many active pharmaceutical ingredients (APIs). Enhancing solubility has become a primary focus in improving API bioavailability. Among the most commonly employed strategies are amorphous solid dispersions (ASDs) and co-amorphous systems, collectively called binary systems. However, these systems often suffer from wettability and physicochemical limitations, which can hinder drug release. Adding a third component to form ternary solid dispersions (TSDs) significantly enhance drug release and bioavailability, ultimately improving therapeutic outcomes. While numerous studies have investigated the application of TSDs in enhancing API pharmacological activity, only limited studies have a comprehensive analysis of this approach. Therefore, this review aims to summarize and elucidate the mechanisms of TSD systems in improving pharmacological activity. The review includes available literature from Scopus, PubMed, and Google Scholar that utilizes the keywords "ternary solid dispersion" and "pharmacological activity", summarizing the importance of TSDs in therapeutic formulations for enhancing pharmacological activity. Various in vitro and in vivo studies consistently demonstrate that TSDs outperform binary systems by significantly enhancing the pharmacological effects of diverse therapeutic agents, including those with antioxidant, anti-inflammatory, anticancer, antibacterial, anticholinesterase, antihyperlipidemic, anti-hypoglycemic, anti-Alzheimer's, antidiabetic, and hepatoprotective properties. This approach holds significant promise as an alternative for the formulation of low-solubility pharmaceuticals.},
}

Humans
Solubility
Biological Availability
Animals
Pharmaceutical Preparations/chemistry/administration & dosage
Drug Compounding
Drug Liberation
Administration, Oral

@article {pmid40625677,
year = {2025},
author = {Felipe, SGB and Printes, CB and Brauner, FO and Sato, DK and Baptista, RR},
title = {Intrinsic capacity, functional and psychosocial aspects of older adults participating in a multicomponent physical exercise program.},
journal = {Frontiers in aging},
volume = {6},
number = {},
pages = {1562383},
pmid = {40625677},
issn = {2673-6217},
abstract = {INTRODUCTION: In 2015, the WHO introduced intrinsic capacity (IC) as a health indicator with five domains to promote healthy aging. Multicomponent exercise programs are recommended to enhance IC, but research in Brazil on their comprehensive impact is limited. This study aimed to evaluate the effects of such a program on IC, functional, and psychosocial aspects in older adults.

METHODS: This pre- and post-study assessed older adults in Brazil enrolled in a multicomponent training program, evaluating IC as the main outcome using specific tests for each domain. Inclusion criteria were: aged 60+, completing assessments in five domains, attending the program at least twice a week, and participating in two exercise modalities per session for 90 min. Exclusion criteria included: history of stroke, Parkinson's or Alzheimer's, recent hand, hip, or knee surgery, or absence for more than 15 consecutive days. A total of 43 older adults were evaluated, and the score was calculated by summing the results of the five domains, yielding a total score ranging from 0 to 10 points. Subsequently, participants underwent a 12-week intervention involving multicomponent exercises and were reassessed.

RESULTS: After 12 weeks of intervention, there was a significant reduction in the proportion of participants with low IC, from 7.0% to 0.0%, and an increase in those with high IC, from 4.7% to 20.0% (p = 0.018). Improvements were seen in cognitive aspects, locomotor dimension (p < 0.001), vitality (p = 0.045) and functional classification (p < 0.001), with the greatest effect in the locomotor domain (es = 1.12). Significant gains were also observed in perceived health, quality of life, and physical activity (p < 0.002; p < 0.004; p < 0.001). Body composition showed improvements, including reduced body fat percentage, increased muscle mass, and better fat classification (p < 0.001), along with reductions in waist and abdominal circumferences (p < 0.001; p = 0.001).

CONCLUSION: The multicomponent exercise program demonstrated a positive influence on composite IC, including functional and psychosocial aspects. These findings highlight the critical role of tailored and supervised exercise interventions in enhancing both physical and psychosocial dimensions of health, contributing to healthier aging trajectories.},
}

@article {pmid40625670,
year = {2025},
author = {Nair, A and Yearwood, AJ and Besednjak, BN and Cully, MM and Turner, R and Bedont, JL},
title = {Cold-raising unmasks sleep disruption in a Drosophila Alzheimer's disease model.},
journal = {microPublication biology},
volume = {2025},
number = {},
pages = {},
pmid = {40625670},
issn = {2578-9430},
abstract = {Chronic sleep loss is a risk factor for Alzheimer's disease (AD), and reduced and fragmented sleep is increasingly appreciated as an early-onset diagnostic and potential therapeutic target for AD. However, robustly modeling AD-like sleep deficits in fruit flies has often been challenging. We report that cold-raising unmasks deficits in sleep duration, fragmentation, and latency in one such model pan-neuronally expressing a highly pathogenic AD-associated amyloid species. This sensitized model provides a promising platform for identifying potential metabolic, proteostatic, glymphatic, and other candidate mediators bidirectionally linking sleep and AD.},
}

@article {pmid40625312,
year = {2025},
author = {Hsieh, SW and Hsiao, CY and Yang, YH and Hsieh, HM},
title = {Healthcare related costs associated with donepezil use in patients with very mild dementia due to Alzheimer's disease: A retrospective observational study.},
journal = {Journal of Alzheimer's disease reports},
volume = {9},
number = {},
pages = {25424823251356233},
pmid = {40625312},
issn = {2542-4823},
abstract = {BACKGROUND: The cost-effectiveness of Donepezil in mild to severe Alzheimer's disease (AD) has been widely studied, but research on very mild dementia (VMD) remains limited.

