@article {pmid41973126,
year = {2026},
author = {Shinde, P and Sathiyanarayanan, A and Lohidasan, S},
title = {Exploration of potential neuroprotective agents from medicinal plants for the treatment of Alzheimer's disease-approach through in silico ADMET, network pharmacology, docking, and dynamics studies.},
journal = {Journal of molecular modeling},
volume = {32},
number = {5},
pages = {},
pmid = {41973126},
issn = {0948-5023},
mesh = {*Alzheimer Disease/drug therapy ; *Molecular Docking Simulation ; *Neuroprotective Agents/chemistry/pharmacology/pharmacokinetics/therapeutic use ; Molecular Dynamics Simulation ; Network Pharmacology ; Humans ; *Plants, Medicinal/chemistry ; *Phytochemicals/chemistry/pharmacology/pharmacokinetics ; },
abstract = {CONTEXT: A degenerative brain disorder that causes memory loss is Alzheimer's disease (AD). Phytoconstituents represent a promising therapeutic strategy due to their diverse bioactivities and favourable safety profiles. This study aimed to identify potential neuroprotective phytoconstituents for AD by pharmacokinetic screening, network pharmacology, molecular docking and molecular dynamics simulation. Among 22 phytoconstituents analysed, the network revealed GSK3β, STAT3, MAOB, ESR1, and PTGS2 as key AD-associated targets. Docking results were supported by dynamic stability analysis. The combined computational results support rosmariquinone as a potential neuroprotective lead compound for AD treatment.

METHODS: Pharmacokinetic and toxicity profiling of 22 phytoconstituents was performed using Swiss ADME and ProTox III software. Target prediction and construction of the phytoconstituent-disease target-gene interaction network were conducted using Swiss Target Prediction, Gene Card and Cytoscape. Pathway enrichment was evaluated via KEGG and GO analysis. Molecular docking of all shortlisted phytoconstituents against AD-related targets was carried out using AutoDock Vina, while 500 ns molecular dynamics simulations were performed using the Desmond module of the Schrödinger Suite to assess complex stability, RMSD, RMSF and hydrogen-bond fluctuation.},
}

*Alzheimer Disease/drug therapy
*Molecular Docking Simulation
*Neuroprotective Agents/chemistry/pharmacology/pharmacokinetics/therapeutic use
Molecular Dynamics Simulation
Network Pharmacology
Humans
*Plants, Medicinal/chemistry
*Phytochemicals/chemistry/pharmacology/pharmacokinetics

@article {pmid41973520,
year = {2026},
author = {Franco Rocha, OY and Janelsins, MC and Magnuson, A},
title = {Decision-making and treatment planning for older adults with pre-existing cognitive impairment and cancer.},
journal = {Current opinion in supportive and palliative care},
volume = {},
number = {},
pages = {},
doi = {10.1097/SPC.0000000000000804},
pmid = {41973520},
issn = {1751-4266},
abstract = {PURPOSE OF REVIEW: The review aims to synthesize the current evidence on decision-making and cancer treatment planning for older adults with pre-existing cognitive impairment, Alzheimer's disease, and other related dementias.

RECENT FINDINGS: Current decision-making practices are not standardized, and evidence suggests that oncology physicians conduct burden-benefit analyses to guide treatment planning. There was a consensus on the importance of involving caregivers into the decision-making process. However, caregivers experience feelings of anxiety, uncertainty, and extra burden when deciding between treatment options and providing care. Nursing home staffs were frequently excluded from the decision-making process and were perceived as unprepared to identify and manage cancer symptoms. The planning and provision of care for this population can be guided by a comprehensive geriatric assessment (CGA). CGA can inform the decision-making process based on the patient's functionality and caregiver's resources, facilitate management of cancer care, guide the identification and management of cancer symptoms, and assist communication with patients and their caregivers.

SUMMARY: Decision-making and treatment planning for older adults with cancer and pre-existing cognitive impairment lacks standardization. CGA offers a standardized approach to guide treatment decisions, manage symptoms, and coordinate care by highlighting the needs and resources of patients and caregivers.},
}

@article {pmid41974642,
year = {2026},
author = {Xing, L and Liu, A and Gao, W and Li, J and Yao, M and Song, J and Duan, P and Li, H},
title = {Beyond the neuron: Exosomes as intercellular modulators of mitochondrial networks in the pathogenesis and treatment of Alzheimer's disease.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {22},
number = {4},
pages = {e71330},
doi = {10.1002/alz.71330},
pmid = {41974642},
issn = {1552-5279},
support = {82105035//National Natural Science Foundation of China/ ; LH2023H064//Nature Science Foundation of Heilongjiang Province/ ; ZHY2024-304//Research Project of the Traditional Chinese Medicine Administration of Heilongjiang Province/ ; },
mesh = {Humans ; *Exosomes/metabolism ; *Alzheimer Disease/metabolism/therapy/pathology ; *Mitochondria/metabolism ; *Neurons/metabolism ; Animals ; Autophagy/physiology ; },
abstract = {Alzheimer's disease (AD) is a devastating neurodegenerative disorder characterized by β-amyloid deposition, hyperphosphorylated tau protein, and progressive neuronal loss. Mitochondria form a dynamic interconnected network within the central nervous system, and their dysfunction plays a central role in AD, involving oxidative stress, kinetic dysregulation, and impaired mitochondrial autophagy. As key mediators of intercellular communication, exosomes carry bioactive components that regulate mitochondrial function in recipient cells. This review summarizes advances in research on exosomes as coordinators of the mitochondrial network in the central nervous system, regulating mitochondrial quality control across different neuronal cell types. It systematically outlines the molecular mechanisms by which exosomes modulate mitochondrial function in AD through regulating mitochondrial biogenesis, fusion-fission dynamics, mitochondrial autophagy, and related signaling pathways. Furthermore, it explores the potential of engineered exosome-based targeted therapies for AD intervention, aiming to provide a theoretical foundation and research direction for developing novel therapeutic strategies targeting mitochondrial dysfunction.},
}

Humans
*Exosomes/metabolism
*Alzheimer Disease/metabolism/therapy/pathology
*Mitochondria/metabolism
*Neurons/metabolism
Animals
Autophagy/physiology

@article {pmid41975594,
year = {2026},
author = {Xu, L and Cheng, G and Hu, F and Duan, T and Han, M and Meng, H and Sun, Y and Zeng, D and Zheng, W and Yang, X and Wang, X and Tan, W and Zeng, Y},
title = {Molecular subtypes of the Alzheimer's disease spectrum: Multimodal biomarker integration, mechanistic validation, and adaptive clinical translation.},
journal = {Neural regeneration research},
volume = {},
number = {},
pages = {},
doi = {10.4103/NRR.NRR-D-25-00911},
pmid = {41975594},
issn = {1673-5374},
abstract = {Alzheimer's disease exhibits considerable heterogeneity in its clinical progression, neuropathological features, and underlying etiological mechanisms. However, current clinical diagnosis and treatment primarily rely on positron emission tomography and evidence-based cerebrospinal fluid biomarkers, with less emphasis on molecular subtypes, thereby limiting meaningful subtype stratification and personalized therapeutic interventions. Given advances in large-scale multi-omics technologies, single-cell genomics, and molecular imaging, research on the molecular subtypes of Alzheimer's disease is gradually increasing. In this review, we evaluate the growing body of studies on molecular subtypes of Alzheimer's disease through a comparative analysis of multimodal biomarkers, including cerebrospinal fluid proteomic profiles, single-nucleus transcriptomic architectures, neuroimaging endophenotypes, and adaptive clinical translation. We also analyze phenotypic variations across the Alzheimer's disease continuum to bridge molecular discoveries with clinical manifestations. Findings include proteomics-driven investigations that have identified five distinct cerebrospinal fluid proteomic subtypes. These subtypes are associated with divergent genetic backgrounds, survival rates, and cortical atrophy patterns, and are mechanistically linked to aberrant neuronal hyperproliferation, dysregulated innate immune activation, abnormalities in RNA splicing and processing, choroid plexus dysfunction, and blood-brain barrier impairment. Parallel progress in single-cell technologies, such as single-nucleus RNA sequencing, single-cell ATAC sequencing, and single-cell RNA sequencing applied to postmortem brain tissues, has enabled precise mapping of pathological cellular states across various brain regions. These approaches have revealed that molecular alterations in Alzheimer's disease exhibit high cell-type specificity and have uncovered novel disease-associated vascular-glial-neuronal co-expression modules, as well as vasculature-specific mechanisms correlated with APOE4 genetic risk. Tau- positron emission tomography neuroimaging studies have delineated four distinct spatiotemporal trajectories of tau accumulation, including temporo-lateral, occipital, hippocampal-sparing, and limbic subtypes, each associated with unique clinical phenotypes. From a genetic perspective, large-scale genome-wide association studies have identified approximately 75 risk loci implicated in Alzheimer's disease pathogenesis, including 42 previously unreported genomic regions, highlighting biological processes such as microglial activation, lipid metabolism, and synaptic function. Multi-omics analyses have further defined three hierarchical subtypes of Alzheimer's disease, which are primarily distinguished by dysregulation in either metabolic pathways, astroglial activation, or vascular and leptomeningeal function. Despite these advances in delineating heterogeneity, the field continues to face significant challenges. Key among these are the lack of cross-cohort reproducibility, standardized subtyping criteria, and evidence-based clinical validation.},
}

@article {pmid41975601,
year = {2026},
author = {Wei, L and Ren, H and Lin, Y and Sun, J and Nie, S and Gao, X and Huang, Y},
title = {Cultivation and transplantation of engineered stem cells: A new strategy for promoting repair of central nervous system injury.},
journal = {Neural regeneration research},
volume = {},
number = {},
pages = {},
doi = {10.4103/NRR.NRR-D-25-01121},
pmid = {41975601},
issn = {1673-5374},
abstract = {Due to the complex pathological microenvironment of nerve injury, the ability for self-repair is extremely limited, posing a major challenge for clinical treatment. Stem cell therapy has brought hope for nerve regeneration; however, natural stem cells have limitations such as low survival rates, poor directional differentiation efficiency, and insufficient secretion of neurotrophic factors. In recent years, the development of engineered stem cells through gene editing, biomaterial co-culture, or pretreatment has emerged as a promising new strategy. This review systematically describes the current application status of engineered stem cells in the repair of nerve injury. It summarizes the pathological mechanisms of nerve injury and the biological processes of endogenous neurogenesis and regeneration, providing a theoretical basis for engineering interventions. It details the engineering strategies used, including engineering methods, cell sources, cell processing technologies, cell delivery vehicles, and cell function regulation. Additionally, it discusses the multiple mechanisms of engineered stem cells, highlighting that their therapeutic effect is not solely dependent on differentiation into neurons or glial cells for replacement. Instead, their therapeutic effects primarily arise from the strong paracrine effects of engineered stem cells: they secrete neurotrophic factors to support the survival of host neurons, regulate the immune microenvironment, release exosomes to deliver repair-related miRNA or proteins, and promote angiogenesis and axon myelination, thereby facilitating the reconstruction of neural circuits. This review provides insights into the application of engineered stem cells in preclinical research, highlighting significant functional improvements in various neurological disease models such as spinal cord injury, stroke, Alzheimer's disease, and Parkinson's disease. Finally, this paper discusses the key challenges facing the clinical translation of this technology, including the risks of tumorigenicity, the long-term survival and safety of transplanted cells, the need for standardized preparation processes, and ethical and regulatory considerations. In summary, engineered stem cells demonstrate therapeutic potential beyond that of natural stem cells through synergistic multi-mechanism effects, providing more precise and efficient strategies for nerve injury repair. This review not only outlines the technological systems and theoretical advancements in this field but also establishes an important academic foundation for promoting the transition from basic research to clinical application. It systematically summarizes the mechanisms and applications of engineered stem cells in neural repair, emphasizing their potential and existing bottlenecks in translational medicine, thus providing a theoretical basis and directional guidance for future research.},
}

@article {pmid41975605,
year = {2026},
author = {Luo, L and Yan, T and Liu, W and Gao, Y and Tang, X and Yang, L and Zhao, M},
title = {Homoplantaginin regulates various pharmacological pathways: Candidate drugs for multi-target relief of cognitive decline and pathological changes in Alzheimer's disease.},
journal = {Neural regeneration research},
volume = {},
number = {},
pages = {},
doi = {10.4103/NRR.NRR-D-25-00660},
pmid = {41975605},
issn = {1673-5374},
abstract = {Alzheimer's disease is an age-associated neurodegenerative disorder with a complex pathogenesis. As a result, multi-target drug strategies have emerged in the development of anti- Alzheimer's disease medications. Natural compounds exhibit various pharmacological effects and low toxicity, making them beneficial for multifaceted intervention. Considering that NOD-like receptor protein 3 inflammasome-mediated inflammation is crucial for the treatment of Alzheimer's disease, we identified natural NOD-like receptor protein 3 inhibitors using molecular docking and a lipopolysaccharide/adenosine triphosphate-induced J774A.1 cell inflammation model. We found that homoplantaginin stably bound to NOD-like receptor protein 3, and surface plasmon resonance experiments further demonstrated that its binding affinity was 86.30 μM. Moreover, homoplantaginin effectively inhibited inflammation mediated by NOD-like receptor protein 3 inflammasome activation in J774A.1 cells by reducing the levels of interleukin-1β, interleukin-18, mature interleukin-1β (p17), and active caspase-1 (p20). Additionally, homoplantaginin treatment inhibited apoptosis and oxidative damage in L-glutamate-induced PC12 cells, as well as in aluminum chloride and D-galactose-induced Alzheimer's disease mice. The effects of homoplantaginin on Alzheimer's disease-like behavioral impairments were evaluated using the open field test, Y-maze, and Morris water maze. Results showed that there was no effect on control mice after administration of homoplantaginin once daily for 30 consecutive days, while locomotor and cognitive impairments in Alzheimer's disease mice were significantly alleviated, exhibiting superior efficacy compared with the positive drug donepezil. Importantly, consistent with the observations in J774A.1 cells, homoplantaginin inhibited the activation of the NOD-like receptor protein 3 inflammasome in the serum and brain tissues of Alzheimer's disease mice. NOD-like receptor protein 3 knockout hindered the improvement effect of homoplantaginin on cognitive deficits in Alzheimer's disease zebrafish induced by AlCl3 and D-gal, indicating that homoplantaginin enhances cognitive function by inhibiting activation of NOD-like receptor protein 3. Furthermore, homoplantaginin treatment reduced amyloid-beta deposition, oxidative stress, and apoptosis in Alzheimer's disease mice. Notably, aging is a major risk factor for Alzheimer's disease, and homoplantaginin prevented cellular senescence by regulating related biomarker levels in Alzheimer's disease mice. These results demonstrate that homoplantaginin may serve as a promising multifunctional candidate for the treatment of Alzheimer's disease.},
}

