@article {pmid40118715,
year = {2025},
author = {Cummings, JL},
title = {Maximizing the benefit and managing the risk of anti-amyloid monoclonal antibody therapy for Alzheimer's disease: Strategies and research directions.},
journal = {Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics},
volume = {},
number = {},
pages = {e00570},
doi = {10.1016/j.neurot.2025.e00570},
pmid = {40118715},
issn = {1878-7479},
abstract = {Anti-amyloid monoclonal antibodies (MABs) have introduced a new era of Alzheimer's disease (AD) therapeutics with disease-targeted drugs. Three agents --- aducanumab, lecanemab, donanemab --- have been approved and others are in development. These agents are administered intravenously, once in the brain they activate microglia to engulf amyloid-beta protein fibrillar plaques. Each approved agent has a specific profile of administration, titration, amyloid target, and adverse events. In 18 month trials of participants with early AD (defined as mild cognitive impairment due to AD or mild AD dementia), anti-amyloid MABs slow cognitive and functional decline by approximately 30 %. Amyloid positron emission tomography reveals marked reductions in amyloid plaque burden; reductions below a threshold of 15-25 Centiloids are associated with clinical benefit. The magnitude, scope, and trajectory of clinical end points provide the basis for interpretations of clinical meaningfulness. Occurrence of amyloid-related imaging abnormalities with intracerebral edema, microhemorrhages, or superficial siderosis must be monitored and managed to prevent serious or rare catastrophic consequences. Infusion reactions occur and anticipatory management is required. Development of subcutaneous formulations and use of blood-based biomarkers for diagnosis and monitoring promises to increase the accessibility and decrease the demands on health care systems associated with these agents. Anti-amyloid MABs provide the foundation for further advances in developing a repertoire of disease-targeted therapies for AD.},
}

@article {pmid40118459,
year = {2025},
author = {Xu, Y and Li, S and Xu, Y and Sun, X and Wei, Y and Wang, Y and Li, S and Ji, Y and Hu, K and Xu, Y and Zhu, C and Lu, B and Wang, D},
title = {Visualize neuronal membrane cholesterol with split- fluorescent protein tagged YDQA sensor.},
journal = {Journal of lipid research},
volume = {},
number = {},
pages = {100781},
doi = {10.1016/j.jlr.2025.100781},
pmid = {40118459},
issn = {1539-7262},
abstract = {Cholesterol is a major component of the cellular plasma membrane (PM), and its homeostasis is essential for brain health. Dysregulated cholesterol homeostasis has been strongly implicated in the pathogenesis of various neurological disorders, including Alzheimer's disease (AD). However, in vivo visualization of cholesterol has remained challenging, hindering a comprehensive understanding of AD pathology. In this study, we generated a new sensor combining the split-fluorescent protein tags with YDQA, a derivate of cholesterol-dependent cytolysin PFO. Through a series of validations in cell and C. elegans models, we demonstrate that the new sensor (name as sfPMcho) efficiently detects neuronal PM cholesterol. We further applied this sensor in 5X FAD and APOE KO mice models and revealed the cholesterol changes within neurons. PM cholesterol became sparse and locally aggregated in neuron bodies but significantly accumulated in nerve fibers. Collectively, this study provides a new tool for detecting neuronal PM cholesterol in vivo and uncovers cholesterol abnormalities in AD-related pathology at the cellular level. Further development based on this sensor or the similar strategy are to be expected.},
}

@article {pmid40118355,
year = {2025},
author = {Chen, F and Wang, Z},
title = {Commentary on "Assessment of sodium-glucose cotransporter 2 inhibitors (SGLT2i) and other antidiabetic agents in Alzheimer's disease: A population-based study".},
journal = {Pharmacological research},
volume = {},
number = {},
pages = {107702},
doi = {10.1016/j.phrs.2025.107702},
pmid = {40118355},
issn = {1096-1186},
}

@article {pmid40118353,
year = {2025},
author = {Garcia-Zamora, M and García-Lluch, G and Moreno, L and Cháfer-Pericas, C and Pardo, J},
title = {Response to letter to the editor: Letter by Chen et al. Regarding Article, "Assessment of sodium-glucose cotransporter 2 inhibitors (SGLT2i) and other antidiabetic agents in Alzheimer's disease: A population-based study".},
journal = {Pharmacological research},
volume = {},
number = {},
pages = {107701},
doi = {10.1016/j.phrs.2025.107701},
pmid = {40118353},
issn = {1096-1186},
}

@article {pmid40118333,
year = {2025},
author = {Cho, W and Choi, SW and Lim, DS and Gwon, HJ and El-Aty, AMABD and Ahmet Aydemir, H and Hong, SA and Jeong, JH and Jung, TW},
title = {Donepezil alleviates hepatic steatosis by mitigating ER stress via the AMPK/autophagy pathway.},
journal = {Molecular and cellular endocrinology},
volume = {},
number = {},
pages = {112523},
doi = {10.1016/j.mce.2025.112523},
pmid = {40118333},
issn = {1872-8057},
abstract = {Donepezil (Do), a drug known for its ability to reduce neuronal inflammation and for its use in the treatment of Alzheimer's disease, has shown promise in combating hepatic lipid accumulation in hyperlipidemic conditions and endoplasmic reticulum (ER) stress, a factor associated with alterations in hepatic lipid metabolism. However, the mechanisms by which these problems are alleviated have not been fully elucidated. In this study, we investigated the effects of Do on hepatic lipid metabolism through both in vitro and in vivo studies. We examined the expression of proteins associated with lipogenesis and ER stress via immunoblot analysis, and hepatic lipid accumulation was assessed via oil red O staining. In addition, autophagosome formation was analyzed by counting MDC-positive cells. Our results demonstrated that Do treatment improved hepatic lipid metabolism and reduced the expression of ER stress markers, resulting in decreased lipogenic lipid deposition and apoptosis in the hepatocytes and livers of hyperlipidemic mice. Mechanistically, knocking down AMPK or inhibiting autophagy with 3-methyladenine (3MA) attenuated the effects of Do on palmitate-exposed hepatocytes. These results suggest that Do alleviates hepatic ER stress via the AMPK/autophagy pathway and AMPK-mediated fatty acid oxidation, resulting in improved hepatic lipid metabolism and reduced hepatic steatosis and apoptosis. Our study provides evidence that Do may be a promising therapeutic approach for Alzheimer's disease patients with metabolic dysfunction-associated steatotic liver disease (MASLD).},
}

@article {pmid40118328,
year = {2025},
author = {Mansour, HM and El-Khatib, AS},
title = {Oligonucleotide-Based Therapeutics for Neurodegenerative Disorders: Focus on Antisense Oligonucleotides.},
journal = {European journal of pharmacology},
volume = {},
number = {},
pages = {177529},
doi = {10.1016/j.ejphar.2025.177529},
pmid = {40118328},
issn = {1879-0712},
abstract = {Antisense oligonucleotides (ASOs) specifically bind to target RNA sequences and regulate protein expression through various mechanisms. ASOs are a promising therapeutic approach for treating neurodegenerative diseases. The ASO field is a growing area of drug development that focuses on targeting the root cause of diseases at the RNA level, providing a promising alternative to therapies that target downstream processes. Addressing challenges related to off-target effects and inadequate biological activity is essential to successfully develop ASO-based therapies. Researchers have investigated various chemical modifications and delivery strategies to overcome these challenges. This review discusses oligonucleotide-based therapies, particularly ASOs. We discuss the chemical modifications and mechanisms of action of ASOs. Additionally, we recap the results of preclinical and clinical studies testing different ASOs in various neurodegenerative disorders, including spinal muscular atrophy, Huntington's disease, amyotrophic lateral sclerosis, Alzheimer's disease, and Parkinson's disease. In conclusion, ASO drugs show promise as a therapeutic option for treating neurodegenerative diseases.},
}

@article {pmid40118248,
year = {2025},
author = {d'Errico, P and Früholz, I and Meyer-Luehmann, M and Vlachos, A},
title = {Neuroprotective and plasticity promoting effects of repetitive transcranial magnetic stimulation (rTMS): a role for microglia.},
journal = {Brain stimulation},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.brs.2025.03.012},
pmid = {40118248},
issn = {1876-4754},
abstract = {Repetitive transcranial magnetic stimulation (rTMS) is a non-invasive brain stimulation technique used to modulate neocortical excitability, with expanding applications in neurological and psychiatric disorders. However, the cellular and molecular mechanisms underlying its effects, particularly the role of microglia-the resident immune cells of the central nervous system-remain poorly understood. This review synthesizes recent findings on how different rTMS protocols influence microglial function under physiological conditions and in disease models. Emerging evidence indicates that rTMS modulates microglial activation, promoting neuroprotective and plasticity-enhancing processes not only in models of brain disorders, such as Alzheimer's and Parkinson's disease, but also in healthy neural circuits. While much of the current research has focused on the inflammatory profile of microglia, critical aspects such as activity-dependent synaptic remodeling, phagocytic activity, and process motility remain underexplored. Given the substantial heterogeneity of microglial responses across brain regions, age, and sex, as well as their differential roles in health and disease, a deeper understanding of their involvement in rTMS-induced plasticity is essential. Future studies should integrate selective microglial manipulation and advanced structural, functional, and molecular profiling techniques to clarify their causal involvement. Addressing these gaps will be pivotal in optimizing rTMS protocols and maximizing its therapeutic potential across a spectrum of neurological and neuropsychiatric conditions.},
}

@article {pmid40118234,
year = {2025},
author = {Cs, P and Oxtoby, NP and Young, AL and Alexander, DC and Zhang, H},
title = {Parsimonious EBM: generalising the event-based model of disease progression for simultaneous events.},
journal = {NeuroImage},
volume = {},
number = {},
pages = {121162},
doi = {10.1016/j.neuroimage.2025.121162},
pmid = {40118234},
issn = {1095-9572},
abstract = {The event-based model of disease progression (EBM) infers a temporal ordering of biomarker abnormalities, defining different disease stages, from short-term data. A key modelling choice of the EBM is that biomarker abnormalities, termed events, are serially ordered. This enforces a strict equality between the number of input biomarkers and the number of model stages, limiting its ability to infer simple staging systems and latent disease processes. To overcome this, we introduce the parsimonious event-based model of disease progression (P-EBM). The P-EBM generalises the EBM to allow multiple new biomarker abnormalities, termed "simultaneous events", at each model stage. We evaluate the P-EBM performance in simulated data to show it accurately estimates orderings with arbitrary event arrangements under realistic experimental conditions. When applied to sporadic AD data from the Alzheimer's Disease Neuroimaging Initiative, the P-EBM estimated a sequence with 7 model stages from a dataset of 12 biomarkers that more closely fitted the data than the EBM. The sets of simultaneous events, such as decreased cerebrospinal fluid total tau and p-tau181, correspond closely to latent disease processes. P-EBM patient stages were strongly associated with clinical diagnosis at baseline and future conversion and could be accurately estimated from a smaller number of biomarkers than the EBM. The P-EBM enables the data-driven discovery of simple disease staging systems which could highlight new latent disease processes and suggest practical strategies for patient staging.},
}

@article {pmid40118165,
year = {2025},
author = {Morais, RF and Pires, R and Jesus, T and Lemos, R and Duro, D and Lima, M and Baldeiras, I and Oliveira, TG and Santana, I},
title = {Cognitive impairment in neurodegenerative diseases: A trans-diagnostic approach using a lesion-symptom mapping analysis.},
journal = {Neuroscience},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.neuroscience.2025.03.034},
pmid = {40118165},
issn = {1873-7544},
abstract = {INTRODUCTION: Neurodegenerative disorders, such as Alzheimer's disease (AD) and frontotemporal dementia (bvFTD), reflect a spectrum of cognitive impairments unified by cognitive decline. Traditional diagnostic approaches often overlook shared landscapes of these disorders. A transdiagnostic approach, cutting across conventional boundaries, may improve understanding of shared mechanisms. This study uses lesion-symptom mapping (LSM) to identify critical brain structures responsible for cognitive impairments.

METHODS: Patients diagnosed with Mild Cognitive Impairment (MCI), probable AD, and probable bvFTD were recruited from our memory clinic. Diagnoses were made by a multidisciplinary team using established criteria. Participants underwent detailed medical and neurological examinations, neuroimaging, cerebrospinal fluid analysis, and neuropsychological assessment. MRI scans were processed using FreeSurfer. LSM was used to assess correlations between brain structures and cognitive performance.

RESULTS: Significant correlations were found between neuropsychological test scores and reduced volume in specific brain regions. The Free and Cued Selective Reminding Test was linked to the right hippocampus and left nucleus accumbens. The Brief Visuospatial Memory Test-Revised correlated with the right hippocampus, left nucleus accumbens, and right middle temporal gyrus. Verbal fluency was linked to the left superior temporal sulcus and left middle temporal gyrus. Digit Span forward correlated with left superior frontal gyrus and left inferior parietal region, while Digit Span backward was linked to the right precuneus. Digit-Symbol Coding was associated with the left inferior parietal region.

CONCLUSIONS: This study highlights common neural targets in MCI, AD, and bvFTD and their link with cognitive impairment, emphasizing the value of LSM within a transdiagnostic approach to neurodegenerative diseases.},
}

@article {pmid40118053,
year = {2025},
author = {Wang, Z and Chen, Y and Gong, K and Zhao, B and Ning, Y and Chen, M and Li, Y and Ali, M and Timsina, J and Liu, M and Cruchaga, C and Jia, J},
title = {Cerebrospinal fluid proteomics identification of biomarkers for amyloid and tau PET stages.},
journal = {Cell reports. Medicine},
volume = {},
number = {},
pages = {102031},
doi = {10.1016/j.xcrm.2025.102031},
pmid = {40118053},
issn = {2666-3791},
abstract = {Accurate staging of Alzheimer's disease (AD) pathology is crucial for therapeutic trials and prognosis, but existing fluid biomarkers lack specificity, especially for assessing tau deposition severity, in amyloid-beta (Aβ)-positive patients. We analyze cerebrospinal fluid (CSF) samples from 136 participants in the Alzheimer's Disease Neuroimaging Initiative using more than 6,000 proteins. We apply machine learning to predict AD pathological stages defined by amyloid and tau positron emission tomography (PET). We identify two distinct protein panels: 16 proteins, including neurofilament heavy chain (NEFH) and SPARC-related modular calcium-binding protein 1 (SMOC1), that distinguished Aβ-negative/tau-negative (A-T-) from A+ individuals and nine proteins, such as HCLS1-associated protein X-1 (HAX1) and glucose-6-phosphate isomerase (GPI), that differentiated A+T+ from A+T- stages. These signatures outperform the established CSF biomarkers (area under the curve [AUC]: 0.92 versus 0.67-0.70) and accurately predicted disease progression over a decade. The findings are validated in both internal and external cohorts. These results underscore the potential of proteomic-based signatures to refine AD diagnostic criteria and improve patient stratification in clinical trials.},
}

@article {pmid40117986,
year = {2025},
author = {Zhao, C and Zhang, X and Ma, C and Xu, W},
title = {The impact of extreme high temperatures on ADRD hospitalization in Guangdong, China, 2017-2019.},
journal = {Economics and human biology},
volume = {57},
number = {},
pages = {101485},
doi = {10.1016/j.ehb.2025.101485},
pmid = {40117986},
issn = {1873-6130},
abstract = {Alzheimer's disease and related dementias (ADRD) have emerged as a major global health challenge due to the aging population. This study is among the first to investigate the impact of extreme high temperatures on ADRD hospitalization in a developing country, leveraging individual-level inpatient medical records. We found that both transient and cumulative exposure to heat waves significantly increased total hospitalization expenses and the length of hospital stay for ADRD patients. Specifically, an additional day with a daily mean temperature exceeding 30 °C in the preceding 7 days, compared to a moderate day with a temperature between 14-18 °C, was associated with a 1.5 % (200.2 yuan) increase in total hospitalization expenses and a 1.8 % (0.2 days) increase in the length of hospital stay. These effects were largely driven by out-of-pocket expenditures on nursing care and were particularly pronounced among male patients and those aged over 75.},
}

@article {pmid40117973,
year = {2025},
author = {Ghorbaninia, M and Doroudgar, S and Ganjalikhany, MR},
title = {Delving into the crucial role of the initial structure in the dynamic and self-assembly of amyloid beta.},
journal = {Biochemical and biophysical research communications},
volume = {758},
number = {},
pages = {151652},
doi = {10.1016/j.bbrc.2025.151652},
pmid = {40117973},
issn = {1090-2104},
abstract = {Alzheimer's disease involves the accumulation of amyloid beta (Aβ) monomers that form oligomers and fibrils in the brain. Studying the Aβ monomer is critical for understanding Aβ assembly and peptide behavior and has implications for drug design. Choosing a starting structure with a higher aggregation tendency for cost-effective MD studies and drug design is crucial. Previous studies have utilized distinct initial conformations, leading to varying results. Hence, this study was conducted to compare different initial conformations using the same MD simulation protocol to investigate the behavior and oligomerization propensity of different starting structures of Aβ during 1μs. The behavior of the monomers and their self-assembly systems were studied thoroughly, and the results revealed that highly helical Aβ monomers which used as starting structures retain high helix content during the simulation, and their tautomerization states did not cause significant changes in the structure. On the other hand, the Aβ extended and S-shaped monomers displayed the fingerprints of the fibril structure, which is believed to be more favorable for self-assembly. Self-assembly behaviors were seen for three S-shaped and three Aβ extended peptides. However, both conformations did not show stable β-sheet intermolecular interaction. For the Aβ16-22 monomer as a fragment of the Aβ that can assemble into fibrils, the impacts of capping and uncapping on the initial structure were also investigated. The results displayed that capped and uncapped structures can form oligomers with β-sheet at termini. However, in the capped state, β-sheet interactions were more stable and remained relatively longer than uncapped.},
}

@article {pmid40117490,
year = {2025},
author = {Fuller, JL and Shi, K and Pockes, S and Finzel, BC and Ashe, KH and Walters, MA},
title = {Reengineering of Circularly Permuted Caspase-2 to Enhance Enzyme Stability and Enable Crystallographic Studies.},
journal = {ACS chemical biology},
volume = {},
number = {},
pages = {},
doi = {10.1021/acschembio.4c00795},
pmid = {40117490},
issn = {1554-8937},
abstract = {Caspase activation has been linked to several diseases, including cancer, neurodegeneration, and inflammatory conditions, generating interest in targeting this family of proteases for drug development. Caspase-2 (Casp2) in particular has been implicated in Alzheimer's Disease (AD) by cleaving tau protein into fragment Δtau314, which reversibly impairs cognitive and synaptic function. Thus, Casp2 inhibition could be a useful strategy for therapeutic treatment of AD. To that end, we have previously synthesized and characterized various series of peptide and peptidomimetic inhibitors that demonstrate potency and selectivity for Casp2 over caspase-3 (Casp3). Despite promising developments in the design of selective Casp2 inhibitors, low expression yields of Casp2 hinder crystallographic experiments and make structure-based design challenging. The design of circularly permuted (cp) Casp2 increased protein yields considerably; however, this protein could not be crystallized. This article describes the characterization of ten novel cpCasp2 mutants, designed with the goal of increasing stability and facilitating crystallization. Gratifyingly, engineered mutant JF1cpCasp2 displayed high relative stability and was readily crystallizable with the canonical Casp2 inhibitor AcVDVAD-CHO, leading to what we believe to be the first crystal structures of any reverse caspase in the PDB. Moreover, we have reported the structure of JF1cpCasp2 with our recently described Casp2-selective inhibitor MUR-65, which revealed a unique interaction with Arg417 in the binding pocket. Overall, JF1cpCasp2 has proven valuable for structure-based design and expanding understanding of Casp2 inhibition, with potential implications for drug discovery and the development of more selective compounds.},
}

@article {pmid40117459,
year = {2025},
author = {Wang, Y and Wang, Y and Xu, Y and Cheng, H and Dagnew, TM and Kang, L and Tocci, D and Shen, IZ and Zhang, C and Wang, C},
title = {Design and Development of a Novel BET Protein-Targeted PET Imaging Probe for In Vivo Characterization of Alzheimer's Disease Pathophysiology.},
journal = {Journal of medicinal chemistry},
volume = {},
number = {},
pages = {},
doi = {10.1021/acs.jmedchem.5c00068},
pmid = {40117459},
issn = {1520-4804},
abstract = {BET proteins are essential epigenetic regulators involved in gene transcription and have been linked to neurodegenerative disorders, such as Alzheimer's disease (AD). In vivo imaging of BET proteins may provide insights into disease pathophysiology and help identify potential therapeutic targets. We developed a carbon-[11]-labeled radiotracer, [[11]C]YL9, which exhibits high binding affinity for BET proteins. It was synthesized via standard methylation and evaluated for brain uptake, binding specificity, and pharmacokinetics in wild-type and AD mouse models using PET imaging and autoradiography. [[11]C]YL9 demonstrated excellent blood-brain barrier penetration, prolonged retention, and strong BET protein binding. In AD mice, [[11]C]YL9 uptake was significantly higher than in wild-type mice, suggesting increased BET protein availability. These findings suggest that [[11]C]YL9 is a promising PET radioligand for noninvasive BET protein imaging. Its high specificity and favorable pharmacokinetics make it a valuable tool for studying BET protein involvement in neurodegeneration.},
}

@article {pmid40117242,
year = {2025},
author = {Wang, Z and Li, Z and Lin, A and Zhang, Q and Chen, Y and Bie, B and Feng, J},
title = {Exploration of small molecules as inhibitors of potential BACE1 protein to treat amyloid cerebrovascular disease by employing molecular modeling and simulation approaches.},
journal = {PloS one},
volume = {20},
number = {3},
pages = {e0317716},
doi = {10.1371/journal.pone.0317716},
pmid = {40117242},
issn = {1932-6203},
mesh = {*Amyloid Precursor Protein Secretases/antagonists & inhibitors/metabolism/chemistry ; *Aspartic Acid Endopeptidases/antagonists & inhibitors/metabolism/chemistry ; Humans ; *Molecular Docking Simulation ; Small Molecule Libraries/chemistry/pharmacology ; Ligands ; Protein Binding ; Molecular Dynamics Simulation ; Binding Sites ; Cerebral Amyloid Angiopathy/drug therapy/metabolism ; Models, Molecular ; Alzheimer Disease/drug therapy/metabolism ; },
abstract = {Amyloid cerebrovascular disease, primarily driven by the accumulation of amyloid-beta (Aβ) peptides, is intricately linked to neurodegenerative disorders like Alzheimer's disease. BACE1 (beta-site amyloid precursor protein cleaving enzyme 1) plays a critical role in the production of Aβ, making it a key therapeutic target. In the current work, a CNS library of ChemDiv database containing 44085 compounds was screened against the BACE1 protein. Initially, a structure-based pharmacophore hypothesis was constructed, followed by virtual screening, with the screened hits docked to the BACE1 protein to determine the optimal binding modes. The docking results were examined using the glide gscore and chemical interactions of the docked molecules. The cutoff value of -5 kcal/mol was used to select hits with high binding affinities. A total of seven hits were chosen based on the glide g score. Furthermore, the possible binding mechanisms of the docked ligands were investigated, and it was discovered that all seven selected ligands occupied the same site in the predicted binding pocket of protein. The bioactivity scores of the compounds demonstrated that the chosen compounds possess the features of lead compounds. The toxicity risks and ADMET features of the selected hits were anticipated, and four compounds, J032-0080, SC13-0774, V030-0915, and V006-5608 were chosen for stability analysis. The selected hits were extremely stable and strongly bound to the BACE1 pocket, and conformational changes caused by RMSD, RMSF, and protein-ligand interactions were assessed using MD modeling. Similarly, principal component analysis revealed a large static number of hydrogen bonds. The MM/GBSA binding free energies maps revealed a significant energy contribution in the binding of selected hits to BACE1. The binding free energy landscapes indicated that the hits were bound with a high binding affinity. Thus, the hits could serve as lead compounds in biophysical investigations to limit the biological activity of the BACE1 protein.},
}

*Amyloid Precursor Protein Secretases/antagonists & inhibitors/metabolism/chemistry
*Aspartic Acid Endopeptidases/antagonists & inhibitors/metabolism/chemistry
Humans
*Molecular Docking Simulation
Small Molecule Libraries/chemistry/pharmacology
Ligands
Protein Binding
Molecular Dynamics Simulation
Binding Sites
Cerebral Amyloid Angiopathy/drug therapy/metabolism
Models, Molecular
Alzheimer Disease/drug therapy/metabolism

@article {pmid40117152,
year = {2025},
author = {Bi, XA and Shen, W and Shan, Y and Chen, D and Xu, L and Chen, K and Liu, Z},
title = {MSAFF: Multi-Way Soft Attention Fusion Framework With the Large Foundation Models for the Diagnosis of Alzheimer's Disease.},
journal = {IEEE transactions on neural networks and learning systems},
volume = {PP},
number = {},
pages = {},
doi = {10.1109/TNNLS.2025.3545101},
pmid = {40117152},
issn = {2162-2388},
abstract = {Complementary information in multi-omics data are crucial for understanding the pathogenesis of Alzheimer's Disease (AD). However, existing studies face challenges in addressing the high-level noise and heterogeneity in multi-omics data. This article presents a novel approach that combines large foundation models (LFMs) with soft attention mechanisms to enhance, select, and fuse multi-omics features, thereby improving the performance of disease classification. Specifically, we first propose a mathematical model based on soft attention mechanisms. This model employs multi-head attention (MHA) and self-attention (SA) for feature selection, and uses cross-attention (CA) for feature fusion. Then, a multi-way soft attention fusion framework (MSAFF) with LFMs is proposed. In this approach, biomedical LFMs are used to construct low-noise biomedical features. The multi-way soft attention algorithm implements effective feature selection and fusion described in the mathematical model. Experimental results on the public imaging genetics datasets demonstrate the advanced performances of MSAFF in both disease classification and AD-related pathogeny discrimination. This article provides intelligent support for the diagnosis and pathogenesis research of AD. Our code can be accessed at github.com/fmri123456/MSAFF.},
}