OBJECTIVE: This retrospective observational study evaluated the efficacy of Donepezil in patients with VMD in two hospitals in southern Taiwan between 2011 and 2019.

METHODS: We recruited 909 VMD patients with a Clinical Dementia Rating (CDR) of 0.5 and used propensity score matching to create two groups: 352 receiving Donepezil and 352 not. Demographic data, Mini-Mental State Examination (MMSE), and healthcare costs were analyzed over 1-year and 3-year periods.

RESULTS: At baseline, Donepezil treatment was associated with lower inpatient, outpatient, and overall healthcare costs. After 1 year, outpatient drug costs increased, while inpatient drug costs decreased, leading to higher overall healthcare drug costs. Over 3 years, outpatient drug continued to rise, while inpatient drug costs remained stable, leading to higher overall healthcare drug costs. Donepezil users had significantly more outpatient visits, but inpatient admissions were unaffected. Patients receiving Donepezil were older and had lower MMSE; male gender, Parkinsonism, chronic lung disease, and liver disease were less common in this group.

CONCLUSIONS: Although Donepezil users initially had lower healthcare costs, overall healthcare drug costs increased in the Donepezil group at both the 1-year and 3-year follow-ups, while inpatient drug costs were only reduced in the short term.},
}

@article {pmid40625200,
year = {2025},
author = {Alves, F and Lane, D and Wahida, A and Jakaria, M and Kalinowski, P and Southon, A and Belaidi, AA and Samperi-Esteve, T and Nguyen, TPM and Lei, P and Krueger, M and Mueller, S and Conrad, M and Agarwal, P and Leurgans, SE and Schneider, J and Bush, AI and Ayton, S},
title = {Aberrant Mitochondrial Metabolism in Alzheimer's Disease Links Energy Stress with Ferroptosis.},
journal = {Advanced science (Weinheim, Baden-Wurttemberg, Germany)},
volume = {},
number = {},
pages = {e04175},
doi = {10.1002/advs.202504175},
pmid = {40625200},
issn = {2198-3844},
support = {GNT2008359//National Health and Medical Research Council/ ; GNT1194028//National Health and Medical Research Council/ ; 2R01AG054057-02/AG/NIA NIH HHS/United States ; },
abstract = {Alzheimer's disease (AD) is defined by β-amyloid plaques and tau-containing neurofibrillary tangles, but the ensuing cellular derangements that culminate in neurodegeneration remain elusive. Here, a mechanistic link between two AD pathophysiological hallmarks: energy insufficiency and oxidative stress is revealed. It is demonstrated that mitochondrial function and glutathione (GSH) flux are coupled, impacting neuronal ferroptosis susceptibility. Analysis of proteomic data from the inferior temporal cortex of 625 subjects along a continuum of clinical and pathological changes in AD, reveals a prominent depletion of mitochondrial proteins. Biogenetic insufficiency in AD is reflected by a concurrent loss of GSH, which requires 2 ATP for its synthesis, and genetic and pharmacologic ATP depletion models confirm that ATP is rate-limiting for GSH. Accordingly, an unbiased association analysis uncovers mitochondrial proteins in positive correlation with total GSH (t-GSH) in AD subjects. But mitochondria also consume GSH via the SLC25A39 transporter. It is found that mitochondrial inhibition either increases or decreases ferroptosis susceptibility in cellular models, depending on contextual factors that dictate whether mitochondria act as a net GSH producer or consumer, respectively. Mitochondria therefore control GSH flux, and loss of energy output is consequently demonstrated as a liability for ferroptosis in AD.},
}

@article {pmid40625063,
year = {2025},
author = {Kiviniemi, V and Helakari, H and Raitamaa, L and Huotari, N and Rajna, Z and Järvelä, M and Elabasy, A and Tuunanen, J and Poltojainen, V and Väyrynen, T and Tuovinen, T and Kananen, J and Korhonen, V},
title = {Ultrafast Imaging of Physiological Brain Pulsations With Magnetic Resonance Encephalography-From Noise to Predictive Clinical Biomarker.},
journal = {NMR in biomedicine},
volume = {38},
number = {8},
pages = {e70092},
doi = {10.1002/nbm.70092},
pmid = {40625063},
issn = {1099-1492},
support = {2022-120//EU JPND/ ; 2017-2021//Jane & Aatos Erkko Foundation/ ; 210043//Jane & Aatos Erkko Foundation/ ; 275342//Research Council of Finland/ ; 338599//Research Council of Finland/ ; 314497//Aivosäätiö TERVA/ ; //Uniogs Oulu Doctoral Program/ ; //Pohjois-Suomen Terveydenhuollon Tukisäätiö/ ; //The Finnish Medical Foundation/ ; //Finnish Neurological Foundation/ ; //Finnish Government Funding for Research/OUH/ ; //Orion Research Foundation/ ; //Medical Research Center (MRC)-OUH/ ; //Maire Taponen Foundation/ ; //The Finnish Brain Foundation/ ; //Instrumentarium Science Foundation/ ; //The University of Oulu Scholarship Foundation/ ; //Emil Aaltonen Foundation/ ; //Suorsa Foundation/ ; },
mesh = {Humans ; *Brain/physiology ; *Magnetic Resonance Imaging/methods ; Biomarkers/metabolism ; Animals ; },
abstract = {Over the past decade, novel in vivo imaging techniques have revealed that physiological pulsations drive the transport of brain solutes and that impairment of fluid flow precedes certain neuropathologies. Although the pioneering investigations on brain solute transport mechanisms mainly employed imaging of exogenous tracers, novel advanced ultrafast functional MRI sequences enable critical sampling of propagating physiological pulsations driving the brain fluids devoid of aliased mixing of signals. In this review, we summarize the emerging magnetic resonance encephalography (MREG) technique, beginning with a historical perspective and physiological background of the phenomena of brain pulsatility as measured in the parenchyma and cerebrospinal fluid (CSF). We give a detailed account of how functional contrast mechanisms evident in the T2(*)-weighted MREG signal enable the simultaneous mapping of three distinct physiological signals. Our narrative review continues with an account of signal analysis and methodological considerations arising from 12 years of experience in ultrafast brain scanning. Our review concludes with a presentation of how sleep-related physiological changes in the driving pulsations influence solute transport in a healthy brain and our perspective on the potential of these pulsations as emerging biomarkers for predictive, diagnostic, and treatment monitoring in the context of Alzheimer's disease and other central nervous system (CNS) conditions.},
}