@article {pmid41975609,
year = {2026},
author = {Cao, K and Xie, J and Liang, X and Li, Y and Gong, H and Luo, H},
title = {Dendritic mesoporous silica nanoparticle-based nasal delivery carriers for passive immunotherapy of Alzheimer's disease.},
journal = {Neural regeneration research},
volume = {},
number = {},
pages = {},
doi = {10.4103/NRR.NRR-D-25-00917},
pmid = {41975609},
issn = {1673-5374},
abstract = {Hyperphosphorylation of tau is a key pathological hallmark of Alzheimer's disease and is closely associated with cognitive impairment. Passive immunotherapy targeting hyperphosphorylated tau is a promising approach to inhibit tau pathology. However, the blood-brain barrier restricts antibodies from reaching the central nervous system and exerting their therapeutic effects. Here, we developed an intranasal biomacromolecule delivery strategy for the treatment of Alzheimer's disease using dendritic mesoporous silica nanoparticles modified with hyaluronic acid as a drug carrier. Ten-month-old C57BL/6J mice, htau mice, and 5×FAD mice were intranasally administered 100 μg of hyaluronic acid-dendritic mesoporous silica nanoparticles@4B1 (antibody dose), and brain tissues were collected to evaluate antibody delivery efficiency. Using this delivery system, the anti-p-tau396,404 antibody 4B1 was efficiently delivered to the brains of 5×FAD mice, with an enrichment of 7.31% ± 0.18% ID/g. Entry of the 4B1 antibody into the brain ameliorated tauopathy in Alzheimer's disease model mice, reduced neuronal loss and neuroinflammation caused by tau pathology, and reversed cognitive dysfunction. These findings suggest that the nasal delivery strategy based on hyaluronic acid-responsive release is an effective method for delivering antibody biomacromolecules to the central nervous system, showing high efficiency of antibody entry into brain tissue and intracellular delivery. Our findings also demonstrate the role of p-tau396,404 in passive immunotherapy for Alzheimer's disease, suggesting that immunotherapy targeting p-tau396,404 is a promising strategy for ameliorating Alzheimer's disease pathology, inhibiting the aggregation of hyperphosphorylated tau, and alleviating neurological damage and cognitive dysfunction.},
}

@article {pmid41975618,
year = {2026},
author = {Chen, S and Li, J and Zhou, J and Xie, W and Li, H and Yang, L and Chen, G and Long, C},
title = {NeuroD1 gene therapy converts reactive astrocytes to functional new neurons in a mouse model of Alzheimer's disease.},
journal = {Neural regeneration research},
volume = {},
number = {},
pages = {},
doi = {10.4103/NRR.NRR-D-25-00721},
pmid = {41975618},
issn = {1673-5374},
abstract = {Alzheimer's disease is characterized by the presence of amyloid-beta plaques, neurofibrillary tangles, and chronic neuroinflammation. Effective therapies capable of restoring neuronal loss, a key pathological feature of Alzheimer's disease are lacking. Our previous studies have demonstrated that overexpression of neuronal differentiation 1 (NeuroD1) in astrocytes can convert astrocytes into neurons in Alzheimer's disease models and this astrocyte-to-neuron conversion technology can rescue pathological features in models of stroke and epilepsy. This study investigated whether NeuroD1-mediated in vivo reprogramming of reactive astrocytes into functional neurons could rescue neurodegeneration and cognitive decline in amyloid precursor protein/presenilin 1 transgenic Alzheimer's disease model mice. Using retro-orbital delivery of AAV-PHP.eB-GFAP-NeuroD1-GFP, we achieved broad astrocyte-to-neuron conversion throughout the brain of 7-month-old Alzheimer's disease mice. Three months post-treatment, immunostaining revealed significant neuronal regeneration in the cortex and hippocampus, accompanied by a marked reduction in neuroinflammatory markers. The converted neurons exhibited mature electrophysiological properties, including action potentials and synaptic activity, which correlated with increased neuronal density in the hippocampus. Morris water maze test demonstrated that NeuroD1-treated mice exhibited restored spatial learning and memory compared with control animals. These findings demonstrate that NeuroD1-driven neuroregeneration via gene therapy not only replenishes neuronal populations but also reduces key pathological features related to Alzheimer's disease, including neuroinflammation and amyloid plaque burden, ultimately reducing cognitive impairment. Our findings highlight in vivo astrocyte-to-neuron reprogramming through systemic astrocyte-to-neuron delivery as a promising and transformative strategy for treating Alzheimer's disease and related neurodegenerative disorders.},
}

@article {pmid41977320,
year = {2026},
author = {Toledano-Pinedo, M and Porro-Pérez, A and Schäker-Hübner, L and Diez-Iriepa, D and Iriepa, I and Siwek, A and Wolak, M and Satała, G and Bojarski, AJ and Doroz-Płonka, A and Handzlik, J and Godyń, J and Dallemagne, P and Rochais, C and Davis, A and Since, M and Pérez, B and Bellver-Sanchis, A and Irisarri, A and Pallàs, M and Solana-Manrique, C and López-Muñoz, F and Ismaili, L and Griñán-Ferré, C and Paricio, N and K Hansen, F and Więckowska, A and Marco-Contelles, J},
title = {Polyfunctionalized N-Arylsulfonyl Indoles: Identification of (E)-N-Hydroxy-3-{3-[(5-(3-(piperidin-1-yl)propoxy]-1H-indol-1-yl)sulfonyl]phenyl}a
crylamide (MTP150) for the Epigenetic-Based Therapy of Parkinson's Disease.},
journal = {International journal of molecular sciences},
volume = {27},
number = {7},
pages = {},
doi = {10.3390/ijms27073135},
pmid = {41977320},
issn = {1422-0067},
support = {PID2019-105813RB-C21//AEI (Government of Spain/ ; },
mesh = {Animals ; *Parkinson Disease/drug therapy/genetics/metabolism ; *Indoles/pharmacology/chemistry/therapeutic use ; Disease Models, Animal ; Caenorhabditis elegans/drug effects/genetics ; Humans ; *Neuroprotective Agents/pharmacology/chemistry ; *Epigenesis, Genetic/drug effects ; Oxidative Stress/drug effects ; *Acrylamides/pharmacology/chemistry ; },
abstract = {Herein, we have identified the polyfunctionalized 1-(phenylsulfonyl)-1H-indole-2-carboxylic acid derivative MTP150 for the treatment of neurodegenerative diseases owing to its efficacy in reducing protein aggregation, modulating matrix metalloproteinase activity, mitigating neuroinflammation, and enhancing DNA damage repair pathways across in vivo Caenorhabditis elegans models of Alzheimer's disease, Parkinson's disease (PD), and Huntington's disease. Further experiments in an in vivo Drosophila model of PD showed that MTP150 increased motor performance, reduced oxidative stress levels, and restored mitochondrial function in model flies. In addition, MTP150 exhibited neuroprotective effects in PD model cells, thereby supporting its therapeutic potential for this disease.},
}

Animals
*Parkinson Disease/drug therapy/genetics/metabolism
*Indoles/pharmacology/chemistry/therapeutic use
Disease Models, Animal
Caenorhabditis elegans/drug effects/genetics
Humans
*Neuroprotective Agents/pharmacology/chemistry
*Epigenesis, Genetic/drug effects
Oxidative Stress/drug effects
*Acrylamides/pharmacology/chemistry

@article {pmid41977439,
year = {2026},
author = {Bougea, A},
title = {Targeting Non-Coding RNAs as a Potential Therapeutic and Delivery Strategy Against Neurodegenerative Diseases.},
journal = {International journal of molecular sciences},
volume = {27},
number = {7},
pages = {},
doi = {10.3390/ijms27073260},
pmid = {41977439},
issn = {1422-0067},
mesh = {Humans ; *Neurodegenerative Diseases/genetics/therapy ; Animals ; *RNA, Untranslated/genetics ; MicroRNAs/genetics ; RNA, Long Noncoding/genetics ; Genetic Therapy/methods ; },
abstract = {Neurodegenerative diseases (NDs), including Alzheimer's disease, Parkinson's disease, Huntington's disease, and amyotrophic lateral sclerosis (ALS), represent a growing global health challenge characterized by progressive neuronal loss and a lack of definitive disease-modifying treatments. This review explores the emerging potential of targeting non-coding RNAs (ncRNAs), such as microRNAs (miRNAs), long non-coding RNAs (lncRNAs), and exosomal RNAs, to modulate pathogenic molecular pathways and address the underlying molecular origins of neurodegeneration. We evaluate the integration of advanced computational techniques for RNA structure prediction and gene regulatory network analysis, alongside chemical engineering strategies-such as Locked Nucleic Acids (LNAs) and phosphorothioate modifications-aimed at enhancing the stability and specificity of RNA-based molecules. Furthermore, we analyze cutting-edge delivery and editing technologies, including nanotechnology-driven solutions for precise neuronal targeting and the CRISPR/Cas13 system for direct ncRNA manipulation.The findings indicate that while challenges in delivery efficiency and long-term efficacy persist, the synergy of chemical engineering and computational modeling significantly improves the therapeutic profile of ncRNAs, with exosomal pathways offering a novel route for intercellular signaling modulation and biomarker discovery. Therapeutic interventions directed at specific clinical targets, such as miR-34a and BACE1-AS, demonstrate the capacity to influence protein aggregation and neuroinflammatory cascades. Although ncRNA-based therapies are currently in nascent stages, ongoing technological advancements in RNA editing and nanotechnology offer a transformative framework that could redefine the future of ND treatment and successfully halt disease progression rather than merely managing symptoms.},
}

Humans
*Neurodegenerative Diseases/genetics/therapy
Animals
*RNA, Untranslated/genetics
MicroRNAs/genetics
RNA, Long Noncoding/genetics
Genetic Therapy/methods

@article {pmid41977460,
year = {2026},
author = {Taboada-Jara, T and Ribalta, M and Romero-Becerra, F and Muixí, J and Bellver-Sanchis, A and Griñán-Ferré, C and Escolano, C and Pallàs, M},
title = {Usefulness of C. elegans Models of Alzheimer's and Huntington's Disease to Evaluate Novel Imidazoline I2 Receptor Ligands.},
journal = {International journal of molecular sciences},
volume = {27},
number = {7},
pages = {},
doi = {10.3390/ijms27073282},
pmid = {41977460},
issn = {1422-0067},
support = {PDC2022-133441-I00//Ministerio de Ciencia, Innovación y Universidades/ ; 2021 SGR 00357//Agència de Gestió d'Ajuts Universitaris i de Recerca/ ; PID2022-138079OB-I00//Ministerio de Ciencia, Innovación y Universidades/ ; N° 19/2015//Ministerio de Economía y Finanzas and Programa Nacional de Becas "Don Carlos Antonio López"/ ; //Càtedra UB Dr. Antoni Esteve i Subirana de Recerca en Farmacologia/ ; },
mesh = {Animals ; *Caenorhabditis elegans/metabolism/genetics ; *Huntington Disease/metabolism/drug therapy/genetics ; Disease Models, Animal ; *Imidazoline Receptors/metabolism ; Ligands ; *Alzheimer Disease/metabolism/drug therapy/genetics ; Oxidative Stress/drug effects ; Humans ; Animals, Genetically Modified ; Caenorhabditis elegans Proteins/metabolism/genetics ; Amyloid beta-Peptides/metabolism/genetics ; *Neuroprotective Agents/pharmacology ; },
abstract = {Neurodegenerative diseases such as Alzheimer's (AD) and Huntington's (HD) remain major therapeutic challenges due to limited treatment efficacy. Imidazoline I2 receptor (I2-IR) ligands have recently emerged as promising neuroprotective agents, with reported roles in modulating oxidative stress, neuroinflammation, and protein aggregation. This study evaluates the therapeutic potential of several I2-IR ligands, including Idazoxan, CR4056, and novel compounds, using Caenorhabditis elegans (C. elegans) models of AD and HD. Transgenic strains CL2006 (expressing human Aβ1-42) and EAK103 (expressing Ht513) were employed to assess locomotor activity, oxidative stress tolerance, Aβ and Ht aggregation, and sod-1 gene expression. Several ligands significantly improved movement, reduced Aβ and Ht aggregates, and enhanced antioxidant gene expression, particularly Idazoxan, LSL42, and PIP01. Notably, some compounds exhibited prooxidant effects, highlighting the utility of C. elegans for early in vivo toxicity screening. Importantly, this study provides the first in vivo evidence of the efficacy of I2-IR ligands in HD models and reinforces their potential as therapeutic candidates for HD. Overall, these findings suggest a potential role for modulation of I2-IR-related pathways in neurodegeneration and support the utility of C. elegans as a rapid, cost-effective platform for preclinical drug evaluation.},
}

Animals
*Caenorhabditis elegans/metabolism/genetics
*Huntington Disease/metabolism/drug therapy/genetics
Disease Models, Animal
*Imidazoline Receptors/metabolism
Ligands
*Alzheimer Disease/metabolism/drug therapy/genetics
Oxidative Stress/drug effects
Humans
Animals, Genetically Modified
Caenorhabditis elegans Proteins/metabolism/genetics
Amyloid beta-Peptides/metabolism/genetics
*Neuroprotective Agents/pharmacology