@article {pmid40117046,
year = {2025},
author = {Li, N and Cui, N and Bakry, IA and Ma, Y and Cheng, Y and Zhao, G and Yang, H and Song, L and Qiao, M and Hai, D and Galaverna, G and Huang, X},
title = {Pea Peptide Modulates Abnormal Aβ Production in PC12 Cells Induced by Lead Exposure.},
journal = {Plant foods for human nutrition (Dordrecht, Netherlands)},
volume = {80},
number = {2},
pages = {98},
pmid = {40117046},
issn = {1573-9104},
mesh = {PC12 Cells ; Animals ; Rats ; *Lead/toxicity ; *Neuroprotective Agents/pharmacology ; *Cell Survival/drug effects ; *Amyloid Precursor Protein Secretases/metabolism ; *Signal Transduction/drug effects ; *Aspartic Acid Endopeptidases/metabolism ; *Amyloid beta-Protein Precursor/metabolism ; *Amyloid beta-Peptides/toxicity/metabolism ; *Proto-Oncogene Proteins c-akt/metabolism ; *Phosphatidylinositol 3-Kinases/metabolism ; Pisum sativum/chemistry ; Alzheimer Disease/metabolism/drug therapy/chemically induced ; Peptides/pharmacology ; },
abstract = {Lead (Pb) exposure poses significant health risks, particularly in neurodegenerative diseases such as Alzheimer's disease (AD). This study investigates the neuroprotective effects of pea peptide (PP4) on PC12 cells exposed to Pb. Using Cell Counting Kit-8 (CCK-8), pretreatment with PP4 at 50 and 200 µM concentrations significantly improved cell viability compared to Pb-only treated cells (P < 0.05), indicating a protective effect. Moreover, Pb exposure led to increased Amyloid Precursor Protein (APP) expression at 10 and 20 µM after 24 h (P < 0.05), while β-site amyloid Precursor Protein Cleaving Enzyme 1 (BACE1) levels were elevated across all concentrations tested (P < 0.05). We established that PP4 can mitigate Pb-induced cytotoxicity and reduce the expression of APP and BACE1 by activating the Phosphoinositide 3-kinase / Protein Kinase (PI3K/AKT) signaling pathway. This study highlights the potential of PP4 as a therapeutic agent in preventing neurotoxic damage associated with lead exposure, suggesting a novel approach for the management of AD.},
}

PC12 Cells
Animals
Rats
*Lead/toxicity
*Neuroprotective Agents/pharmacology
*Cell Survival/drug effects
*Amyloid Precursor Protein Secretases/metabolism
*Signal Transduction/drug effects
*Aspartic Acid Endopeptidases/metabolism
*Amyloid beta-Protein Precursor/metabolism
*Amyloid beta-Peptides/toxicity/metabolism
*Proto-Oncogene Proteins c-akt/metabolism
*Phosphatidylinositol 3-Kinases/metabolism
Pisum sativum/chemistry
Alzheimer Disease/metabolism/drug therapy/chemically induced
Peptides/pharmacology

@article {pmid40117043,
year = {2025},
author = {Sidhu, RK and Maparu, K and Singh, S and Aran, KR},
title = {Unveiling the role of Na[+]/K[+]-ATPase pump: neurodegenerative mechanisms and therapeutic horizons.},
journal = {Pharmacological reports : PR},
volume = {},
number = {},
pages = {},
pmid = {40117043},
issn = {2299-5684},
abstract = {Sodium and potassium-activated adenosine 5'-triphosphatase (Na+/K+-ATPase) is a pivotal plasma membrane enzyme involved in neuronal activity and cellular homeostasis. The dysregulation of these enzymes has been implicated in a spectrum of neurodegenerative disorders like Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), and neurodevelopmental disorders including autism spectrum disorder (ASD), psychiatric disorders such as schizophrenia, and neurological problems like epilepsy. A hallmark of these disorders is the gradual loss of neuronal integrity and function, often exacerbated by protein accumulation within brain cells. This review delves into the multifaceted role of Na[+]/K[+]-ATPase dysfunction in driving oxidative stress, excitotoxicity, and neuroinflammation, contributing to synaptic and neuronal damage. Emerging therapeutic strategies, such as gene therapy and developing isoform-specific enzyme modulators, offer promising avenues for targeted interventions. Furthermore, this review highlights innovative research directions, including the role of Na[+]/K[+]-ATPase in synaptic plasticity, the identification of endogenous regulators, and its contribution to neuroinflammatory pathways. Personalized medicine and advanced gene-editing technologies are positioned as transformative tools for crafting safer and more precise therapies tailored to individual patients. This comprehensive exploration underscores the enzyme's therapeutic potential and sets the stage for developing novel targeted strategies to mitigate the burden of Na[+]/K[+]-ATPase-linked neurological disorders.},
}

@article {pmid40117001,
year = {2025},
author = {Aghdam, MA and Bozdag, S and Saeed, F and , },
title = {Machine-learning models for Alzheimer's disease diagnosis using neuroimaging data: survey, reproducibility, and generalizability evaluation.},
journal = {Brain informatics},
volume = {12},
number = {1},
pages = {8},
pmid = {40117001},
issn = {2198-4018},
support = {R35GM153434/NH/NIH HHS/United States ; OAC-2312599//Division of Computing and Communication Foundations/ ; },
abstract = {Clinical diagnosis of Alzheimer's disease (AD) is usually made after symptoms such as short-term memory loss are exhibited, which minimizes the intervention and treatment options. The existing screening techniques cannot distinguish between stable MCI (sMCI) cases (i.e., patients who do not convert to AD for at least three years) and progressive MCI (pMCI) cases (i.e., patients who convert to AD in three years or sooner). Delayed diagnosis of AD also disproportionately affects underrepresented and socioeconomically disadvantaged populations. The significant positive impact of an early diagnosis solution for AD across diverse ethno-racial and demographic groups is well-known and recognized. While advancements in high-throughput technologies have enabled the generation of vast amounts of multimodal clinical, and neuroimaging datasets related to AD, most methods utilizing these data sets for diagnostic purposes have not found their way in clinical settings. To better understand the landscape, we surveyed the major preprocessing, data management, traditional machine-learning (ML), and deep learning (DL) techniques used for diagnosing AD using neuroimaging data such as structural magnetic resonance imaging (sMRI), functional magnetic resonance imaging (fMRI), and positron emission tomography (PET). Once we had a good understanding of the methods available, we conducted a study to assess the reproducibility and generalizability of open-source ML models. Our evaluation shows that existing models show reduced generalizability when different cohorts of the data modality are used while controlling other computational factors. The paper concludes with a discussion of major challenges that plague ML models for AD diagnosis and biomarker discovery.},
}

@article {pmid40116949,
year = {2025},
author = {Zhang, X and Irish, M and Piguet, O and Ahmed, RM},
title = {Behavioural and cognitive profiles in frontotemporal dementia and Alzheimer's disease: a longitudinal study.},
journal = {Journal of neurology},
volume = {272},
number = {4},
pages = {279},
pmid = {40116949},
issn = {1432-1459},
support = {GNT1037746//National Health and Medical Research Council/ ; GNT2008020//National Health and Medical Research Council/ ; CE11000102//Australian Research Council/ ; GNT2024329//Department of Health and Aged Care, Australian Government/ ; },
mesh = {Humans ; *Frontotemporal Dementia/diagnosis/physiopathology/psychology ; Female ; Male ; Longitudinal Studies ; Aged ; *Alzheimer Disease/diagnosis ; Middle Aged ; Disease Progression ; Neuropsychological Tests ; },
abstract = {INTRODUCTION: Longitudinal comparative characterisation of dementia syndromes may aid differential diagnosis, prognostication and intervention implementation.

METHODS: We compared the behavioural and cognitive characteristics of 84 behavioural variant frontotemporal dementia (bvFTD), 29 left and 14 right-dominant semantic dementia (SDL and SDR) and 49 Alzheimer's disease (AD) patients over a follow-up period of 2.4 ± 1.6 years using the Cambridge Behavioural Inventory Revised (CBI-R) and Addenbrooke's Cognitive Examination third edition (ACE-III).

RESULTS: Linear mixed modelling of time effects found progression of all CBI-R domains, aside from sleep, beliefs and mood domains, and all ACE-III domains. Modelling of group effects found that bvFTD had greater symptoms than AD in most CBI-R domains. Notably, SDL and SDR compared differently with AD and bvFTD; whilst SDR did not differ significantly from bvFTD in any CBI-R domain, SDL had less severe symptoms than bvFTD in everyday skills, motivation, sleep and eating habits; whilst SDL had greater disturbances in abnormal behaviour and stereotypic behaviour than AD, SDR had greater disturbances in addition in motivation and eating habits. Motivation, eating habits, abnormal behaviour and stereotypic behaviour were the most frequently different behavioural domains between groups.

CONCLUSION: We have shown that the combined, longitudinal use of existing behavioural and cognitive assessments could capture distinct clinical profiles of common and rare dementia syndromes. Our findings also highlight the importance of select behavioural domains such as motivation and the usefulness of separate clinical characterisations of SDL and SDR.},
}

Humans
*Frontotemporal Dementia/diagnosis/physiopathology/psychology
Female
Male
Longitudinal Studies
Aged
*Alzheimer Disease/diagnosis
Middle Aged
Disease Progression
Neuropsychological Tests

@article {pmid40116743,
year = {2025},
author = {Yu, Y and Wang, J and Li, D and Lu, Y and Lu, L and Qu, M},
title = {Application of mini-mental state examination and Montreal Cognitive Assessment in the diagnosis of dementia with Lewy bodies and Alzheimer's disease.},
journal = {Applied neuropsychology. Adult},
volume = {},
number = {},
pages = {1-10},
doi = {10.1080/23279095.2025.2478204},
pmid = {40116743},
issn = {2327-9109},
abstract = {BACKGROUND: Dementia with Lewy Bodies (DLB) and Alzheimer's disease (AD) are two types of dementia with a relatively high incidence, and their clinical manifestations are easily confused. However, the cognitive impairment characteristics of the two diseases are different, and the results of cognitive assessment can help the diagnosis of the disease.

OBJECTIVE: To explore the different characteristics of Mini-mental State Examination (MMSE) and Montreal Cognitive Assessment Scale (MoCA) in DLB and AD patients, and to explore potential markers to distinguish AD and DLB.

METHODS: This study included 66 patients with DLB, 81 with AD, and 58 cognitively normal subjects. All of them completed MMSE, MoCA, and Clinical Dementia Rating (CDR).

RESULTS: Compared with NC, both DLB and AD participants demonstrated statistically lower scores in the total and subitem domains of MMSE and MoCA (p < 0.05). When CDR was less than 2, DLB patients had better performance than AD in two subtests including memory and orientation (p < 0.05), demonstrated worse performance in most subtest including executive function, writing, visuospatial abilities, and attention (p < 0.05). Nonetheless, no notable distinction in scores existed for the DLB and AD groups with a CDR score of 2 (p > 0.05).

CONCLUSION: We observed distinct cognitive performances in subjects from both the DLB and AD groups across different stages of dementia. Our study confirms the high value of MMSE and MoCA in distinguishing patients with DLB and AD in the early stages of the disease, and they can improve the differential diagnosis of DLB and AD.},
}

@article {pmid40116704,
year = {2025},
author = {de Rijke, TJ and Vasseur, D and van der Flier, WM and Minkman, MM and Rhodius-Meester, HF and Verwey, NA and Smets, EM and Visser, LN},
title = {Exploring interdisciplinary perspectives on the implementation of personalized medicine and patient-orchestrated care in Alzheimer's disease: A qualitative study within the ABOARD research project.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877251326166},
doi = {10.1177/13872877251326166},
pmid = {40116704},
issn = {1875-8908},
abstract = {BackgroundThe concepts of 'personalized medicine' and 'patient-orchestrated care' in Alzheimer's disease (AD) lack standard conceptualization, which presents challenges for collaborative and interdisciplinary care.ObjectiveWe explored the interpretations and perspectives of professionals involved in interdisciplinary work on a large-scale project, "ABOARD", with the aim to implement personalized medicine and patient-orchestrated care in AD.MethodsSemi-structured interviews were conducted with 30 professionals and audio-recorded. Two researchers independently coded the data inductively, followed by a thematic analysis.ResultsAccording to professionals across different disciplinary backgrounds (mean age 45.7 years; 53.3% female), personalized medicine pertains to the relevant options that an individual has, informed by biomedical and psychosocial factors, whereas patient-orchestrated care captures factors relevant to the decision-making process. Professionals differed in their views on patient-orchestrated care regarding its desirability and feasibility. The concepts were viewed as similar by professionals, as both involve personal preferences while ultimately assigning responsibility to the clinician. However, implementation challenges persist, and no thematic differences were found between clinicians and other AD-related professionals.ConclusionsAD professionals have shared interpretations and perspectives on implementation of personalized medicine but differed in their views on patient-orchestrated care. Personal preferences are seen as part of personalized medicine, but not yet reflected in definitions in the AD field and beyond. Critical discussions on the challenges and existing doubts are necessary for both personalized medicine and patient-orchestrated care. Multi-level implementation changes are needed for both concepts, which warrants stakeholder involvement as well as support and resources from the entire AD field.},
}

@article {pmid40116699,
year = {2025},
author = {Kang, BR and Bae, YH and Park, SH and Kang, HY},
title = {Feasibility of a developed cognitive training system based on virtual reality with smart mirror for expert in community older cognitive disabled persons setting.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877251330147},
doi = {10.1177/13872877251330147},
pmid = {40116699},
issn = {1875-8908},
abstract = {BackgroundNumerous stroke survivors reintegrating into the community experience cognitive challenges that restrict their engagement, subsequently contributing to additional cognitive decline and adversely affecting their quality of life.ObjectiveThis study seeks to feasibility a cognitive training system based on virtual reality with a smart mirror designed for cognitive disabled persons with chronic stroke in the community setting.MethodsTen cognitive disabled persons with chronic stroke aged 60 years older, each with independent mobility in the community, were involved in this study. The validation process included a 30-min cognitive training session administered twice a week for eight weeks. The feasibility of cognitive function assessments employed the MoCA-K and CoSAS. Additionally, a usability test was performed at the end of the experiment using SUS and the Adapted IMI. The Wilcoxon signed rank test was then employed to compare pre- and post-cognitive function results.ResultsThe feasibility of the implemented cognitive training system based on virtual reality with smart mirror revealed significant differences in the total score, delayed recall, and orientation items of the MoCA-K (p < 0.05). Additionally, a notable improvement was observed in the accuracy and response time of task performance in the CoSAS (p < 0.05). Usability test results indicated an SUS mean score of 73.5 (SD 17.25) and an Adapted IMI score of 5.63 (SD 1.55), surpassing suggested thresholds for usability tests.ConclusionsProviding a cognitive training system tailored for the community, this approach aims to the prevention and recovery of cognitive issues in the older cognitive disabled persons with chronic stroke.},
}

@article {pmid40116694,
year = {2025},
author = {Sordu, P and Alaylıoğlu, M and Samancı, B and Bulu, E and Güleç, ZEK and Bilgiç, B and Hanağası, HA and Gürvit, İH and Ulutin, T and Dursun, E and Gezen-Ak, D},
title = {Cerebrospinal fluid HSP90AA1, HSPA4, and STUB1/CHIP levels in Alzheimer's disease, mild cognitive impairment, and frontotemporal dementia.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877251329540},
doi = {10.1177/13872877251329540},
pmid = {40116694},
issn = {1875-8908},
abstract = {BackgroundThe data that we gathered from a protein-protein interaction (PPI) prediction tool, FpClass, and a limited number of studies indicated that the chaperones HSP90AA1, HSPA4, STUB1/CHIP might interact with amyloid-β (Aβ) and/or tau and could subsequently be co-released into the cerebrospinal fluid (CSF). Therefore, we investigated CSF levels of HSP90AA1, HSPA4, and STUB1/CHIP in Alzheimer's disease (AD), Non-AD mild cognitive impairment (Non-AD MCI), and frontotemporal dementia (FTD) cases.MethodsThe CSF levels of HSP90AA1, HSPA4, STUB/CHIP, and core AD biomarkers were determined by ELISA in AD (n = 90), Non-AD MCI (n = 27), FTD (n = 15), and subjective cognitive impairment (SCI) (n = 20) subjects.ResultsHSP90AA1 levels were significantly higher in AD cases compared to the SCI subjects. The CSF levels of STUB1/CHIP were significantly lower in AD, Non-AD MCI and FTD cases compared to the SCI subjects. STUB1/CHIP levels of FTD cases were significantly lower than all other groups. HSPA4 levels was correlated with core AD biomarkers (Aβ 1-42, p-Tau, t-Tau) regardless of disease. Non-APOE ε4 carrier FTD cases also had significantly lower STUB1/CHIP levels than other groups.ConclusionsThe STUB1/CHIP holds promise as a potential biomarker for distinguishing between SCI subjects, AD, and FTD. Furthermore, APOE might serve as an additional discriminatory factor that might be integrated with this chaperone for enhanced discrimination.},
}

@article {pmid40116691,
year = {2025},
author = {Asada, T and Kakuma, T and Tanaka, M and Araki, W and Lebowitz, AJ and Momose, T and Matsuda, H},
title = {A statistical method for predicting amyloid-β deposits from severity, extend, and ratio indices of the [99m]Tc-ECD SPECT.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877251324222},
doi = {10.1177/13872877251324222},
pmid = {40116691},
issn = {1875-8908},
abstract = {BackgroundAmyloid-β (Aβ) deposit prediction accuracy is necessary for clinicians treating patients desiring Alzheimer's disease (AD) modifying drugs. Aβ-PET imaging is useful for diagnosis, but high in cost compared to brain perfusion SPECT. However, SPECT displays regional cerebral blood flow (rCBF) and does not detect Aβ deposits, therefore requiring additional clinical information.ObjectiveThis article describes a novel statistical method to predict amyloid deposits via PET images (Aβ+ or Aβ-) using the three indices of the [99m]Tc-ECD SPECT - severity, extend, and ratio - for the three ROIs.MethodsCandidate patients (N = 114 patients [55% male], 81 Aβ+ 33 Aβ-, mean age 74.2 ± 6.6 years, mean MMSE score 23.7 ± 2.8) underwent MRI and [99m]Tc-ECD SPECT scanning. After examining SPECT index, demographic, and age data, age and sex were treated as confounders in one, two, and three-index logistic additive models with severity, extend, and ratio as explanatory variables. Area under curve (AUC), sensitivity and specificity were used as statistical indices for model fitness and accuracies. Three-hold cross validation analyses were conducted to evaluate error rates.ResultsAccording to ROC analysis, best scores for fitness and accuracy were obtained from the three-index model with patients' age and sex for the configured ROIs including precuneus, posterior cingulate and temporal-parietal region of SPECT (AUC: 0.818, Sensitivity: 0.803, Specificity: 0.727).ConclusionsThis technique using [99m]Tc-ECD SPECT data can predict amyloid deposits with acceptable accuracy. To confirm the reliability and validity, a multicenter SPECT study is needed.},
}

@article {pmid40116690,
year = {2025},
author = {Kraake, S and Luppa, M and Saur, D and Dietzel, J and Bach, JP and Riedel-Heller, SG and Stein, J},
title = {Social functioning in individuals with Alzheimer's disease and the situation of caregivers.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877251326029},
doi = {10.1177/13872877251326029},
pmid = {40116690},
issn = {1875-8908},
abstract = {BackgroundChanges in social functioning may be a significant parameter for the early detection of Alzheimer's disease (AD). Currently, research on social functioning in AD across the entire spectrum of the disease is lacking.ObjectiveThe aim of this study was to describe the social functioning of persons with AD at each stage of the disease and to investigate how impaired social functioning affects caregiver burden.MethodsCross-sectional data was derived from memory clinics across Germany as part of the pilot study "Social functioning in individuals with AD and the situation of caregivers". A total of N = 87 relatives providing care for individuals with mild (n = 20), moderate (n = 40), and severe (n = 23) AD were included. Social functioning of individuals with AD was measured via the caregiver-rated German version of the Social Functioning in Dementia Scale (SF-DEM); caregiver burden was assessed using the Zarit Caregiver Burden Interview (ZBI-12). Differences between mild, moderate, and severe AD in terms of sociodemographic characteristics and the level of social functioning were examined. A robust linear regression analysis was conducted to examine the association between social functioning and caregiver burden.ResultsSocial functioning was lower in moderate and severe AD than in mild AD. Higher levels of social functioning were associated with less caregiver burden.ConclusionsThis study highlights the importance of integrating social functioning assessments into clinical practice for improving the early detection, diagnosis and interventions for AD. Early interventions to enhance social functioning may diminish caregiver burden.},
}

@article {pmid40116688,
year = {2025},
author = {Williams, JP and Zhu, Y and Singh, RK and Beyene, K and Rani, R and Kapetanakos, X and Dias, A and McGuire, K and Kolady, R and Lipsey, K and Ramaswamy, SG and Thotakura, V and Trani, JF and Babulal, GM},
title = {The effect of anti-seizure medications on Alzheimer's disease (AD) risk and AD-related symptoms: A scoping review.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877251324663},
doi = {10.1177/13872877251324663},
pmid = {40116688},
issn = {1875-8908},
abstract = {BackgroundAs the fastest-growing segment of the population, adults over 65 are at the most significant risk for Alzheimer's disease (AD). Older adults often use anti-seizure medications (ASMs), which can negatively impact cognitive function, mood, and behavior, mimicking AD or its symptoms. Understanding the effects of ASMs across diverse older adults is crucial, given that some ethnoracial groups are at higher risk for AD or more severe symptoms compared to non-Hispanic Whites.ObjectiveTo summarize the current evidence on the association of ASMs with AD risk and AD-related symptoms and explore the inclusion of ethnoracial minority groups in these studies.MethodsData sources included PubMed/MEDLINE, EMBASE, and SCOPUS for English-language studies published between 1990-2024. Selected studies were peer-reviewed, cross-sectional, longitudinal, case-control, and clinical trials on AD dementia or related symptoms and ASMs. Study quality was rated by the Oxford Centre for Evidence-Based Research Medicine.ResultsA total of 27 studies with 1,241,796 participants were included. Data on AD risk from level IB-IIIB evidence studies showed mixed results, with some indicating an increased association with ASM use [OR = 1.05-1.16, 95% CI: 1.01-1.24]. Studies on AD-related symptoms from level IB-IV evidence also showed mixed results. Only three North American studies explicitly included race/ethnicity; most were conducted in European countries.ConclusionsASM use may be modestly associated with an increased risk of AD among the older adult population, but current data are inconclusive. The association of ASMs on AD-related symptoms varied. Future studies should emphasize reporting sociodemographic data and include diverse cohorts to enhance the applicability of findings.},
}

@article {pmid40116687,
year = {2025},
author = {Arriola-Infante, JE and García-Roldán, E and García-Solís, D and Marín-Cabañas, AM and Luque-Tirado, A and Almodóvar-Sierra, Á and Sánchez-Arjona, MB and Maillet, D and Franco-Macías, E},
title = {TMA-93 (binding by images): Cutoffs optimization based on Alzheimer's disease biomarkers.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877251325759},
doi = {10.1177/13872877251325759},
pmid = {40116687},
issn = {1875-8908},
abstract = {BackgroundWith the arrival of new disease-modifying treatments for Alzheimer's disease (AD), feasible cognitive tests, also for illiterate patients, are needed to screen those requiring deeper evaluation among individuals presenting with memory complaints. The TMA-93, a brief binding memory test, has proven useful for diagnosing early AD, and is supported by normative data that accounts for age and cognitive reserve.ObjectiveTo compare the sensitivity of different TMA-93 cutoffs in detecting AD pathology.MethodsA retrospective analysis was performed on a biobank sample of patients with confirmed AD pathology via amyloid PET or cerebrospinal fluid (CSF) biomarkers. The sensitivity of six TMA-93 cutoffs was evaluated: the 10th, 15th, and 20th percentiles based on traditional norming (TN) and regression-based norming (RBN). False negatives (FN) characteristics were also analyzed.ResultsA total of 270 AD-positive patients (96 by amyloid-PET, 174 by CSF biomarkers) were included, comprising 224 with mild cognitive impairment and 46 with mild dementia. The 15th percentile using RBN demonstrated substantial sensitivity (80.4%), higher than that of the 10th percentile, and also provided a more uniform distribution across normative groups compared to the TN approach. Higher global cognition (Mini-Mental State Examination score) and, in patients over 70, lower cognitive reserve (Cognitive Reserve Questionnaire), were linked to a greater likelihood of FN results.ConclusionsThe 15th percentile cutoff based on RBN, accounting for age and cognitive reserve, improves sensitivity for detecting AD pathology, making it a valuable screening tool for memory complaints. Future normative data from biomarker-negative subjects may enhance the sensitivity of cognitive tests.},
}

@article {pmid40116686,
year = {2025},
author = {MacIver, MB and Pearce, RA},
title = {Reduced GABAA, slow synaptic inhibition in Alzheimer's disease.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877251328940},
doi = {10.1177/13872877251328940},
pmid = {40116686},
issn = {1875-8908},
abstract = {Altered synaptic physiology clearly contributes to memory loss and other CNS symptoms in Alzheimer's disease. A new paper in this issue of the Journal of Alzheimer's Disease, from Zhe Jin's group in Uppsala, Sweden, adds important new information to help us understand how. A powerful, yet largely uncharacterized form of neuronal inhibition-GABAA, slow synaptic current-was studied using whole-cell recordings in hippocampal brain slices from AD model mice (tg-APPSwe). The investigators found that GABAA, slow inhibition was significantly reduced in dentate granule neurons from aged AD mice, compared to both wild type and adult non-aged AD mice. This reduction would nicely explain the change in excitatory-inhibitory balance previously reported in this and other AD model animals, as well as impairments in pattern separation and theta-gamma cross-frequency coupling that are early manifestations of AD.},
}