Humans
*Brain/physiology
*Magnetic Resonance Imaging/methods
Biomarkers/metabolism
Animals

@article {pmid40624899,
year = {2025},
author = {Herman, P and Sanggaard, S and James, SD and Akif, A and Mishra, SK and Sanganahalli, BG and Verhagen, JV and Blumenfeld, H and Hyder, F},
title = {Mapping of neurovascular and neurometabolic couplings by multimodal optical imaging.},
journal = {Cerebral cortex (New York, N.Y. : 1991)},
volume = {35},
number = {7},
pages = {},
doi = {10.1093/cercor/bhaf165},
pmid = {40624899},
issn = {1460-2199},
support = {R21- AG085366//National Institute of Health/ ; R01-AG084681//National Institute of Health/ ; R01 NS100106/NS/NINDS NIH HHS/United States ; R01-MH067528//National Institute of Health/ ; },
mesh = {Animals ; *Neurovascular Coupling/physiology ; *Optical Imaging/methods ; Mice ; Spectroscopy, Near-Infrared/methods ; Mice, Transgenic ; Calcium/metabolism ; Glucose/metabolism ; *Multimodal Imaging/methods ; Male ; *Brain/metabolism/blood supply/diagnostic imaging ; Cerebral Blood Volume/physiology ; Neurons/metabolism ; Mice, Inbred C57BL ; },
abstract = {Neurovascular coupling links calcium (Ca2+)-dependent neuronal activity to cerebral blood volume changes, whereas neurometabolic coupling describes alterations of neuronal activity and glucose uptake. While mesoscale optical imaging of neurovascular coupling is prevalent, neurometabolic coupling has been explored much less. We describe a multiplexed optical system with a closed cranial window setup for longitudinal studies in Thy1-jRGECO1a mice where neuronal activity is measured with Ca2+-dependent red fluorescence, glucose uptake with bolus injections of 2NBDG with green fluorescence, and cerebral blood volume (CBV) with near-infrared spectroscopy (NIRS). Genetically encoded calcium indicators (GECIs) provide strong fluorescent signals for assessing Ca2+-dependent neuronal activity. Thy1-jRGECO1a, a novel GECI with red fluorescence emission that penetrates deeper into tissue, allows for simultaneous imaging of metabolic activity using a green-fluorescent glucose analog, 2-(N-(7-nitrobenz-2-oxa-1,3-diazol-4-yl)amino)-2-deoxyglucose (2NBDG), which is taken up like glucose and then phosphorylated. Dual-fluorescent (red, green) and NIRS recordings confirm strong neurovascular coupling during hindpaw stimuli (Ca2+-CBV; P = 0.0033, r2 = 0.91), whereas neurometabolic coupling (Ca2+-2NBDG; P < 0.001) was three times stronger during stimulation (r2 = 0.75; slope = 0.6) compared to rest (r2 = 0.49; slope = 0.23). In summary, multiplexed optical imaging can be used to reveal mechanisms of neurovascular and neurometabolic (un)couplings during ischemia, traumatic brain injury, aging, and Alzheimer's disease.},
}

Animals
*Neurovascular Coupling/physiology
*Optical Imaging/methods
Mice
Spectroscopy, Near-Infrared/methods
Mice, Transgenic
Calcium/metabolism
Glucose/metabolism
*Multimodal Imaging/methods
Male
*Brain/metabolism/blood supply/diagnostic imaging
Cerebral Blood Volume/physiology
Neurons/metabolism
Mice, Inbred C57BL