@article {pmid41977473,
year = {2026},
author = {Bivona, G and Ghersi, G},
title = {Microglia-Astrocyte Cooperation and Peripheral T Cells in Alzheimer's Disease: State-of-the-Art and Treatment Perspectives.},
journal = {International journal of molecular sciences},
volume = {27},
number = {7},
pages = {},
doi = {10.3390/ijms27073295},
pmid = {41977473},
issn = {1422-0067},
mesh = {*Alzheimer Disease/immunology/therapy/pathology/metabolism ; Humans ; *Microglia/metabolism/pathology/immunology ; *T-Lymphocytes/immunology/metabolism ; *Astrocytes/metabolism/pathology/immunology ; Animals ; Amyloid beta-Peptides/metabolism ; },
abstract = {Alzheimer's disease (AD) is a neurodegenerative disorder first described more than one century ago. Over this time, many features of the disease have been discovered and, consequently, many different approaches in the diagnosis and treatment of AD have been developed. A major assumption has guided research on AD in the past: this fatal form of cognitive decline is believed to have a pathogenic basis in the deposition of amyloid beta (Aβ) aggregates throughout the brain. Consequently, a main goal of AD therapy is to reduce Aβ load, and several monoclonal antibodies targeting amyloid are among the most recent approaches to AD treatment. However, the effectiveness of these drugs is limited, as they cannot block the progression of the disease; they only slow it down in certain conditions. Many other causative factors are known to promote the development of the disease, with immune system involvement being the most investigated. Indeed, it has been well documented that the microglial response enhances the deposition of other altered proteins, such as Tau, and induces a neurotoxic microenvironment that promotes neuronal loss. In this scenario, the interaction between microglia and astrocytes is known to accelerate pathogenic processes, and a possible role for peripheral T lymphocytes in AD pathology has also been described. An interesting hypothesis is that immune cells driving chronic inflammation might worsen AD progression and, therefore, could represent a target for treatment strategies in this disease. Thus, this review article aims to summarise the role of brain and peripheral immune molecules and cells in AD. Also, immune-based treatments for AD are described, including those targeting microglia and T cells.},
}

*Alzheimer Disease/immunology/therapy/pathology/metabolism
Humans
*Microglia/metabolism/pathology/immunology
*T-Lymphocytes/immunology/metabolism
*Astrocytes/metabolism/pathology/immunology
Animals
Amyloid beta-Peptides/metabolism

@article {pmid41980328,
year = {2026},
author = {Uti, DE and Alum, EU and Okpe, JM and Egbung, JE and Mbah, JO},
title = {Blood-brain barrier modulation for targeted central nervous system drug delivery in neurodegenerative and demyelinating disorders.},
journal = {Tissue & cell},
volume = {101},
number = {},
pages = {103524},
doi = {10.1016/j.tice.2026.103524},
pmid = {41980328},
issn = {1532-3072},
abstract = {The blood-brain barrier (BBB) plays an indispensable role in central nervous system homeostasis but it has remained a key barrier to successful treatment of neurodegenerative and demyelinating diseases. This review discusses the basis for BBB structural and functional regulation and critically discusses emerging strategies to improve therapeutic delivery in neurodegenerative diseases (Alzheimer's disease, Parkinson's disease, and multiple sclerosis). Across pharmacological, nanotechnological, physical and genetic platforms, comes a common thread of ideas; rational and temporally-controlled BBB modulation is the uniting theme that underlies effective and safe brain-targeted therapy. Approaches such as receptor-mediated transcytosis, ligand-engineered nanocartiers, focused ultrasound with microbubbles, osmotic disruption, and electroporation or molecular or viral engineering have expanded the therapeutic landscape, but potential translational application relies upon reversibility, spatial selection, and preservation of neurovascular integrity. The discipline is shifting past proof-of-concept research to clinically-incrementally actionable paradigms anchored on pharmacokinetic accuracy, biomarker-directed goal involvement, and safety strict examination. The growing body of evidence has implied that bio-modulation of the BBB can augment the delivery of neuroprotective, anti-amyloid, anti-a-synuclein, and remyelinating therapeutic treatment with minimal systemic exposure and off-target damage. Together, BBB modulation is transitioning to become an experimental strategy of delivery, but with great clinical potential as a precision therapeutic strategy.},
}

@article {pmid41980337,
year = {2026},
author = {Pattanaik, SK and Mohanty, D and Ray, A and Jena, S and Pattanaik, S and Rath, D},
title = {Phytotherapy for ageing-related multimorbidity: Systems-level insights into Centella asiatica in diabetes and Alzheimer's Disease.},
journal = {Phytomedicine : international journal of phytotherapy and phytopharmacology},
volume = {155},
number = {},
pages = {158026},
doi = {10.1016/j.phymed.2026.158026},
pmid = {41980337},
issn = {1618-095X},
abstract = {BACKGROUND: The increasing burden of age-related illnesses underscores the urgent necessity for integrative treatment approaches that simultaneously address the complex connections between metabolic and neurodegenerative disorders. Diabetes mellitus (DM) and Alzheimer's disease (AD) are strongly interconnected through shared pathological mechanisms. Plant-based therapeutics with their rich diversity of multitarget bioactive compounds are able to compromise such a complex network. Centella asiatica (l.) Urb. (C. asiatica), A medicinal herb, it has garnered significant attention for its metabolic and neuroprotective activities in ethnopharmacology, as well as preclinical and clinical studies.

PURPOSE: In this study, we employ a computational approach to elucidate the key bioactive constituents of C. asiatica and their ability to modulate shared pathological mechanisms linking DM and AD. Provide a scientific rationale for its use as a multitarget phyto-therapeutic candidate against ageing-associated comorbidities.

METHODS: Relevant keywords were used to search databases Scopus, Science Direct, PubMed, Google Scholar and WOS. To gather the scientific evidence of its phytoconstituents, anti-diabetic activity and anti-Alzheimer's activity. Further, a network pharmacology-based approach was adopted.

RESULTS: From the identified phytoconstituents, fifty-four have favourable oral bioavailability, targeting 486 proteins. Venn interaction revealed 404 genes are cross-linked among C. asiatica, DM, and AD. Network pharmacology and enrichment analysis suggested that the PI3K-Akt signalling pathway is the key regulatory axis.

CONCLUSION: C. asiatica demonstrates potential as a multi-target phyto-therapeutic agent for managing interconnected ageing disorders, i.e., DM and AD, through modulation of the PI3K-Akt signalling pathway.},
}

@article {pmid41980560,
year = {2026},
author = {Hoffmann, D and Ahola, V and Huber, N and Natunen, T and Leskelä, S and Takalo, M and Martiskainen, H and Ballweg, S and Vorontsov, E and Selzer, S and Kallio, P and Pike, I and Sirviö, J and Haapasalo, A and Hiltunen, M},
title = {Lithium chloride alters Tau phosphorylation, kinase activity, and Rho GTPase signaling in cell models.},
journal = {Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie},
volume = {198},
number = {},
pages = {119347},
doi = {10.1016/j.biopha.2026.119347},
pmid = {41980560},
issn = {1950-6007},
abstract = {Hyperphosphorylation and intracellular aggregation of Tau are pathological hallmarks of several neurodegenerative diseases, including Alzheimer's disease (AD). Clinical trials involving protein kinase inhibitors to modulate Tau phosphorylation in AD patients have shown mixed outcomes. For clinical trials using lithium salts, this could be explained by sequestration of lithium by β-amyloid and might be circumvented by selection of lithium salts with low affinity to Aβ fibrils and oligomers, promoting improved therapeutic efficacy and positive outcomes in future clinical trials. Here, we assessed the effects of lithium chloride (LiCl), a potent inhibitor of the serine/threonine kinase GSK-3β, on Tau phosphorylation and kinase activity using two cell models: the U2OS cell line overexpressing human triple mutant Tau-tGFP and a mouse cortical neuron/BV-2 co-culture model with inflammation-induced Tau hyperphosphorylation. We show that in the co-culture model, induction of inflammation led to increased Tau phosphorylation at the assessed phosphosites. LiCl reduced Tau phosphorylation depending on the concentration and the targeted phosphosites. Proteomics data from the U2OS cell line showed that LiCl treatment led to decreased phosphorylation at most of the examined phosphosites, which was consistent with the biochemical data. Our data suggest that LiCl may affect other kinases beyond GSK-3β. Additionally, we observed changes in the phosphorylation status of several proteins belonging to different Rho GTPase cycles, known to play a role in AD pathogenesis. Taken together, our data expand the understanding of the effects of LiCl on Tau phosphosites, kinases, and other AD-relevant pathways, such as Rho GTPases.},
}

@article {pmid41980692,
year = {2026},
author = {Aslam, S and Tulain, UR and Zahid, F and Ali, Z and Erum, A and Alamri, AH and Al Fatease, A and Amin, M and Wan, G and Din, FU},
title = {Brain-targeted mucoadhesive in situ gel incorporating quercetin-PEG conjugate and rivastigmine-loaded chitosan nanoparticles for Alzheimer's therapy.},
journal = {International journal of biological macromolecules},
volume = {},
number = {},
pages = {151998},
doi = {10.1016/j.ijbiomac.2026.151998},
pmid = {41980692},
issn = {1879-0003},
abstract = {Alzheimer's dementia (AD) is a progressive neurodegenerative impairment driven by a pronounced cholinergic deficit. Quercetin (QUE) and rivastigmine (RVS) have been used in the treatment of AD, however, clinical translation of QUE and RVS is limited by poor solubility, and short half-life, respectively. To overcome these limitations, QUE was PEG-conjugated (Q-PEG) and co-encapsulated with RVS in chitosan nanoparticles (CNPs) and further incorporated in mucoadhesive in situ gel for nose-to-brain delivery. Q-PEG conjugation was confirmed by Fourier transform infrared spectroscopy (FTIR) and Proton nuclear magnetic resonance ([1]HNMR). The RVS-Q-PEG-CNPsG was optimized through systematic formulation development. The optimized formulation exhibited a mean particle size (134.7 ± 0.35 nm), narrow size distribution (0.213 ± 0.01), optimal zeta potential (+21.5 ± 0.45 mV) and suitable entrapment efficiency of QUE (92.3 ± 0.50%) and RVS (81.5 ± 0.81%). Structural characterization using Transmission electron microscopy (TEM), FTIR, X-Ray diffraction (XRD), and Differential scanning calorimetry (DSC) confirmed spherical morphology, components compatibility, amorphous nature and thermal stability, respectively. Moreover, the poloxamer based in situ gel demonstrated homogeneity, optimal viscosity and robust mucoadhesive strength, thereby markedly enhancing drug retention of CNPs at the administration site. Moreover, it depicted a sustained drug release profile in vitro, and enhanced nasal permeation, ex vivo. Additionally, histopathological evaluation validated the safety and mucosal compatibility of the formulation. Furthermore, pharmacokinetic studies demonstrated significantly enhanced brain bioavailability of RVS-Q-PEG-CNPsG (5.6 ~ fold and 12.6 ~ fold) compared to intranasal free RVS and QUE. These findings suggested that intranasally administered RVS-Q-PEG-CNPsG provides effective brain delivery, which may be a promising approach for the treatment of AD.},
}

@article {pmid41981183,
year = {2026},
author = {Belhaj, I and Åmellem, I and Tartanoglu, CH and Weidemann, HM and Vallenari, EM and Yang, M and Chaudhry, FA and Bjørås, M and Storm-Mathisen, J and Bergersen, LH},
title = {Lactate treatment improves brain biochemistry and cognitive function in transgenic Alzheimer's and wild-type mice.},
journal = {Scientific reports},
volume = {},
number = {},
pages = {},
doi = {10.1038/s41598-026-48154-6},
pmid = {41981183},
issn = {2045-2322},
}

@article {pmid41966729,
year = {2026},
author = {Stinson, SE and Shadrin, AA and Rahman, Z and Rødevand, L and Broce, IJ and Selbæk, G and Stefansson, H and Haavik, J and Parker, N and Koch, E and Frei, O and O'Connell, KS and Smeland, OB and Djurovic, S and Dale, AM and van der Meer, D and Andreassen, OA},
title = {Distinct metabolic signatures of Alzheimer's and Parkinson's disease revealed through genetic overlap.},
journal = {EBioMedicine},
volume = {127},
number = {},
pages = {106254},
doi = {10.1016/j.ebiom.2026.106254},
pmid = {41966729},
issn = {2352-3964},
abstract = {BACKGROUND: Metabolic dysfunction is a major risk factor for neurodegeneration, yet the genetic architecture linking systemic metabolism to Alzheimer's disease (AD) and Parkinson's disease (PD) remains unclear.

METHODS: We integrated genome-wide association data for 249 circulating metabolites and proglucagon with summary statistics for AD, PD, and cardiometabolic traits. Genetic correlations, polygenic overlap, causal relationships, and shared genetic loci were quantified using linkage disequilibrium score regression, high-definition likelihood, bivariate mixture modelling, Mendelian randomisation, and conjunctional false discovery rate analyses, followed by functional and tissue-specific enrichment analyses.

FINDINGS: AD displayed a metabolic-genetic profile aligned with body mass index, type 2 diabetes, coronary artery disease, and stroke, whereas PD exhibited largely opposing patterns (Spearman's rs = -0.26). Mendelian randomization analyses supported causal effects of lipoprotein subclasses, glutamine, and proglucagon on AD risk, with opposite or null effects in PD. Shared loci between metabolites and AD were enriched for lipid metabolism and cholesterol transport, whereas PD-associated loci were enriched for mitochondrial function, vesicle trafficking, and stress-response signalling.

INTERPRETATION: AD and PD are shaped by fundamentally distinct metabolic-genetic architectures. Metabolically targeted interventions, particularly those modulating lipid, amino acid, and proglucagon pathways, may require disease-specific and genetically informed strategies for prevention and treatment of neurodegenerative diseases.