@article {pmid40116682,
year = {2025},
author = {Yang, B and Teymur, A and Tang, C and Wu, T},
title = {V-set and immunoglobulin domain containing 4 as a potential predictor of Alzheimer's disease and advanced aging.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877251329463},
doi = {10.1177/13872877251329463},
pmid = {40116682},
issn = {1875-8908},
abstract = {BackgroundV-set and immunoglobulin domain containing 4 (VSIG4) emerges as a significant player in the immune system pathways. It has been previously identified as a potential hub gene for Alzheimer's disease (AD) and aging, underscoring its importance in understanding these conditions.ObjectiveThis study aimed to evaluate the diagnostic potential of serum VSIG4 and identify trends in serum VSIG4 in relationship with other biomarkers and neurological tests.MethodsELISA was used to measure the serum concentration of VSIG4 in AD, compared to healthy subjects. The relationship between VSIG4 levels and the age of the subjects, as well as other AD-related serum proteins and various measures of cognition was examined.ResultsVSIG4 was significantly elevated in the serum of AD patients compared to healthy controls (p = 0.0074). Significant correlations were identified between serum VSIG4 and other notable proteins related to AD and inflammation, such as total tau, neurofilament light (NfL), YKL-40, CD14, FABP3, and TNF-α. Significant correlations were also identified between VSIG4 concentration and the results of neurological tests.ConclusionsSerum VSIG4 may reflect neuroinflammation and altered lipid processing, affecting the cognitive performance of AD and aging.},
}

@article {pmid40116680,
year = {2025},
author = {LoBue, C and Stopschinski, BE and Calveras, NS and Salter, A and Galasko, D and Giza, C and Cullum, CM and Douglas, PM and Hart, J},
title = {A preliminary study on plasma markers across cognitive stages and links to a history of mild traumatic brain injury.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877251325757},
doi = {10.1177/13872877251325757},
pmid = {40116680},
issn = {1875-8908},
abstract = {Potential implications of a history of mild traumatic brain injury (mTBI) during aging are understudied. Seven plasma markers were measured in matched participants having normal cognition, mild cognitive impairment (MCI) and dementia of the Alzheimer's type (DAT) with and without a history of mTBI. Phosphorylated tau181 showed a moderate effect size for being greater in mTBI + individuals having MCI and DAT, and effect sizes for lower amyloid-β 42/40 and higher neurofilament light were seen for mTBI + DAT individuals. This preliminary report shows a potential role of plasma-derived markers in detecting associations between mTBI history and the development of Alzheimer's disease and related disorders.},
}

@article {pmid40116675,
year = {2025},
author = {Monteiro-Junior, RS},
title = {Virtual reality-based interventions for individuals with dementia: A potential further treatment and new perspectives.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877251328723},
doi = {10.1177/13872877251328723},
pmid = {40116675},
issn = {1875-8908},
abstract = {This commentary highlights issues regarding virtual reality (VR)-based interventions for individuals with Alzheimer's disease, emphasizing their potential to improve cognitive function and delay decline. The aim of this manuscript is to present current findings and critically synthesize the practical applications of VR interventions. A recent meta-analysis demonstrates promising results, with VR interventions enhancing memory, executive functions, and overall cognition. Despite the limited number of studies and small sample sizes, findings suggest that engaging VR environments can motivate patients, fostering adherence to treatment. This commentary underscores the need for further research to validate these results and establish standardized methodologies for the effective use of VR in dementia care. Several methodological aspects and new perspectives are highlighted herein.},
}

@article {pmid40116674,
year = {2025},
author = {Richter, N and Breidenbach, L and Schmieschek, MH and Heiss, WD and Fink, GR and Onur, OA},
title = {Alzheimer-typical temporo-parietal atrophy and hypoperfusion are associated with a more significant cholinergic impairment in amnestic neurodegenerative syndromes.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877251324080},
doi = {10.1177/13872877251324080},
pmid = {40116674},
issn = {1875-8908},
abstract = {BackgroundTo date, cholinomimetics remain central in the pharmacotherapy of Alzheimer's disease (AD) dementia. However, postmortem investigations indicate that the AD-typical progressive amnestic syndrome may also result from predominantly limbic non-AD neuropathology such as TDP-43 proteinopathy and argyrophilic grain disease. Experimental evidence links a beneficial response to cholinomimetics in early AD to reduced markers of cholinergic neurotransmission. However, the cholinergic impairment varies among patients with a clinical AD presentation, likely due to non-AD (co)-pathologies.ObjectiveThis study examines whether AD-typical atrophy and hypoperfusion can provide information about the cholinergic system in clinically diagnosed AD.MethodsThirty-two patients with amnestic mild cognitive impairment or mild dementia due to AD underwent positron emission tomography (PET) with the tracer N-methyl-4-piperidyl-acetate (MP4A) to estimate acetylcholinesterase (AChE) activity, neurological examinations, cerebral magnetic resonance imaging (MRI) and neuropsychological assessment. The 'cholinergic deficit' was computed as the deviation of AChE activity from cognitively normal controls across the cerebral cortex and correlated gray matter (GM) and perfusion of temporo-parietal cortices typically affected by AD and basal forebrain (BF) GM.ResultsTemporo-parietal perfusion and GM, as well as the inferior temporal to medial temporal ratio of perfusion correlated negatively with the 'cholinergic deficit'. A smaller Ch4p area of the BF was associated with a more significant 'cholinergic deficit', albeit to a lesser degree than cortical measures.ConclusionsIn clinically diagnosed AD, temporo-parietal GM and perfusion are more closely associated with the 'cholinergic deficit' than BF volumes, making them possible markers for cholinergic treatment response in amnestic neurodegeneration.},
}

@article {pmid40116671,
year = {2025},
author = {Li, F and Zheng, M and Jia, J},
title = {Validate association of gene loci and establish genetic risk prediction models for late-onset Alzheimer's disease in Chinese populations.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877251326283},
doi = {10.1177/13872877251326283},
pmid = {40116671},
issn = {1875-8908},
abstract = {BackgroundMore than 60 independent single-nucleotide polymorphisms (SNPs) have been associated with Alzheimer's disease risk by genome-wide association studies in European.ObjectiveWe aimed to confirm these SNPs in Chinese Han populations and investigate the utility of these genetic markers.MethodsAltogether 1595 late-onset Alzheimer's disease (LOAD) patients and 2474 controls from Chinese population were recruited. We replicated the association of 68 SNPs with LOAD and established polygenetic risk score (PRS) prediction model using significant SNPs. Meta-analysis for MS4A6A rs610932 and PICALM rs3851179 were performed.ResultsAccording to our findings, 14 out of 68 SNPs are validated significantly associated with LOAD (adjusted p < 0.05) after adjusting age and sex in the Chinese population. Besides, after stratification by APOE ε4 status, almost all SNPs retain markedly relationship with LOAD in APOE ε4 noncarriers. However, few loci retain correlation in APOE ε4 carriers. Furthermore, the area under the receiver operating characteristic curve prediction model for distinguishing LOAD patients from normal subjects were 0.614 for PRS and 0.689 for PRS and APOE. In addition, meta-analysis including this study of East Asian populations confirmed that rs610932 and rs3851179 were dramatically related to the LOAD (OR = 0.85, 95% CI = 0.74-0.97; OR = 0.87, 95% CI = 0.83-0.91).ConclusionsDespite genetic heterogeneity, there are still common loci among different races. PRS based on AD risk-associated SNPs may supplement APOE for better assessing individual risk for AD in Chinese. Besides, interactions between genes and gene environment affect the impact of risk allele on diverse populations.},
}

@article {pmid40116653,
year = {2025},
author = {Dong, F and Anderson, AR and Hodgson, NA},
title = {Associations among diurnal cortisol, melatonin, and agitation in people living with cognitive impairment.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877251322206},
doi = {10.1177/13872877251322206},
pmid = {40116653},
issn = {1875-8908},
abstract = {BackgroundWhile the underlying mechanisms of agitation are not fully understood in people with Alzheimer's disease and related disorders, research suggests that dysregulated neuroendocrine processes, including the hypothalamic-pituitary-adrenal axis, may play a role.ObjectiveThis study aimed to explore the associations between salivary cortisol, melatonin at baseline, and agitation both at baseline and at post-intervention.MethodsThis study was a secondary analysis of a two-group, randomized, parallel designed clinical trial of 210 people living with cognitive impairment. Agitation, salivary cortisol, and salivary melatonin were measured at baseline and four weeks. Salivary cortisol and melatonin indicators were generated through three timepoints of cortisol and melatonin collection across the two consecutive days. Presence of agitation was measured using the Neuropsychiatric Inventory. Logistic regressions were conducted to achieve the aim.ResultsA significant association was found at baseline between diurnal cortisol slope and agitation (OR = 0.03, p = 0.029), there were no relationships between all other cortisol or melatonin indicators with agitation. Cortisol awaking response (OR = 0.16, p = 0.048), its percentage (OR = 0.27, p = 0.021) and its increase higher than 50% (OR = 0.09, p = 0.009), were significant with agitation at four weeks.ConclusionsGiven the potential link between cortisol and agitation, exploring cortisol-lowering interventions like minimizing environmental stressors, smoothing transitions to different situations, stress-reduction techniques, and behavioral therapies may aid in managing agitation in older adults with cognitive impairment.},
}

@article {pmid40116645,
year = {2025},
author = {Liu, J and Liu, D and Xie, XY and Cai, C and Zhang, JJ and Cheng, GR and Hu, FF and Nie, QQ and Zhou, J and Zeng, DY and Liu, XC and Song, D and Wang, JY and Li, SY and Cui, YY and Hu, CL and Fu, YD and Cai, WY and Li, YQ and Li, CL and Pei, MD and Lou, XY and Zhang, BY and Ren, HW and Huang, JL and Wang, D and Huang, ZL and Han, GB and Huang, LY and Yang, X and Zeng, Y},
title = {Association between home dwelling situations, neighborhood social interactions, and subjective cognitive decline plus among older adults: A cross-sectional study.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877251322805},
doi = {10.1177/13872877251322805},
pmid = {40116645},
issn = {1875-8908},
abstract = {BackgroundHome-dwelling situations (HDS) and neighborhood social interactions (NSI) significantly impact older adults' post-retirement lives. However, their relationship with subjective cognitive decline plus (SCD-plus), a potential biomarker of preclinical Alzheimer's disease (AD), remains uncertain.ObjectiveTo explore the association between NSI, HDS and SCD-plus among older adults.MethodsThis cross-sectional study utilized data from the Hubei Memory and Aging Cohort Study (HMACS, 2018-2022), examining the relationship between HDS, NSI, and SCD-plus status and feature scores, using logistic and linear regression models.ResultsAmong 3514 adults (age: ≥ 65 y; female: 52.44%), 1329 had SCD-plus status (37.82%). After adjusting for covariates, living with spouse only was associated with lower odds of SCD-plus (odds ratio [OR] = 0.72, 95% confidence interval [CI] [0.55, 0.95]) compared to living alone. Frequent NSI was linked to lower odds of SCD-plus (OR = 0.65, 95% CI [0.54, 0.80]) and reduced feature scores (regression coefficient [β] = -0.16, 95% CI [-0.25, -0.07]). Compared to living alone - no NSI, all other combinations showed better SCD-plus status, especially living with spouse only with frequent NSI, which demonstrated a 55% reduction in likelihood (OR = 0.45, 95% CI [0.28, 0.73]).ConclusionsLiving with spouse only and frequent NSI significantly lowers the odds of SCD-plus, providing a basis for further exploration of the impact of social interactions on cognitive health.},
}

@article {pmid40116643,
year = {2025},
author = {Xu, X and Mo, X and Zhang, W and Liu, D and Chen, Q and Lu, J and Zhu, Y and Chen, J and Zhang, X and Zhu, Z and Chen, Y and Shi, Q and Dai, Y and Liu, M and Tong, Y and Zhang, J and Zhang, G and Wang, Z and Zhang, B},
title = {Local and distant atrophy mediate the relationship between tau pathology and cognition in temporoparietal region in Alzheimer's disease.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877251322539},
doi = {10.1177/13872877251322539},
pmid = {40116643},
issn = {1875-8908},
abstract = {BackgroundTau pathology is closely associated with brain atrophy and cognitive decline, but how it specifically influences local and distant gray matter volume (GMV) and cognitive function remains unclear.ObjectiveThis study aims to explore the spatial relationships between tau pathology, GMV and cognition using hybrid positron emission tomography/magnetic resonance imaging (PET/MRI).MethodsTwenty amyloid-β (Aβ)-positive Alzheimer's disease (AD) patients, 14 mild cognitive impairment (MCI) patients, and 22 Aβ-negative normal controls (NC) underwent standardized neuropsychological assessments and [18]F-fortaucipir PET/MRI scans. We investigated the associations between regional tau standardized uptake value ratio (SUVR) and GMV in AD signature regions. Mediation analyses were conducted to explore the potential mediating effects of local and distant GMV in the relationship between tau pathology and cognition.ResultsThe study indicated that increased [18]F-fortaucipir SUVR and decreased GMV were related to cognitive performance in MCI and AD patients. Compared to NC group, the number of brain regions with local and distant correlations between GMV and SUVR was greater in AD/MCI group. Mediation analysis revealed that GMV served as a significant mediator between tau pathology and cognition in local regions. Furthermore, distant effects were also observed, with hippocampal atrophy partially mediated the relationship between entorhinal cortex tau pathology and cognition. Meanwhile, medial parietal lobe atrophy partially mediated the relationship between medial temporal lobe tau deposition and cognition.ConclusionsOur findings provide an anatomically detailed insight into relationships between tau, GMV and cognition, especially in entorhinal cortex-hippocampus, temporal-parietal lobe cortical circuits.},
}

@article {pmid40116640,
year = {2025},
author = {Abdullah, L and Zhou, Z and Hall, J and Petersen, M and Zhang, F and O'Bryant, S},
title = {Association of Alzheimer's disease biomarkers with low premorbid intellectual functioning in a multi-ethnic community-dwelling cohort: A cross-sectional study of HABS-HD.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877251322966},
doi = {10.1177/13872877251322966},
pmid = {40116640},
issn = {1875-8908},
abstract = {Background: Individuals with intellectual disability (ID) may have a five-fold increased risk for developing Alzheimer's disease (AD). However, studies investigating brain aging among individuals with ID without Down syndrome (DS) are lacking. To begin addressing this gap, our study utilized word reading, a widely recognized indicator of an individual's premorbid intellectual ability (pIQ), to examine the effects of ID without DS on plasma AD biomarker outcomes. Objective: To investigate the relationship between premorbid intellectual ability (pIQ) and plasma AD biomarkers in individuals with ID without DS, while considering ethnic differences in these associations. Methods: Participants from the Health & Aging Brain Study - Health Disparities (HABS-HD) were categorized into low (z ≤ -2.00) or average (z = 0.00 ± 1.00) pIQ groups based on word reading scores. Plasma biomarkers including Aβ40, Aβ42, Aβ42/40, phosphorylated tau 181 (p-Tau181), neurofilament light chain (NfL), and total tau (t-tau) were assayed using Simoa technology. Results: Individuals with low pIQ exhibited significantly higher levels of p-Tau181 (p < 0.05), NfL (p < 0.05), and t-tau (p < 0.05) compared to those with average pIQ. Stratified analysis by ethnicity revealed differential associations, with Hispanic and non-Hispanic White (NHW) participants showing distinct biomarker profiles relative to non-Hispanic Black (NHB) individuals. Conclusions: The findings demonstrate that low pIQ is a reliable factor associated with plasma AD biomarker outcomes. Ethnicity appears to modulate these associations, suggesting complex interactions between factors driving AD susceptibility across diverse populations. This study highlights the importance of considering both pIQ and ethnicity in neurodegenerative processes, particularly in individuals with non-DS intellectual developmental disability.},
}

@article {pmid40116546,
year = {2025},
author = {Nataraj, A and Blahna, K and Ježek, K},
title = {Insights From TgF344-AD, a Double Transgenic Rat Model in Alzheimer's Disease Research.},
journal = {Physiological research},
volume = {74},
number = {1},
pages = {1-17},
pmid = {40116546},
issn = {1802-9973},
mesh = {Animals ; *Alzheimer Disease/genetics/pathology/metabolism ; *Rats, Transgenic ; *Disease Models, Animal ; Rats ; Humans ; Amyloid beta-Protein Precursor/genetics/metabolism ; Rats, Inbred F344 ; Presenilin-1/genetics ; Brain/pathology/metabolism ; },
abstract = {Alzheimer's disease (AD), a leading cause of dementia worldwide, is a multifactorial neurodegenerative disorder characterized by amyloid-beta plaques, tauopathy, neuronal loss, neuro-inflammation, brain atrophy, and cognitive deficits. AD manifests as familial early-onset (FAD) with specific gene mutations or sporadic late-onset (LOAD) caused by various genetic and environmental factors. Numerous transgenic rodent models have been developed to understand AD pathology development and progression. The TgF344-AD rat model is a double transgenic model that carries two human gene mutations: APP with the Swedish mutation and PSEN-1 with delta exon 9 mutations. This model exhibits a complete repertoire of AD pathology in an age-dependent manner. This review summarizes multidisciplinary research insights gained from studying TgF344-AD rats in the context of AD pathology. We explore neuropathological findings; electrophysiological assessments revealing disrupted synaptic transmission, reduced spatial coding, network-level dysfunctions, and altered sleep architecture; behavioral studies highlighting impaired spatial memory; alterations in excitatory-inhibitory systems; and molecular and physiological changes in TgF344-AD rats emphasizing their age-related effects. Additionally, the impact of various interventions studied in the model is compiled, underscoring their role in bridging gaps in understanding AD pathogenesis. The TgF344-AD rat model offers significant potential in identifying biomarkers for early detection and therapeutic interventions, providing a robust platform for advancing translational AD research. Key words Alzheimer's disease, Transgenic AD models, TgF344-AD rats, Spatial coding.},
}

Animals
*Alzheimer Disease/genetics/pathology/metabolism
*Rats, Transgenic
*Disease Models, Animal
Rats
Humans
Amyloid beta-Protein Precursor/genetics/metabolism
Rats, Inbred F344
Presenilin-1/genetics
Brain/pathology/metabolism

@article {pmid40116426,
year = {2025},
author = {Retout, M and Lepeintre, V and Amer, L and Yim, W and Jokerst, JV},
title = {Activatable Photoacoustic Probe for Imaging Infection: Gold Nanorod Dissociation In Vivo Reports Bacterial Protease Activity.},
journal = {ACS nano},
volume = {},
number = {},
pages = {},
doi = {10.1021/acsnano.4c17874},
pmid = {40116426},
issn = {1936-086X},
abstract = {We present a strategy for constructing activatable photoacoustic imaging (PAI) probes for in vivo enzyme activity measurements, based on a dissociation strategy previously applied to in vitro sensing. Unlike conventional nanoparticle aggregation strategies, dissociation minimizes false positives and functions effectively in complex biological environments. Overcoming the challenge of dissociating nanostructure aggregates, which arises from the strong van der Waals forces at short distances, we demonstrate the controlled assembly and dissociation of citrate-capped gold nanorods (AuNRs-citrate) using a diarginine peptide additive and a thiolated polyethylene glycol (HS-PEG-OMe), respectively. This assembly dissociation mechanism enables precise control of the optical and photoacoustic (PA) properties of AuNRs in both in vitro and in vivo settings. Building on these findings, we engineered an enzyme-sensitive PAI probe (AuNRs@RgpB) composed of AuNR assemblies and a PEG-peptide conjugate with a protease-specific cleavage sequence. The probe detects Arg-specific gingipain (RgpB), a protease expressed by Porphyromonas gingivalis associated with periodontal disease and Alzheimer's disease. Proteolytic cleavage of the peptide sequence triggers AuNR dissociation, resulting in enhanced PA signal output. The probe was designed to be injected intrathecally for preclinical trials to image gingipains and investigate the value of gingipain inhibitors developed for Alzheimer's disease. The probe's performance was characterized in vitro using UV-vis spectroscopy and PAI, achieving detection limits of 5 and 20 nM, respectively. In vivo studies involved intracranial injection of AuNRs@RgpB into RgpB-containing murine models, with PA monitoring over time. RgpB activity produced a four-fold PA signal increase within 2 h, while P. gingivalis-infected mice showed similar signal enhancement. Specificity was confirmed by negligible responses to Fusobacterium nucleatum, a non-RgpB-producing bacterium. Additionally, the system demonstrated utility in drug development by successfully monitoring the inhibition of RgpB activity using RgpB inhibitors (leupeptin and KYT-1) in vivo models. Beyond its immediate application to RgpB detection, this modular approach to plasmonic-based sensing holds significant potential for detecting other proteases, advancing both nanotechnology and protease-targeted diagnostics.},
}

@article {pmid40116132,
year = {2025},
author = {Lozupone, M and Dibello, V and Daniele, A and Panza, F},
title = {An update on emerging anti-amyloid-β monoclonal antibodies for treating Alzheimer's disease: the role of apolipoprotein E.},
journal = {Expert opinion on emerging drugs},
volume = {},
number = {},
pages = {},
doi = {10.1080/14728214.2025.2481847},
pmid = {40116132},
issn = {1744-7623},
}

@article {pmid40116124,
year = {2025},
author = {Kim, JE and Min, KS and Go, J and Park, HY and Choi, YK and Lee, IB and Shin, J and Cho, HJ and Kim, HS and Hwang, DY and Oh, WK and Kim, KS and Lee, CH},
title = {Water extract of Humulus japonicus improves age‑related cognitive decline by inhibiting acetylcholinesterase activity and the acetylcholine signaling pathway.},
journal = {Molecular medicine reports},
volume = {31},
number = {5},
pages = {},
doi = {10.3892/mmr.2025.13496},
pmid = {40116124},
issn = {1791-3004},
mesh = {Animals ; *Plant Extracts/pharmacology/chemistry ; *Acetylcholinesterase/metabolism ; Mice ; *Cognitive Dysfunction/drug therapy/metabolism/chemically induced ; *Signal Transduction/drug effects ; *Acetylcholine/metabolism ; Male ; *Aging/drug effects ; *Scopolamine ; Cyclic AMP Response Element-Binding Protein/metabolism ; Maze Learning/drug effects ; Water/chemistry ; Cholinesterase Inhibitors/pharmacology ; Glycogen Synthase Kinase 3 beta/metabolism ; Neurogenesis/drug effects ; Proto-Oncogene Proteins c-akt/metabolism ; Disease Models, Animal ; Hippocampus/drug effects/metabolism ; },
abstract = {The aging process is associated with a decline in certain cognitive abilities, including learning and memory. This age‑related cognitive decline is associated with a reduction in neurogenesis and alterations in the cholinergic system. Humulus japonicus (HJ), an ornamental plant in the family Cannabaceae, has been reported to exert beneficial effects against neurodegenerative pathophysiologies in mouse models of disorders such as Alzheimer's and Parkinson's disease. Despite the increasingly aging populations of numerous societies, no study has yet investigated the effects of HJ on cognitive decline associated with normal aging. The present study therefore aimed to examine the protective potential of HJ water (HJW) extract against age‑related cognitive decline and scopolamine‑induced cognitive impairment. The analyses revealed that the oral administration of HJW markedly improved novel objective recognition and spatial learning in the novel object recognition and Morris water maze tests, respectively, in aged mice. The administration of 600 mg/kg HJW further increased neurogenesis and CA1 thickness in the hippocampi of aged mice. In scopolamine‑induced cognitive impairment, administration of 400 or 600 mg/kg HJW markedly increased novel object recognition performance in scopolamine‑treated mice. The inhibitory effect of HJW on acetylcholinesterase (AChE) and the activation effects of HJW on the calcium/calmodulin‑dependent kinase (CaMK)IIα‑cAMP response element‑binding protein (CREB) and AKT‑glycogen synthase kinase‑3 β (GSK3β) pathways were further demonstrated. Overall, these results indicate that HJW administration improves cognitive function through the regulation of AChE activity and CaMKIIα‑CREB and AKT‑GSK3β pathways.},
}

Animals
*Plant Extracts/pharmacology/chemistry
*Acetylcholinesterase/metabolism
Mice
*Cognitive Dysfunction/drug therapy/metabolism/chemically induced
*Signal Transduction/drug effects
*Acetylcholine/metabolism
Male
*Aging/drug effects
*Scopolamine
Cyclic AMP Response Element-Binding Protein/metabolism
Maze Learning/drug effects
Water/chemistry
Cholinesterase Inhibitors/pharmacology
Glycogen Synthase Kinase 3 beta/metabolism
Neurogenesis/drug effects
Proto-Oncogene Proteins c-akt/metabolism
Disease Models, Animal
Hippocampus/drug effects/metabolism

@article {pmid40115874,
year = {2025},
author = {Nakashima, S and Sato, K and Niimi, Y and Toda, T and Iwatsubo, T},
title = {Factors affecting participation in web-based Alzheimer's questionnaire surveys: Lessons from the Japanese trial-ready cohort.},
journal = {JAR life},
volume = {14},
number = {},
pages = {100008},
pmid = {40115874},
issn = {2534-773X},
abstract = {BACKGROUND: Web-based approach is considered helpful for the research focused on screening and early detection of individuals with preclinical Alzheimer's disease (AD); obtaining sufficient responses is critical to the success of such online study.

OBJECTIVES: This study examined factors influencing response rates to an online survey about disease-modifying drugs for AD among participants in the Japanese Trial-Ready Cohort (J-TRC) webstudy.

DESIGN: This was a retrospective observational study.

SETTINGS: Online survey in Japan using Google Forms.

PARTICIPANTS: We enrolled the eligible J-TRC webstudy participants who had registered before September 2023. We sent them an invitation e-mail including a questionnaire web address on November-December 2023, in order to conduct an online survey regarding their perceptions of disease-modifying therapy drug that was approved in July 2023, Japan.

MEASUREMENTS: We analyzed the impact of mailed day of the week (DOW), participant gender, age, employment status, and educational background with/without response to the invitation, quantified by the odds ratio of response.