@article {pmid40624757,
year = {2025},
author = {Bonomini, MP and Ghiglioni, E and Ríos, NB},
title = {Graph Spectral Analysis Using Electroencephalography in Alzheimer Disease and Frontotemporal Dementia Patients.},
journal = {International journal of neural systems},
volume = {35},
number = {9},
pages = {2550048},
doi = {10.1142/S0129065725500480},
pmid = {40624757},
issn = {1793-6462},
mesh = {Humans ; *Alzheimer Disease/physiopathology/diagnosis ; *Frontotemporal Dementia/physiopathology/diagnosis ; *Electroencephalography/methods ; Male ; Aged ; Female ; Middle Aged ; *Cerebral Cortex/physiopathology ; *Brain Waves/physiology ; Signal Processing, Computer-Assisted ; },
abstract = {Graph theory has proven to be useful in studying brain dysfunction in Alzheimer's disease using MagnetoEncephaloGraphy (MEG) and fMRI signals. However, it has not yet been tested enough with reduced sets of electrodes, as in the 10-20 EEG. In this paper, we applied techniques from the Graph Spectral Analysis (GSA) derived from EEG signals of patients with Alzheimer, Frontotemporal Dementia and control subjects. A collection of global GSA metrics were computed, accounting for general properties of the adjacency or Laplacian matrices. Also, regional GSA metrics were calculated, disentangling centrality measures in five cortical regions (frontal, central, parietal, temporal and occipital). These two sort of measures were then utilized in a binary AD/controls classification problem to test their utility in AD diagnosis and identify most valuable parameters. The Theta band appeared as the most connected and synchronizable rhythm for all three groups. Also, it was the rhythm with most preserved connections among temporal electrodes, exhibiting the shortest average distances among [Formula: see text], [Formula: see text], [Formula: see text] and [Formula: see text]. In addition, Theta emerged as the rhythm with the highest classification performances based on regional parameters according to a [Formula: see text] cross-validation scheme (mean [Formula: see text], mean [Formula: see text] and mean F1-[Formula: see text]). In general, regional parameters produced better classification performances for most of the rhythms, encouraging further investigation into GSA parameters with refined spatial and functional specificity.},
}

Humans
*Alzheimer Disease/physiopathology/diagnosis
*Frontotemporal Dementia/physiopathology/diagnosis
*Electroencephalography/methods
Male
Aged
Female
Middle Aged
*Cerebral Cortex/physiopathology
*Brain Waves/physiology
Signal Processing, Computer-Assisted

@article {pmid38617285,
year = {2025},
author = {Salcedo-Tacuma, D and Asad, N and Anderson, R and Smith, DM},
title = {Hyperactive 20S Proteasome Enhances Proteostasis and ERAD in C. elegans via degradation of Intrinsically Disordered Proteins.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.1101/2024.04.04.588128},
pmid = {38617285},
issn = {2692-8205},
support = {P20 RR016440/RR/NCRR NIH HHS/United States ; R01 GM107129/GM/NIGMS NIH HHS/United States ; P30 RR032138/RR/NCRR NIH HHS/United States ; P30 GM103488/GM/NIGMS NIH HHS/United States ; R01 AG064188/AG/NIA NIH HHS/United States ; },
abstract = {UNLABELLED: Age-related proteinopathies, including Alzheimer's and Parkinson's disease, are driven by the toxic accumulation of misfolded proteins, particularly intrinsically disordered proteins (IDPs), that overwhelm cellular proteostasis. The proteasome is responsible for the clearance of these proteins, but it is unclear why it fails to do so in these diseases. Here, we report a novel strategy employing a C. elegans model with a hyperactive 20S proteasome (α3ΔN) to achieve selective activation. This activation robustly enhances the degradation of IDPs and misfolded proteins, markedly reduces oxidative damage, and significantly improves ER-associated degradation (ERAD). Notably, aggregation-prone substrates, such as endogenous vitellogenins and human alpha-1 antitrypsin (ATZ), are efficiently cleared. Proteomic and transcriptomic reprogramming reveals systemic adaptations characterized by increased protein turnover and enhanced oxidative stress resistance, independent of superoxide dismutases. Strikingly, proteasome hyperactivation extends lifespan and enhances stress resistance independently of known proteostasis pathways including the canonical unfolded protein response mediated by xbp-1. Our findings provide substantial support for a "20S pathway" of proteostasis that alleviates protein aggregation and oxidative stress, offering a promising therapeutic strategy for neurodegenerative diseases.

TEASER: Enhanced disordered protein clearance by the 20S proteasome in worms prevents toxic protein buildup and promotes stress resistance and longevity.},
}

@article {pmid40625801,
year = {2024},
author = {Wu, H and Wang, L and Qian, X and Wang, W and Si, Y and Sun, R and Akkaya, EU},
title = {Benzothiazole-endoperoxide conjugates protect PC12 cells against β-amyloid-induced cell death via singlet oxygen mediated oxidative detoxification of fibrils.},
journal = {Smart molecules : open access},
volume = {2},
number = {2},
pages = {e20230019},
pmid = {40625801},
issn = {2751-4595},
abstract = {Metastable endoperoxides with beta-amyloid fibrils targeting benzothiazole moieties were designed and synthesized. Singlet oxygen released from these endoperoxides by thermal cycloreversion reaction was shown to cause significant structural changes on the amyloid assemblies. Most importantly, the cytotoxicity of the beta-amyloid fibrils on the PC12 cells were significantly reduced in the presence of endoperoxides. This observation, coupled with the fact that neither external oxygen, nor light is needed for this transformation, is very promising.},
}

@article {pmid35132414,
year = {2025},
author = {Shen, WB and Elahi, M and Logue, J and Yang, P and Baracco, L and Albert Reece, E and Wang, B and Li, L and Blanchard, TG and Han, Z and Rissman, RA and Frieman, MB and Yang, P},
title = {WITHDRAWN: SARS-CoV-2 invades cognitive centers of the brain and induces Alzheimer's-like neuropathology.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.1101/2022.01.31.478476},
pmid = {35132414},
issn = {2692-8205},
support = {P30 AG066530/AG/NIA NIH HHS/United States ; },
abstract = {The authors have withdrawn this manuscript because the data is being questioned by the authors. Therefore, the authors do not wish this work to be cited as reference for the project. If you have any questions, please contact the corresponding author.},
}

@article {pmid40624639,
year = {2025},
author = {Huang, T and Beydoun, MA and Kianersi, S and Redline, S and Launer, LJ},
title = {Multi-dimensional sleep health and dementia risk: a prospective study in the UK Biobank.},
journal = {BMC medicine},
volume = {23},
number = {1},
pages = {410},
pmid = {40624639},
issn = {1741-7015},
support = {ZIAAG000530/AG/NIA NIH HHS/United States ; 24POST1188091//American Heart Association/ ; },
abstract = {BACKGROUND: The intricate interplay of various sleep characteristics may influence dementia risk through different pathogenic pathways. However, few studies have examined multi-dimensional sleep health in relation to dementia risk or explored potential etiologic heterogeneity by dementia subtypes.