FUNDING: Novo Nordisk Foundation (NNF23OC0099658), Marie Skłodowska-Curie Actions (801133), the Research Council of Norway (334920, 351751, 296030, 324252, 324499, 326813), the National Institutes of Health (U24DA041123, R01AG076838, U24DA055330, OT2HL161847, 5R01MH124839-02), NordForsk (164218), South-Eastern Norway Regional Health Authority (2020060), and the European Union's Horizon 2020 (847776, 964874, 101057454).},
}

@article {pmid41966804,
year = {2026},
author = {Tejero, A and Benito-Patón, V and Griñán-Ferré, C and Pallás, M and León-Navarro, D and Martín, M},
title = {Resveratrol induces molecular changes in cholesterol homeostasis in SAMP8 mice cerebellum.},
journal = {Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie},
volume = {198},
number = {},
pages = {119319},
doi = {10.1016/j.biopha.2026.119319},
pmid = {41966804},
issn = {1950-6007},
abstract = {Resveratrol (Rsv) is a natural polyphenol with neuroprotective properties that modulates several pathways implicated in Alzheimer's disease (AD). Cholesterol homeostasis is disrupted in AD patients, and this imbalance plays a key role in amyloid precursor protein (APP) processing, β-amyloid aggregation and membrane stability. The effect of Rsv on the cerebellum, an emerging structure in cognitive networks and AD pathology due to its high connectivity with other brain regions, remains largely unexplored. This study aims to characterize the effects of Rsv on the cerebellum of SAMP8 mice, an animal model of AD, at different ages (5- and 7-month-old mice) and to investigate how it act as a neuroprotective polyphenol in this structure via modulation of cholesterol metabolism. Aging caused a significant increase in cerebellar membrane free cholesterol levels, which were reversed by Rsv treatment. HMG-CoA reductase levels were significantly reduced by Rsv treatment in 5-month-old mice, suggesting that this polyphenol modulates cholesterol synthesis. Parameters related to cholesterol trafficking were also modulated, with increased LDL receptor levels, but without affecting ApoE. Mitochondrial electron transport chain complexes were also upregulated by Rsv treatment in 5-month-old animals, without affecting mitochondrial dynamics. Collectively, these data demonstrate-for the first time-that Rsv modulates key aspects of cholesterol metabolism and mitochondrial function in the cerebella of SAMP8 mice.},
}

@article {pmid41968216,
year = {2026},
author = {Zhu, S and Li, Y and Lin, C and Liu, X and Luo, Y and Qian, H and Tang, Z},
title = {Combined with network pharmacology, the therapeutic effect and mechanism of coumarins from Chimonanthus praecox extract in the treatment of Alzheimer's disease were investigated.},
journal = {Naunyn-Schmiedeberg's archives of pharmacology},
volume = {},
number = {},
pages = {},
pmid = {41968216},
issn = {1432-1912},
support = {grant number 82360873//National Natural Science Foundation General Project/ ; No: Qiankeheji-ZK [2022]- General 471//Guizhou Provincial Department of Science and Technology Project/ ; Contract No.: YCXKYB2023017//Construction Task of Graduate Education Innovation Plan Project of Guizhou University of Traditional Chinese Medicine/ ; },
abstract = {The objective of this study is to investigate the therapeutic potential and underlying mechanisms of Chimonanthus praecox-derived coumarins in Alzheimer's disease (AD)-related neuroinflammatory and cognitive impairments. Network pharmacology was employed to identify active components and targets of Chimonanthus praecox-derived coumarins, followed by intersection analysis with AD-related genes. A protein-protein interaction (PPI) network was constructed and subjected to functional enrichment analysis. Molecular docking was performed to validate the binding affinity between key compounds and core targets. An AD-like rat model characterized by aging-related cognitive impairment and neuroinflammation was established using D-galactose and aluminum chloride, and therapeutic effects of coumarin treatment were evaluated via behavioral testing, HE staining, immunohistochemistry, Western blotting, and electroencephalography (EEG). Four active compounds, 58 drug targets, and 19 AD-related intersecting targets were identified, primarily enriched in neuroinflammation-related pathways including NF-κB p65, NLRP3, and Alzheimer's disease-related pathways. Molecular docking showed strong binding of key coumarin derivatives to amyloid precursor protein (APP), apolipoprotein E4 (APOE4), NF-κB p65, and prostaglandin-endoperoxide synthase 2 (PTGS2). In vivo, Chimonanthus praecox-derived coumarin treatment improved aging-associated cognitive deficits, alleviated hippocampal neuronal injury, inhibited APP and APOE4 expression, and significantly downregulated NF-κB p65, PTGS2, IL-6, and NLRP3 levels. EEG analysis further confirmed attenuation of abnormal neural activity. Chimonanthus praecox-derived coumarins exert neuroprotective and anti-inflammatory effects through multi-target modulation, supporting their potential as candidate agents for AD-related neuroinflammatory and cognitive dysfunction.},
}

@article {pmid41968555,
year = {2026},
author = {Kaur, K and Goel, H and Chawla, PA and Chawla, V},
title = {Trends and Perspectives in the Targeting of Brain Through Ethosomal Formulations.},
journal = {Recent advances in drug delivery and formulation},
volume = {},
number = {},
pages = {},
doi = {10.2174/0126673878418338251203100909},
pmid = {41968555},
issn = {2667-3886},
abstract = {Neurological diseases such as Alzheimer's disease, Schizophrenia, anxiety, Parkinson's disease, and migraine are serious conditions that continue to threaten mankind. The cases of brainrelated disorders are increasing worldwide and are closely related to physiological, genetic, and environmental factors. Direct drug delivery to the brain is crucial for the effective treatment and prevention of these conditions. However, due to the presence of a lipophilic barrier, i.e., the bloodbrain barrier, the entry of therapeutic agents into the brain is restricted, resulting in a lower concentration at the targeted site. As a solution to this problem, the direct nose-to-brain connection is attracting attention for its effective, precise, non-invasive delivery of drugs via the olfactory and trigeminal pathways. However, there are some limitations, like permeability across the nasal mucosa and mucociliary clearance. Therefore, to overcome these restrictions, the use of nanocarriers, particularly ethosomes, is being attempted. This review paper delves into recent research papers and reports on ethosomes developed for intranasal delivery towards the management of neurological conditions. Ethosomes demonstrated an exceptional capacity to facilitate drug accumulation at targeted sites, owing to their ability to bypass first-pass metabolism, their flexible nature, and the presence of penetration enhancers. The high ethanol content in the composition significantly increases the fluidity of the lipid bilayer, allowing for better interaction of this vesicular system with the blood-brain barrier. Furthermore, the functionalization of ethosomes can enhance the specific delivery of drugs, increase patient compliance, and minimize side effects. However, no intranasal ethosomes for direct brain delivery have progressed from preclinical testing to the bedside of patients. They are still in the experimental phase, particularly in animals or in vivo lab models. The possibilities of toxic effects, the use of high amounts of ethanol, and irregular nasal absorption are a few concerns that need to be addressed. The increasing demand for intranasal delivery suggests that ethosomes may play a pivotal role in the management and treatment of brain-related conditions, but this will only occur after a substantial number of clinical trials confirm their safety and efficacy for human consumption. This review explores such possibilities and highlights current trends and future perspectives in targeting the brain with ethosomal formulations.},
}

@article {pmid41969035,
year = {2026},
author = {Shum, CK and Shea, YF and Au Yeung, TW and Chan, CCY and Chan, WC and Cheng, WK and Cheung, NYF and Cho, DHY and Chow, TK and Fong, GCY and Ip, BYM and Kwok, JSH and Lai, BMH and Lam, LCW and Lee, ATC and Lok, CM and Mok, KY and Ng, DKK and Siu, DYW and Yeung, PY and Tam, SKF},
title = {Consensus statement on the use of Alzheimer's disease biomarkers and anti-amyloid therapies in Hong Kong.},
journal = {Hong Kong medical journal = Xianggang yi xue za zhi},
volume = {},
number = {},
pages = {},
doi = {10.12809/hkmj2514198},
pmid = {41969035},
issn = {1024-2708},
abstract = {Alzheimer's disease (AD) is the most common aetiology of cognitive impairment worldwide and in Hong Kong. There have been rapid advances in the use of biomarkers for the diagnosis of AD and in the availability of anti-amyloid therapies (AAT) to slow cognitive and functional decline. At present, there is no consensus in Hong Kong regarding the application of AD biomarkers or the use of AAT. A multidisciplinary group of 20 medical specialists from five professional societies discussed issues related to the application of biomarkers for the diagnosis of AD pathology and the use of AAT, and reviewed the evidence in the context of local experience to inform recommendations. A modified Delphi approach was adopted to finalise the recommendations. Consensus was defined as ≥75% agreement on a 9-point Likert scale among panellists. The panel finalised 26 consensus statements addressing the use of AD biomarkers, including neuroimaging and fluid biomarkers, as well as the use of AAT, including inclusion criteria, serial neuroimaging monitoring during treatment, and management of infusion reactions. These recommendations are relevant to the Hong Kong healthcare setting and may serve as guidance for doctors across specialties to facilitate appropriate management of AD.},
}

@article {pmid41969962,
year = {2026},
author = {İlhan, N and Keskin, E and Şahin, E and Alaylıoğlu, M and Samancı, B and Çamoğlu, T and Yurttaş, Z and Sordu, P and Ildız, S and Ayaz, G and Yediel, BŞ and Azzouz, SS and Bilgiç, B and Hanağası, HA and Gürvit, İH and Ak, DG and Dursun, E},
title = {The mRNA Expression Levels of General Transcription Factors Altered in Alzheimer Cases Possibly Due to Amyloid Beta 1-42 Exposure.},
journal = {Noro psikiyatri arsivi},
volume = {63},
number = {},
pages = {341-349},
pmid = {41969962},
issn = {1300-0667},
abstract = {INTRODUCTION: Given the global gene expression alterations associated with amyloid beta (Aβ), a hallmark of Alzheimer's disease (AD) pathology, this study aimed to investigate its potential role in modulating gene expression through the regulation of specific transcription factors (TFs).

METHODS: Using a combination of protein-protein interaction prediction tools and transcriptional regulatory interaction databases, we identified JUN, FOS, ATF2, ATF4, RELA, NF-κB, SMAD3, STAT1, STAT3, and SP1 as potential candidate TFs that might be involved in Aβ1-42 related pathways. We then conducted in vitro studies to demonstrate a direct effect of Aβ on these TFs and a case-control study to investigate any alterations of selected TFs in human samples. In vitro studies included HEK293 T cells treated with 0.09 µM and 10 µM Aβ1-42. The expression levels of the TFs were assessed by qRT-PCR. The mRNA expression levels of selected target transcription factors that have the highest PPI scores, namely JUN, FOS, and RELA, were also investigated in blood samples from core Alzheimer's disease (AD) cerebrospinal fluid (CSF) biomarker-confirmed AD cases and plasma ALZpath pTau217-confirmed healthy subjects.

RESULTS: In vitro studies indicated that the mRNA expression of most of the TFs was altered due to either the dose of Aβ or the period of treatments. JUN, FOS, NFKB, and SP1 mRNA expression were increased, while STAT1 and ATF2 were decreased within 24 hours of at least one dose of Aβ treatment. At 48 hours of treatment, FOS, STAT1, STAT3, ATF2, and SP1 were higher, whereas RELA, SMAD3, and NFKB were lower in Aβ-treated groups. At 72h of treatments, the ATF4 and NFKB expressions were high, whereas JUN FOS, RELA, STAT1, STAT3, ATF2, and SP1 were low in Aβ treated groups. Human samples showed that the mRNA levels of JUN and RELA were significantly higher in blood samples from AD cases compared to those from healthy individuals.

CONCLUSION: Alterations in the expression levels of TFs in response to Aβ exposure may explain the alterations of the expression levels of genes that these TFs regulate. Given that, understanding the transcriptional effects of Aβ and its regulatory role on TFs may provide a perspective for the physiological roles of Aβ and the molecular pathways underlying AD pathogenesis.},
}

@article {pmid41970152,
year = {2026},
author = {Lourdel, C and Launay, A and Couteau, A and Bomia, D and Pointereau, S and Bulteau, S and Tessier, F and Thevenet, S and Ahoure, C and Belloeil, V and Robert, G and Taudin, N and Manivel, L and Daucé-Fleuret, L and Richomme, C and Camus, V and Brit, S and Léger, J and Desmidt, T},
title = {The I-Learn Cognition and Behavior program for non-pharmacological treatment of agitation in nursing home residents with neurocognitive disorders: A cluster randomized trial.},
journal = {Alzheimer's & dementia (New York, N. Y.)},
volume = {12},
number = {2},
pages = {e70232},
pmid = {41970152},
issn = {2352-8737},
abstract = {INTRODUCTION: The "I-Learn Cognition and Behavior" program, integrating e-learning and simulation, aims to equip long-term care facility staff with non-pharmacological approaches for managing agitation in residents with neurocognitive disorders. This study evaluated the program's effectiveness.

METHOD: In this multicenter cluster-randomized trial, long-term care facilities served as the randomization units for a population of residents with neurocognitive disorders and agitation who underwent blinded assessments at baseline, 3, 6, and 10 months. Assessments included the Cohen-Mansfield Agitation Inventory (CMAI) as the primary outcome, the Neuropsychiatric Inventory-Nursing Home (NPI-NH), the Quality of Life in Alzheimer's Disease questionnaire, the Maslach Burnout Inventory (MBI), psychotropic use, and hospitalizations. Mixed-effects models analyzed changes in outcomes.

RESULTS: Twelve long-term care facilities were randomized to receive the I-Learn program (intervention) or usual care (control). One hundred sixty-nine residents were enrolled. There were no significant differences in total CMAI score changes between groups. The intervention group demonstrated significant reduced CMAI non-aggressive verbal agitation, MBI depersonalization, and psychotropic medication use (higher withdrawal rates and lower dosage increases) compared to the control group. NPI-NH scores decreased less in the intervention group.

DISCUSSION: The I-Learn program demonstrated potential for improving specific aspects of agitation in residents and well-being in caregivers while significantly reducing psychotropic medication use. "I-Learn Cognition and Behavior" is an easily accessible program with the potential for widespread distribution, contributing to improved well-being and quality of care in long-term care facilities for managing agitation in residents with neurocognitive disorders.},
}

@article {pmid41970809,
year = {2026},
author = {Kherachi, R and Daoud, I and Melkem, N and Chelihi, A and Al-Shuhaib, MBS and Hamouda, S and Meawad, SB and El-Arabey, AA and Abdalla, M},
title = {In silico investigation of 4-(Trifluoromethyl)benzohydrazide derivatives as potential anti-Alzheimer's agents by targeting acetylcholinesterase and butyrylcholinesterase.},
journal = {In silico pharmacology},
volume = {14},
number = {1},
pages = {111},
pmid = {41970809},
issn = {2193-9616},
abstract = {UNLABELLED: Alzheimer's disease (AD) is a condition that mostly affects individuals in the latter stages of life. Due to the importance of inhibiting acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) in improving cholinergic transmission in the brain, both enzymes were targeted to provide a direct therapeutic approach against AD. In this study, we examined a novel set of derivatives of 4-(Trifluoromethyl)benzohydrazide, which have been identified for their potential to prevent the progression of the aforementioned illness. In this study, various computational techniques, including molecular docking, molecular dynamics (MD) simulations, bioisosteric replacement, and ADMET predictions, were utilized to discover potential inhibitors of AChE and BuChE from a set of twenty-five compound derivatives. The most promising inhibitors for each target, namely 2 s for AChE (- 7.674 kcal/mol) and 2r for BuChE (- 6.144 kcal/mol), along with their isosteres, were identified based on their high docking scores. Furthermore, the stability of these inhibitors was confirmed through MD simulation, and they exhibited favorable drug-likeness properties and safety profiles. Hence, it is essential to do more research to advance their potential as pharmaceutical agents for the treatment of AD.

SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s40203-026-00605-8.},
}

@article {pmid41971324,
year = {2026},
author = {Wang, B and Deng, F and Liu, Z and Tian, J and Li, Y and Mao, Y and Song, H},
title = {Clinical application of fecal microbiota transplantation and its influencing factors.},
journal = {Frontiers in microbiology},
volume = {17},
number = {},
pages = {1807071},
pmid = {41971324},
issn = {1664-302X},
abstract = {Fecal microbiota transplantation (FMT) is an emerging therapy that has received significant attention in recent years, although its origins can be traced back to 4th-century China. In modern medicine, FMT has been incorporated into clinical guidelines for the treatment of recurrent Clostridioides difficile infection. By re-establishing a healthy gut microbiota and regulating the immune system, FMT has potential therapeutic effects on various diseases, such as gastrointestinal diseases, diabetes, tumors, Alzheimer's disease, and liver disease. However, its efficacy varies based on the type of disease and individual differences. The clinical application of FMT is influenced by multiple factors, including fecal matter processing, administration route, dosage, donor screening, and recipient detection. Currently, FMT faces numerous challenges, including the need to verify the stability and durability of its efficacy, standardize donor screening criteria, and optimize fecal processing and administration. Future research is expected to reveal the mechanisms of action of FMT, optimize treatment protocols, and refine its safety, efficacy, and convenience, thereby bringing hope for patients with complex and challenging diseases.},
}

@article {pmid41971579,
year = {2026},
author = {Gu, S and Yin, W and Xie, M and He, C and Bian, Y and Li, L and Lu, W and Wang, Q},
title = {Isoquinoline alkaloids in Coptis chinensis to treat Alzheimer's disease through promoting growth of Bifidobacterium breve inhibiting abnormal autophagy using a novel AI high-content intelligent imaging system.},
journal = {Chinese herbal medicines},
volume = {18},
number = {2},
pages = {405-419},
pmid = {41971579},
issn = {2589-3610},
abstract = {OBJECTIVE: Coptis chinensis has been shown to increase beneficial intestinal bacteria and treat Alzheimer's disease (AD). Bifidobacterium breve can effectively treat AD through the gut-brain axis. Therefore, this study aimed to study the joint effects of C. chinensis and B. breve in the treatment of AD.

METHODS: 16S rRNA was used to test the abundance of bacterial flora in APPswe/PS1ΔE9 mice after C. chinensis administration. To determine the efficacy of C. chinensis combined with B. breve on AD, pathological section staining, Barnes maze, Western blotting and ELISA were utilized to confirm the improvement of cognitive dysfunction in AD mice after administration. In order to elucidate the pharmacodynamic components of monomers in C. chinensis, network pharmacology was used to screen the components related to autophagy and confirm the pharmacodynamic effects by artificial intelligence (AI) high-content intelligent imaging.

RESULTS: The results of 16S rRNA sequencing indicated that C. chinensis could modulate the abundance of B. breve in AD mice. Pathological assessments, Barnes maze testing, and additional experiments have shown that C. chinensis combined with B. breve can improve the memory and learning ability of AD mice by reducing neuronal apoptosis and amyloid-β (Aβ) peptide deposition. Network pharmacology combined with AI high-content intelligent imaging technology and Western blotting experiments demonstrated that magnoflorine, 13-methylberberine and palmatrubine in C. chinensis could exert neuroprotective effects in AD mice by up-regulating p62 protein expression while down-regulating Beclin-1 and microtubule-associated protein 1 light chain 3 II (LC3II) protein levels, thereby modulating autophagy-related pathways.

CONCLUSION: C. chinensis can enhance the abundance of beneficial bacteria in the gut and ameliorate cognitive dysfunction in AD mice by interacting with B. breve. Moreover, magnoflorine, 13-methylberberine, and palmatrubine within C. chinensis can also mitigate excessive autophagy and oxidative stress in nerve cells.},
}

@article {pmid41972397,
year = {2026},
author = {Schurman, CA and Kaur, G and Kaya, S and Bons, J and Aguirre, CG and Liu, Q and King, CD and Wilson, KA and Baker, HL and Hady, M and Luna, NM and Bieri, G and Villeda, SA and Ellerby, LM and Schilling, B and Alliston, T},
title = {Alzheimer's Disease Risk Factor APOE4 Exerts Dimorphic Effects on Female Bone.},
journal = {Advanced science (Weinheim, Baden-Wurttemberg, Germany)},
volume = {},
number = {},
pages = {e23511},
doi = {10.1002/advs.202523511},
pmid = {41972397},
issn = {2198-3844},
support = {/NH/NIH HHS/United States ; P30AR075055/AR/NIAMS NIH HHS/United States ; R01DE019284-14S1-Alzheimer's/DE/NIDCR NIH HHS/United States ; Disease Supplement: R01DE01928-11A1/DE/NIDCR NIH HHS/United States ; R01AG067740/AG/NIA NIH HHS/United States ; R01AG077770/AG/NIA NIH HHS/United States ; P01AG066591/AG/NIA NIH HHS/United States ; S10OD028654/AG/NIA NIH HHS/United States ; T32AG000266/AG/NIA NIH HHS/United States ; },
abstract = {Individuals with Alzheimer's disease (AD) are at an increased risk of bone fracture, while osteoporosis in women is one of the earliest predictors of AD. Yet the mechanisms linking cognitive decline and skeletal deterioration remain poorly defined. Proteomic analysis of cortical bone from aged 21-month-old mice revealed strong enrichment of neurodegeneration-associated proteins, including apolipoprotein E (Apoe) and amyloid precursor protein. Apoe localized specifically to osteocytes, with expression in aged female bone nearly twice that of young 4-month-old male bone. Because human APOE alleles confer different age-related AD risks, we examined their roles in bone using humanized APOE2, APOE3, and APOE4 knock-in mice and analyzed bone and hippocampus from the same animals. APOE4 produced marked sex-specific effects on the bone transcriptome and proteome compared with APOE2 or APOE3. Strikingly, APOE4-associated proteomic disruptions were stronger in female bone than in the hippocampus. Functionally, APOE4 caused bone fragility in females without altering cortical structure. These deficits stemmed from impaired osteocyte perilacunocanalicular remodeling. Our findings identify APOE4 as a molecular driver of early osteocyte dysfunction and reduced bone quality, disproportionately affecting females. These findings highlight osteocytes as potential targets for early diagnosis of age-related cognitive impairment and treatment for bone fragility, in females.},
}

@article {pmid41972598,
year = {2026},
author = {Travers-Lesage, V and Since, M and Wang, A and Davis, A and Fayolle, D and Bernay, B and Modeste, F and Nachon, F and Brazzalotto, X and Crouzier, L and Sopkova-De Oliveira Santos, J and Maurice, T and Dallemagne, P and Rochais, C},
title = {Rational Design and Evaluation of Rivastigmine-Based Pleiotropic Prodrugs for the Treatment of Alzheimer's Disease.},
journal = {ACS chemical neuroscience},
volume = {},
number = {},
pages = {},
doi = {10.1021/acschemneuro.6c00170},
pmid = {41972598},
issn = {1948-7193},
abstract = {The multifactorial origin of Alzheimer's disease (AD) is currently being addressed with the development of combination therapy or multitarget directed ligands. If the conventional approach of targeting acetylcholinesterase (AChE) for AD treatment has limitations, it could offer opportunities for a polypharmacological approach by designing covalent pseudoirreversible prodrugs inspired by rivastigmine's mechanism of action. This study focuses on introducing aminated drugs to the rivastigmine carbamate moiety, namely, fluoxetine and memantine, which have shown synergy with cholinesterase inhibition. These innovative carbamates target sustained drug release through covalent pseudoirreversible cholinesterase inhibition, strategically balancing inhibitory potency, selectivity, mechanism, and reactivation kinetics. This comprehensive approach demonstrates the potential of targeting ChE via a covalent mechanism and provides valuable insights into the structure-activity relationships of these derivatives. Interestingly, this study provides a useful biochemical toolbox for characterizing pseudoirreversible cholinesterase carbamate-type inhibitors. The most promising compound was evaluated in in cellulo and in vivo AD models, highlighting the potential of polypharmacological interventions as innovative and multifaceted anti-AD drugs.},
}

@article {pmid41972916,
year = {2026},
author = {Li, Y and Wang, G and Xiong, C and Shan, G and Cao, Y and Llibre-Guerra, J and Hassenstab, J and McDade, E and Bateman, RJ},
title = {Statistical models for Alzheimer's disease clinical trials: Lessons learned from the DIAN-TU Platform Trial.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261441645},
doi = {10.1177/13872877261441645},
pmid = {41972916},
issn = {1875-8908},
abstract = {BackgroundAlzheimer's disease (AD) clinical trials often involve uneven follow-up durations and long-term open-label extensions (OLE), yet conventional statistical models are typically designed for fixed schedules, limiting their efficiency in such settings.ObjectiveTo describe and illustrate alternative statistical modeling approaches developed and implemented in the Dominantly Inherited Alzheimer Network Trials Unit platform trial to optimally leverage data with irregular and extended follow-up.MethodsWe present three complementary models: (1) a Cox proportional hazards model for recurrent disease progression events that uses all observed worsening events rather than only the first event; (2) a parametric disease progression model based on estimated years from expected symptom onset that estimates proportional slowing or time delay in disease progression; and (3) piecewise linear mixed-effects models tailored to the "gap" period between the double-blind phase and OLE, accommodating variable off-treatment intervals and missing interim data. All methods are illustrated with hypothetical examples, and ready-to-use SAS code is provided in the Supplemental Material.ResultsThe proposed models successfully handle complex longitudinal data structures typical trials with OLE phases, offering greater statistical efficiency and more comprehensive capture of treatment effects over extended periods compared with traditional approaches.ConclusionsThese flexible, efficient statistical models are well-suited for rare disease and long-duration AD trials. Wider adoption and further validation of these approaches may enhance the power and interpretability of future neurodegenerative disease trials.},
}

@article {pmid41972921,
year = {2026},
author = {Harrington, EE and Bock, JE},
title = {Honor culture and cognitive aging: Honor endorsement and deficits in memory aging and Alzheimer's disease knowledge.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261441602},
doi = {10.1177/13872877261441602},
pmid = {41972921},
issn = {1875-8908},
abstract = {BackgroundIdentifying deficits in the public's memory aging knowledge is a promising avenue for improving our understanding of Alzheimer's disease (AD) risk and developing effective education and intervention strategies. Yet, it is important to contextualize knowledge within culturally relevant frameworks that may not only contribute to the extent of individuals' knowledge, but also to the reception of developed educational and intervention programs.ObjectiveOne prominent culture within the United States (U.S.) that has largely been neglected within AD research is the culture of honor, or those that prioritize the defense and maintenance of reputation.MethodsUsing an online sample, the present study examined 998 U.S. adults' endorsement of honor culture norms and knowledge of normal and pathological memory aging knowledge, as well as AD specific knowledge. Hierarchical linear regression analyses (controlling for age, sex, race/ethnicity, educational attainment, and dementia experience) examined associations between honor endorsement and each type of memory aging knowledge.ResultsGreater honor endorsement was associated with worse knowledge of normal memory aging, pathological memory aging, and AD. Exploratory analyses that examined links to domains of AD knowledge revealed that greater honor endorsement was specifically linked with worse knowledge related to AD risk factors, symptoms, treatment and management, life impact, and caregiving.ConclusionsThe present research advances our understanding of deficits in the public's memory aging knowledge within the context of U.S. honor cultures and highlights a need for the developmental of culturally relevant education and intervention efforts.},
}

@article {pmid41962336,
year = {2026},
author = {Kumar, A and Khan, MN and Tiwari, AK and Islam, MM and Judder, MI},
title = {Targeting GPX4 in neurodegenerative disorder: Unlocking ferroptosis as a therapeutic frontier.},
journal = {Tissue & cell},
volume = {101},
number = {},
pages = {103523},
doi = {10.1016/j.tice.2026.103523},
pmid = {41962336},
issn = {1532-3072},
abstract = {Ferroptosis is a regulated form of cell death characterized by iron-dependent lipid peroxidation and disruption of cellular redox homeostasis. Among the key regulators of this process, glutathione peroxidase 4 (GPX4) plays a central role in maintaining membrane lipid integrity by reducing phospholipid hydroperoxides using glutathione as a cofactor. Impairment of GPX4 activity leads to the accumulation of toxic lipid peroxides, ultimately triggering ferroptotic cell death. Increasing evidence suggests that dysregulation of GPX4-mediated antioxidant defense contributes to the pathogenesis of several neurodegenerative disorders, including Alzheimer's disease, Parkinson's disease, and other neurodegenerative conditions characterized by oxidative stress and iron imbalance. In recent years, targeting GPX4 and its associated metabolic pathways has emerged as a promising therapeutic strategy for modulating ferroptosis. This review summarizes the molecular mechanisms governing GPX4 regulation, including its interaction with glutathione metabolism, lipid peroxidation pathways, and iron homeostasis. Furthermore, we discuss emerging pharmacological modulators of GPX4 and ferroptosis, highlighting their potential applications in the treatment of neurological diseases. Understanding the regulatory network surrounding GPX4 may provide new insights into ferroptosis-based therapeutic interventions and facilitate the development of targeted strategies for the management of neurodegenerative disorders.},
}