RESULTS: Among approximately 10,400 J-TRC web study participants who sent invitation emails, the overall response rate was approximately 20 %, without significant influence depending on the DOW when the survey invitation was sent. Individuals who were older (50s-70s), retired, or had higher education levels were significantly more likely to respond, regardless of the DOW. Differences in response rates by sex/gender were observed, but were largely influenced by the employment status.

CONCLUSIONS: In order to improve response rates and enhance data quality, these findings provide valuable insights for optimizing the design of future online studies/surveys in the field of AD and dementia, particularly for targeting cognitively unimpaired middle-aged and older populations.},
}

@article {pmid40115175,
year = {2025},
author = {Jiao, B and Ouyang, Z and Xiao, X and Zhang, C and Xu, T and Yang, Q and Zhu, Y and Liu, Y and Liu, X and Zhou, Y and Liao, X and Luo, S and Tang, B and Li, Z and Shen, L},
title = {Development and validation of machine learning models with blood-based digital biomarkers for Alzheimer's disease diagnosis: a multicohort diagnostic study.},
journal = {EClinicalMedicine},
volume = {81},
number = {},
pages = {103142},
pmid = {40115175},
issn = {2589-5370},
abstract = {BACKGROUND: Alzheimer's disease (AD) involves complex alterations in biological pathways, making comprehensive blood biomarkers crucial for accurate and earlier diagnosis. However, the cost-effectiveness and operational complexity of method using blood-based biomarkers significantly limit its availability in clinical practice.

METHODS: We developed low-cost, convenient machine learning-based with digital biomarkers (MLDB) using plasma spectra data to detect AD or mild cognitive impairment (MCI) from healthy controls (HCs) and discriminate AD from different types of neurodegenerative diseases. Retrospective data were gathered for 1324 individuals, including 293 with amyloid beta positive AD, 151 with mild cognitive impairment (MCI), 106 with Lewy body dementia (DLB), 106 with frontotemporal dementia (FTD), 135 with progressive supranuclear palsy (PSP) and 533 healthy controls (HCs) between July 2017 and August 2023.

FINDINGS: Random forest classifier and feature selection procedures were used to select digital biomarkers. MLDB achieved area under the curves (AUCs) of 0.92 (AD vs. HC, Sensitivity 88.2%, specificity 84.1%), 0.89 (MCI vs. HC, Sensitivity 88.8%, specificity 86.4%), 0.83 (AD vs. DLB, Sensitivity 77.2%, specificity 74.6%), 0.80 (AD vs. FTD, sensitivity 74.2%, specificity 72.4%), and 0.93 (AD vs. PSP, sensitivity 76.1%, specificity 75.7%). Digital biomarkers distinguishing AD from HC were negatively correlated with plasma p-tau217 (r = -0.22, p < 0.05) and glial fibrillary acidic protein (GFAP) (r = -0.09, p < 0.05).

INTERPRETATION: The ATR-FTIR (Attenuated Total Reflectance-Fourier Transform Infrared) plasma spectra features can identify AD-related pathological changes. These spectral features serve as digital biomarkers, providing valuable support in the early screening and diagnosis of AD.

FUNDING: The National Natural Science Foundation of China, STI2030-Major Projects, National Key R&D Program of China, Outstanding Youth Fund of Hunan Provincial Natural Science Foundation, Hunan Health Commission Grant, Science and Technology Major Project of Hunan Province, Hunan Innovative Province Construction Project, Grant of National Clinical Research Center for Geriatric Disorders, Xiangya Hospital and Postdoctoral Fellowship Program of CPSF.},
}

@article {pmid40115072,
year = {2025},
author = {Li, J and Hu, X and Tao, X and Li, Y and Jiang, W and Zhao, M and Ma, Z and Chen, B and Sheng, S and Tong, J and Zhang, H and Shen, B and Gao, X},
title = {Deconstruct the link between gut microbiota and neurological diseases: application of Mendelian randomization analysis.},
journal = {Frontiers in cellular and infection microbiology},
volume = {15},
number = {},
pages = {1433131},
pmid = {40115072},
issn = {2235-2988},
mesh = {Humans ; *Mendelian Randomization Analysis ; *Gastrointestinal Microbiome/genetics ; *Nervous System Diseases/genetics/microbiology ; Brain-Gut Axis ; Genome-Wide Association Study ; },
abstract = {BACKGROUND: Recent research on the gut-brain axis has deepened our understanding of the correlation between gut bacteria and the neurological system. The inflammatory response triggered by gut microbiota may be associated with neurodegenerative diseases. Additionally, the impact of gut microbiota on emotional state, known as the "Gut-mood" relationship, could play a role in depression and anxiety disorders.

RESULTS: This review summarizes recent data on the role of gut-brain axis in the pathophysiology of neuropsychiatric and neurological disorders including epilepsy, schizophrenia, Alzheimer's disease, brain cancer, Parkinson's disease, bipolar disorder and stroke. Also, we conducted a Mendelian randomization study on seven neurological disorders (Epilepsy, schizophrenia, Alzheimer's disease, brain cancer, Parkinson's disease, bipolar disorder and stroke). MR-Egger and MR-PRESSO tests confirmed the robustness of analysis against horizontal pleiotropy.

CONCLUSIONS: By comparing the protective and risk factors for neurological disorders found in our research and other researches, we can furtherly determine valuable indicators for disease evolution tracking and potential treatment targets. Future research should explore extensive microbiome genome-wide association study datasets using metagenomics sequencing techniques to deepen our understanding of connections and causality between neurological disorders.},
}

Humans
*Mendelian Randomization Analysis
*Gastrointestinal Microbiome/genetics
*Nervous System Diseases/genetics/microbiology
Brain-Gut Axis
Genome-Wide Association Study

@article {pmid40115030,
year = {2025},
author = {Chong, S and Wang, S and Gao, T and Yuan, K and Han, Y and Shi, L and Li, P and Lin, X and Lu, L and , },
title = {Glymphatic function decline as a mediator of core memory-related brain structures atrophy in aging.},
journal = {Journal of translational internal medicine},
volume = {13},
number = {1},
pages = {65-77},
pmid = {40115030},
issn = {2450-131X},
abstract = {BACKGROUND AND OBJECTIVES: This study aimed to elucidate the role of the glymphatic system-a crucial pathway for clearing waste in the brain-in the aging process and its contribution to cognitive decline. We specifically focused on the diffusion tensor imaging analysis along the perivascular space (ALPS) index as a noninvasive biomarker of glymphatic function.

METHODS: Data were drawn from the Alzheimers Disease Neuroimaging Initiative (ADNI) database and a separate validation cohort to analyze the ALPS index in cognitively normal older adults. The relationships among the ALPS index, brain morphometry, and memory performance were examined.

RESULTS: As a biomarker of glymphatic function, the ALPS index appeared to decline with age in both cohorts. According to the brain morphology analysis, the ALPS index was positively correlated with the thickness of the left entorhinal cortex (r = 0.258, P false discovery rate (FDR) = 2.96 × 10[-4]), and it played a mediating role between aging and left entorhinal cortex thinning. The independent cohort further validated the correlation between the ALPS index and the left entorhinal cortex thickness (r = 0.414, P FDR = 0.042). Additionally, in both the primary and validation cohorts, the ALPS index played a significant mediating role in the relationship between age and durable or delayed memory decline.

CONCLUSION: This study highlights the ALPS index as a promising biomarker for glymphatic function and links it to atrophy of the core memory brain regions during aging. Furthermore, these results suggest that targeting glymphatic dysfunction could represent a novel therapeutic approach to mitigate age-related memory decline.},
}

@article {pmid40115028,
year = {2025},
author = {Zhang, L and Santoni, L and Ngo, NA and Simayi, R and Ficiará, E and de Vivo, L and Bellesi, M},
title = {Rocking during sleep reduces motor deficits and beta-amyloid levels in an Alzheimer's mouse model.},
journal = {iScience},
volume = {28},
number = {3},
pages = {112036},
pmid = {40115028},
issn = {2589-0042},
abstract = {Alzheimer's disease (AD) is a neurodegenerative disorder characterized by cognitive decline, beta-amyloid plaques, and tau tangles. Growing evidence suggests a strong link between sleep disturbances and AD progression, with disrupted sleep exacerbating AD progression through increased beta-amyloid and tau accumulation. This relationship indicates that improving sleep quality could slow disease progression and mitigate its effects on the brain. We investigated whether vestibular stimulation (rocking) could mitigate AD pathology in 3xTg mice (n = 58, males). Starting in early adulthood (p60), mice underwent 12-h daily rocking during the light period for four months. Rocking increased non-rapid eye movement (NREM) sleep initially, although habituation reduced this effect over time. Despite habituation, rocking slowed motor decline and reduced beta-amyloid levels in the cerebral cortex and hippocampus. However, tau levels remained unaffected. In conclusion, our findings highlight the potential of non-pharmacological methods to enhance NREM sleep and modify disease trajectory in AD models.},
}

@article {pmid40114925,
year = {2025},
author = {Ullah, S and Park, TJ and Park, JS and Atiq, A and Ali, J and Kang, MH and Ali, W and Choe, K and Kim, MO},
title = {Ambroxol attenuates detrimental effect of LPS-induced glia-mediated neuroinflammation, oxidative stress, and cognitive dysfunction in mice brain.},
journal = {Frontiers in immunology},
volume = {16},
number = {},
pages = {1494114},
pmid = {40114925},
issn = {1664-3224},
mesh = {Animals ; *Oxidative Stress/drug effects ; *Lipopolysaccharides ; *Ambroxol/pharmacology/therapeutic use ; Mice ; *Cognitive Dysfunction/drug therapy/metabolism/chemically induced ; *Neuroinflammatory Diseases/drug therapy/metabolism ; *Neuroglia/drug effects/metabolism ; *Brain/metabolism/drug effects/pathology ; Male ; *Neuroprotective Agents/pharmacology/therapeutic use ; Disease Models, Animal ; Antioxidants/pharmacology ; Mice, Inbred C57BL ; },
abstract = {Neurodegenerative diseases, such as Alzheimer's disease (AD) and Parkinson's disease (PD), are multifactorial. Among various factors, lipopolysaccharides (LPSs) from Gram-negative bacteria, such as E. coli, are considered potential causative agents. Despite significant advancements in the field, there is still no cure. In this study, we investigated the neuroprotective effects of ambroxol against LPS-induced neuroinflammation, oxidative stress, neurodegeneration, and the associated cognitive dysfunction. Intraperitoneal injection of LPS (250 µg/kg every alternative day for a total of seven doses over 14 days) triggered glial cell activation, neuroinflammation, oxidative stress, and neurodegeneration in the mouse brain. Ambroxol treatment (30 mg/kg/day for 14 days) significantly reduced neuroinflammation and oxidative stress compared to LPS-treated mice. Immunoblotting and immunofluorescence results showed that ambroxol reduced levels of Toll-like receptor 4 (TLR4) and oxidative stress kinase phospho-c-Jun N-terminal Kinase 1 (p-JNK). It also decreased astrocyte and microglia activation in the cortex and hippocampus of LPS+ Amb-treated mice, as indicated by the downregulation of GFAP and Iba-1. Furthermore, ambroxol-reversed LPS-induced neuroinflammation by inhibiting inflammatory mediators, such as IL-1β and TNF-α, through regulation of the transcription factor p-NFkB. Persistent neuroinflammation disrupted the natural antioxidant mechanisms, leading to oxidative stress. Ambroxol treatment upregulated antioxidant markers, including Nrf-2, HO-1, and SOD, which were downregulated in the LPS-treated group. Additionally, ambroxol-inhibited lipid peroxidation, maintaining malondialdehyde levels in the mouse brain. Ambroxol also improves synaptic integrity by upregulating synaptic biomarkers, including PSD-95 and SNAP-23. Overall, ambroxol demonstrated anti-inflammatory, antioxidant, and neuroprotective effects in LPS-treated mice, highlighting its potential benefits in neurological disorders.},
}

Animals
*Oxidative Stress/drug effects
*Lipopolysaccharides
*Ambroxol/pharmacology/therapeutic use
Mice
*Cognitive Dysfunction/drug therapy/metabolism/chemically induced
*Neuroinflammatory Diseases/drug therapy/metabolism
*Neuroglia/drug effects/metabolism
*Brain/metabolism/drug effects/pathology
Male
*Neuroprotective Agents/pharmacology/therapeutic use
Disease Models, Animal
Antioxidants/pharmacology
Mice, Inbred C57BL

@article {pmid40114707,
year = {2025},
author = {Kumari, A and Rahaman, A and Zeng, XA and Baloch, Z},
title = {Therapeutic potential and microRNA regulating properties of phytochemicals in Alzheimer's disease.},
journal = {Molecular therapy. Nucleic acids},
volume = {36},
number = {1},
pages = {102439},
pmid = {40114707},
issn = {2162-2531},
abstract = {Alzheimer's disease (AD) is the leading cause of dementia in the elderly and is characterized by the aggregation of Aβ (peptide) and neurofibrillary tangles along with inflammatory processes. Aging is a significant driver of these alterations, and dementia is a major cause of disability and mortality. Despite extensive clinical trials over the past two decades, no effective drug has been developed to improve AD symptoms or slow its progression, indicating the inefficiency of current treatment targets. In AD development, the molecular microenvironment plays a significant role. MicroRNAs (miRNAs) are a key component of this microenvironment, regulate post-transcriptional gene expression, and are expressed more abundantly in the brain than in other tissues. Several dysregulated miRNAs in AD have been linked to neuropathological changes, such as plaque and tangle accrual, as well as altered expression of notorious molecules. Preclinical studies have confirmed the efficacy of phytochemicals/food bioactive compounds (PCs/FBCs) in regulating miRNA expression, which makes them immensely beneficial for targeting miRNA-altered expression patterns in neuronal diseases. This review highlights the potential of miRNAs in driving AD pathology and its development. Furthermore, it discusses the therapeutic efficacy of PCs/FBCs and their miRNA-regulatory properties, especially focusing on antiinflammatory and antioxidant capacities for their development as effective AD agents.},
}

@article {pmid40114609,
year = {2025},
author = {Wolf, T and Moss, L and Hudson, C and Winters, AM and Abdelmaboud, SS and Avlas, M and Wohlfahrt, J and Guergues, J and Bickford, PC and Stevens, SM},
title = {Chronic alcohol exposure during young adulthood attenuates microglial reactivity and downstream immune response pathways in a mouse model of tauopathy later in life.},
journal = {Alcohol, clinical & experimental research},
volume = {},
number = {},
pages = {},
doi = {10.1111/acer.70034},
pmid = {40114609},
issn = {2993-7175},
support = {R01AA026082/AA/NIAAA NIH HHS/United States ; IK6BX004214//U.S. Department of Veterans Affairs/ ; },
abstract = {BACKGROUND: Alzheimer's disease (AD) is a progressive neurodegenerative disorder marked by the buildup of amyloid-β and tau protein tangles. Alcohol use has been identified as a risk factor for AD; however, the molecular mechanisms underlying this potential causal link remain elusive. An emerging area of research focuses on the role of microglia, the brain's innate immune cells, in AD pathogenesis, with evidence suggesting that alcohol exposure may prime microglia to exhibit an exaggerated immune response when they are subsequently exposed to proinflammatory stimuli.

METHODS: We used a single 10-day chronic-plus-binge alcohol exposure model in male and female C57BL/6J mice aged 8-10 weeks One month later, tauopathy was induced via adenoviral vector (AAV)-mediated overexpression of h-p301L Tau. After 2.5 months, the mice underwent behavioral and cognitive testing. Two weeks later, microglia were collected using fluorescence-activated cell sorting (FACS) and processed for unbiased, mass spectrometry-based proteomic analysis to determine the molecular pathways related to microglial reactivity.

RESULTS: Microglia from mice exposed to alcohol in young adulthood exhibited a blunted immune response when challenged with AAV-mediated delivery and accumulation of human tau later in life. This was characterized by decreased expression of MHC II- and interferon-associated proteins and bioinformatic prediction of inhibited inflammation-related pathways in the absence of gross histological, behavioral, or cognitive deficits. These results demonstrate unique, temporally specific microglial reactivity to tau that is modulated by early adulthood alcohol exposure, implicating a microglial response that could negatively affect the mechanisms necessary for tau clearance and potentially exacerbate tau pathogenesis.

CONCLUSIONS: This study provides novel insights into the long-term effects of alcohol exposure in early adulthood on microglial function and the complexity of context-dependent microglial involvement in tauopathy. Consideration of early-adulthood environmental factors is critical for understanding and potentially mitigating the risk of neurodegenerative diseases, such as AD.},
}

@article {pmid40114579,
year = {2025},
author = {Ahmad, F},
title = {Nano-healing: Exploring the Therapeutic Potentials of Nanomedicine for CNS Disorders.},
journal = {Current pharmaceutical design},
volume = {},
number = {},
pages = {},
doi = {10.2174/0113816128362577250227081919},
pmid = {40114579},
issn = {1873-4286},
abstract = {INTRODUCTION: Nanomedicine offers immense potential in the field of Central Nervous System (CNS) disorder treatment, encompassing conditions such as Alzheimer's disease, Parkinson's disease, multiple sclerosis, epilepsy, and stroke.

METHOD: Through the utilization of nanotechnology-driven drug delivery systems, the efficacy of drugs can be amplified, their toxicity minimized, and their bioavailability increased, enabling them to effectively reach the intended site within the CNS. This review aims to examine the therapeutic possibilities that nanomedicine presents in addressing these debilitating disorders. This exploration entails an analysis of diverse nanotechnology- based approaches for CNS drug delivery, including polymeric nanoparticles, liposomes, dendrimers, and carbon nanotubes. Moreover, notable advancements in nanotechnology-based therapeutics for CNS disorders are highlighted, such as the application of nanoparticles for delivering curcumin in Alzheimer's disease, liposomes for delivering L-DOPA in Parkinson's disease, and dendrimers for delivering interferon-beta in multiple sclerosis.

RESULTS: Additionally, the potential of nanotechnology-based approaches in the treatment of epilepsy and stroke is discussed. The review concludes by addressing the challenges faced and emphasizes the significant potential of clinical trials in enhancing drug delivery and future prospects in the development of nanotechnology- based therapeutics for CNS disorders.

CONCLUSION: Overall, the therapeutic potential of nanomedicine in CNS disorder treatment is vast, instilling optimism for the creation of safe and effective therapies for these devastating conditions.},
}

@article {pmid40114567,
year = {2025},
author = {Puranik, N and Song, M},
title = {Oxidative Stress and the Role of Immune Cells in Alzheimer's Disease: Therapeutic Implications and Future Perspectives.},
journal = {CNS & neurological disorders drug targets},
volume = {},
number = {},
pages = {},
doi = {10.2174/0118715273355336250226055826},
pmid = {40114567},
issn = {1996-3181},
abstract = {The most common neurodegenerative illness and leading cause of death in the world is Alzheimer's disease (AD), which is extremely expensive to treat. None of the AD treatments that are currently in the market with approval have any effect on disease progression. However, numerous clinical studies aimed at reducing amyloid beta (Aβ) plaque development, boosting Aβ clearance, or reducing neurofibrillary tangle (NFT) failed or had conflicting results. As oxidative stress (OS), mitochondrial dysfunction, and chronic neuroinflammation are implicated in numerous interconnected vicious cascades, research has revealed new therapeutic targets, including enhancing mitochondrial bioenergetics and quality control, reducing oxidative stress, or modulating neuroinflammatory pathways. This review examines the role of oxidative stress (OS), mitochondrial dysfunction, neuroinflammation, and the interplay between peripheral and central immune systems in the pathogenesis of AD. We highlight how OS and immune dysregulation drive chronic neuroinflammation, exacerbating AD progression. Immune cells and inflammatory molecules emerge as critical players in disease pathology. Overall, this review concludes that targeting OS and immune system crosstalk represents promising therapeutic strategies for mitigating AD progression, providing a foundation for future interventions.},
}

@article {pmid40114475,
year = {2025},
author = {McCann, SJH},
title = {The relation of implicit age bias based on negative age stereotypes to the American state prevalence of older adult Alzheimer's disease.},
journal = {The Journal of social psychology},
volume = {},
number = {},
pages = {1-16},
doi = {10.1080/00224545.2025.2479777},
pmid = {40114475},
issn = {1940-1183},
abstract = {This study determined the relation of Implicit Age Bias among respondents aged 20-59 years of age to the 2020 Alzheimer's disease (AD) prevalence among residents 65 years and over with the 48 contiguous American states as analytic units. This implicit measure of state ambient ageism correlated .69 with state AD prevalence and persisted in multiple regression equations considering several controls including older adult poverty rate, high school graduation, bachelor's degree attainment, and multiple chronic conditions. Based on stereotype embodiment theory, the assumption is that the influence of external state-level age bias combined with the personal experiences of state residents leads to the general internalization of negative age stereotypes and ultimately to higher state AD prevalence. The speculation is that such internalization at the individual level leads to adoption of unhealthy behaviors and stress accumulation that eventually produces immunological deficiencies, infections, and inflammation conducive to AD onset and progression.},
}

@article {pmid40114449,
year = {2025},
author = {Khan, S and Iqbal, T and Zahoor, T and Hussain, R and Islam, MS and Dahlous, KA},
title = {Insight the confirmation of benzothiazolidinone-derived thiadiazole scaffolds as promising antiurease and anti-Alzheimer agents: synthesis, in vitro, and in silico investigations.},
journal = {Zeitschrift fur Naturforschung. C, Journal of biosciences},
volume = {},
number = {},
pages = {},
pmid = {40114449},
issn = {1865-7125},
abstract = {Alzheimer's disease is a serious neurological disorder, and traditional therapies for Alzheimer's, like radiation and surgical procedures, as well as chemotherapeutics, are usually linked with multiple negative consequences. Finding a novel therapeutic anti-Alzheimer agent with high efficacy and minimal side effects, we have designed and synthesized benzothiazolidinone-derived thiadiazole-based Schiff base derivatives (1-15). Biological assessment of these compounds was carried out against acetylcholinesterase and butyrylcholinesterase, and all the derivatives showed varying degrees of inhibitory activity. Analog 8 (IC50 = 3.60 ± 0.20 and 4.10 ± 0.20 μM for acetylcholinesterase and butyrylcholinesterase, respectively) demonstrated spellbinding efficacy in contrast to standard donepezil (IC50 = 50 ± 0.10 and 8.10 ± 0.20 μM). The surpassing inhibition of analog 8 is due to highly reactive CF3 moiety at the para-position, inhibiting the enzymes via strong hydrogen bond. Analog 7 with IC50 value of 5.70 ± 0.10 and 6.20 ± 0.40 μM was also found with strong therapeutic potential than standard drug. The strong inhibition potential of lead compounds was also evaluated under enzyme kinetics and spellbinding potential was observed. Biological effectiveness of potent compounds was validated by visualizing the binding interactions via in silico molecular docking study and prediction of drug-likeness via ADME analysis. All the synthesized compounds were analyzed for their structural confirmation via [1]HNMR, [13]CNMR, and HREI-MS.},
}

@article {pmid40114424,
year = {2025},
author = {Jauregi-Zinkunegi, A and Wilson, RE and E Langhough, R and Ashton, NJ and Blennow, K and Johnson, SC and Zetterberg, H and Bruno, D and Mueller, KD},
title = {Associations between the logical memory test story recall metrics and plasma biomarkers for Alzheimer's disease in individuals free of dementia.},
journal = {The Clinical neuropsychologist},
volume = {},
number = {},
pages = {1-20},
doi = {10.1080/13854046.2025.2481119},
pmid = {40114424},
issn = {1744-4144},
abstract = {Objective: Blood-based biomarkers are valued for their lower cost and less invasive nature, though issues with widespread implementation and accessibility remain. Process-based scores from story recall have been shown to detect neuronal network disturbances typical of Alzheimer's disease (AD) pathology more effectively than traditional metrics. This study examined the associations between process-based scores and concurrent plasma AD biomarkers in older adults without dementia, while also comparing them to traditional metrics. Additionally, it also investigated the diagnostic utility of these metrics in detecting plasma p-tau217 positivity. Methods: Data from 416 participants (mean age = 66.6 ± 7) free of dementia were extracted from the Wisconsin Registry for Alzheimer's Prevention (WRAP). Logical Memory Test (LMT) and plasma p-tau217, p-tau181, p-tau231, Aβ42/Aβ40 ratio, GFAP and NfL levels were analyzed. Bayesian regression models assessed associations between plasma biomarkers and both process-based and traditional LMT scores, controlling for the covariates. Results: The best-fitting model for plasma p-tau217 included Total ratio (Tr) and Immediate recall (BF10=573), but Tr showed stronger evidence of association (mean coefficient = 0.208; BFinclusion=14.4) than Immediate recall (mean coefficient=-0.007; BFinclusion=1.7). Tr was also the best predictor of plasma p-tau181 (mean coefficient = 0.144; BF10=10.5) and GFAP (mean coefficient = 0.141; BF10=5.8), outperforming traditional LMT scores. No memory scores were associated with plasma p-tau231 or Aβ42/40 ratio levels. Tr score was the strongest single predictor of p-tau217 positivity (BF10=38). Conclusions: These findings suggest that process-based memory scores might be useful in enhancing the detection of neuronal network disturbances associated with AD pathology, especially in settings where biomarker testing is unavailable.},
}

@article {pmid40114266,
year = {2025},
author = {Slayo, M and Rummel, C and Singhaarachchi, PH and Feldotto, M and Spencer, SJ},
title = {The role of n-3-derived specialised pro-resolving mediators (SPMs) in microglial mitochondrial respiration and inflammation resolution in Alzheimer's disease.},
journal = {Molecular neurodegeneration},
volume = {20},
number = {1},
pages = {35},
pmid = {40114266},
issn = {1750-1326},
mesh = {*Alzheimer Disease/metabolism/pathology ; *Microglia/metabolism ; *Mitochondria/metabolism ; Humans ; Animals ; *Fatty Acids, Omega-3/metabolism ; Inflammation/metabolism ; Inflammation Mediators/metabolism ; Amyloid beta-Peptides/metabolism ; },
abstract = {Alzheimer's disease (AD) is the most common form of dementia globally and is characterised by reduced mitochondrial respiration and cortical deposition of amyloid-β plaques and neurofibrillary tangles comprised of hyper-phosphorylated tau. Despite its characterisation more than 110 years ago, the mechanisms by which AD develops are still unclear. Dysregulation of microglial phagocytosis of amyloid-β may play a key role. Microglia are the major innate immune cell of the central nervous system and are critical responders to pro-inflammatory states. Typically, microglia react with a short-lived inflammatory response. However, a dysregulation in the resolution of this microglial response results in the chronic release of inflammatory mediators. This prolongs the state of neuroinflammation, likely contributing to the pathogenesis of AD. In addition, the microglial specialised pro-resolving mediator (SPM) contribution to phagocytosis of amyloid-β is dysregulated in AD. SPMs are derivatives of dietary n-3 polyunsaturated fatty acids (PUFAs) and potentially represent a strategic target for protection against AD progression. However, there is little understanding of how mitochondrial respiration in microglia may be sustained long term by n-3-derived SPMs, and how this affects their clearance of amyloid-β. Here, we re-evaluate the current literature on SPMs in AD and propose that SPMs may improve phagocytosis of amyloid-β by microglia as a result of sustained mitochondrial respiration and allowing a pro-resolution response.},
}

*Alzheimer Disease/metabolism/pathology
*Microglia/metabolism
*Mitochondria/metabolism
Humans
Animals
*Fatty Acids, Omega-3/metabolism
Inflammation/metabolism
Inflammation Mediators/metabolism
Amyloid beta-Peptides/metabolism

@article {pmid40114255,
year = {2025},
author = {Pu, Y and Beck, D and Verspoor, K},
title = {Enriched knowledge representation in biological fields: a case study of literature-based discovery in Alzheimer's disease.},
journal = {Journal of biomedical semantics},
volume = {16},
number = {1},
pages = {3},
pmid = {40114255},
issn = {2041-1480},
support = {CI70200030//Australian Research Council/ ; },
mesh = {*Alzheimer Disease ; Humans ; Knowledge Discovery/methods ; },
abstract = {BACKGROUND: In Literature-based Discovery (LBD), Swanson's original ABC model brought together isolated public knowledge statements and assembled them to infer putative hypotheses via logical connections. Modern LBD studies that scale up this approach through automation typically rely on a simple entity-based knowledge graph with co-occurrences and/or semantic triples as basic building blocks. However, our analysis of a knowledge graph constructed for a recent LBD system reveals limitations arising from such pairwise representations, which further negatively impact knowledge inference. Using LBD as the context and motivation in this work, we explore limitations of using pairwise relationships only as knowledge representation in knowledge graphs, and we identify impacts of these limitations on knowledge inference. We argue that enhanced knowledge representation is beneficial for biological knowledge representation in general, as well as for both the quality and the specificity of hypotheses proposed with LBD.