METHODS: Our study included 313,248 UK Biobank participants aged ≥ 50 years who were dementia-free in 2006-2010. Incident dementia was identified using validated algorithms through primary care, hospital admissions, or death records through 2022. Multi-dimensional sleep health was evaluated based on seven self-reported sleep-related factors and assessed in two ways: (1) using an a priori sleep health score (SHS) ranging from 0 to 7, with higher scores indicating healthier sleep, and (2) through data-driven sleep health patterns identified by latent class analysis. We used Cox proportional hazards models to estimate the associations between multi-dimensional sleep health and risk of all-cause dementia, vascular dementia (VaD), and Alzheimer's disease (AD).

RESULTS: There were 7458 incident all-cause dementia cases (1636 VaD, 3376 AD) after 4,165,352 person-years of follow-up. After adjusting for potential confounders, the hazard ratio (95% CI) comparing participants with SHS of 0-2 (worst sleep) vs 6-7 (best sleep) was 1.76 (1.52, 2.05) for all-cause dementia (p-trend < 0.0001), 2.13 (1.61, 2.83) for VaD (p-trend < 0.0001), and 1.55 (1.22, 1.97) for AD (p-trend < 0.57). We identified six multi-dimensional sleep health patterns, including relatively healthy sleep, insomnia with short sleep duration, non-restorative sleep with evening chronotype, insomnia with non-restorative sleep, snoring with daytime sleepiness and napping, and severely disturbed sleep with multiple symptoms and daytime impairment. Compared with the healthy sleep pattern, all other five sleep patterns were significantly associated with 8-85% higher all-cause dementia risk and 11-148% higher VaD risk, whereas only the severely disturbed sleep pattern was associated with 56% higher AD risk (95% CI: 1.21, 2.01).

CONCLUSIONS: Poor multi-dimensional sleep health, either assessed by a simple SHS or characterized by sleep clusters, was associated with higher incident dementia risk. There is substantial heterogeneity in multi-dimensional sleep health patterns and their associations with different dementia outcomes. Understanding the specific sleep health profiles associated with dementia risk may help to identify high-risk populations and inform more targeted interventions.},
}

@article {pmid40624595,
year = {2025},
author = {Price, D and Cramer, J and Rogers, CB and Prajapati, P and Shakhashiro, Y and Nelson, PT and Wang, WX},
title = {Immunoelectron microscopy and biochemical studies using three anti-tau antibodies in human brains: associations between pTau and ribosomes.},
journal = {Acta neuropathologica communications},
volume = {13},
number = {1},
pages = {150},
doi = {10.1186/s40478-025-02072-2},
pmid = {40624595},
issn = {2051-5960},
support = {P20GM103436/NH/NIH HHS/United States ; P30 AG072946/NH/NIH HHS/United States ; },
abstract = {The hallmark neuropathological lesions of Alzheimer's disease (AD) are extracellular amyloid-beta (Aβ) plaque deposits and intracellular Tau neurofibrillary tangles (NFTs). Identifying the intracellular localization of early pathologic changes can enhance our understanding of disease mechanisms and stimulate new approaches in diagnosis and treatment. Despite extensive biochemical studies of AD-related protein aggregates, there have been relatively few studies recently in terms of transmission electron microscopy of proteinaceous lesions in human brains across a range of disease severity. Here we performed immunoelectron microscope studies used three anti-Tau antibodies (MC-1, AT8, and PHF-1) on short post-mortem interval (PMI) human brain tissues obtained from the University of Kentucky Alzheimer's Disease Research Center (UK-ADRC) autopsy cohort, along with corresponding biochemical and immunofluorescent studies. Although these three antibodies have been reported to label different phases of NFT formation, in our hands they all tended to stain pathologic structures along a continuum that included pretangles and mature NFTs. Immunoelectron microscopy studies, augmented by serial sectioning, revealed that all three Tau antibodies recognize both granular and fibrillary structures in pretangles and early-stage NFTs. Phosphorylated Tau (pTau) immunoreactivity often exhibited a peri-nuclear distribution. The pTau was frequently found localized to ribosomes, either free within the cytoplasm or attached to the endoplasmic reticulum (ER). This observation aligns with previous descriptions, but the enhanced ultrastructural preservation provided improved resolution. Subcellular fractionation and Western blot analyses confirmed the enrichment of pTau in the ER fractions in AD brains. Interestingly, total Tau (including non-phosphorylated Tau) did not preferentially co-purify with the ER in non-AD brains. Immunofluorescent staining revealed that pTau immunoreactivity evolved from cytoplasmic granules in pretangles, with an intracytoplasmic distribution that overlapped complementarily with ribosome and ER markers. Our results suggest that biochemical associations between pTau with ribosomes and ER are a common phenomenon in human aged brains.},
}

@article {pmid40624486,
year = {2025},
author = {Wang, Y and Yu, Q and Chen, B and Zhou, J and Li, Z and Liao, W and Liu, J and Yang, A},
title = {Two cases of Amyloid-Related Imaging Abnormalities (ARIA) following lecanemab treatment for alzheimer's disease and a literature review.},
journal = {BMC neurology},
volume = {25},
number = {1},
pages = {281},
pmid = {40624486},
issn = {1471-2377},
abstract = {OBJECTIVE: To investigate the imaging characteristics and management strategies of amyloid-related imaging abnormalities (ARIA) in Alzheimer's disease (AD) patients treated with lecanemab.