@article {pmid41962454,
year = {2026},
author = {Fin, S and Moayedikia, A and Wiil, UK},
title = {Dual-model deep learning for Alzheimer's prognostication.},
journal = {Computers in biology and medicine},
volume = {208},
number = {},
pages = {111672},
doi = {10.1016/j.compbiomed.2026.111672},
pmid = {41962454},
issn = {1879-0534},
abstract = {Disease-modifying therapies for Alzheimer's disease demand precise timing decisions, yet current predictive models require longitudinal clinical observations and provide no uncertainty quantification-rendering them impractical at the critical first-visit encounter when treatment decisions must be made. We developed PROGRESS (PRognostic Generalization from REsting Static Signatures), a dual-model deep learning framework that transforms a single baseline cerebrospinal fluid (CSF) biomarker assessment into actionable prognostic estimates without requiring prior clinical history. The framework addresses two complementary clinical questions: a probabilistic trajectory network predicts individualized cognitive decline parameters with calibrated uncertainty bounds that achieve near-nominal coverage, enabling honest prognostic communication rather than false precision; and a deep survival model estimates time-to-conversion from mild cognitive impairment to dementia. Using data from over 3000 participants across 43 Alzheimer's Disease Research Centers in the National Alzheimer's Coordinating Center database, PROGRESS substantially outperforms existing approaches including Cox proportional hazards, Random Survival Forests, and gradient boosting methods for survival prediction. Risk stratification identifies patient groups with seven-fold differences in conversion rates, enabling clinically meaningful treatment prioritization. Leave-one-center-out validation demonstrates robust generalizability, with survival discrimination remaining strong across all held-out clinical sites despite heterogeneous measurement conditions spanning four decades of assay technologies. By combining superior survival prediction with trustworthy trajectory uncertainty quantification, PROGRESS bridges the gap between biomarker measurement and personalized clinical decision-making-providing the prognostic timeline that current staging approaches cannot offer.},
}

@article {pmid41964075,
year = {2026},
author = {Andreozzi, E and Yagi, T and Wildsmith, K and Rawal, S and Horie, K and Boyd, P and Takahashi, E and Barthélemy, NR and Aluri, J and Charil, A and Reilhac, A and Gordon, BA and Flores, S and Verbel, D and Sauter, N and Benzinger, TLS and McDade, E and Mummery, C and , and , and Zhou, J and Bateman, RJ and Reyderman, L},
title = {Etalanetug (E2814) in dominantly inherited Alzheimer's disease: an open-label phase 1b/2 study to assess safety and target engagement in participants with mild to moderate cognitive impairment.},
journal = {Alzheimer's research & therapy},
volume = {},
number = {},
pages = {},
doi = {10.1186/s13195-026-02047-y},
pmid = {41964075},
issn = {1758-9193},
abstract = {INTRODUCTION: Etalanetug (E2814) is designed to delay the clinical progression of Alzheimer's disease (AD) by binding to the microtubule binding region (MTBR) of tau implicated in seeding and spreading of tau pathology. Dominantly inherited Alzheimer's disease (DIAD) is a rare form of the disease (< 1%), having similar changes in the tau distribution and pathology to sporadic AD. Herein, we report the safety, pharmacology and biomarker results of the etalanetug Study 103 in DIAD patients.

METHODS: Study 103 enrolled participants with mild-to-moderate cognitive impairment due to DIAD who received etalanetug intravenously every 4 weeks escalating from 750 mg, 1500 mg, 3000 mg, to 4500 mg. After ascending to 4500 mg, patients received 4500 mg for up to 108 weeks. Tau pathology biomarkers, ptau217 and MTBR-tau243 were measured in CSF. Additional assessments included tau PET ([[18]F]MK-6240) and MRI. Pharmacodynamic effects of etalanetug on biomarkers were evaluated. Untreated participants from the DIAN Observational and DIAN-TU studies trial served as natural history controls.

RESULTS: Overall, 8 participants enrolled in Study 103. Etalanetug reduced concentrations of ptau217 30.4% after 12 weeks (n = 7), 48.6% at 36 weeks (n = 5), and 57.9% at 108 weeks (n = 2). Etalanetug treatment reduced concentrations of MTBR-tau243 by 50.6% in DIAD participants (n = 7) after 12 weeks of treatment. Maximal reduction in MTBR-tau243 levels (71.6%) was observed at week 36 (n = 4) and was sustained to 108 weeks (n = 2). In healthy volunteers who lack tau pathology, etalanetug had no effect on MTBR-tau243 or ptau217 after 12 weeks of treatment. Three DIAD patients had tau PET acquired at week 60 and week 108. The data indicate that the tau PET SUVr signal remains stable overall, with a trend towards decrease over time. At 108 weeks, no tau accumulation was observed via tau PET in any of the 3 patients. Three participants experienced treatment-related adverse events (AEs) with the 3000 mg dose; additionally, 5 serious AEs total were reported in 3 participants.

DISCUSSION: Etalanetug treatment in these symptomatic participants with DIAD was tolerated across dose levels, and immunogenicity was found to be minimal. Etalanetug demonstrated effects on both hyperphosphorylated tau and tau tangle pathology. Taken together, the data support continued evaluation of etalanetug as an AD disease-modifying therapy.

TRIAL REGISTRATION: NCT04971733 (registration date: 2021-07-20).},
}

@article {pmid41964934,
year = {2026},
author = {Ghosh, N and Pathak, S and Bera, R and Sharma, A and Kakkar, D and Kurmi, BD and Srivasatava, P and Ghosh, M and Karwasra, R and Ansori, ANM and Das, S and Sharma, N},
title = {Biomimetic nanocarriers as advanced drug delivery strategies in neurological disorders.},
journal = {Expert opinion on drug delivery},
volume = {},
number = {},
pages = {},
doi = {10.1080/17425247.2026.2659924},
pmid = {41964934},
issn = {1744-7593},
abstract = {INTRODUCTION: Neurological disorders represent a major and growing global health challenge due to complex central nervous system pathology and limited drug penetration across the blood - brain barrier. Conventional therapies are largely symptomatic and often fail to achieve sufficient brain bioavailability or disease modification. Biomimetic nanocarriers have emerged as a promising strategy to improve brain targeting and therapeutic efficacy.

AREAS COVERED: This review discusses recent advances in biomimetic nanocarriers for the treatment and diagnosis of neurological disorders. We summarize the pathological mechanisms underlying central nervous system diseases and discuss how cell membrane-coated nanocarriers derived from red blood cells, platelets, immune cells, stem cells, and cancer cells can enhance BBB penetration, immune evasion, and targeted delivery. A comprehensive literature search was conducted using PubMed, Scopus, Web of Science, and Google Scholar to evaluate therapeutic and diagnostic applications in Alzheimer's disease, Parkinson's disease, multiple sclerosis, autism spectrum disorder, ischemic stroke, and glioblastoma.

EXPERT OPINION: Biomimetic nanocarriers offer a promising strategy to overcome biological barriers and improve central nervous system drug delivery. However, clinical translation remains challenged by membrane source standardization, scalability, and safety concerns. Future research should focus on reproducible manufacturing, regulatory frameworks, and long-term toxicity evaluation to accelerate clinical adoption.},
}

@article {pmid41964958,
year = {2026},
author = {Fukui, M and Kaise, T and Masaki, T and Sakamoto, T and Kageyama, R},
title = {Activation of neurogenesis improves amyloid-β pathology and cognitive function through AMP kinase signaling in Alzheimer's disease model mice.},
journal = {Cell reports},
volume = {45},
number = {4},
pages = {117250},
doi = {10.1016/j.celrep.2026.117250},
pmid = {41964958},
issn = {2211-1247},
abstract = {Adult hippocampal neurogenesis declines with aging and in neurological disorders, leading to cognitive impairment. We previously showed that inducing Plagl2 and antagonizing Dyrk1a (iPaD) rejuvenates aged neural stem cells (NSCs), enhancing neurogenesis and cognition in aged mice. Here, we found that NSC-specific iPaD treatment activates neurogenesis, reduces amyloid-β deposition, and improves cognition in Alzheimer's disease model mice. Transcriptomic analysis revealed widespread changes in gene expression in the hippocampus after iPaD treatment. The upregulated genes include those associated with astrocyte and microglial activation involved in amyloid-β clearance, while several genes upregulated in Alzheimer's disease are downregulated. Among the latter genes, knockdown of Prkag2 in the hippocampus most effectively enhances neurogenesis and reduces amyloid-β accumulation. Notably, both iPaD treatment and Prkag2 knockdown activate AMP-activated protein kinase signaling, upregulating genes involved in autophagy and cellular homeostasis. These results suggest that Prkag2 may represent a promising therapeutic target for neurodegenerative diseases, including Alzheimer's disease.},
}

@article {pmid41965638,
year = {2026},
author = {Khan, AJ and Rahman, I and Beg, HA and Akter, S and Haque, R and Monsur, DT and Rani, H and Dom, TNM},
title = {Association of periodontitis and tooth loss with cognitive decline in the older adults - a systematic review.},
journal = {BMC oral health},
volume = {},
number = {},
pages = {},
doi = {10.1186/s12903-026-08310-w},
pmid = {41965638},
issn = {1472-6831},
abstract = {BACKGROUND: The increasing global burden of dementia highlights the importance of identifying factors that may contribute to cognitive decline in later life. Growing evidence suggests that chronic oral conditions, particularly periodontitis (PD) and tooth loss, may be associated with Alzheimer's disease (AD) and related dementias. This study synthesizes current observational evidence on the association between PD, tooth loss, and cognitive impairment (CI) among older adults.

METHODS: A comprehensive literature search was conducted in PubMed, the Cochrane Library, Embase, Scopus, and Google Scholar for English-language studies published between 2010 and 2025. Cross-sectional and longitudinal cohort studies examining associations between PD, tooth loss, and CI were included. Study selection, data extraction, and quality assessment were performed in accordance with PRISMA 2020 guidelines.

RESULTS: Thirteen studies met the inclusion criteria, with sample sizes ranging from 40 participants to over 500,000 individuals in large population-based cohorts. Most studies focused on adults aged ≥ 50 years, particularly those aged 60 years and above. Periodontal status, tooth loss, and cognitive outcomes were assessed using heterogeneous diagnostic methods. Most studies reported significant associations between PD or tooth loss and CI, dementia, or AD. Periodontal treatment appeared protective in several studies, although some associations weakened after adjustment for confounders.

CONCLUSIONS: The findings support PD and tooth loss are consistently associated with adverse cognitive outcomes, although causal relationships cannot be established due to methodological heterogeneity and residual confounding. Integrating oral health care into geriatric and dementia-prevention strategies may help preserve cognitive function and improve quality of life among older adults.},
}

@article {pmid41965896,
year = {2026},
author = {Wang, J and Chen, L and Wang, Z and Chen, XY and Zhang, S and Ding, D and Zhou, Y and Rager-Aguiar, R and Lin, G and Zhang, H and Boda, VK and Ortyl, TC and Nelson, PT and Bezprozvanny, I and Zhou, FM and Du, J and Wu, Z and Li, W and Liao, FF},
title = {Pyrazole-derived TRPC3 antagonist ameliorates synaptic dysfunctions and memory deficits in Alzheimer's disease models.},
journal = {Molecular psychiatry},
volume = {},
number = {},
pages = {},
pmid = {41965896},
issn = {1476-5578},
abstract = {Transient receptor potential canonical (TRPC) channels are widely expressed in the brain; however, their precise roles in neurodegenerative diseases, such as Alzheimer's disease (AD), remain elusive. We found that TRPC3 expression is upregulated in excitatory neurons of brains with AD. We tested a selective inhibitor (JW-65) for TRPC3 over TRPC6 to investigate the potentially distinct role of TRPC3 in AD. JW-65 treatment significantly restored impaired synaptic plasticity and learning memory in acute and chronic experimental AD models. JW-65 treatment of late symptomatic 5XFAD transgenic mice reversed the impaired LTP, correlating with their significantly corrected synaptic gene expression based on hippocampal RNA-seq data analysis. JW-65 also provided synaptic protection in primary rat hippocampal neurons against soluble β-amyloid oligomers (AβOs), primarily via restoring the AβOs-impaired Ca[2+]/calmodulin-mediated signaling pathways. JW-65 treatment also significantly prevented Ca[2+] overload induced by AβOs. These findings suggest that aberrantly upregulated TRPC3, as a novel non-selective ion channel, significantly contributes to Ca[2+] dyshomeostasis in AD. Our work identifies TRPC3 as a potential therapeutic target for treating or preventing synaptic dysfunction of AD.},
}

@article {pmid41966037,
year = {2026},
author = {Qudoos, MA and Elliott, DP},
title = {Review of Donanemab and Lecanemab in Mild Dementia Stage of Alzheimer's Disease: Progress and Challenges.},
journal = {The Senior care pharmacist},
volume = {41},
number = {3},
pages = {98-108},
doi = {10.4140/TCP.n.2026.98},
pmid = {41966037},
issn = {2639-9636},
mesh = {Humans ; *Alzheimer Disease/drug therapy ; *Antibodies, Monoclonal, Humanized/therapeutic use/adverse effects ; *Antibodies, Monoclonal/therapeutic use/adverse effects ; Amyloid beta-Peptides/metabolism ; },
abstract = {Alzheimer's disease (AD) is a progressive neurodegenerative disorder marked by cognitive decline and functional impairment, primarily driven by the accumulation of amyloid-beta (Aβ) plaques and tau tangles. Historically, treatments have focused on symptomatic relief; however, recent therapeutic advances have focused on disease-modifying monoclonal antibodies (mAbs), notably lecanemab and donanemab, which target Aβ pathology in early-stage AD. This review explores the clinical efficacy, safety profile, and limitations of lecanemab and donanemab, emphasizing key findings from the CLARITY-AD and TRAILBLAZER-ALZ 2 trials. In these studies, lecanemab was shown to slow cognitive decline by 27% over 18 months, while donanemab achieved a 28.9% reduction over 76 weeks, with the greatest benefits observed in patients presenting with lower baseline tau pathology.Despite these promising outcomes, challenges remain, including possible reduced efficacy in women based on subgroup analyses of trial data, racial disparities in trial representation, adverse effects such as amyloid-related imaging abnormalities (ARIA), and substantial cost and accessibility barriers. This review underscores the need for more inclusive research, personalized treatment strategies, and continued exploration of AD's complex pathology beyond amyloid clearance.},
}

Humans
*Alzheimer Disease/drug therapy
*Antibodies, Monoclonal, Humanized/therapeutic use/adverse effects
*Antibodies, Monoclonal/therapeutic use/adverse effects
Amyloid beta-Peptides/metabolism