RESULTS: Based on a systematic analysis of one co-occurrence-based LBD system focusing on Alzheimer's Disease, we identify 7 types of limitations arising from the exclusive use of pairwise relationships in a standard knowledge graph-including the need to capture more than two entities interacting together in a single event-and 3 types of negative impacts on knowledge inferred with the graph-Experimentally infeasible hypotheses, Literature-inconsistent hypotheses, and Oversimplified hypotheses explanations. We also present an indicative distribution of different types of relationships. Pairwise relationships are an essential component in representation frameworks for knowledge discovery. However, only 20% of discoveries are perfectly represented with pairwise relationships alone. 73% require a combination of pairwise relationships and nested relationships. The remaining 7% are represented with pairwise relationships, nested relationships, and hypergraphs.

CONCLUSION: We argue that the standard entity pair-based knowledge graph, while essential for representing basic binary relations, results in important limitations for comprehensive biological knowledge representation and impacts downstream tasks such as proposing meaningful discoveries in LBD. These limitations can be mitigated by integrating more semantically complex knowledge representation strategies, including capturing collective interactions and allowing for nested entities. The use of more sophisticated knowledge representation will benefit biological fields with more expressive knowledge graphs. Downstream tasks, such as LBD, can benefit from richer representations as well, allowing for generation of implicit knowledge discoveries and explanations for disease diagnosis, treatment, and mechanism that are more biologically meaningful.},
}

*Alzheimer Disease
Humans
Knowledge Discovery/methods

@article {pmid40114234,
year = {2025},
author = {Chung, SJ and Kang, SH and Kang, M and Choi, Y and Park, YJ and Kim, H and Oh, K and Koh, SB and Kim, JB},
title = {Impact of sleep apnea on alzheimer's disease in relation to sex: an 8-year longitudinal follow-up study of a nationwide cohort.},
journal = {Alzheimer's research & therapy},
volume = {17},
number = {1},
pages = {65},
pmid = {40114234},
issn = {1758-9193},
support = {2022R1I1A1A01056956//National Research Foundation of Korea/ ; O2400251//Korea University Guro Hospital/ ; },
mesh = {Humans ; Male ; Female ; *Sleep Apnea Syndromes/epidemiology/complications ; Aged ; *Alzheimer Disease/epidemiology/complications ; Middle Aged ; Longitudinal Studies ; Follow-Up Studies ; Republic of Korea/epidemiology ; Sex Factors ; Obesity/epidemiology/complications ; Cohort Studies ; Sex Characteristics ; Proportional Hazards Models ; Aged, 80 and over ; Risk Factors ; },
abstract = {BACKGROUND: We aimed to investigate the association between sleep apnea and incident dementia (dementia of the Alzheimer type [DAT] and vascular dementia) and whether differences in the effects of sleep apnea on dementia depend on sex. Furthermore, we sought to determine whether obesity affects the sex-specific relationship between sleep apnea and dementia.

METHODS: We used de-identified data on patients with sleep apnea and a control group aged ≥ 50 years from the Korean National Health Insurance Service. After propensity score matching to balance age and sex between the patient and control groups, 30,111 individuals with sleep apnea (patient group) and 121,528 individuals without sleep apnea (control group) were included. To investigate the impact of sleep apnea on the development of dementia, we used Cox proportional hazards regression after controlling for potential confounders.

RESULTS: Sleep apnea was predictive of developing DAT in both women (hazard ratio [HR] = 1.30, 95% confidence interval [CI] 1.16-1.44, p < 0.001) and men (HR = 1.13, 95% CI 1.03-1.24, p = 0.012). The adverse effects of sleep apnea on DAT were more prominent in women than in men (p = 0.015 for sleep apnea×sex). Furthermore, obesity affected the sex-specific relationship between sleep apnea and DAT. Specifically, the adverse effects of obese sleep apnea on the DAT were more pronounced in women than in men (p = 0.002 for obese sleep apnea×sex). In contrast, there were no differences in the effects of non-obese sleep apnea on DAT between women and men (p = 0.667 for non-obese sleep apnea×sex).

CONCLUSIONS: Our results highlight sex differences in the adverse effects of sleep apnea on DAT. Furthermore, these results suggest that sex-specific strategies for controlling sleep apnea are necessary to prevent DAT.},
}

Humans
Male
Female
*Sleep Apnea Syndromes/epidemiology/complications
Aged
*Alzheimer Disease/epidemiology/complications
Middle Aged
Longitudinal Studies
Follow-Up Studies
Republic of Korea/epidemiology
Sex Factors
Obesity/epidemiology/complications
Cohort Studies
Sex Characteristics
Proportional Hazards Models
Aged, 80 and over
Risk Factors

@article {pmid40114204,
year = {2025},
author = {Suman, PR and Kincheski, GC and Frozza, RL and De Felice, FG and Ferreira, ST},
title = {Neonatal maternal separation causes depressive-like behavior and potentiates memory impairment induced by amyloid-β oligomers in adult mice.},
journal = {Behavioral and brain functions : BBF},
volume = {21},
number = {1},
pages = {8},
pmid = {40114204},
issn = {1744-9081},
support = {E-26/210.699/2023//Fundação Carlos Chagas Filho de Amparo à Pesquisa do Estado do Rio de Janeiro/ ; E-26/200.169/2023//Fundação Carlos Chagas Filho de Amparo à Pesquisa do Estado do Rio de Janeiro/ ; #26.201.030/2022//Fundação Carlos Chagas Filho de Amparo à Pesquisa do Estado do Rio de Janeiro/ ; #E-26/010.0421/2019//Fundação Carlos Chagas Filho de Amparo à Pesquisa do Estado do Rio de Janeiro/ ; #302702/2017-2//Conselho Nacional de Desenvolvimento Científico e Tecnológico/ ; #403032/2021-0//Conselho Nacional de Desenvolvimento Científico e Tecnológico/ ; },
mesh = {Animals ; Female ; *Maternal Deprivation ; *Amyloid beta-Peptides/metabolism ; Mice ; Male ; *Depression/metabolism/psychology/etiology ; *Memory Disorders/metabolism/chemically induced/etiology/psychology ; *Animals, Newborn ; Serotonin/metabolism ; Hippocampus/metabolism ; Alzheimer Disease/metabolism/chemically induced/psychology ; Dopamine/metabolism ; Behavior, Animal/drug effects ; },
abstract = {BACKGROUND: Alzheimer's disease (AD) is characterized by memory decline and mood alterations. A growing body of evidence implicates stress and other social determinants of health as potential contributors to the progressive cerebral alterations that culminate in AD. In the current study, we investigated the impact of neonatal maternal separation (MS) on the susceptibility of male and female mice to AD-associated memory impairments and depressive-like behavior in adulthood, and on brain levels of pro-inflammatory cytokines and neurotransmitters.

METHODOLOGY: Male and female Swiss mice were exposed to MS for 180 min daily from post-natal day 1 to 10. Seventy days post-MS, mice received an intracerebroventricular infusion of amyloid-β oligomers (AβOs), and memory and mood were evaluated. Levels of TNF-α, IL-1β, serotonin, dopamine, and related metabolites were determined in the cortex and hippocampus.

RESULTS: Previous exposure to MS alone did not cause memory impairments in adult mice. Interestingly, however, MS increased the susceptibility of adult male mice to memory impairment and depressive-like behavior induced by AβOs, and potentiated the inhibitory impact of AβOs on memory in adult females. Females were more susceptible to depressive-like behavior caused by a low dose of AβOs, regardless of MS. No changes in IL-1β were found. A decrease in TNF-α was selectively found in females exposed to MS that received an infusion of 1 pmol AβOs. MS led to an increase in serotonin (5-HT) in the hippocampus of male mice, without influencing the levels of the serotonin metabolite, 5-HIAA. Changes in serotonin turnover were predominantly observed in the cortex of female mice. No changes in dopamine or its metabolites were induced by MS or AβOs in male or female mice.

CONCLUSIONS: Neonatal MS enhances the susceptibility of adult mice to AD-associated cognitive deficits and depressive-like behavior in a sex-specific manner. This suggests that early life stress may play a role in the development of AD.},
}

Animals
Female
*Maternal Deprivation
*Amyloid beta-Peptides/metabolism
Mice
Male
*Depression/metabolism/psychology/etiology
*Memory Disorders/metabolism/chemically induced/etiology/psychology
*Animals, Newborn
Serotonin/metabolism
Hippocampus/metabolism
Alzheimer Disease/metabolism/chemically induced/psychology
Dopamine/metabolism
Behavior, Animal/drug effects

@article {pmid40114191,
year = {2025},
author = {Dongre, P and Ramesh, M and Govindaraju, T and Inamdar, MS},
title = {Asrij/OCIAD1 depletion reduces inflammatory microglial activation and ameliorates Aβ pathology in an Alzheimer's disease mouse model.},
journal = {Journal of neuroinflammation},
volume = {22},
number = {1},
pages = {89},
pmid = {40114191},
issn = {1742-2094},
support = {CRG/2021/003566//Science and Engineering Research Board/ ; CRG/2021/003566//Science and Engineering Research Board/ ; JCB/2019/000020//Department of Science and Technology, Ministry of Science and Technology, India/ ; },
mesh = {Animals ; *Alzheimer Disease/pathology/metabolism ; Mice ; *Microglia/metabolism/pathology ; *Disease Models, Animal ; *Mice, Transgenic ; *Amyloid beta-Peptides/metabolism ; Neuroinflammatory Diseases/metabolism/pathology ; Plaque, Amyloid/pathology/metabolism ; Mice, Inbred C57BL ; },
abstract = {BACKGROUND: Alzheimer's disease (AD) is a neurodegenerative disorder characterized by the accumulation of amyloid-beta (Aβ) plaques and neurofibrillary tangles, neuroinflammation, and glial activation. Asrij/OCIAD1 (Ovarian Carcinoma Immunoreactive Antigen Domain containing protein 1) is an AD-associated factor. Increased Asrij levels in the brains of AD patients and mouse models are linked to the severity of neurodegeneration. However, the contribution of Asrij to AD progression and whether reducing Asrij levels is sufficient to mitigate Aβ pathology in vivo is unclear.

METHODS: To explore the impact of Asrij on AD pathology, we deleted asrij in the APP/PS1 mouse model of AD and analyzed the effects on AD hallmarks. We used the Morris water maze and open field test to assess behavioral performance. Using immunohistochemistry and biochemical analyses, we evaluated Aβ plaque load, neuronal and synaptic damage, and gliosis. Further, we utilized confocal microscopy imaging, flow cytometry, and RNA sequencing analysis to comprehensively investigate changes in microglial responses to Aβ pathology upon Asrij depletion.

RESULTS: Asrij depletion ameliorates cognitive impairments, Aβ deposition, neuronal and synaptic damage, and reactive astrogliosis in the AD mouse. Notably, Asrij-deficient microglia exhibit reduced plaque-associated proliferation and decreased phagocytic activation. Transcriptomic analyses of AD microglia reveal upregulation of energy metabolism pathways and downregulation of innate immunity and inflammatory pathways upon Asrij depletion. Mechanistically, loss of Asrij increases mitochondrial activity and impedes the acquisition of a pro-inflammatory disease-associated microglia (DAM) state. Reduced levels of proinflammatory cytokines and decreased STAT3 and NF-κB activation indicate protective changes in AD microglia. Taken together, our results suggest that increased Asrij levels reported in AD, may suppress microglial metabolic activity and promote inflammatory microglial activation, thereby exacerbating AD pathology.

CONCLUSIONS: In summary, we show that Asrij depletion ameliorates Aβ pathology, neuronal and synaptic damage, gliosis, and improves behavioral performance in APP/PS1 mice. This supports that Asrij exacerbates the AD pathology. Mechanistically, Asrij is critical for the development of DAM and promotes neuroinflammatory signaling activation in microglia, thus restricting neuroprotective microglial responses. Hence, reducing Asrij in this context may help retard AD. Our work positions Asrij as a critical molecular regulator that links microglial dysfunction to AD pathogenesis.},
}

Animals
*Alzheimer Disease/pathology/metabolism
Mice
*Microglia/metabolism/pathology
*Disease Models, Animal
*Mice, Transgenic
*Amyloid beta-Peptides/metabolism
Neuroinflammatory Diseases/metabolism/pathology
Plaque, Amyloid/pathology/metabolism
Mice, Inbred C57BL

@article {pmid40114073,
year = {2025},
author = {Joe, EB and Segal-Gidan, F},
title = {The role of a specialized memory clinic supporting primary care providers in a safety net health system.},
journal = {BMC primary care},
volume = {26},
number = {1},
pages = {74},
pmid = {40114073},
issn = {2731-4553},
support = {UL1TR001855//NIH/NCATS/ ; R03AG082997//NIH/NIA/ ; R03AG082997//NIH/NIA/ ; },
mesh = {Humans ; Male ; *Primary Health Care/organization & administration ; Female ; Aged ; *Safety-net Providers/organization & administration ; *Dementia/therapy/epidemiology/diagnosis ; *Referral and Consultation ; Middle Aged ; Cognitive Dysfunction/diagnosis/epidemiology/therapy ; Aged, 80 and over ; Alzheimer Disease/therapy/diagnosis/epidemiology ; Ambulatory Care Facilities/organization & administration/statistics & numerical data ; Memory Disorders/therapy/diagnosis/epidemiology ; },
abstract = {BACKGROUND: Although most dementia care occurs in primary care, consultation with dementia specialty care is sometimes indicated. Access to dementia specialists is limited, particularly in resource-limited environments such as the public health safety net, which may require triaging referrals to preserve access for patients with needs that can not be met in a primary care setting.

METHODS: The eConsult system for primary care providers to refer patients to a subspecialty memory clinic is described for a large safety net health system. Demographic and clinical characteristics are presented for patients evaluated within the memory clinic setting compared to the health system overall. ICD-10-CM codes were used to identify cognitive diagnoses and medical comorbidities. Chi-squared tests were used to compare categorical variables and t-tests for continuous variables.

RESULTS: 94 individuals age 50 or older were seen in the memory clinic in 2019, of whom 43 were new evaluations. The most common visit diagnoses for new memory clinic patients were Alzheimer's disease (33%), no cognitive diagnosis (28%), unspecified dementia (19%), and mild cognitive impairment (12%); for follow up patients, the most common diagnoses were Alzheimer's disease (49%), unspecified dementia (18%), no cognitive diagnosis (14%), and mild cognitive impairment (10%). For those without a cognitive diagnosis, common visit diagnoses included cognitive symptoms, mood or sleep disorders, and metabolic disturbances. Of the 11 new internal referrals with a prior coded diagnosis of dementia, median time from first diagnosis to their initial memory clinic visit was 224 days.

CONCLUSIONS: Despite clear systemwide parameters for referral and extensive pre-referral screening via an eConsult system, the most common diagnosis for memory clinic patients was Alzheimer's disease. Direct studies of eConsult are needed to determine primary care providers' needs when referring patients with dementia to a memory clinic setting.},
}

Humans
Male
*Primary Health Care/organization & administration
Female
Aged
*Safety-net Providers/organization & administration
*Dementia/therapy/epidemiology/diagnosis
*Referral and Consultation
Middle Aged
Cognitive Dysfunction/diagnosis/epidemiology/therapy
Aged, 80 and over
Alzheimer Disease/therapy/diagnosis/epidemiology
Ambulatory Care Facilities/organization & administration/statistics & numerical data
Memory Disorders/therapy/diagnosis/epidemiology

@article {pmid40113535,
year = {2025},
author = {Rao, C and Semrau, S and Fossati, V},
title = {Decoding microglial functions in Alzheimer's disease: insights from human models.},
journal = {Trends in immunology},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.it.2025.02.011},
pmid = {40113535},
issn = {1471-4981},
abstract = {Microglia, key orchestrators of the brain's immune responses, play a pivotal role in the progression of Alzheimer's disease (AD). Emerging human models, including stem cell-derived microglia and cerebral organoids, are transforming our understanding of microglial contributions to AD pathology. In this review, we highlight how these models have uncovered human-specific microglial responses to amyloid plaques and their regulation of neuroinflammation, which are not recapitulated in animal models. We also illustrate how advanced human models that better mimic brain physiology and AD pathology are providing unprecedented insights into the multifaceted roles of microglia. These innovative approaches, combined with sophisticated technologies for cell editing and analysis, are shaping AD research and opening new avenues for therapeutic interventions targeting microglia.},
}

@article {pmid40113179,
year = {2025},
author = {Chen, Y and Wu, Y and Wang, D and Yang, Y and Guo, Q and Qiu, Q and Wan, C and Li, X},
title = {Delayed niacin skin flush response identifies cognitive impairment in late-life depression.},
journal = {Journal of affective disorders},
volume = {379},
number = {},
pages = {772-781},
doi = {10.1016/j.jad.2025.03.095},
pmid = {40113179},
issn = {1573-2517},
abstract = {OBJECTIVE: This research aimed to inspect the discriminative and predictive utility of the niacin skin flush response (NSFR) in patients with late-life depression (LLD) with cognitive impairment (CI).

METHODS: This study consisted of 86 LLD patients (46 with CI and 40 without CI), along with 22 Alzheimer's disease (AD) patients and 32 healthy elderly controls (HCs) as positive and negative controls, respectively. A subset of 74 LLD patients were reassessed after six months. The Montreal Cognitive Assessment (MoCA) was administered to assess cognitive capabilities. NSFR tests were performed using a modified protocol. Group differences in NSFR and clinical parameters were examined using multivariate ANOVA analysis. Model performance was evaluated using receiver operating characteristic (ROC) curves derived from NSFR measurements.

RESULTS: NSFR showed a significant inverse correlation with cognitive functions in LLD patients (R = -0.456, P < .001). Moreover, the parameter logEC50, which quantifies the NSFR rate, was elevated in the LLD with CI group. LogEC50 had an AUC of 0.767 (95 % CI: 0.667-0.867) in distinguishing LLD with CI from those without CI, which increased to 0.961 (95%CI:0.925-0.998) when combined with C- reactive protein. The predictive capacity of the baseline logEC50 for cognitive prognosis (decline versus preservation) in LLD patients was statistically significant (AUC = 0.826, 95 % CI 0.731-0.921), which increased to 0.857 (95%CI:0.775-0.941) when combined with baseline MoCA.

CONCLUSION: A delayed NSFR represents a promising biomarker for identifying CI and predicting cognitive trajectories in patients with LLD. This study elucidates a novel methodology for the precise identification and prognostic evaluation of CI in LLD.},
}

@article {pmid40113024,
year = {2025},
author = {Agnello, L and Gambino, CM and Ciaccio, AM and Salemi, G and Brighina, F and Ragonese, P and Piccoli, T and Blandino, V and Di Stefano, V and Cacciabaudo, F and Masucci, A and Vassallo, R and Scazzone, C and Del Ben, F and Ciaccio, M},
title = {The value of serum glial fibrillary acidic protein as a biomarker of astrogliosis in different neurological diseases.},
journal = {Clinica chimica acta; international journal of clinical chemistry},
volume = {572},
number = {},
pages = {120248},
doi = {10.1016/j.cca.2025.120248},
pmid = {40113024},
issn = {1873-3492},
abstract = {BACKGROUND: Glial Fibrillary Acidic Protein (GFAP) is a well-established biomarker of astrocytes and astrogliosis, a pathological response observed in various neurological diseases. This study aimed to evaluate the diagnostic performance of serum GFAP in Alzheimer's disease (AD), multiple sclerosis (MS), and transthyretin amyloidosis (ATTR) polyneuropathy.

METHODS: We performed a retrospective observational study, including 498 participants (337 healthy controls and 161 patients with AD, MS, or ATTR amyloidosis). Serum GFAP levels were measured using the Lumipulse G1200 platform, and statistical analyses were performed to compare levels across disease groups and assess their diagnostic accuracy.

RESULTS: GFAP levels were significantly elevated in all neurological disease groups compared to age-matched controls, with the highest levels found in AD (79.4 pg/mL vs. 39.5 pg/mL, p = 2.55 × 10[-12]). ROC curve analysis revealed that GFAP had strong diagnostic performance for AD (AUC = 0.86), moderate performance for ATTR amyloidosis (AUC = 0.67), and poor performance for MS (AUC = 0.61).

CONCLUSIONS: These findings suggest that GFAP is a promising biomarker for AD, reflecting astrocytic activation and neuroinflammatory processes. Its diagnostic utility in ATTR amyloidosis is moderate, while its role in MS remains limited.},
}

@article {pmid40112890,
year = {2025},
author = {Ying, M and Cheng, Z and Hirth, RA and Hollenbeck, BK and Joynt Maddox, KE and Shahinian, VB and Li, Y},
title = {Skilled Nursing Facility Utilization Among Community-Dwelling Older Adults With Alzheimer's Disease and Related Dementias During the COVID-19 Pandemic.},
journal = {Journal of the American Medical Directors Association},
volume = {},
number = {},
pages = {105551},
doi = {10.1016/j.jamda.2025.105551},
pmid = {40112890},
issn = {1538-9375},
abstract = {OBJECTIVE: To assess the association between skilled nursing facility (SNF) utilization and Alzheimer's disease and related dementias (ADRD) both before and during the COVID-19 pandemic.

DESIGN: An observational cohort study.

SETTING AND PARTICIPANTS: The study included community-dwelling respondents aged 65 or older.

METHODS: This study analyzed data from 3 waves of the Health and Retirement Study and employed multivariable, individual-level regressions. The primary outcomes were any SNF stays, the number of SNF stays, and the total number of SNF days, in the past 2 years of the survey. Respondents were classified as cognitively normal, having cognitive impairment but not dementia (CIND), or having ADRD.

RESULTS: The study included 23,654 respondent-years, representing 12,529 unique respondents. Before the pandemic, differences in any SNF stays, and the number of SNF stays between the cognitively normal and CIND and ADRD groups were statistically insignificant in multivariable regressions. During the pandemic, compared with respondents with normal cognition, those with CIND had higher odds of any SNF stays (OR, 1.53; 95% CI, 1.06-2.20) and more SNF stays (incidence rate ratio [IRR], 2.40; 95% CI, 1.30-4.40); similarly, the ADRD group showed higher odds of any SNF stays (OR, 1.68; 95% CI, 1.08-2.59) and more SNF stays (IRR, 2.48; 95% CI, 1.36-4.47) than cognitively normal older adults. The total number of SNF days for CIND and ADRD respondents remained statistically insignificantly different from those of the cognitively normal group, both before and during the pandemic, in regression analyses.