METHODS: We report two clinical cases of ARIA following lecanemab treatment and analyze the imaging features, risk factors, and management strategies of ARIA based on the latest literature.

RESULTS: The occurrence of ARIA is associated with risk factors such as advanced age, ApoE ε4 carrier status, cerebral amyloid angiopathy (CAA), and a history of cerebrovascular disease.

CONCLUSION: During lecanemab treatment for AD, it is essential to fully understand the mechanisms, imaging characteristics, and management strategies of ARIA. Close monitoring of clinical symptoms and imaging changes is crucial for the timely detection and appropriate management of ARIA.},
}

@article {pmid40624483,
year = {2025},
author = {Zhang, J and Huang, X and Ling, Y and Xie, X and Zeng, X and Lyu, J and Huang, L},
title = {Associations of cardiometabolic multimorbidity with all-cause dementia, alzheimer's disease, and vascular dementia: a cohort study in the UK biobank.},
journal = {BMC public health},
volume = {25},
number = {1},
pages = {2397},
pmid = {40624483},
issn = {1471-2458},
support = {21623316//the Fundamental Research Funds for Central Universities/ ; 21623316//the Fundamental Research Funds for Central Universities/ ; 2024A04J4175//the Guangzhou Science and Technology Project - Basic and applied basic research/ ; 2023A04J1913//the Guangzhou Science and Technology Project - Basic and applied basic research/ ; 82201438//the National Natural Science Foundation of China/ ; 2022A1515012563//the Natural Science Foundation of Guangdong Province/ ; 2022A1515012563//the Natural Science Foundation of Guangdong Province/ ; },
abstract = {BACKGROUND: Cardiometabolic diseases (CMDs) including type 2 diabetes, heart disease, and stroke, increase the risk of dementia. However, the correlation between CMDs and dementia in different subgroups and the underlying pathophysiological mechanisms linking CMDs with dementia warrant further investigation.

METHODS: This prospective cohort study included a total of 287,748 individuals from the UK Biobank. The outcome measures included all-cause dementia (ACD), Alzheimer's disease (AD) and vascular dementia (VD). Cox regression models and subgroup analyses were used to assess the association between CMD status and dementia, while mediation analysis was evaluated potential roles of inflammatory/metabolic markers in the observed associations.

RESULTS: Compared with those without CMD, those with CMD multimorbidity had an elevated risk of ACD (hazard ratio [HR]: 2.27, 95% confidence interval [95% CI]: 1.95-2.63), AD (HR: 1.49, 95% CI: 1.13-1.97), and VD (HR: 3.70, 95% CI: 2.93-4.69). According to the subgroup analyses, the positive correlations between CMDs and ACD, as well as AD, were stronger in individuals who were under the age of 60 or female. Mediation analysis indicated that neutrophils mediated 2.43% of the association of CMDs with ACD, while glucose and hemoglobin A1c mediated 9.22% and 11.85% of the association of CMDs with ACD, respectively.

CONCLUSION: This study further expands the research on cardiometabolic multimorbidity and dementia, highlighting the need for focused attention on specific populations, such as younger individuals and women. Additionally, inflammatory and metabolic biomarkers, as potential mediators, provide critical insights into the complex pathophysiological mechanisms.},
}

@article {pmid40624281,
year = {2025},
author = {Jia, W and Zhu, K and Shi, J and Yong, F},
title = {Association between dietary copper intake and cognitive function in American older adults: NHANES 2011-2014.},
journal = {Scientific reports},
volume = {15},
number = {1},
pages = {24334},
pmid = {40624281},
issn = {2045-2322},
mesh = {Humans ; Male ; Female ; Aged ; *Cognition/drug effects ; *Copper/administration & dosage ; Nutrition Surveys ; Cross-Sectional Studies ; *Diet ; United States/epidemiology ; Middle Aged ; Aged, 80 and over ; },
abstract = {This cross-sectional observational study examined the association between dietary copper intake and cognitive function in American older adults, using data from the 2011 to 2014 National Health and Nutrition Examination Survey (NHANES). Analyzing a total of 2420 participants, dietary copper intake was determined by averaging two 24-h dietary recalls, whereas cognitive function was assessed by the Digit Symbol Substitution Test (DSST), the Animal Fluency Test (AFT), a Consortium to Establish a Registry for Alzheimer's disease (CERAD) subtest and global cognition Z score. Multivariate linear regression models were used to explore the association between copper levels and cognitive function. Higher copper intake was associated with higher cognitive scores. In the fully adjusted model, compared to the lowest quartile (Q1), the highest quartile (Q4) of copper intake was associated with related to higher cognitive scores (DSST: β = 3.80, 95% CI 1.90,5.70; AFT: β = 1.23, 95% CI 0.48,1.99; CERAD-IRT: β = 0.58, 95% CI - 0.06,1.22; CERAD-DRT: β = 0.47, 95% CI 0.15,0.80; Z score: β = 0.20, 95% CI 0.10,0.29), particularly in participants with a history of stroke. Multivariate smooth spline analysis revealed that dietary copper intake was related to DSST, AFT and Z score in an inverted L-shaped nonlinear manner. The inflection point of copper was 1.63 mg/day for DSST, 1.42 mg/day for AFT and 1.22 mg/day for the Z score. Further longitudinal research is necessary to substantiate these findings.},
}