@article {pmid41966346,
year = {2026},
author = {Matuszewska, M and Cieślik, M and Sulejczak, D and Wilkaniec, A and Czapski, GA},
title = {BET protein inhibitor JQ1 reduces inflammationand hippocampal amyloid-β level without altering Tau phosphorylation in LPS-challenged adult wild-type mice.},
journal = {Brain research},
volume = {},
number = {},
pages = {150318},
doi = {10.1016/j.brainres.2026.150318},
pmid = {41966346},
issn = {1872-6240},
abstract = {A growing body of evidence highlights the role of infection and inflammation in the progression of Alzheimer's disease (AD). In this study, we aimed to analyze the impact of JQ1, an inhibitor of bromodomain and extraterminal domain (BET) proteins, which are key readers of the epigenetic acetylation code, on AD-related gene expression changes and biochemical alterations in the hippocampus during a lipopolysaccharide (LPS)-induced systemic inflammatory response in mice. JQ1 and LPS were administered intraperitoneally to adult male wild-type C57BL/6J mice. Changes in selected general and brain-specific parameters were measured for up to 12 h. Our results demonstrated that inhibition of BET proteins reduced LPS-induced sickness behavior and time-dependent elevation of proinflammatory signaling. LPS did not significantly alter amyloid-β (Aβ) levels; however, a significant reduction in Aβ load was observed in JQ1-treated animals overall, suggesting that BET proteins play a crucial role in regulating Aβ levels in the brain. At the same time, JQ1 treatment did not affect LPS-induced increases in phospho-Tau levels. Our results suggest that inhibiting BET proteins, in addition to their anti-inflammatory action, may be an effective strategy for reducing Aβ levels in the brain. However, a mechanistic explanation of this phenomenon requires further investigation.},
}

@article {pmid41966670,
year = {2026},
author = {Kaur, N and Gupta, S and Bansal, G and Bansal, Y},
title = {BACE-1 inhibitors as potential drug candidates for treatment of Alzheimer's disease: a systematic review.},
journal = {Molecular diversity},
volume = {},
number = {},
pages = {},
pmid = {41966670},
issn = {1573-501X},
}

@article {pmid41956234,
year = {2026},
author = {Alves, SS and Manzine, PR and Dos Santos, FM and Migliaccio, MM and de Carvalho Alves, LV and da Silva Junior, RMP and Becerra-Hernández, LV and González-Acosta, CA and Buriticá-Ramírez, E and Cominetti, MR and Camins, A and Garcia-Cairasco, N},
title = {From comorbidity to continuum: Alzheimer's disease and epilepsy are connected-now what?.},
journal = {Neuroscience and biobehavioral reviews},
volume = {},
number = {},
pages = {106682},
doi = {10.1016/j.neubiorev.2026.106682},
pmid = {41956234},
issn = {1873-7528},
abstract = {Alzheimer's disease (AD) and epilepsy are increasingly recognized not merely as comorbid conditions but as disorders lying along a shared pathophysiological continuum, characterized by overlapping clinical features, network hyperexcitability, and convergent molecular mechanisms. Although bidirectional interactions between AD and epilepsy are now well established, critical questions remain regarding how this knowledge can be translated into improved risk prediction, prevention, and treatment. Classical mechanisms such as amyloid-β and tau pathology, neuroinflammation, and synaptic dysfunction, together with less explored processes including brain insulin resistance, converge on shared downstream effects that promote both neurodegeneration and epileptogenesis. However, marked mechanistic heterogeneity across individuals, limits standardized therapeutic approaches and complicates the prediction of seizure risk in AD and dementia risk in epilepsy. In this review, we synthesize evidence supporting the AD-epilepsy continuum, integrating molecular pathways, genetic and metabolic modifiers, fluid biomarkers, and neuroimaging signatures that may enable earlier identification of vulnerable trajectories. We critically examine pharmacological strategies with dual effects on neuroprotection and seizure control and discuss how targeting shared mechanisms may shift interventions from symptomatic management toward disease modification. Importantly, we highlight current gaps and emerging hypotheses that define the next steps for the field, including patient stratification, early biomarker-guided trial design, and precision-based therapeutic strategies. By moving beyond descriptive associations, this review outlines a framework for translating mechanistic insight into actionable approaches aimed at early detection, personalized intervention, and improved outcomes in individuals at risk across the AD-epilepsy spectrum.},
}

@article {pmid41956992,
year = {2026},
author = {Papapanagiotou, O and Cotton, K and Edwards, C and Michod, D and Crompton, L and Craig, T and Niklison-Chirou, MV},
title = {Lipid droplets in neurodegenerative diseases: pathological drivers and therapeutic vulnerabilities.},
journal = {Cell death discovery},
volume = {},
number = {},
pages = {},
doi = {10.1038/s41420-026-03096-w},
pmid = {41956992},
issn = {2058-7716},
abstract = {Lipid droplets (LDs) are dynamic intracellular organelles traditionally associated with energy storage, which have become increasingly recognised for their versatile roles in cellular metabolism and signalling. In the brain, LDs have emerged as critical regulators in neurodegenerative diseases (NDDs) such as Alzheimer's disease (AD), Parkinson's disease (PD), and Hereditary Spastic Paraplegia (HSP). LDs contribute to neurodegeneration by influencing lipid metabolism, oxidative stress, and inflammatory responses. For instance, in AD, dysregulated lipid metabolism and impaired Apolipoprotein E 4 (ApoE4) function lead to LD accumulation associated with neuroinflammation and amyloid plaque formation. In PD, interactions between LDs and α-synuclein suggest a potential link between lipid dysregulation and neurotoxicity. Mutations in LD-associated proteins, such as spastin and DDH2 in HSP, highlight the importance of proper LD regulation for neuronal health. While LD accumulation can be protective by mitigating lipotoxicity, prolonged dysregulation can exacerbate NDD pathology. Targeting LD metabolism, through enhancing lipophagy or modulating LD-associated proteins, represents a promising therapeutic avenue. This review highlights the dual roles of LDs in the brain, acting both neuroprotectively and neurotoxically, and the therapeutic potential of targeting LD dynamics for NDD treatment.},
}

@article {pmid41957314,
year = {2026},
author = {Park, Y and Chae, H and Yoon, E and Kim, Y and Han, JW and Woo, SJ and Yoo, S and Kim, KW},
title = {Restoration of gamma center frequency via personalized entrainment marks cognitive preservation in early Alzheimer's disease.},
journal = {GeroScience},
volume = {},
number = {},
pages = {},
pmid = {41957314},
issn = {2509-2723},
support = {NRF-2017R1A5A1014708//National Research Foundation of Korea/ ; RS-2025-02223212//Korea Health Industry Development Institute/Republic of Korea ; },
abstract = {Gamma entrainment shows promise for Alzheimer's disease (AD) treatment in preclinical models, but human trials have yielded heterogeneous results. We hypothesized that the clinical efficacy of gamma entrainment depends on individual neurophysiological receptivity, specifically the capacity for neural circuit plasticity. In this open-label pilot study, we screened 37 individuals and enrolled 16 participants with early AD (CDR 0.5-1.0, amyloid-positive) who completed 12 weeks of home-based flickering light stimulation at individually optimized gamma frequencies (32-40 Hz). Pre- and post-intervention assessments included 64-channel EEG recordings and MMSE. Participants demonstrated dichotomous neurophysiological responses: 43.8% showed center frequency (CF) increase (increased CF [ICF+]) while 56.3% showed no change/decrease (non-increased CF [ICF-]). CF restoration was significantly associated with cognitive preservation (r = 0.52, p = 0.039). Notably, future responders exhibited distinct baseline signatures of "neural reserve," characterized by higher temporal gamma power (Cohen's d = 0.70-0.92) and stronger frontotemporal connectivity (Cohen's d = 1.11-1.47). Almost 30% of screened candidates failed to show baseline entrainment, highlighting a distinct "non-responsive" biological subtype. CF restoration following personalized gamma entrainment identifies a neurophysiological subtype capable of meaningful plasticity. Rather than a universal remedy, gamma entrainment appears to act on specific neural substrates preserved in a subset of patients. These findings suggest that baseline electrophysiological profiling could unlock gamma entrainment's therapeutic potential by stratifying likely responders for precision neuromodulation.},
}

@article {pmid41957960,
year = {2022},
author = {Li, CT and Fuh, JL and Yang, BH and Hong, CJ and Chang, CW and Tu, PC and Jeng, JS and Chen, MH and Tsai, SJ and Bai, YM and Su, TP and Lee, H and Huang, WS},
title = {Global cognitive dysfunction and β-amyloid neuropathology in late-life and treatment-resistant major depression.},
journal = {Psychological medicine},
volume = {52},
number = {16},
pages = {4116-4126},
doi = {10.1017/S0033291721001070},
pmid = {41957960},
issn = {1469-8978},
abstract = {BACKGROUND: Cognitive impairment is common in late-life depression, which may increase Alzheimer disease (AD) risk. Therefore, we aimed to investigate whether late-life major depressive disorder (MDD) has worse cognition and increases the characteristic AD neuropathology. Furthermore, we carried out a comparison between treatment-resistant depression (TRD) and non-TRD. We hypothesized that patients with late-life depression and TRD may have increased β-amyloid (Aβ) deposits in brain regions responsible for global cognition.

METHODS: We recruited 81 subjects, including 54 MDD patients (27 TRD and 27 non-TRD) and 27 matched healthy controls (HCs). Neurocognitive tasks were examined, including Mini-Mental State Examination and Montreal Cognitive Assessment to detect global cognitive functions. PET with Pittsburgh compound-B and fluorodeoxyglucose were used to capture brain Aβ pathology and glucose use, respectively, in some patients.

RESULTS: MDD patients performed worse in Montreal Cognitive Assessment (p = 0.003) and had more Aβ deposits than HCs across the brain (family-wise error-corrected p < 0.001), with the most significant finding in the left middle frontal gyrus. Significant negative correlations between global cognition and prefrontal Aβ deposits existed in MDD patients, whereas positive correlations were noted in HCs. TRD patients had significantly more deposits in the left-sided brain regions (corrected p < 0.001). The findings were not explained by APOE genotypes. No between-group fluorodeoxyglucose difference was detected.

CONCLUSIONS: Late-life depression, particularly TRD, had increased brain Aβ deposits and showed vulnerability to Aβ deposits. A detrimental role of Aβ deposits in global cognition in patients with late-onset or non-late-onset MDD supported the theory that late-life MDD could be a risk factor for AD.},
}

@article {pmid41959105,
year = {2026},
author = {Burberry, A and Benchek, P and Lowe, M and Shin, W and McCourt, B and Beamon, Q and Chakrabarti, S and Ramaiah, S and Woidke, E and Khrestian, M and Maecker, H and Bekris, LM and Rao, S and Ontaneda, D and Leverenz, JB and Bush, W and Pillai, JA},
title = {Early peripheral immune signaling precedes tau elevation and blood-brain barrier disruption in Alzheimer's disease.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.04.02.716122},
pmid = {41959105},
issn = {2692-8205},
abstract = {Neuroinflammation, along with amyloid beta (Aβ) deposition, phospho-tau (ptau) accumulation, blood-brain barrier (BBB) disruption, and cognitive decline are recognized components of Alzheimer's disease (AD). However, the timing and nature of peripheral immune changes across AD biological and clinical stages remain poorly understood. Here we performed mass cytometry profiling of whole blood and cerebrospinal fluid (CSF) immune cells from 351 human samples across two independent clinical cohorts spanning the AD continuum. We identify coordinated peripheral immune signaling signatures that emerge during preclinical stage of AD and precede significant elevation of plasma ptau217, CSF ptau181 and BBB disruption measured by dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI). AD-enriched immune features, including increased phospho-Akt signaling in naï ve T killer cells and phospho-PLCγ2 signaling in granulocytes, were not observed in patients with Frontotemporal lobar degeneration or treatment-naï ve multiple sclerosis. Furthermore, these immune signaling states could be induced in healthy donor immune cells following exposure to plasma or CSF from individuals with AD, indicating that circulating factors can drive these peripheral immune alterations. Together, our findings demonstrate that dynamic peripheral immune state changes arise early in AD and precede canonical biomarker and vascular changes, highlighting immune signaling pathways as potential targets for early therapeutic intervention.},
}

@article {pmid41959530,
year = {2026},
author = {Pandey, S and Talo, M and Siderovski, DP and Sumien, N and Bozdag, S},
title = {From General-Purpose to Disease-Specific Features: Aligning LLM Embeddings on a Disease-Specific Biomedical Knowledge Graph for Drug Repurposing.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.03.07.707871},
pmid = {41959530},
issn = {2692-8205},
abstract = {Identifying new therapeutic uses for existing drugs is a major challenge in biomedicine, especially for complex neurodegenerative conditions such as Alzheimer disease and related dementias (ADRD), where treatment options remain limited and relevant data are often sparse, heterogeneous, and difficult to integrate. Although general-purpose Large Language Model (LLM) embeddings encode rich semantic information, they often lack the task-specific biomedical context needed for inference tasks such as computational drug repurposing. We introduce Contextualizing LLM Embeddings via Attention-based gRaph learning (CLEAR), a multimodal representation-fusion framework that aligns LLM embeddings with the topological structure of a context-specific Knowledge Graph (KG). Across five benchmark datasets, CLEAR achieved state-of-the-art results, improving predictive performance (e.g., F1 score) by up to 30% over prior methods. We further applied CLEAR to identify FDA-approved drugs with potential for repurposing for ADRD, including Parkinson disease-related dementia and Lewy Body dementia. CLEAR learned a biologically coherent embedding space, prioritized leading ADRD drug candidates, and accurately summarized known therapeutic relationships for FDA-approved Alzheimer disease drugs. Overall, CLEAR shows that grounding biomedical LLM embeddings with context-specific KG signals can improve drug repurposing in data-sparse, real-world settings. GitHub: https://github.com/bozdaglab/CLEAR.},
}