CONCLUSIONS AND IMPLICATIONS: This cohort study suggests that the pandemic was associated with increased differences in any SNF stays and number of transitions to SNFs between cognitively normal individuals and those with CIND or ADRD. These findings provide a foundation for understanding the potential impact of a public health emergency on post-acute care utilization among older adults with varying degrees of cognitive impairment.},
}

@article {pmid40112813,
year = {2025},
author = {Li, Z and Martens, YA and Ren, Y and Jin, Y and Sekiya, H and Doss, SV and Kouri, N and Castanedes-Casey, M and Christensen, TA and Miller Nevalainen, LB and Takegami, N and Chen, K and Liu, CC and Soto-Beasley, A and Boon, BDC and Labuzan, SA and Ikezu, TC and Chen, Y and Bartkowiak, AD and Xhafkollari, G and Wetmore, AM and Bennett, DA and Reichard, RR and Petersen, RC and Kanekiyo, T and Ross, OA and Murray, ME and Dickson, DW and Bu, G and Zhao, N},
title = {APOE genotype determines cell-type-specific pathological landscape of Alzheimer's disease.},
journal = {Neuron},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.neuron.2025.02.017},
pmid = {40112813},
issn = {1097-4199},
abstract = {The apolipoprotein E (APOE) gene is the strongest genetic risk modifier for Alzheimer's disease (AD), with the APOE4 allele increasing risk and APOE2 decreasing it compared with the common APOE3 allele. Using single-nucleus RNA sequencing of the temporal cortex from APOE2 carriers, APOE3 homozygotes, and APOE4 carriers, we found that AD-associated transcriptomic changes were highly APOE genotype dependent. Comparing AD with controls, APOE2 carriers showed upregulated synaptic and myelination-related pathways, preserving synapses and myelination at the protein level. Conversely, these pathways were downregulated in APOE3 homozygotes, resulting in reduced synaptic and myelination proteins. In APOE4 carriers, excitatory neurons displayed reduced synaptic pathways similar to APOE3, but oligodendrocytes showed upregulated myelination pathways like APOE2. However, their synaptic and myelination protein levels remained unchanged or increased. APOE4 carriers also showed increased pro-inflammatory signatures in microglia but reduced responses to amyloid-β pathology. These findings reveal APOE genotype-specific molecular alterations in AD across cell types.},
}

@article {pmid40112772,
year = {2025},
author = {Bao, H and Zheng, S and Shen, Y},
title = {Sexual dimorphism in cerebrovascular dysfunction: The pivotal role of endothelial CD2AP in Alzheimer's disease.},
journal = {Neuron},
volume = {113},
number = {6},
pages = {797-800},
doi = {10.1016/j.neuron.2025.02.022},
pmid = {40112772},
issn = {1097-4199},
mesh = {*Alzheimer Disease/genetics/physiopathology/metabolism ; Humans ; *Sex Characteristics ; *Cerebrovascular Disorders/physiopathology/genetics/metabolism ; Female ; Animals ; Male ; Endothelium, Vascular/physiopathology/metabolism ; Cerebrovascular Circulation/physiology ; Cytoskeletal Proteins ; Adaptor Proteins, Signal Transducing ; },
abstract = {Why there is sex-biased susceptibility to cerebrovascular dysfunction remains enigmatic. Vandal et al.[1] reveal a sex-specific vulnerability to endothelial deficiency in CD2AP, an Alzheimer's disease risk gene, with impaired cerebrovascular reactivity, compromised cerebrovascular function, and cognitive decline, highlighting sex as an important biological variable in Alzheimer's disease.},
}

*Alzheimer Disease/genetics/physiopathology/metabolism
Humans
*Sex Characteristics
*Cerebrovascular Disorders/physiopathology/genetics/metabolism
Female
Animals
Male
Endothelium, Vascular/physiopathology/metabolism
Cerebrovascular Circulation/physiology
Cytoskeletal Proteins
Adaptor Proteins, Signal Transducing

@article {pmid40112745,
year = {2025},
author = {Saikia, J and Sarkar, M and Ramakrishnan, V},
title = {Factors affecting the physical stability of peptide self-assembly in neurodegenerative disorders.},
journal = {Neuropeptides},
volume = {111},
number = {},
pages = {102517},
doi = {10.1016/j.npep.2025.102517},
pmid = {40112745},
issn = {1532-2785},
abstract = {Biological systems comprise of diverse biomolecules, including proteins, nucleic acids, lipids, and carbohydrates. Peptides, which are short chains of amino acids, exhibit unique properties when assembled to nano-level architectures. Self-assembling peptides possess a remarkable ability to organize into structured aggregates such as nanofibers, nanotubes, nanoribbons, and nanovesicles. These intricate structures are linked to neurodegenerative diseases, including Alzheimer's disease, Parkinson's disease, Prion disease, Huntington's disease, and type II diabetes. Peptide nano assembly can be guided by external stimuli, such as temperature, pH, ultrasound, electric and magnetic fields. In this review, the discussion will be centred around the various factors that influence the self-assembly of peptides alongside therapeutic interventions that align with the fundamental principles of thermodynamics and kinetics to modulate the aggregation characteristics of peptide self-assembly.},
}

@article {pmid40112330,
year = {2025},
author = {Vasileva-Metodiev, SZ and Spargo, D and Klein, EG and Quevenco, FC and Cotton, S and Sanchez-Juan, P and Niimi, Y and Fowler, NR},
title = {Diagnostic journey and management of patients with mild cognitive impairment and Alzheimer's disease dementia: A multinational, real-world survey.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877251322978},
doi = {10.1177/13872877251322978},
pmid = {40112330},
issn = {1875-8908},
abstract = {BackgroundAn Alzheimer's disease (AD) diagnosis made in the earliest symptomatic stages substantially benefits patients and their care partners. However, little is known regarding the clinical, healthcare system-level, and patient-specific barriers that hinder timely diagnosis and treatment.ObjectiveTo explore real-world practices surrounding the diagnostic journey and management of mild cognitive impairment (MCI)/AD dementia patients.MethodsData were drawn from Adelphi Real World Dementia Disease Specific Programme™, a cross-sectional survey of physicians treating MCI/AD dementia patients in France, Germany, Italy, Spain, the United Kingdom, the United States, and Japan between 2022 and 2024.ResultsOverall, 779 physicians reported data on 5551 patients. Physicians indicated current disease severity for 5421 patients; 37.2% had MCI (87.3% with suspected prodromal AD and 12.7% undetermined etiology), 17.2% AD with mild dementia, 31.1% AD with moderate dementia, and 14.5% AD with severe dementia. When not immediately diagnosed, the median time from first consultation to initial diagnosis was 8.9 and 12.6 weeks when patients first consulted and were diagnosed by either a primary care practitioner (PCP) or a specialist, respectively, compared with 21.6 weeks when a PCP referred to a specialist for diagnosis. Diagnostic delays were predominantly due to specialist wait times. Few patients had diagnostic AD biomarker tests (cerebrospinal fluid testing 9.5%, amyloid positron emission tomography 3.7%, AD-blood tests 5.3%).ConclusionsTimely MCI and AD diagnosis is impeded by referral delays and limited use of biomarker testing. Addressing these critical care gaps requires enhanced physician training, reduced wait times and increased biomarker utilization for early management.},
}

@article {pmid40112328,
year = {2025},
author = {Høilund-Carlsen, PF and Werner, TJ and Alavi, A},
title = {The unsafe profile of lecanemab.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877251325891},
doi = {10.1177/13872877251325891},
pmid = {40112328},
issn = {1875-8908},
abstract = {Lack of data from the US Food and Drug Administration (FDA) Adverse Event System makes analyses of the risks of newly approved anti-Alzheimer's antibodies inadequate to determine whether such risks justify the minimal clinical benefits reported. A recent disproportionate analysis in the Journal of Alzheimer's Disease by Ge et al. is a case in point. Among serious adverse effects, it only addresses amyloid associated imaging abnormalities, whereas the even more threatening ones, brain tissue loss and therapy-related death, are not mentioned. We urge the FDA to prioritize monitoring of all adverse effects and encourage transparency from the drug manufacturers.},
}

@article {pmid40112326,
year = {2025},
author = {Ayaz, G and Sordu, P and Küçüksezer, UC and Hanağası, H and Alaylıoğlu, M and Gürvit, H and Gezen-Ak, D and Bilgiç, B and Dursun, E and Ulutin, T},
title = {Association of glycoprotein 1b and miR-26a-5p levels with platelet function in Alzheimer's disease.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877251326204},
doi = {10.1177/13872877251326204},
pmid = {40112326},
issn = {1875-8908},
abstract = {BackgroundAlterations in biochemical and molecular pathways in Alzheimer's disease (AD) may be evident in the brain, blood cells, and vessels. Platelets regulate blood hemostasis and play key roles in neurodegenerative diseases like AD. miR-26a-5p and GP1b may affect platelet functions (PF), with miR-26a-5p as a diagnostic/therapeutic target and GP1b linking vascular and neurological disorders in AD progression.ObjectiveThis study explores the roles of GP1b and hsa-miR-26a-5p in regulating PF in AD.Methods85 participants, including 43 AD, and 45 controls, were included. PF induced by ADP were assessed by optical density and white matter changes by MRI Axial FLAIR. Serum levels of von Willebrand Factor and GP1b were measured by ELISA. Platelet receptor expressions of CD62P and CD42b (GPIb) were measured by flow cytometry, and levels of hsa-miR-26a-5p and hsa-miR-24-3p by qRT-PCR.ResultsADP-induced PF was significantly reduced in AD (p = 0.016). Flow cytometry showed significantly low CD42b and high CD62P expression in AD, respectively (p < 0.0001, p = 0.014). Serum GP1b levels were significantly higher in AD (p = 0.018). Additionally, hsa-miR-26a-5p expression was significantly low in AD (p = 0.001), and a positive correlation was found between the expression levels of hsa-miR-24-3p and hsa-miR-26a-5p in both controls; and AD (r = 0.4149, p = 0.0051, 95% CI = 0.1256-0.6392; r = 0.6820, p = 0.0023, 95% CI 0.4728-0.8184).ConclusionsThis study highlights increased serum GP1b levels with decreased both platelet surface GP1b levels and hsa-miR-26a-5p expressions in AD. GP1b and hsa-miR-26a-5p might have essential roles on PF in AD.},
}

@article {pmid40112322,
year = {2025},
author = {Hu, D and Chen, M and Li, X and Daley, S and Morin, P and Han, Y and Hemberg, M and Weiner, HL and Xia, W},
title = {ApoE ε4-dependent Alteration of CXCR3 [+] CD127[+] CD4[+] T cells associates with elevated plasma neurofilament light chain in Alzheimer's disease.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877251320123},
doi = {10.1177/13872877251320123},
pmid = {40112322},
issn = {1875-8908},
abstract = {BackgroundRecent findings indicate a correlation between the peripheral adaptive immune system and neuroinflammation in Alzheimer's disease (AD).ObjectiveTo characterize the composition of adaptive immune cells in the peripheral blood of AD patients.MethodsWe utilized single-cell mass cytometry (CyTOF) to profile peripheral blood mononuclear cells (PBMCs). Concurrently, we assessed the concentration of proteins associated with AD and neuroinflammation in the plasma of the same subjects.ResultsWe found that the abundance of proinflammatory CXCR3 [+] CD127[+] Type 1 T helper (Th1) cells in AD patients was negatively correlated with the abundance of neurofilament light chain protein. This correlation is apolipoprotein E (ApoE) ε4-dependent. Analyzing public single-cell RNA-sequencing (scRNA-seq) data, we found that, contrary to the scenario in the peripheral blood, the cell frequency of CXCR3 [+] CD127[+] Th1 cells in the cerebrospinal fluid (CSF) of AD patients was increased compared to healthy controls (HCs). Moreover, the proinflammatory capacity of CXCR3[+] CD127[+] Th1 cells in the CSF of AD patients was further increased compared to HCs.ConclusionsThese results reveal an association of a peripheral T-cell change with neuroinflammation in AD and suggest that dysregulation of peripheral adaptive immune responses, particularly involving CXCR3 [+] CD127[+] Th1 cells, may potentially be mediated by factors such as ApoE ε4 genotype.},
}

@article {pmid40112321,
year = {2025},
author = {Katonova, A and Andel, R and Jurasova, V and Veverova, K and Angelucci, F and Matoska, V and Hort, J},
title = {Associations of KLOTHO-VS heterozygosity and α-Klotho protein with cerebrospinal fluid Alzheimer's disease biomarkers.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877251326199},
doi = {10.1177/13872877251326199},
pmid = {40112321},
issn = {1875-8908},
abstract = {BackgroundKLOTHO-VS heterozygosity (KL-VSHET) and soluble α-Klotho (sαKl) protein interfere with Alzheimer's disease (AD) pathophysiology, but the specific relationships remain unclear. This study explored these associations across the AD continuum, focusing on core AD biomarkers and markers of neurodegeneration, neuroinflammation, and synaptic dysfunction.ObjectiveWe investigated whether 1) KL-VSHET is associated with lower AD biomarker burden (Aβ42, Aβ42/40 ratio, P-tau181, T-tau) and neurodegeneration (NfL); 2) sαKl relates to AD biomarkers, neurodegeneration (NfL), neuroinflammation (GFAP), and synaptic dysfunction (Ng); 3) associations vary by APOE ε4 status and clinical subgroup.MethodsParticipants (n = 223) were categorized as cognitively healthy (n = 38), aMCI-AD (n = 94), and AD dementia (n = 91). KLOTHO genotyping was available for 128 participants; 138 had cerebrospinal fluid (CSF) and serum sαKl measurements; and 42 had both. Multiple linear regression evaluated associations between KL-VSHET, sαKl levels, and biomarkers, stratified by APOE ε4 status and clinical subgroup.ResultsOverall, the associations between KL-VSHET and higher CSF Aβ42 and Aβ42/40 ratio were non-significant (ps ≥ 0.059) except when restricted to APOE ε4 carriers only (β = 0.11, p = 0.008 and β = 0.16, p = 0.033, respectively). Within clinical subgroups, KL-VSHET was positively associated with Aβ42/40 ratio only in aMCI-AD (β = 0.23, p = 0.034). No significant associations were observed between KL-VSHET and tau biomarkers or NfL. For sαKl, associations with biomarkers were non-significant except for a negative association of serum sαKl with P-tau181 in aMCI-AD (β = -0.25, p = 0.036) and a positive association with Aβ42/40 ratio in APOE ε4 non-carriers (β = 0.24 p = 0.047).ConclusionsKL-VSHET may help protect against amyloid pathology, particularly in the presence of APOE ε4, and regardless of APOE status in aMCI-AD.},
}

@article {pmid40089222,
year = {2025},
author = {Kim, D and Huang, Y and Liu, J},
title = {Non-invasive MRI measurements of age-dependent in vivo human glymphatic exchange using magnetization transfer spin labeling.},
journal = {NeuroImage},
volume = {310},
number = {},
pages = {121142},
doi = {10.1016/j.neuroimage.2025.121142},
pmid = {40089222},
issn = {1095-9572},
abstract = {BACKGROUND: The water exchange between brain parenchyma and cerebrospinal fluid (CSF) is considered to be responsible for glymphatic clearance of solutes and metabolic wastes from the brain, including amyloid-β, a biomarker in neurodegeneration. Despite the potential significance, no noninvasive technique for in vivo measurement of parenchyma-CSF water exchange has been demonstrated in humans, capable of investigating age-related changes in glymphatic clearance.

PURPOSE: To demonstrate a noninvasive, translatable MRI technique capable of measuring glymphatic water exchange in humans and to apply this technique to examine age-related changes in the glymphatic exchange measures in healthy subjects.

METHODS: Repeating on-resonance magnetization transfer (MT) RF pulses were applied to saturate macromolecules within the brain parenchyma and label its interstitial water, followed by measuring partial CSF saturation resulting from the parenchyma-CSF water exchange. Bloch simulations and phantom experiments determined the extent of direct CSF saturation by the MT pulses. An additional labeling nulling experiment was performed by preemptively saturating parenchyma spins to disable the following MT-based spin labeling, to examine non-exchange contributions to the observed CSF saturation. These techniques were applied to young (n = 6; ages 25-41) and elder (n = 6; ages 53-66) healthy participants to examine age-related changes in their saturation-based exchange measurements.

RESULTS: Both Bloch simulations and phantom experiments indicated small (0.4-0.7 %) direct CSF saturation when B0 inhomogeneities and CSF T2 variations were considered. A statistically significant (P = 0.037) difference was observed in the average CSF saturation ratio within the subarachnoid space (SAS) between the young (4.7 %±0.5 %) and the elder (3.5 %±1.2 %) subjects, with their ages negatively correlating with this exchange metric (R[2]=0.34, P = 0.046). The substantial saturation reductions in the labeling nulling experiment (40-50 % in young; 10-30 % in elder) suggested parenchyma-CSF exchange as a substantial source of the observed saturation signal. These findings survived when the exchange metrics were compensated for potential atrophy-related dilution effect caused by variations in intra-voxel CSF volume.

CONCLUSION: Optimized MT-based parenchyma spin labeling followed by CSF partial saturation measurement demonstrated feasibility of a noninvasive MRI approach to detect glymphatic water exchange between human brain parenchyma and CSF in vivo, with statistically significant findings of age-related differences in the exchange measures.},
}

@article {pmid39964126,
year = {2025},
author = {McIntyre, RS and Rasgon, N and Goldberg, J and Wong, S and Le, GH and Mansur, RB and Rosenblat, JD and Teopiz, KM and Stahl, SM},
title = {The effect of glucagon-like peptide-1 and glucose dependent insulinotropic polypeptide receptor agonists on neurogenesis, differentiation, and plasticity (Neuro-GDP): potential mechanistically informed therapeutics in the treatment and prevention of mental disorders.},
journal = {CNS spectrums},
volume = {30},
number = {1},
pages = {e23},
doi = {10.1017/S1092852925000124},
pmid = {39964126},
issn = {1092-8529},
mesh = {Humans ; *Mental Disorders/drug therapy ; *Neuronal Plasticity/drug effects ; *Receptors, Gastrointestinal Hormone/agonists ; *Neurogenesis/drug effects ; Animals ; *Glucagon-Like Peptide 1/agonists/metabolism ; Glucagon-Like Peptide-1 Receptor ; },
abstract = {Glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) receptor agonists (RAs) mimic naturally occurring GLP-1 and GIP and are highly effective anti-diabetic and anti-obesity agents. In addition to their robust acute and long-term effects on weight, metabolism, and blood pressure, these agents also reduce cardiovascular mortality as well as stroke risk and associated consequences. A replicated and convergent body of preclinical evidence also indicates that incretin receptor agonists activate molecular effectors critical to neuroplasticity, neuroprotection, and anti-apoptosis. Herein, we propose that GLP-1 RAs and GIP RAs are promising transdiagnostic mechanistically informed therapeutics in the treatment and prevention of multiple domains of psychopathology, including general cognitive, reward, and motivation systems and mental disorders. Major neurocognitive disorders (eg, Alzheimer's Disease, Parkinson's Disease), alcohol and substance use disorders, traumatic brain injury, and depressive disorders are near-term therapeutic targets. In addition, GLP-1 RAs and GIP RAs have robust effects on comorbidities that differentially affect persons with mental disorders (eg, cardiovascular, cerebrovascular, and metabolic disorders) and psychotropic drug-related weight gain.},
}

Humans
*Mental Disorders/drug therapy
*Neuronal Plasticity/drug effects
*Receptors, Gastrointestinal Hormone/agonists
*Neurogenesis/drug effects
Animals
*Glucagon-Like Peptide 1/agonists/metabolism
Glucagon-Like Peptide-1 Receptor

@article {pmid36583247,
year = {2025},
author = {De Wit, L and Goldstein, FC and Loring, DW},
title = {Clinical value of the Montreal Cognitive Assessment free recall condition alone versus cued recall and recognition conditions to detect true memory impairment.},
journal = {Applied neuropsychology. Adult},
volume = {32},
number = {1},
pages = {168-173},
doi = {10.1080/23279095.2022.2161050},
pmid = {36583247},
issn = {2327-9109},
mesh = {Humans ; *Mental Recall/physiology ; Aged ; Female ; Male ; *Cues ; *Recognition, Psychology/physiology ; *Memory Disorders/diagnosis/etiology/physiopathology ; *Cognitive Dysfunction/diagnosis/physiopathology ; *Mental Status and Dementia Tests/standards ; Aged, 80 and over ; Middle Aged ; Verbal Learning/physiology ; Sensitivity and Specificity ; },
abstract = {The Montreal Cognitive Assessment (MoCA) is widely used as a screener to characterize cognition. Although only the delayed free recall condition is required for administration, performance on the optional cued recall and multiple-choice recognition conditions may improve diagnostic accuracy over free recall alone. Data on 719 individuals with MCI and 601 controls were obtained from the Alzheimer's Disease Neuroimaging Initiative (ADNI) database. The Rey Auditory Verbal Learning Test (AVLT) delayed free recall condition was used as the gold standard of memory status. Participants with T-scores ≤30 (≤2 SDs below the mean) were classified as memory "impaired." Binary logistic regressions assessed if combined MoCA cued recall/recognition predicted impaired delayed recall on the AVLT beyond the contribution of MoCA free recall. Results showed that MoCA free recall predicted AVLT delayed recall, and that the addition of combined MoCA cued recall/recognition improved the ability to detect impaired AVLT recall, with a better overall model fit. The combined MoCA cued recall/recognition score also had higher specificity and likelihood ratios in detecting memory impairment than MoCA free recall, while higher sensitivity values were present for free recall. Thus, the additional administration of the MoCA cued recall and recognition is recommended.},
}

Humans
*Mental Recall/physiology
Aged
Female
Male
*Cues
*Recognition, Psychology/physiology
*Memory Disorders/diagnosis/etiology/physiopathology
*Cognitive Dysfunction/diagnosis/physiopathology
*Mental Status and Dementia Tests/standards
Aged, 80 and over
Middle Aged
Verbal Learning/physiology
Sensitivity and Specificity

@article {pmid36416227,
year = {2025},
author = {Hromas, G and Rolin, S and Davis, JJ},
title = {Racial differences in positive findings on embedded performance validity tests.},
journal = {Applied neuropsychology. Adult},
volume = {32},
number = {1},
pages = {28-36},
pmid = {36416227},
issn = {2327-9109},
support = {P50 AG005142/AG/NIA NIH HHS/United States ; P50 AG016573/AG/NIA NIH HHS/United States ; P50 AG047266/AG/NIA NIH HHS/United States ; P30 AG010161/AG/NIA NIH HHS/United States ; P50 AG025688/AG/NIA NIH HHS/United States ; P50 AG005133/AG/NIA NIH HHS/United States ; P20 AG068077/AG/NIA NIH HHS/United States ; P30 AG010129/AG/NIA NIH HHS/United States ; P30 AG019610/AG/NIA NIH HHS/United States ; P50 AG033514/AG/NIA NIH HHS/United States ; P30 AG013854/AG/NIA NIH HHS/United States ; P30 AG053760/AG/NIA NIH HHS/United States ; P20 AG068082/AG/NIA NIH HHS/United States ; P30 AG010124/AG/NIA NIH HHS/United States ; P50 AG023501/AG/NIA NIH HHS/United States ; P20 AG068053/AG/NIA NIH HHS/United States ; P50 AG005131/AG/NIA NIH HHS/United States ; P30 AG010133/AG/NIA NIH HHS/United States ; P50 AG016574/AG/NIA NIH HHS/United States ; P50 AG005146/AG/NIA NIH HHS/United States ; U24 AG072122/AG/NIA NIH HHS/United States ; P30 AG035982/AG/NIA NIH HHS/United States ; P50 AG008702/AG/NIA NIH HHS/United States ; U01 AG016976/AG/NIA NIH HHS/United States ; P30 AG008051/AG/NIA NIH HHS/United States ; P50 AG005681/AG/NIA NIH HHS/United States ; P30 AG013846/AG/NIA NIH HHS/United States ; P50 AG047270/AG/NIA NIH HHS/United States ; P50 AG005136/AG/NIA NIH HHS/United States ; P30 AG049638/AG/NIA NIH HHS/United States ; P30 AG012300/AG/NIA NIH HHS/United States ; P50 AG005134/AG/NIA NIH HHS/United States ; P30 AG008017/AG/NIA NIH HHS/United States ; P30 AG066546/AG/NIA NIH HHS/United States ; P50 AG005138/AG/NIA NIH HHS/United States ; P50 AG047366/AG/NIA NIH HHS/United States ; P20 AG068024/AG/NIA NIH HHS/United States ; P30 AG072958/AG/NIA NIH HHS/United States ; P30 AG072959/AG/NIA NIH HHS/United States ; P30 AG028383/AG/NIA NIH HHS/United States ; },
mesh = {Humans ; Male ; Female ; Aged ; *White People/ethnology ; *Black or African American/ethnology ; Aged, 80 and over ; *Neuropsychological Tests/standards/statistics & numerical data ; Cognitive Dysfunction/diagnosis/ethnology ; Middle Aged ; Aging/physiology ; Mental Status and Dementia Tests/standards ; Reproducibility of Results ; White ; },
abstract = {INTRODUCTION: Embedded performance validity tests (PVTs) may show increased positive findings in racially diverse examinees. This study examined positive findings in an older adult sample of African American (AA) and European American (EA) individuals recruited as part of a study on aging and cognition.

METHOD: The project involved secondary analysis of deidentified National Alzheimer's Coordinating Center data (N = 22,688). Exclusion criteria included diagnosis of dementia (n = 5,550), mild cognitive impairment (MCI; n = 5,160), impaired but not MCI (n = 1,126), other race (n = 864), and abnormal Mini Mental State Examination (MMSE < 25; n = 135). The initial sample included 9,853 participants (16.4% AA). Propensity score matching matched AA and EA participants on age, education, sex, and MMSE score. The final sample included 3,024 individuals with 50% of participants identifying as AA. Premorbid ability estimates were calculated based on demographics. Failure rates on five raw score and six age-adjusted scaled score PVTs were examined by race.

RESULTS: Age, education, sex, MMSE, and premorbid ability estimate were not significantly different by race. Thirteen percent of AA and 3.8% of EA participants failed two or more raw score PVTs (p < .0001). On age-adjusted PVTs, 20.6% of AA and 5.9% of EA participants failed two or more (p < .0001).