Humans
Male
Female
Aged
*Cognition/drug effects
*Copper/administration & dosage
Nutrition Surveys
Cross-Sectional Studies
*Diet
United States/epidemiology
Middle Aged
Aged, 80 and over

@article {pmid40624195,
year = {2025},
author = {Aman, Y},
title = {Tau PET positivity marks early clinical transition in Alzheimer's disease progression.},
journal = {Nature aging},
volume = {},
number = {},
pages = {},
doi = {10.1038/s43587-025-00932-z},
pmid = {40624195},
issn = {2662-8465},
}

@article {pmid40624099,
year = {2025},
author = {Zhang, Q and Sheng, J and Zhou, R and Zhang, Q and Wang, B and Zhang, R},
title = {Enhanced particle swarm optimization for feature selection in SVM-based Alzheimer's disease diagnosis.},
journal = {Scientific reports},
volume = {15},
number = {1},
pages = {24243},
pmid = {40624099},
issn = {2045-2322},
support = {LZ24F010007//Natural Science Foundations of Zhejiang Province/ ; 62271177//National Natural Science Foundations of China/ ; 62271177//National Natural Science Foundations of China/ ; },
mesh = {*Alzheimer Disease/diagnosis/diagnostic imaging ; Humans ; *Support Vector Machine ; Magnetic Resonance Imaging/methods ; Algorithms ; Aged ; Male ; Gray Matter/diagnostic imaging/pathology ; Female ; Brain/diagnostic imaging/pathology ; White Matter/diagnostic imaging/pathology ; Particle Swarm Optimization ; },
abstract = {Alzheimer's Disease (AD) is a progressive neurodegenerative disorder marked by neuronal loss, leading to cognitive and behavioral decline. With the aging global population, AD incidence and its socioeconomic burden are increasing. Developing effective early diagnostic methods is thus critical for improving patient outcomes and slowing disease progression. In this paper, an enhanced Particle Swarm Optimization (PSO) algorithm, which integrates opposition-based Latin squares sampling initialization (OL) with dynamic inertia weights and learning factors (D), termed OLDPSO, is proposed to improve feature selection and classification within a Support Vector Machine (SVM) model for AD diagnosis using magnetic resonance imaging (MRI) data. MRI, as a non-invasive modality, reveals structural brain changes, particularly in gray matter (GM) and white matter (WM) volumes, which are key biomarkers for AD. However, extracting essential features from complex GM and WM data remains a significant challenge. To address this, the proposed OLDPSO, which adaptively balances global exploration and local exploitation, overcomes traditional PSO limitations. Benchmark experiments show that OLDPSO outperforms existing PSO variants in solution quality and convergence speed. Validated with data from the AD Neuroimaging Initiative (ADNI), the OLDPSO-SVM model demonstrates superior performance in differentiating AD, mild cognitive impairment (MCI), and normal control (NC) groups, particularly in classifying MCI subtypes (MCI-NC and MCI-C). Results show that combining GM and WM features yields higher diagnostic accuracy than using either alone, and the model identified key brain regions associated with AD progression. Specifically, the model achieved accuracies of 99.11%, 89.76%, 99.07%, 88.38%, 94.69%, and 87.96% in the diagnosis of AD vs. NC, NC vs. MCI-NC, NC vs. MCI-C, MCI-NC vs. MCI-C, MCI-NC vs. AD, and MCI-C vs. AD, respectively. Through optimized feature selection, the OLDPSO-SVM model enhances diagnostic performance and provides valuable insights for developing MRI-based multimodal diagnostic tools for AD.},
}

*Alzheimer Disease/diagnosis/diagnostic imaging
Humans
*Support Vector Machine
Magnetic Resonance Imaging/methods
Algorithms
Aged
Male
Gray Matter/diagnostic imaging/pathology
Female
Brain/diagnostic imaging/pathology
White Matter/diagnostic imaging/pathology
Particle Swarm Optimization

@article {pmid40623989,
year = {2025},
author = {Yazdanpanah Moghadam, E and Sonenberg, N and Packirisamy, M},
title = {Alzheimer model chip with microglia BV2 cells.},
journal = {Microsystems & nanoengineering},
volume = {11},
number = {1},
pages = {135},
doi = {10.1038/s41378-024-00862-7},
pmid = {40623989},
issn = {2055-7434},
abstract = {Amyloid beta oligomers (AβO) are pivotal in Alzheimer's Disease (AD), cleared by microglia cells, as immune cells in the brain. Microglia cells exposed to AβO are involved with migration, apoptosis, phagocytosis, and activated microglial receptors through AβO, impacting cellular mechanobiological characteristics such as microglial adhesion strength to the underlying substrate. Herein, a label-free microfluidic device was used to detect advancing AD conditions with increasing AβO concentrations on microglia BV2 cells by quantitatively comparing the cell-substrate adhesion. The microfluidic device, acting as an AD model, comprises a single channel, which functions as a cell adhesion assay. To assess cell-substrate adhesion under different AβO concentrations of 1 µM, 2.5 µM, and 5 µM, the number of the cells attached to the substrate was counted by real-time microscopy when the cells were under the flow shear stress of 3 Pa and 7.5 Pa corresponding to Reynolds number (Re) of 10 and 25, respectively. The data showed that quantifying the cell-substrate adhesion using the microfluidic device could successfully identify conditions of advancing AβO concentrations. Our findings indicated that the increased incubation time with AβO caused reduced cell-substrate adhesion strength. Additionally, increased AβO concentration was another factor that weakened microglial interaction with the substrate. The quantification of cell-substrate adhesion using 3 Pa compared to 7.5 Pa clearly demonstrated advancing AβO in AD. This study using the chip provides an AD model for a deeper understanding mechanobiological behaviors of microglia exposed to AβO corresponding to diagnosed AD conditions under an in vitro microenvironment.},
}

@article {pmid40623471,
year = {2025},
author = {Nasiri, H and Azargoonjahromi, A},
title = {Response to "Reevaluating leucine's effects on Alzheimer's disease: evidence of potential benefits overlooked".},
journal = {Neuroscience},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.neuroscience.2025.07.006},
pmid = {40623471},
issn = {1873-7544},
}

@article {pmid40623303,
year = {2025},
author = {Weil, RS},
title = {Seeing the trees in the wood: the importance of co-pathologies in Alzheimer's disease and dementia with Lewy bodies.},
journal = {Brain : a journal of neurology},
volume = {148},
number = {7},
pages = {2233-2234},
doi = {10.1093/brain/awaf197},
pmid = {40623303},
issn = {1460-2156},
}

@article {pmid40623182,
year = {2025},
author = {Fallot, LB and Pinc, JR and Buselmeier, JE and Palchak, JC and Shroff, SS and Zang, K and Rinauro, DJ and Bacon, KM and Nguyen, M and Schleck, MC and Cornell, AR and Oshidar, A and Darrell, DJ and Gabriel, JM and Wright, AK and Sasser, LR and Kreiser, RP and Burpo, FJ and Santambrogio, A and Xu, P and Kubiak, RW and Loverde, J and Jaffett, VA and Toole, JR and Barbut, D and Zasloff, M and Chiti, F and Dear, AJ and Vendruscolo, M and Limbocker, R},
title = {An aminosterol breaks the autocatalytic cycle of Aβ42 aggregation and protects cell membranes from its soluble aggregates.},
journal = {Proceedings of the National Academy of Sciences of the United States of America},
volume = {122},
number = {28},
pages = {e2417944122},
doi = {10.1073/pnas.2417944122},
pmid = {40623182},
issn = {1091-6490},
support = {SARI//DOD | Defense Threat Reduction Agency (DTRA)/ ; N/A//DOD | Office of the Under Secretary of Defense for Research and Engineering (USDR&E)/ ; N/A//DOD | USA | AFC | CCDC | DEVCOM Army Research Laboratory (DEVCOM ARL)/ ; N/A//DOD | ARPA | Defense Sciences Office, DARPA (DSO)/ ; N/A//Photonics Research Center/ ; },
mesh = {*Amyloid beta-Peptides/metabolism/chemistry ; Humans ; *Cell Membrane/metabolism/drug effects ; *Peptide Fragments/metabolism/chemistry ; *Protein Aggregates/drug effects ; Alzheimer Disease/metabolism/drug therapy ; *Protein Aggregation, Pathological/metabolism ; Amyloid/metabolism ; Cell Line, Tumor ; },
abstract = {Aberrant aggregates of the 42-residue form of the amyloid-β peptide (Aβ42) are cytotoxic in Alzheimer's disease (AD). Cost-effective and chronically safe disease-modifying therapeutics are needed to address the AD medical emergency worldwide. To increase our understanding of the mechanisms of Aβ42-induced cytotoxicity and to investigate clinically relevant aminosterols, we study the impact of claramine on the aggregation kinetics and properties of Aβ42 aggregates, as well as the ability of these proteotoxic species to bind and disrupt cell membranes. Whereas previously studied aminosterols accelerated Aβ42 aggregation, we show that claramine potently inhibits Aβ42 amyloid fibril formation. We find that claramine stabilizes soluble Aβ42, speeding up primary and secondary nucleation into species with antiparallel β-sheet structure that are elongation incompetent, thereby depleting Aβ42 monomers from the aggregation reaction. This steroid-polyamine also dissociates Aβ42 fibrillar aggregates, resulting in the abrogation of the autocatalytic capacity of Aβ42 fibrils, and it also inhibits the aggregation of a tau fragment relevant to AD. Upon exposure of human neuroblastoma cells to stabilized Aβ42 oligomers, claramine effectively neutralized Aβ42 oligomer-induced cytotoxicity by preventing their binding to cell membranes. Owing to the unique mechanism of action of aminosterols to reduce the toxicity of soluble Aβ42 aggregates by protecting cell membranes, and the newly characterized ability of claramine to inhibit Aβ42 fibril formation and dissociate fibrillar Aβ42 resulting in the interruption of the positive feedback loop in Aβ42 aggregation, our findings further emphasize the relevance of this family of natural products as potential treatments for AD and other protein misfolding diseases.},
}

*Amyloid beta-Peptides/metabolism/chemistry
Humans
*Cell Membrane/metabolism/drug effects
*Peptide Fragments/metabolism/chemistry
*Protein Aggregates/drug effects
Alzheimer Disease/metabolism/drug therapy
*Protein Aggregation, Pathological/metabolism
Amyloid/metabolism
Cell Line, Tumor