CONCLUSIONS: PVT failure rates were significantly higher among AA participants. Findings indicate a need for cautious interpretation of embedded PVTs with underrepresented groups. Adjustments to embedded PVT cutoffs may need to be considered to improve diagnostic accuracy.},
}

Humans
Male
Female
Aged
*White People/ethnology
*Black or African American/ethnology
Aged, 80 and over
*Neuropsychological Tests/standards/statistics & numerical data
Cognitive Dysfunction/diagnosis/ethnology
Middle Aged
Aging/physiology
Mental Status and Dementia Tests/standards
Reproducibility of Results
White

@article {pmid40112319,
year = {2025},
author = {Fuseya, K and Mimura, Y and Nakajima, S and Mimura, M and Kasanuki, K and Noda, Y},
title = {A systematic review and meta-analysis on the characteristics of transcranial magnetic stimulation treatment protocols for patients with Alzheimer's disease.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877251325887},
doi = {10.1177/13872877251325887},
pmid = {40112319},
issn = {1875-8908},
abstract = {BackgroundAlzheimer's disease (AD) is the most common neurodegenerative condition causing dementia. Currently, there has been no established non-pharmacological treatment for cognitive decline in patients with AD. Recent evidence suggests that repetitive transcranial magnetic stimulation (rTMS) may be effective as a non-invasive treatment for improving cognitive function in AD.ObjectiveThis study aimed to examine the characteristics of rTMS treatment protocols for patients with ADMethodsWe conducted a systematic literature search on clinical trials on rTMS for improving cognitive decline in patients with AD, using the PubMed, PsycINFO, and Scopus databases and performed a meta-analysis according to the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines. To clarify which cognitive domains in AD are improved by rTMS, meta-analyses were conducted on both global cognitive function and on each cognitive domain including verbal memory, processing speed, and executive function. In addition, sub-analyses of the treatment details of rTMS parameters including stimulation sites, stimulation frequency, stimulation intensity, and with/without the neuro-navigation technique and meta-regression analyses adjusting for gender, education, and the number of rTMS pulses were performed.ResultsThe results showed significant improvements in global cognitive function, while no significant findings in verbal memory, processing speed and executive function. No significant results were found in subgroup analysis or meta-regression.ConclusionsTo enrich the evidence for cognitive enhancement in AD with rTMS, the randomized controlled trials using a unified rTMS protocol with a larger sample size are warranted.},
}

@article {pmid40112274,
year = {2025},
author = {Jeong, SY and Suh, CH and Lim, JS and Shim, WH and Heo, H and Choi, Y and Kim, HS and Kim, SJ and Lee, JH},
title = {Incidence of Amyloid-Related Imaging Abnormalities in Phase III Clinical Trials of Anti-Amyloid-β Immunotherapy: An Updated Meta-Analysis.},
journal = {Neurology},
volume = {104},
number = {8},
pages = {e213483},
doi = {10.1212/WNL.0000000000213483},
pmid = {40112274},
issn = {1526-632X},
mesh = {Humans ; *Amyloid beta-Peptides ; *Alzheimer Disease/genetics/epidemiology/drug therapy ; *Immunotherapy/methods/adverse effects ; *Clinical Trials, Phase III as Topic ; Incidence ; *Apolipoprotein E4/genetics ; *Randomized Controlled Trials as Topic ; Cognitive Dysfunction/epidemiology ; },
abstract = {BACKGROUND AND OBJECTIVES: Amyloid-related imaging abnormalities (ARIA) are key safety considerations in anti-amyloid-β (Aβ) immunotherapy. ARIA can be categorized into 2 types: ARIA characterized by edema and effusion (ARIA-E) or microhemorrhages and superficial siderosis (ARIA-H). In this study, we assessed the incidence of ARIA in phase 3 randomized controlled trials (RCTs) of anti-Aβ immunotherapy and compared the incidence among different agents and APOE ε4 carrier status.

METHODS: PubMed and Embase databases were searched for phase 3 RCTs of anti-Aβ immunotherapy published on or before May 23, 2024. The inclusion criteria were phase 3 trials of anti-Aβ immunotherapy for mild cognitive impairment due to Alzheimer disease (AD) or mild AD dementia, with sufficient data on ARIA-E/H. The pooled incidences of ARIA and subgroup analyses according to various agents and APOE ε4 carrier status were calculated. A sensitivity analysis excluding outliers was performed. The pooled odds ratio (OR) of ARIA-E according to the APOE ε4 carrier status was also calculated.

RESULTS: Nine phase 3 RCT cohorts from 8 eligible studies were identified, analyzing data from 6,315 patients. The pooled incidence of ARIA-E was 9.5% (95% CI 2.8%-27.3%), and the adjusted pooled incidence of ARIA-E was 25.5% (95% CI 20.4%-31.8%) in the sensitivity analysis. The pooled incidence of symptomatic ARIA-E was 6.7% (95% CI 3.5%-12.5%) and that of severe ARIA-E was 3.5% (95% CI 13.8%-8.4%). The pooled incidence of ARIA-H was 17.8% (95% CI 11.0%-27.5%), with the incidence of superficial siderosis was 9.3% (95% CI 6.1%-13.9%). The pooled incidence of isolated ARIA-H was 8.7% (95% CI 7.6%-10.1%). Subgroup analysis showed that homozygous APOE ε4 carriers had significantly higher odds of developing ARIA-E (OR 5.6, 95% CI 3.8-8.2, p < 0.001) than noncarriers. Heterozygous APOE ε4 carriers also had significantly higher odds of developing ARIA-E (OR 1.9, 95% CI 1.5-2.4, p < 0.001) than noncarriers.

DISCUSSION: Although limited by small sample size and cohort-level data, our meta-analysis shows the adjusted pooled incidence of ARIA-E was 25.5% and the pooled incidence of ARIA-H was 17.8% in the recent phase 3 RCTs of anti-Aβ immunotherapy. Homozygous APOE ε4 carriers have a 5.6-fold higher risk of developing ARIA-E than noncarriers.},
}

Humans
*Amyloid beta-Peptides
*Alzheimer Disease/genetics/epidemiology/drug therapy
*Immunotherapy/methods/adverse effects
*Clinical Trials, Phase III as Topic
Incidence
*Apolipoprotein E4/genetics
*Randomized Controlled Trials as Topic
Cognitive Dysfunction/epidemiology

@article {pmid40111940,
year = {2025},
author = {Lastuka, A and Breshock, MR and Taylor, KV and Dieleman, JL},
title = {The costs of dementia care by US state: Medical spending and the cost of unpaid caregiving.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877251326231},
doi = {10.1177/13872877251326231},
pmid = {40111940},
issn = {1875-8908},
abstract = {BackgroundThere are 5.5 million people living with dementia in the United States (US), with the cost of unpaid care making up a significant portion of the care costs.ObjectiveSummarize variation in the cost of dementia care across the US and examine the association between medical spending and costs of unpaid care at the state level.MethodsWe estimated total cost for dementia by combining recent medical spending estimates from the Disease Expenditure project and unpaid care cost estimates from Lastuka and colleagues. Hours of unpaid care were valued as the hourly wage of a home health aide. We used linear regression to measure the association between the cost of unpaid care and medical spending. The spending that would have occurred if unpaid care had been provided by professional home health care workers was used to measure the cost of unpaid care.ResultsThe annual cost of care attributable to dementia in 2019 was $53,502 (95% uncertainty interval [UI] 46,135-60,594) per case. The contribution of unpaid care to total costs varied by state, ranging from 70.2% (95% UI 64.3-75.4) in the District of Columbia to 89.9% (95% UI 87.8-91.5) in Arizona. We found that higher costs of unpaid care were associated with lower medical spending on nursing facility care.ConclusionsThe large variation in total costs of dementia shows that the economic burden of dementia care is distributed unevenly throughout the US.},
}

@article {pmid40111937,
year = {2025},
author = {Wimo, A and Handels, R and Blennow, K and Kirsebom, KB and Selnes, P and Bon, J and Emersic, A and Gonzalez-Ortiz, F and Gregoric Kramberger, M and Sköldunger, A and Speh, A and Timón-Reina, S and Vromen, E and Jelle Visser, P and Winblad, B and Fladby, T},
title = {Cost-effectiveness of diagnosing and treating patients with early Alzheimer's disease with anti-amyloid treatment in a clinical setting.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877251323231},
doi = {10.1177/13872877251323231},
pmid = {40111937},
issn = {1875-8908},
abstract = {BackgroundThe introduction of anti-amyloid treatments (AAT) for Alzheimer's disease (AD) has put the cost-effectiveness into focus.ObjectiveEstimate the potential cost-effectiveness of diagnostic pathways combined with AAT for early AD.MethodsDiagnostic accuracy of blood-based (BBM) and cerebrospinal fluid (CSF) biomarkers was obtained from Norwegian memory clinics using positron emission tomography (PET) as reference standard. In a health-economic model, the cost-effectiveness of three diagnostic strategies was estimated relying either on BBM (p-tau 217), CSF (Aβ42/40 ratio), and BBM with CSF confirmatory testing and compared with standard of care (SoC) and compared with CSF-AAT. The model consisted of a decision tree reflecting the diagnostic process and a subsequent Markov cohort model starting at mild cognitive impairment due to AD. All strategies except SoC were combined with AAT including costs of treatment (assumed €5000/year), infusions and monitoring.ResultsCompared with SoC all three strategies (CSF-AAT, BBM-AAT, and BBM-CSF-AAT) resulted in QALY gains at higher costs, with an incremental cost-effectiveness ratio (ICER) of 110k€, 141k€ and 110k€ respectively. Compared with CSF-AAT both BBM-AAT and BBM-CSF-AAT strategies resulted in QALYs lost at lower costs, with an ICER of 27k€ and 109k€ respectively. Results were particularly sensitive to the price of AAT and possible subcutaneous administration.ConclusionsCompared with SoC all three strategies are potentially not cost-effective as they exceeded the Swedish maximum willingness to pay threshold of €94,800 per QALY gained. BBM-CSF-AAT versus CSF-AAT is potentially cost-effective if willing to accept its QALY loss. Discussions on budget impact on different payers are needed after introducing AAT.},
}

@article {pmid40111935,
year = {2025},
author = {Alami, M and Zerif, E and Khalil, A and Hajji, N and Ramassamy, C and Lacombe, G and Laurent, B and Cohen, AA and Wikowski, JM and Gris, D and Bunt, T and van Tellingen, O and Hirokawa, K and Fulop, T and Berrougui, H},
title = {Neuroprotective effects of SGLT2 inhibitors empagliflozin and dapagliflozin on Aβ1-42-induced neurotoxicity and neuroinflammation in cellular models of Alzheimer's disease.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877251329474},
doi = {10.1177/13872877251329474},
pmid = {40111935},
issn = {1875-8908},
abstract = {BackgroundAlzheimer's disease (AD) is a chronic brain degenerative disease that leads to dementia.ObjectiveThe aim of the present study is to investigate the neuroprotective impact of sodium-glucose cotransporter-2 inhibitors (SGLT2i) (empagliflozin and dapagliflozin) on tau phosphorylation, oxidative stress, and neuroinflammation.MethodsWe used MTT (3-(4, 5-dimethylthiazolyl-2)-2, 5-diphenyltetrazolium bromide) assay, annexin-V-FITC kit, and DCFH-DA (dichloro-dihydro-fluorescein diacetate) to respectively evaluate the effect of the SGLT2i (empagliflozin and dapagliflozin) on amyloid-β (Aβ)1-42-induced neuronal death, apoptosis, and oxidative stress. The expression of NLRP3-inflammasome, phospho-Tau181, glycogen synthase kinase-3 beta (GSK-3β), cyclin-dependent kinase 5 (CdK5), and histone deacetylase 6 (HDAC6), was quantified by flow cytometry. Drug distribution in the mice's brains was assessed by liquid chromatography-mass spectrometry (LC-MS).ResultsAβ1-42 significantly reduced cell viability and increased apoptosis, which was reversed by using gliflozins. SGLT2i significantly reduced Aβ1-42-induced reactive oxygen species generation, downregulated NLRP3-inflammasome, and diminished tau pathology. Mechanistically, the last effect involved the modulation of GSK-3β and CdK5 protein expression. However, the tested treatments did not modify the Aβ1-42-stimulating effect of HDAC6. Gliflozins are substrates of drug transporters ATP-binding cassette sub-family B member 1 and/or ATP binding cassette subfamily G member 2 (ABCB1 and ABCG2), and Elacridar significantly enhances their brain distribution.ConclusionsSGLT2i empagliflozin and dapagliflozin exhibited neuroprotective actions against human Aβ1-42-induced neurotoxicity.},
}

@article {pmid40111934,
year = {2025},
author = {Gui, S and Zeng, F and Wu, Z and Nonaka, S and Sano, T and Ni, J and Nakanishi, H and Moriyama, M and Kanematsu, T},
title = {Lipopolysaccharides from Porphyromonas gingivalis indirectly induce neuronal GSK3β-dependent synaptic defects and cause cognitive decline in a low-amyloid-β-concentration environment in Alzheimer's disease.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877251326879},
doi = {10.1177/13872877251326879},
pmid = {40111934},
issn = {1875-8908},
abstract = {BackgroundLipopolysaccharides from Porphyromonas gingivalis (P.gLPS) are involved in the pathology of Alzheimer's disease (AD). However, the effect of P.gLPS on synaptic defects remains unclear.ObjectiveIn this study, we tested our hypothesis that P.gLPS induces synaptic defects in a low-amyloid-beta (Aβ)-concentration environment.MethodsMG6 microglia or N2a neurons was treated with P.gLPS (0.1 μg/mL), soluble Aβ42 (0.1 μM) or AL (combined P.gLPS and soluble Aβ42 at 0.1 μM).ResultsIn cultured MG6 microglia, increased the mRNA expression of TNF-α, IL-1β and IL-6 and the TNF-α release in parallel with increased NF-κB activation. In cultured N2a neurons, treatment with Aβ42, P.gLPS, and AL did not affect the mRNA expression of synapsin1 (SYN1) or post-synaptic density protein-95 (PSD-95). However, the treatment with conditioned medium from AL-exposed MG6 microglia (AL-MCM) significantly reduced the mRNA and protein expression of SYN1, PSD-95, and nuclear translocation of repressor element-1 silencing transcription factor (REST) but significantly increased the mRNA expression of TNF receptor type I (at 48 h) and glycogen synthase kinase (GSK)3β (at 24 h). TWS119 pretreatment (5 μM), a GSK3β specific inhibitor, significantly reversed the AL-MCM-induced reduction in the mRNA expression of SYN1 and PSD-95 and nuclear translocation of REST in cultured N2a neurons. In APP[NL-F/NL-F] mice, the immunofluorescence intensity of SYN1 and PSD-95 in cortical neurons was positively correlated with the index of the memory test but negatively correlated with that of TNF-α-positive microglia.ConclusionsThese observations demonstrate that P.gLPS induces neuronal GSK3β-dependent synaptic defects in a low-Aβ concentration environment via microglial activation.},
}

@article {pmid40111925,
year = {2025},
author = {Shi, N and Bakulski, KM and Burke, JF and Brouwer, AF},
title = {Predictors of transitions between normal cognition, cognitive impairment, and dementia in a longitudinal cohort.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877251324236},
doi = {10.1177/13872877251324236},
pmid = {40111925},
issn = {1875-8908},
abstract = {BackgroundUnderstanding how sociodemographic characteristics and medical history are associated with progression (or regression) of Alzheimer's disease and related dementias could inform intervention strategies, personalized prognoses, and projections of population-level burden.ObjectiveWe estimated transition rates for progression and reversion between normal cognition, cognitive impairment, dementia, and death in a longitudinal cohort, as well as associations with sociodemographic characteristics and medical history.MethodsWe applied a multistate transition model to a cohort of 960 participants (with 2-16 (median 3) annual visits; 2006-24). Covariate hazard ratios (HRs) were estimated in models adjusted for age group.ResultsSeveral covariates were associated with faster progression from normal cognition to cognitive impairment but slower progression from cognitive impairment to dementia. For example, non-Hispanic Black participants transitioned from normal to cognitive impairment at higher rates (HR: 2.29, 95% CI: 1.63, 3.21) and to dementia at lower rates (HR: 0.12, 95% CI: 0.06, 0.23) than non-Hispanic White participants. Additionally, amnestic versus non-amnestic impairment emerged as a strong predictor of transitions from cognitive impairment by reducing reversion to normal cognition (HR: 0.51, 95% CI: 0.35, 0.74) and accelerating progression to dementia (HR: 2.51, 95% CI: 1.49, 4.22). History of traumatic brain injury was associated with reversion from cognitive impairment to normal cognition (HR: 2.43, 95% CI: 1.13, 5.23).ConclusionsA better understanding and measurement of cognitive impairment is needed to explain and predict both reversion to normal cognition and why factors associated with faster onset of impairment may be associated with delayed onset of dementia.},
}

@article {pmid40111924,
year = {2025},
author = {Lalive, HM and Griffa, A and Pini, L and Rouaud, O and Allali, G},
title = {Biomarkers do not paint the whole picture: The role of clinical expertise and advanced neuroimaging for Alzheimer's disease diagnosis.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877251328953},
doi = {10.1177/13872877251328953},
pmid = {40111924},
issn = {1875-8908},
abstract = {Accurate diagnosis of Alzheimer's disease (AD) in Memory Clinics remains challenging due to the limited specificity of conventional clinical assessment and structural imaging. The recent commentary by Vyhnalek and colleagues advocates for the incorporation of molecular biomarkers for AD diagnosis in clinical practice. However, this approach only partially captures the complexity of disease expression due to co-pathologies such as limbic-predominant age-related TDP-43 encephalopathy, a mimic of AD. At the era of immunotherapy for AD, clinical expertise remains essential to identify AD from its mimics, especially when both entities co-exist, and may rely on advanced neuroimaging techniques such as brain connectivity.},
}

@article {pmid40111921,
year = {2025},
author = {Mews, MA and Naj, AC and Griswold, AJ and , and Below, JE and Bush, WS},
title = {Brain and blood transcriptome-wide association studies identify five novel genes associated with Alzheimer's disease.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877251326288},
doi = {10.1177/13872877251326288},
pmid = {40111921},
issn = {1875-8908},
abstract = {BackgroundGenome-wide association studies (GWAS) have identified numerous genetic variants associated with Alzheimer's disease (AD), but their functional implications remain unclear. Transcriptome-wide association studies (TWAS) offer enhanced statistical power by analyzing genetic associations at the gene level rather than at the variant level, enabling assessment of how genetically-regulated gene expression influences AD risk. However, previous AD-TWAS have been limited by small expression quantitative trait loci (eQTL) reference datasets or reliance on AD-by-proxy phenotypes.ObjectiveTo perform the most powerful AD-TWAS to date using summary statistics from the largest available brain and blood cis-eQTL meta-analyses applied to the largest clinically-adjudicated AD GWAS.MethodsWe implemented the OTTERS TWAS pipeline to predict gene expression using the largest available cis-eQTL data from cortical brain tissue (MetaBrain; N = 2683) and blood (eQTLGen; N = 31,684), and then applied these models to AD-GWAS data (Cases = 21,982; Controls = 44,944).ResultsWe identified and validated five novel gene associations in cortical brain tissue (PRKAG1, C3orf62, LYSMD4, ZNF439, SLC11A2) and six genes proximal to known AD-related GWAS loci (Blood: MYBPC3; Brain: MTCH2, CYB561, MADD, PSMA5, ANXA11). Further, using causal eQTL fine-mapping, we generated sparse models that retained the strength of the AD-TWAS association for MTCH2, MADD, ZNF439, CYB561, and MYBPC3.ConclusionsOur comprehensive AD-TWAS discovered new gene associations and provided insights into the functional relevance of previously associated variants, which enables us to further understand the genetic architecture underlying AD risk.},
}

@article {pmid40111920,
year = {2025},
author = {Cooper, JK},
title = {Differences between East and West may affect dementia studies: Thoughts from the KSA dementia prevalence study.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877251328965},
doi = {10.1177/13872877251328965},
pmid = {40111920},
issn = {1875-8908},
abstract = {While science is the same in the East and West, certain personal characteristics may distort scientific results. This is more likely in the East. An example may be a recent project in the East that measured the prevalence of Alzheimer's disease dementia in a very large group. They found it to be near 1%, which seems very low. Studies that show a low prevalence of Alzheimer's disease dementia could be due to an examination of a very healthy group with very few older people, and/or poor/inaccurate testing (none of which were in this study). Another possibility is that the person, their family or their doctor aim at ignoring or hiding a diagnosis of dementia.},
}

@article {pmid40111918,
year = {2025},
author = {Zhen, Y and Gao, L and Chen, J and Gu, L and Zhang, Z},
title = {Altered face perception in amnestic mild cognitive impairment: Evidence from representational similarity analysis of event-related potential.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877251326294},
doi = {10.1177/13872877251326294},
pmid = {40111918},
issn = {1875-8908},
abstract = {BackgroundStructural changes in medial temporal lobes including the fusiform gyrus, a critical area in face recognition, precede the progression of amnestic mild cognitive impairment (aMCI) to Alzheimer's disease (AD). However, how the neural correlates of face processing altered in aMCI, as well as their association with cognitive impairments, remain unclear.ObjectiveUsing electroencephalogram (EEG), we explored the electrophysiological markers of face-specific visual processing alterations in aMCI and examined their relationship with cognitive deficits.MethodsWe recruited participants with aMCI (n = 32) and healthy controls (HC, n = 41) and used a passive viewing task to measure the event-related potential (ERP) in response to faces and non-face objects. To compare face processing in aMCI patients and HCs, we adopted mass univariate analysis and representational similarity analysis (RSA) to explore aMCI-related alterations in ERPs.ResultsWe found that face inversion effect (FIE) in P1 amplitudes was absent in aMCI patients. Also, compared to HCs, aMCI patients exhibited a lack of right hemisphere advantage in N170 in response to faces. Furthermore, representation similarity analysis of ERP in posterior-temporal regions revealed that aMCI patients represent face and non-face objects distinctively from HCs in the early processing stage. Additionally, the FIE in P1 amplitude positively correlated to aMCI patients' visuospatial functions.ConclusionsThese findings showed aMCI-related changes in the early perceptual processing of faces and highlights the potential of the FIE in P1 amplitude and ERP patterns over occipital-temporal regions as electrophysiological markers for aMCI and AD.},
}

@article {pmid40111916,
year = {2025},
author = {Qiu, SD and Zhang, DD and Ma, LY and Li, QY and Wang, LY and Wang, YD and Wang, YC and Xiong, SY and Tan, L},
title = {Associations of metabolic syndrome with risks of dementia and cognitive impairment: A systematic review and meta-analysis.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877251326553},
doi = {10.1177/13872877251326553},
pmid = {40111916},
issn = {1875-8908},
abstract = {BackgroundPrevious studies have linked metabolic syndrome (MetS) to dementia risk.ObjectiveWe conducted a systematic review and meta-analysis to assess the association between MetS and dementia as well as cognitive impairment, with additional focus on individual MetS components.MethodsWe systematically searched the PubMed, Embase, and Cochrane Library databases from inception through July 2024. We used random-effects models to calculate relative risks (RRs) and odds ratios (ORs) with 95% confidence intervals (CIs). Publication bias was evaluated using the Egger's test, while potential sources of heterogeneity were investigated through meta-regression, subgroup, and sensitivity analyses.ResultsOur analysis included 21 studies with a total of 411,810 participants. MetS was associated with increased risks of all-cause dementia (RR = 1.33, 95% CI = 1.03-1.71, I[2] = 85.8%) and vascular dementia (RR = 2.07, 95% CI = 1.32-3.24, I[2] = 10.1%), but not Alzheimer's disease (RR = 1.10, 95% CI = 0.64-1.91, I[2] = 81.8%). Regarding cognitive impairment, longitudinal studies showed an increased risk (OR = 1.38, 95% CI = 1.24-1.53, I[2] = 3.3%), with similar findings in cross-sectional studies (OR = 1.65, 95% CI = 1.19-2.28, I[2] = 85.3%).ConclusionsThis study found that MetS is significantly associated with increased risks of dementia and cognitive impairment, with each component potentially being a modifiable factor. These findings may help guide clinicians in recommending lifestyle interventions to prevent cognitive decline and promote brain health.},
}

@article {pmid40111912,
year = {2025},
author = {Ye, J and Dai, X and Zhang, C and Duan, Z and Zhou, G and Wang, J},
title = {Investigating the causal relationships between mitochondrial proteins and dementia with Lewy bodies.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877251328882},
doi = {10.1177/13872877251328882},
pmid = {40111912},
issn = {1875-8908},
abstract = {BackgroundDisruptions in mitochondrial function have been implicated in various neurodegenerative diseases. However, the specific role of mitochondrial proteins in the pathogenesis of dementia with Lewy bodies (DLB) remains poorly understood.ObjectiveThis study aims to investigate potential causal relationships between mitochondrial proteins and DLB risk using Mendelian randomization (MR) analysis.MethodsCausal associations between 66 mitochondrial proteins (MPs) and DLB were assessed by MR analysis, utilizing data from comprehensive genome-wide association studies (GWAS), with various analytical methods, including the inverse variance weighted, MR-Egger, and weighted median. Cochran's Q statistics assessed the heterogeneity of instrumental variables.ResultsGenetic predispositions to increased levels of ES1 protein homolog and apoptosis-inducing factor 1 (AIF-1) were associated with an elevated risk of DLB. Conversely, genetic predispositions to increased levels of glutaredoxin-2 (GLRX-2), complement component 1 Q subcomponent-binding protein (C1QBP), and mitochondrial glutamate carrier 2 (GC2) were found to be protective against DLB. Sensitivity analyses revealed no heterogeneity or horizontal pleiotropy among the selected instrumental variables.ConclusionsOur MR study identifies specific MPs potentially causally linked to DLB risk. These findings offer new insights into the MP-related mechanisms underlying DLB pathogenesis and highlight potential therapeutic targets.},
}

@article {pmid40111762,
year = {2025},
author = {Phillips, JM and Dumitrescu, LC and Archer, DB and Regelson, AN and Mukherjee, S and Lee, ML and Choi, SE and Scollard, P and Trittschuh, EH and Kukull, WA and Biber, S and Mez, J and Mahoney, ER and Clifton, M and Libby, JB and Walters, S and Bush, WS and Engelman, CD and Lu, Q and Fardo, DW and Widaman, KF and Buckley, RF and Mormino, EC and Sanders, RE and Clark, LR and Gifford, KA and Vardarajan, B and Cuccaro, ML and Pericak-Vance, MA and Farrer, LA and Wang, LS and Schellenberg, GD and Haines, JL and Jefferson, AL and Johnson, SC and Albert, MS and Keene, CD and Saykin, AJ and Risacher, SL and Larson, EB and Sperling, RA and Mayeux, R and Goate, AM and Renton, AE and Marcora, E and Fulton-Howard, B and Patel, T and Bennett, DA and Schneider, JA and Barnes, LL and Cruchaga, C and Hassenstab, J and Belloy, ME and Andrews, SJ and Resnick, SM and Bilgel, M and An, Y and Beason-Held, LL and Walker, KA and Duggan, MR and Klinedinst, BS and Crane, PK and Hohman, TJ},
title = {Novel modelling approaches to elucidate the genetic architecture of resilience to Alzheimer's disease.},
journal = {Brain : a journal of neurology},
volume = {},
number = {},
pages = {},
doi = {10.1093/brain/awaf106},
pmid = {40111762},
issn = {1460-2156},
abstract = {Up to 30% of older adults meet pathological criteria for a diagnosis of Alzheimer's disease at autopsy yet never show signs of cognitive impairment. Recent work has highlighted genetic drivers of this resilience, or better-than-expected cognitive performance given a level of neuropathology, that allow the aged brain to protect itself from the downstream consequences of amyloid and tau deposition. However, models of resilience have been constrained by reliance on measures of neuropathology, substantially limiting the number of participants available for analysis. We sought to determine if novel approaches using APOE allele status, age, and other demographic variables as a proxy for neuropathology could still effectively quantify resilience and uncover novel genetic drivers associated with better-than-expected cognitive performance while vastly expanding sample size and statistical power. Leveraging 20,513 participants from eight well-characterized cohort studies of aging, we determined the effects of genetic variants on resilience metrics using mixed-effects regressions. The outcome of interest was residual cognitive resilience, quantified from residuals in three cognitive domains (memory, executive function, and language) and built within two frameworks: "silver" models, which obviate the requirement for neuropathological data (n=17,241), and "gold" models, which include post-mortem neuropathological assessments (n=3,272). We then performed cross-ancestry genome wide association studies (European ancestry n=18,269, African ancestry n=2,244), gene and pathway-based tests, and genetic correlation analyses. All analyses were conducted across all participants and repeated when restricted to those with unimpaired cognition at baseline. Despite different modeling approaches, the silver and gold phenotypes were highly correlated (R=0.77-0.88) and displayed comparable performance in quantifying better-than or worse-than-expected cognition, enabling silver-gold meta-analyses. Genetic correlation analyses highlighted associations of resilience with multiple neuropsychiatric and cardiovascular traits (PFDR values < 5.0x10-2). In pathway-level tests, we observed three significant associations with resilience: metabolism of amino acids and derivatives (PFDR=4.1x10-2), negative regulation of transforming growth factor beta production (PFDR=1.9x10-2), and severe acute respiratory syndrome (PFDR=3.9x10-4). Finally, in single-variant analyses, we identified a locus on chromosome 17 approaching genome-wide significance among cognitively unimpaired participants (index single nucleotide polymorphism: rs757022, minor allele frequency = 0.18, β=0.08, P=1.1x10-7). The top variant at this locus (rs757022) was significantly associated with expression of numerous ATP-binding cassette genes in brain. Overall, through validating a novel modeling approach, we demonstrate the utility of silver models of resilience to increase statistical power and participant diversity.},
}

@article {pmid40111696,
year = {2025},
author = {Zeng, Y and Lin, D and Chen, A and Ning, Y and Li, X},
title = {Periodontal Treatment to Improve General Health and Manage Systemic Diseases.},
journal = {Advances in experimental medicine and biology},
volume = {1472},
number = {},
pages = {245-260},
pmid = {40111696},
issn = {0065-2598},
mesh = {Humans ; *Periodontitis/microbiology/therapy/immunology ; Dysbiosis/therapy/microbiology ; Microbiota ; Cardiovascular Diseases/therapy/microbiology/immunology ; },
abstract = {Periodontitis is increasingly recognized for its role in overall health and its associations with systemic conditions. Shared etiological factors, including microbiological, immunological, genetic, and environmental influences, have prompted interest in the potential impact of periodontal therapy on broader health outcomes. The oral microbiome plays a key role in the pathogenesis of periodontitis, with microbial imbalances (dysbiosis) contributing to inflammation and systemic disease progression. Additionally, immune responses to periodontal infection, such as chronic inflammation and dysregulated immune activity, are central to linking periodontitis with conditions like diabetes, cardiovascular disease, and autoimmune disorders. This chapter explores the connections between periodontal treatment and systemic diseases, such as diabetes, rheumatoid arthritis, cardiovascular disease, chronic kidney disease, Alzheimer's disease, digestive disorders, and respiratory disease. It also reviews the current research on the mechanisms, including microbial and immune factors, that underlie these associations. By emphasizing the role of periodontal health, the oral microbiome, and immune regulation in disease prevention and management, this chapter underscores the importance of integrated healthcare approaches to improve patient outcomes.},
}

Humans
*Periodontitis/microbiology/therapy/immunology
Dysbiosis/therapy/microbiology
Microbiota
Cardiovascular Diseases/therapy/microbiology/immunology

@article {pmid40111692,
year = {2025},
author = {Gao, C and Kang, J},
title = {Oral Diseases Are Associated with Cognitive Decline and Dementia.},
journal = {Advances in experimental medicine and biology},
volume = {1472},
number = {},
pages = {171-183},
pmid = {40111692},
issn = {0065-2598},
mesh = {Humans ; *Dementia/epidemiology/etiology ; *Cognitive Dysfunction/epidemiology ; Risk Factors ; Mouth Diseases/epidemiology ; Oral Health ; },
abstract = {Common oral diseases, including periodontitis and dental caries, and their endpoint as tooth loss are controllable yet highly prevalent among adults worldwide. Cognitive decline also poses significant global public health challenges during the aging process, especially the pathological form of cognitive decline such as dementia. Dementia is irreversible and is one of the leading causes of death, disability, and dependency in the aging population. Emerging research suggests a bidirectional association between oral diseases and cognitive decline or dementia. This potential link has implications for designing better oral care plans for patients with dementia and recognizing oral diseases as modifiable risk factors for dementia prevention.This chapter provides an overview of the association between oral diseases and cognitive decline, followed by a discussion of current evidence on such associations in two directions: (1) the impact of cognitive decline or dementia on oral health and (2) the role of oral diseases as modifiable risk factors for dementia. We critically evaluate several hypotheses regarding the underlying mechanisms of this association, including (1) life-course hypothesis, (2) shared inflammation and bacterial infection mechanisms, (3) malnourishment mechanism, (4) pain pathway, and (5) sensory feedback pathway.However, the association between oral diseases and cognitive decline or dementia remains controversial due to limited high-quality evidence, particularly from biomedical research. Much of the existing evidence is from observational studies prone to confounding bias, with inconclusive questions about causation and the direction of causality.This chapter concludes by emphasizing the need for future studies with robust methodological designs, including randomized controlled trials, biomedical studies, and innovative research techniques such as Mendelian randomization. Such studies are crucial for disease prevention and enhancing patient care and quality of life. By providing a comprehensive overview, this chapter contributes to an advanced understanding of this field, addresses current study gaps, and suggests future research directions.},
}

Humans
*Dementia/epidemiology/etiology
*Cognitive Dysfunction/epidemiology
Risk Factors
Mouth Diseases/epidemiology
Oral Health

@article {pmid40111689,
year = {2025},
author = {Mattos, MCO and Vivacqua, A and Carneiro, VMA and Grisi, DC and Guimarães, MDCM},
title = {Interaction of the Systemic Inflammatory State, Inflammatory Mediators, and the Oral Microbiome.},
journal = {Advances in experimental medicine and biology},
volume = {1472},
number = {},
pages = {121-132},
pmid = {40111689},
issn = {0065-2598},
mesh = {Humans ; *Microbiota/immunology ; *Mouth/microbiology/immunology ; *Inflammation Mediators/metabolism ; *Inflammation/microbiology/immunology ; *Periodontitis/microbiology/immunology ; Dysbiosis/microbiology/immunology ; Animals ; },
abstract = {Humans are biological units that host numerous microbial symbionts and their genomes, which together form a superorganism or holobiont. Changes in the balance of the oral ecosystem can have consequences for both general and oral health, such as cavities, gingivitis, and periodontitis. Periodontitis is initiated by a synergistic and dysbiotic microbial community that causes local inflammation and destruction of the tooth's supporting tissues, potentially leading to systemic inflammation. This inflammation caused by periodontal disease has been associated with various systemic alterations, and the immune system is largely responsible for the body's exacerbated response, which can induce and exacerbate chronic conditions. Studies indicate that subgingival microorganisms found in periodontitis reach the bloodstream and are distributed throughout the body and, therefore, can be found in distant tissues and organs. Among all diseases associated with periodontal disease, diabetes mellitus presents the strongest and most elucidated link, and its bidirectional relationship has already been demonstrated. Chronic hyperglycemia favors the worsening of periodontal parameters, while the aggravation of periodontal parameters can promote an increase in glycemic indexes. Other systemic diseases have been related to periodontitis, such as Alzheimer's, chronic kidney disease, atherosclerosis, and respiratory diseases. The importance of periodontal control may suggest a reduction in the chances of developing chronic inflammatory diseases because these two alterations often share inflammatory pathways and, for this reason, may influence each other.},
}

Humans
*Microbiota/immunology
*Mouth/microbiology/immunology
*Inflammation Mediators/metabolism
*Inflammation/microbiology/immunology
*Periodontitis/microbiology/immunology
Dysbiosis/microbiology/immunology
Animals

@article {pmid40111670,
year = {2025},
author = {Serag, I and Abouzid, M and Moawad, MHED and Jaradat, JH and Hendawy, M and Hendi, NI and Alkhawaldeh, IM and Abdullah, JA and Elsakka, MM and Muneer, MA and Elnagar, MA and Fakher, MA and Elkenani, AJ and Abbas, A},
title = {Vaccines for Alzheimer's disease: a brief scoping review.},
journal = {Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology},
volume = {},
number = {},
pages = {},
pmid = {40111670},
issn = {1590-3478},
abstract = {BACKGROUND: Alzheimer's disease (AD) is a neurodegenerative disorder and the most common cause of dementia among older adults. Existing treatments-such as cholinesterase inhibitors, N-methyl-D-aspartate receptor antagonists, and monoclonal antibodies targeting amyloid beta-can improve functional and neuropsychiatric outcomes but fail to prevent disease onset, halt progression, or adequately reduce amyloid-beta burden. Consequently, research efforts have shifted to primary prevention through immunization, although the efficacy of these strategies remains uncertain. This review explores the efficacy, safety, and adverse events of current immunotherapies for AD and discusses future research and clinical implications.

METHODS: A scoping review was conducted following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses for Scoping Reviews (PRISMA-SR) checklist. A systematic search was carried out using PubMed, Scopus, and Web of Science.

RESULTS: A total of 145 studies were included. Preclinical research often employed transgenic mouse models to investigate AD pathology and vaccine benefits, while Phase I and II clinical trials centered on safety and preliminary efficacy in humans. Most studies were conducted in the USA, China, and Japan, highlighting these countries' strong clinical trial infrastructure. Vaccination frequently reduced amyloid-beta or tau pathology in preclinical settings, although cognitive outcomes were inconsistent. Clinical trials primarily focused on safety and immune response, with newer vaccines such as ABvac40 demonstrating encouraging results and minimal adverse events.

CONCLUSION: Although AD vaccines show promise in preclinical settings, longer and more comprehensive clinical trials are necessary to determine their long-term efficacy and safety. Standardized protocols and efforts to reduce regional disparities in research would facilitate better comparability and generalizability of findings, thereby guiding the future development of effective immunotherapies for Alzheimer's disease.},
}

@article {pmid40111590,
year = {2025},
author = {Azargoonjahromi, A and Eivazi, M and Nasiri, H and Tarhriz, V and Payandeh, Z and , },
title = {Elevated CSF GAP-43 in Mild Cognitive Impairment Linked to Cognitive Impairment Through Increased Amyloid-β Accumulation, with a Shift to Reduced Amyloid-β Accumulation in Alzheimer's Disease.},
journal = {Journal of molecular neuroscience : MN},
volume = {75},
number = {2},
pages = {39},
pmid = {40111590},
issn = {1559-1166},
mesh = {Humans ; *Alzheimer Disease/cerebrospinal fluid/metabolism ; Male ; Female ; *Amyloid beta-Peptides/cerebrospinal fluid/metabolism ; Aged ; *GAP-43 Protein/metabolism ; *Cognitive Dysfunction/cerebrospinal fluid/metabolism/diagnostic imaging ; Aged, 80 and over ; Biomarkers/cerebrospinal fluid ; Positron-Emission Tomography ; Brain/metabolism/diagnostic imaging ; },
abstract = {Growth-associated protein 43 (GAP-43), a key regulator of synaptic plasticity, neuronal growth, and memory, has recently been identified as a crucial biomarker for synaptic dysfunction in mild cognitive impairment (MCI) and Alzheimer's disease (AD) dementia. This study aimed to explore the mechanisms underlying GAP-43's role in cognitive impairment by examining the relationship between CSF GAP-43 levels and amyloid-β (Aβ) accumulation in brain regions like the frontal, temporal, and parietal lobes. This study included 332 participants sourced from the Alzheimer's Disease Neuroimaging Initiative (ADNI), categorized into three groups: 93 cognitively normal (CN), 218 with MCI, and 21 with AD dementia. Cognitive status was assessed with ADAS-Cog 13, CSF GAP-43 levels via ELISA, and Aβ accumulation using florbetapir PET imaging and Syngo.PET for SUVr values in key brain regions. The results revealed that CSF GAP-43 levels were highest in the AD dementia group, followed by the MCI group, and lowest in the CN group, with a significant difference (p < 0.001), indicating a link between elevated CSF GAP-43 and cognitive impairment. In MCI group, CSF GAP-43 positively correlated with Aβ accumulation in all regions: Globally (β = 0.362, p < 0.001), frontal (β = 0.388, p < 0.001), temporal (β = 0.382, p < 0.001), and parietal lobes (β = 0.344, p < 0.001). In contrast, the AD dementia group exhibited negative correlations between CSF GAP-43 levels and Aβ accumulation, significantly in the frontal (β = - 0.513, p = 0.035) and parietal lobes (β = - 0.513, p = 0.035), suggesting a shift in the CSF GAP-43-Aβ relationship in AD dementia. Mediation analysis, adjusted for age, gender, education, and ApoE ɛ4 status, revealed that elevated CSF GAP-43 is linked to increased cognitive impairment via increasing Aβ accumulation solely in MCI, with significant effects in global (β = 0.0894, CI: [0.0427, 0.1457]), frontal (β = 0.0895, CI: [0.0422, 0.1443]), temporal (β = 0.0941, CI: [0.0466, 0.1522]), and parietal (β = 0.0499, CI: [0.0100, 0.0945]) regions. Thus, elevated CSF GAP-43 may contribute to cognitive impairment by promoting Aβ accumulation in individuals with MCI, while in AD dementia, it may be associated with reduced Aβ accumulation, potentially reflecting a compensatory or disease-stage-dependent effect. This dynamic relationship suggests that GAP-43 could play a dual role in neurodegeneration, influencing Aβ pathology differently across disease stages.},
}

Humans
*Alzheimer Disease/cerebrospinal fluid/metabolism
Male
Female
*Amyloid beta-Peptides/cerebrospinal fluid/metabolism
Aged
*GAP-43 Protein/metabolism
*Cognitive Dysfunction/cerebrospinal fluid/metabolism/diagnostic imaging
Aged, 80 and over
Biomarkers/cerebrospinal fluid
Positron-Emission Tomography
Brain/metabolism/diagnostic imaging

@article {pmid40111567,
year = {2025},
author = {Bhratee, A and Chatterjee, D and Kaur, R and Singh, S},
title = {Protective mechanism of apigenin in proton pump inhibitor-associated progressive cognitive impairment in adult zebrafish via targeting GSK-3β pathway.},
journal = {Metabolic brain disease},
volume = {40},
number = {4},
pages = {155},
pmid = {40111567},
issn = {1573-7365},
mesh = {Animals ; *Zebrafish ; *Apigenin/pharmacology/therapeutic use ; *Glycogen Synthase Kinase 3 beta/metabolism/antagonists & inhibitors ; *Cognitive Dysfunction/chemically induced/drug therapy/metabolism/prevention & control ; *Neuroprotective Agents/pharmacology/therapeutic use ; *Proton Pump Inhibitors/pharmacology ; Oxidative Stress/drug effects ; Signal Transduction/drug effects ; Male ; },
abstract = {Cognitive impairment is characterized by memory loss and difficulty in focusing, remembering, adhering to directions, and solving problems; commonly seen in an elderly population. Apigenin (APG) (4', 5, 7-trihydroxyflavone) is a flavonoid with several positive health benefits, including chemoprevention, antioxidant and can suppress inflammatory responses by inhibiting TNF-α and IL-1β levels. In this experimental study, we observed the possible neuroprotective effects of APG in the zebrafish model exposed to Lansoprazole (LPZ), a proton pump inhibitor known to induce cognitive impairment through hyperactivation of GSK-3β pathway. This experiment involves 12 adult zebrafish per group, where one group received LPZ (100 mg) as a toxin for 7 days and APG (25, 50, and 100 mg/kg) as treatment, while DPZ (5 mg/kg) served as a standard comparison over the same period. Neurobehavioral tests such as T-Maze, Novel Tank Test (NTT), and Novel Object Recognition (NOR) were performed. Several biochemical assessments were also performed to evaluate the level of lipid peroxidation (LPO), glutathione (GSH), nitrite (NO), acetylcholinesterase activity (AChEs), catalase activity, neurotransmitters (GABA and glutamate), neuroinflammatory markers (IL-1β, TNF-α, and IL-10), and histopathological analysis. The results showed that apigenin enhanced memory function, improved neurotransmitter balance, decreased oxidative stress markers, regulated the production of proinflammatory cytokines, and inhibited GSK-3β activity. Additionally, the co-administration of a GSK-3β inhibitor further promoted neuroprotection and cognitive enhancement facilitated by apigenin, highlighting the importance of the GSK-3β signaling pathway. These findings highlight the potential of apigenin as a natural compound for mitigating cognitive dysfunction. However, this study should also include long-term toxicity assessments and deeper molecular analysis to elucidate Apigenin's mechanism of action fully. Future research should address these gaps to validate its therapeutic potential.},
}

Animals
*Zebrafish
*Apigenin/pharmacology/therapeutic use
*Glycogen Synthase Kinase 3 beta/metabolism/antagonists & inhibitors
*Cognitive Dysfunction/chemically induced/drug therapy/metabolism/prevention & control
*Neuroprotective Agents/pharmacology/therapeutic use
*Proton Pump Inhibitors/pharmacology
Oxidative Stress/drug effects
Signal Transduction/drug effects
Male

@article {pmid40111522,
year = {2025},
author = {Alsabbagh, MM and Bakhiet, M and Taha, S},
title = {Transcriptome dissection reveals the molecular basis of systemic associations in psoriasis.},
journal = {Archives of dermatological research},
volume = {317},
number = {1},
pages = {607},
pmid = {40111522},
issn = {1432-069X},
support = {Reference Number E005-PI-04/17//Arabian Gulf University/ ; },
}

@article {pmid40110699,
year = {2025},
author = {Safai, A and Buckingham, WR and Jonaitis, EM and Langhough, RE and Johnson, SC and Powell, WR and Kind, AJ and Bendlin, BB and Tiwari, P},
title = {Association of neighborhood disadvantage with cognitive function and cortical disorganization in an unimpaired cohort: An exploratory study.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21},
number = {3},
pages = {e70095},
doi = {10.1002/alz.70095},
pmid = {40110699},
issn = {1552-5279},
support = {R01 MD010243/MD/NIMHD NIH HHS/United States ; R01AG070883/AG/NIA NIH HHS/United States ; RF1AG057784/AG/NIA NIH HHS/United States ; R01AG027161/AG/NIA NIH HHS/United States ; //UW-Madison Radiology start up fund/ ; R01 MD010243/MD/NIMHD NIH HHS/United States ; },
mesh = {Humans ; Male ; Female ; Aged ; *Cognition/physiology ; Cohort Studies ; *Cognitive Dysfunction/pathology ; Alzheimer Disease/pathology ; Neuropsychological Tests/statistics & numerical data ; Cerebral Cortex/pathology/diagnostic imaging ; Residence Characteristics ; Magnetic Resonance Imaging ; Neighborhood Characteristics ; Middle Aged ; Wisconsin/epidemiology ; },
abstract = {INTRODUCTION: Neighborhood disadvantage has been shown to impact health and cognitive outcomes, while morphological similarity network (MSN) can elucidate structural morphological patterns underlying cognitive functions. We hypothesized MSNs could provide cortical patterns linked with neighborhood disadvantage and cognitive function, explaining the potential risk of cognitive impairment in disadvantaged neighborhoods.

METHODS: For cognitively unimpaired participants from the Wisconsin Alzheimer's Disease Research Center or Wisconsin Registry for Alzheimer's Prevention (n = 524), and the Alzheimer's Disease Neuroimaging Initiative (ADNI) cohort (n = 100), neighborhood disadvantage was obtained using Area Deprivation Index (ADI) and its association with cognitive performance and MSN features was analyzed using linear regression and mediation analysis.

RESULTS: Neighborhood disadvantage was associated with worse cognitive performance on memory, executive function, processing speed, and preclinical Alzheimer's tests on both datasets. Local morphological organization of predominantly the frontal and temporal regions showed association trends with ADI.

DISCUSSION: Morphological patterns associated with ADI, in-part, may explain the risk for poor cognitive functioning in a neighborhood disadvantaged population.

HIGHLIGHTS: Social determinants of health such as neighborhood context can be studied using ADI. High neighborhood disadvantage was related to worse performance on category fluency, implicit learning speed, story recall memory and pre-clinical Alzheimer's cognitive composite. In this exploratory study, using morphological brain networks that indicate similarity in distribution of cortical thickness between regions, we observed that centrality of predominantly frontal and temporal regions was marginally linked with neighborhood disadvantage status and also partially mediated its association with preclinical Alzheimer's composite test. There is a potential role for considering neighborhood status in early screening of cognitive impairment and dementia.},
}

Humans
Male
Female
Aged
*Cognition/physiology
Cohort Studies
*Cognitive Dysfunction/pathology
Alzheimer Disease/pathology
Neuropsychological Tests/statistics & numerical data
Cerebral Cortex/pathology/diagnostic imaging
Residence Characteristics
Magnetic Resonance Imaging
Neighborhood Characteristics
Middle Aged
Wisconsin/epidemiology

@article {pmid40110691,
year = {2025},
author = {Guzmán-Hernández, R and Fossati, S},
title = {Fibrillar tau alters cerebral endothelial cell metabolism, vascular inflammatory activation, and barrier function in vitro and in vivo.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21},
number = {3},
pages = {e70077},
doi = {10.1002/alz.70077},
pmid = {40110691},
issn = {1552-5279},
support = {R01NS104127/GF/NIH HHS/United States ; R01AG062572/GF/NIH HHS/United States ; //Pennsylvania Department of Health Collaborative Research on Alzheimer's Disease (PA Cure)/ ; //Pennsylvania Department of Health/ ; R01NS104127/NS/NINDS NIH HHS/United States ; R01AG062572/AG/NIA NIH HHS/United States ; },
mesh = {Animals ; *Blood-Brain Barrier/metabolism ; Mice ; *Endothelial Cells/metabolism ; *tau Proteins/metabolism ; Tauopathies/metabolism/pathology ; Mice, Transgenic ; Alzheimer Disease/metabolism/pathology ; Brain/metabolism/pathology ; Glycolysis/physiology/drug effects ; Disease Models, Animal ; Humans ; },
abstract = {INTRODUCTION: The presence of tau aggregates in and around the brain vasculature in Alzheimer's disease (AD) and tauopathies suggests its possible pathogenicity to cerebral endothelial cells (ECs).

METHODS: We used an in vitro model of the blood-brain barrier (BBB) to understand the mechanisms of fibrillar tau-mediated cerebral EC and BBB pathology, confirming our findings in 3-month-old P301S mice brains and extracted microvessels.

RESULTS: Protofibrillar and fibrillar tau species induce endothelial barrier permeability through an increase in glycolysis, which activates ECs toward a pro-inflammatory phenotype, inducing loss of junction protein expression and localization. The Warburg-like metabolic shift toward glycolysis and increased vascular pathological phenotypes are also present in young P301S mice.

DISCUSSION: In sum, our work reveals that fibrillar tau species, by enhancing endothelial glycolytic metabolism, promote vascular inflammatory phenotypes and loss of BBB function, highlighting the importance of addressing and targeting early tau-mediated neurovascular damage in AD and tauopathies.

HIGHLIGHTS: We improve the understanding of the mechanisms of vascular pathology in tauopathies. Fibrillar tau mediates vascular metabolic changes, inflammation, and blood-brain barrier (BBB) dysfunction. These events are replicated at early stages in a tauopathy mouse model. Inhibiting altered glycolysis reduces BBB permeability and endothelial activation.},
}

Animals
*Blood-Brain Barrier/metabolism
Mice
*Endothelial Cells/metabolism
*tau Proteins/metabolism
Tauopathies/metabolism/pathology
Mice, Transgenic
Alzheimer Disease/metabolism/pathology
Brain/metabolism/pathology
Glycolysis/physiology/drug effects
Disease Models, Animal
Humans