@article {pmid41959743,
year = {2026},
author = {Guo, Y and Jiang, Q and Gu, Z and Cao, H and Zuo, C and Huang, Y and Song, Y and Chen, X and Wang, F},
title = {ACSL4 in Alzheimer's disease: Pathogenetic mechanisms and potential therapeutic targets.},
journal = {Genes & diseases},
volume = {13},
number = {4},
pages = {101858},
pmid = {41959743},
issn = {2352-3042},
abstract = {Iron metabolism plays a vital role in maintaining physiological homeostasis, and its dysregulation is implicated in a range of pathological consequences and illnesses, including Alzheimer's disease (AD). Prior studies have demonstrated that Tau protein and amyloid precursor protein are involved in iron homeostasis disorder. Ferroptosis, an iron-dependent form of regulated cell death, has emerged as a key contributor to AD pathogenesis and a promising therapeutic target. Acyl-CoA synthetase long-chain family 4 (ACSL4) is a lipid metabolizing enzyme that enhances ferroptosis sensitivity by promoting the incorporation of oxidizable polyunsaturated fatty acids into membrane phospholipids. Beyond ferroptosis, ACSL4 also plays crucial roles in neuroinflammation and oxidative stress, which are implicated in AD progression. Therefore, targeting ACSL4 is fantastic and has a lot of promise for treating AD. Nevertheless, the precise mechanisms through which ACSL4 contributes to AD pathology have yet to be fully elucidated. This review reveals a potentially vital role of ACSL4 in AD, focusing on its involvement in ferroptosis, oxidative stress, and neuroinflammation. Additionally, we describe some natural and synthetic compounds targeting ACSL4 with therapeutic potential in AD. Building on the theoretical findings of earlier studies about focused interventions of the ACSL4 path, our evaluation provided a broad basis for the clinical transformation in the treatment of AD strategies.},
}

@article {pmid41961243,
year = {2026},
author = {Porsteinsson, AP and Chumki, SR and Wang, D and Such, P and Palma, AM and Zhang, Z and Shah, A and Kalu, U and Montano, CB},
title = {Short-Term and Long-Term Safety Analyses of Brexpiprazole for Agitation Associated with Dementia due to Alzheimer's Disease: Timing and Duration of Adverse Events.},
journal = {Drug safety},
volume = {},
number = {},
pages = {},
pmid = {41961243},
issn = {1179-1942},
abstract = {INTRODUCTION: Agitation symptoms are a common and burdensome aspect of Alzheimer's dementia. Historically, agitation has been managed using off-label treatments such as atypical antipsychotics, but this approach is associated with safety concerns in older, more vulnerable patients. Brexpiprazole is an atypical antipsychotic that has been recently approved in several countries for the treatment of agitation associated with dementia due to Alzheimer's disease. Previous analyses show that brexpiprazole was efficacious and generally well tolerated for up to 24 weeks. Building upon previous work, this post hoc analysis aimed to evaluate the timing and duration of treatment-emergent adverse events (TEAEs) during brexpiprazole treatment.

METHODS: In a 12-week analysis, data were pooled from three phase 3, randomized, double-blind, placebo-controlled trials of brexpiprazole in participants with agitation associated with dementia due to Alzheimer's disease. In a separate 24-week analysis, brexpiprazole data were combined from a 12-week randomized trial and a 12-week active-treatment extension trial. The median time from starting treatment to first reporting a TEAE and the median duration of all TEAEs were determined.

RESULTS: A total of 1043 participants received at least one dose of trial medication. Over 12 weeks, brexpiprazole 2 or 3 mg/day (the approved therapeutic dosages in the United States, N = 366) compared to placebo (N = 388) had similar time to first TEAE (32 days and 28 days, respectively), similar duration of all TEAEs (6 days and 4 days), and longer time to discontinuation due to adverse events (47 days and 30 days). Over 24 weeks (N = 163), the time to first TEAE on brexpiprazole 2 or 3 mg/day was 52 days, and the duration of all TEAEs was 3 days. Among participants who did not report a TEAE in the 12-week parent trial, TEAEs were rare throughout the 12-week extension trial.

CONCLUSIONS: These exploratory analyses reinforce that brexpiprazole is generally well tolerated over 12 weeks, and also over 24 weeks among patients who tolerated the first 12 weeks of treatment. The results provide a practical clinical insight into the safety of brexpiprazole over time in patients with agitation associated with dementia due to Alzheimer's disease.

TRIAL REGISTRATION: Post hoc analysis of NCT01862640, NCT01922258, NCT03548584, NCT03594123 (ClinicalTrials.gov).},
}

@article {pmid41961641,
year = {2026},
author = {Yang, L and Zhao, W and Zhao, J and Chen, S and Qin, X and Yang, Z and Kong, D and Zhang, W},
title = {Effects of ononin on cognitive and learning-memory functions in mild cognitive impairment.},
journal = {Neuroreport},
volume = {},
number = {},
pages = {},
doi = {10.1097/WNR.0000000000002264},
pmid = {41961641},
issn = {1473-558X},
abstract = {OBJECTIVE: This study aimed to investigate the potential of ononin in alleviating mild cognitive impairment (MCI) and to determine whether its effects depend on the functional recovery of neurons in the nucleus tractus solitarius (NTS).

METHODS: Four-month-old APP/PS1 mice were treated with 30-mg/kg ononin via oral gavage for 8 consecutive days. Cognitive behavior was assessed using the novel object recognition test, Y-maze test, and open field test. Cortical perfusion was measured by laser speckle contrast imaging. The activation of NTS neurons was detected using c-Fos immunofluorescence staining, while dendritic complexity and neuronal firing frequency were evaluated via Golgi staining and patch-clamp electrophysiology, respectively.

RESULTS: Ononin treatment significantly improved the novel object recognition index and spontaneous alternation rate in the Y-maze test in APP/PS1 mice. It also enhanced cerebral blood flow perfusion and increased the number of c-Fos-positive cells in the NTS, hippocampal CA1 region, and cortex. Furthermore, ononin increased dendritic intersections and restored dendritic spine density in NTS neurons to normal levels, along with significantly elevating their firing frequency.

CONCLUSION: Ononin may ameliorate MCI-like cognitive deficits in APP/PS1 mice by activating NTS neurons, restoring synaptic plasticity, and improving cerebral perfusion. These findings suggest that the NTS could serve as a potential target for early intervention in Alzheimer's disease.},
}

@article {pmid41962111,
year = {2026},
author = {Sobiech, L and Wójcik, L and Jankowska, N and Turżańska, K},
title = {Periodontitis as a systemic inflammatory disorder - implications for cardiovascular and neurodegenerative diseases.},
journal = {Wiadomosci lekarskie (Warsaw, Poland : 1960)},
volume = {79},
number = {3},
pages = {646-650},
doi = {10.36740/WLek/218274},
pmid = {41962111},
issn = {0043-5147},
mesh = {Humans ; *Cardiovascular Diseases/etiology ; *Neurodegenerative Diseases/etiology ; *Periodontitis/complications/microbiology ; *Inflammation/complications ; },
abstract = {OBJECTIVE: Aim: Periodontitis is a chronic inflammatory condition associated with oral microbiome dysbiosis and the dominance of Gram-negative bacteria such as Porphyromonas gingivalis. It is characterized by progressive destruction of the supporting tissues of the tooth, leading to loss of connective tissue attachment, resorption of the alveolar bone, and, consequently to tooth loosening and loss. If left untreated, it leads to recurrent bacteremia and persistent systemic inflammation. The aim of this study is to discuss the mechanisms linking periodontitis to cardiovascular and neurodegenerative diseases.

PATIENTS AND METHODS: Materials and Methods: A comprehensive literature review was conducted examining clinical studies, systematic reviews, and meta-analyses assessing the impact of periodontal disease on the development of cardiovascular and neurodegenerative diseases.

CONCLUSION: Conclusions: Chronic activation of the immune response, oxidative stress, and lipid metabolism disorders promote endothelial dysfunction and the progression of atherosclerosis, increasing the risk of cardiovascular events. At the same time, systemic inflammation can affect the permeability of the blood-brain barrier and exacerbate neuroinflammatory processes, promoting β-amyloid accumulation and the progression of Alzheimer's disease. Analysis of the literature indicates the significant, albeit complex, nature of these relationships, emphasizing the importance of prevention and treatment of periodontal disease as part of comprehensive patient care. The key in the approach to periodontal patients is an interdisciplinary perspective, integrating dentistry, cardiology, neurology, and geriatrics.},
}

Humans
*Cardiovascular Diseases/etiology
*Neurodegenerative Diseases/etiology
*Periodontitis/complications/microbiology
*Inflammation/complications

@article {pmid41962274,
year = {2026},
author = {Dong, Y and Wang, Y and Chen, K and Sun, G and Cao, X and Li, X and Lu, W and Dai, X and Huang, B and Chen, Y},
title = {Engineering versatile nanoplatforms for calcium homeostasis modulation and broad-spectrum disease therapies.},
journal = {Biomaterials},
volume = {333},
number = {},
pages = {124207},
doi = {10.1016/j.biomaterials.2026.124207},
pmid = {41962274},
issn = {1878-5905},
abstract = {Calcium ions (Ca[2+]) serve as a pivotal intracellular second messenger, participating in core physiological processes including cell proliferation, neurotransmission, and apoptosis. The maintenance of calcium homeostasis depends on the precise interplay of plasma membrane channels and intracellular organelle stores. Dysregulation of calcium signaling is implicated in the pathogenesis of multiple diseases, including Alzheimer's disease, cancer, and cardiovascular disorders. Conventional pharmacological interventions are limited by off-target effects, insufficient bioavailability, and a lack of temporal and spatial control. Ca[2+]-regulated nanoplatform achieves spatiotemporally controlled drug release and responsive calcium level modulation through advanced surface engineering and stimulus-responsive design, substantially improving therapeutic precision and efficacy. Furthermore, nanoprobes permit real-time monitoring of calcium dynamics with high sensitivity and resolution. This comprehensive review systematically summarizes and highlights significant advances in engineering versatile nanoplatforms for calcium homeostasis modulation, focusing on constructed nanocarriers for drug delivery, functional nano-regulators for calcium flux intervention, and sensitive nanoprobes for real-time calcium imaging and quantification. Current challenges and future directions are also discussed to inspire the development of next-generation nanotheranostic platforms for precise diagnosis and treatment of calcium homeostasis-related diseases.},
}

@article {pmid41606687,
year = {2026},
author = {Wang, Y and Mohammadi, B and Hartmann, C and Hartmann, K and Thies, E and Matamoros-Angles, A and Fang, C and Harris, DA and Tatzelt, J and Altmeppen, HC and Sepulveda-Falla, D and Strittmatter, SM and Glatzel, M and Krasemann, S},
title = {Presymptomatic pharmacological inhibition of mGluR5 improves survival in a mouse model of prion diseases.},
journal = {Acta neuropathologica communications},
volume = {14},
number = {1},
pages = {},
pmid = {41606687},
issn = {2051-5960},
support = {P30 AG066508/AG/NIA NIH HHS/United States ; R01 AG034924/AG/NIA NIH HHS/United States ; },
abstract = {UNLABELLED: Toxic signaling of oligomeric protein species via binding to the cellular prion protein (PrP[C]) is implicated in various neurodegenerative diseases, including Alzheimer’s (AD) and Parkinson’s disease (PD). Metabotropic glutamate receptor 5 (mGluR5) has been identified as a PrP[C] signaling partner, and pharmacological inhibition of mGluR5 was shown to improve cognitive performance and rescue long-term-potentiation (LTP) impairment in both in vitro and in vivo models of AD and PD. Prion diseases are another group of fatal neurodegenerative disorders that are characterized by templated misfolding of endogenous PrP[C] itself into the disease-driving counterpart PrP[Sc]. Besides its role in the self-propagating misfolding cascade and aggregation, PrP[Sc] also acts as a toxic PrP[C] ligand in aberrant signaling through mGluR5. Therefore, targeting metabotropic glutamate receptors has been proposed as a therapeutic strategy for the intervention of prion disease. In this study, we investigated the impact of long-term oral administration of two different selective mGluR5 inhibitors, the negative allosteric inhibitor CTEP and a Silent Allosteric mGluR5 Modulator (SAM), in a mouse model of prion disease. Our findings demonstrate that treatment initiated during the preclinical phase significantly prolonged the survival of mice, whereas treatment starting after the onset of symptoms was no longer effective. Early treatment also delayed the formation of spongiosis, a pathological hallmark of prion diseases, but did not alter PrP[Res] levels. Preclinical dysregulation of mGluR5 could be shown in the mouse and a non-human primate model for prion diseases. Interestingly, in primary neurons, subacute treatment with CTEP blocked Aβ-induced, but not PrP[Sc]-associated synaptotoxicity. Thus, modes of action might differ markedly from those observed in models of Alzheimer’s disease. Together, although our data show that targeting mGluR5 may be an efficient therapy, however, since treatment needs to be started early during prion disease progression, the narrow therapeutic window limits its therapeutic application in human prion diseases.

SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s40478-026-02235-9.},
}

@article {pmid41772032,
year = {2026},
author = {Zolfaghari, S and Gholizadeh, E and Garehdaghi, F},
title = {Integrating attractor dynamics and connectivity features for EEG-based dementia classification.},
journal = {Scientific reports},
volume = {16},
number = {1},
pages = {},
pmid = {41772032},
issn = {2045-2322},
abstract = {The precise differentiation between Alzheimer’s disease (AD) and frontotemporal dementia (FTD) presents a clinical challenge, as both conditions share overlapping symptoms yet diverge in their pathophysiological mechanisms and treatment strategies. Electroencephalography (EEG), characterized by its higher temporal resolution and widespread applicability, provides the opportunity to uncover subtle discrepancies in brain dynamics that may be difficult to detect with conventional neuroimaging techniques. This paper presents a system that combines nonlinear attractor-based features derived from phase-space representations with phase-locking value connectivity features to encapsulate both local and global brain dynamics. In this regard, resting-state EEG recordings from 36 AD patients, 23 FTD patients, and 29 healthy controls (HC) were preprocessed and analyzed to extract dynamic and network features. Multiple classifiers were then used to assess these features under stratified 10-fold cross-validation. The results showed that the support vector machine achieved the highest performance for AD vs. FTD (81.7%), logistic regression performed well for FTD vs. HC (81.0%), and gradient boosting reached 82.9% for AD vs. HC. These findings illustrate the capability of EEG as a low-cost diagnostic technique, suggest that attractor dynamics and connectivity can offer complementary perspectives on the brain alterations linked to dementia, and enhance classification performance.},
}

@article {pmid41772634,
year = {2026},
author = {Das, RK and Sahoo, N and Roy, D and Nguyen, L and Rodrigo, H and Duttaroy, AK and Fields, JA and Roy, U},
title = {Interferon-induced protein IFIT3 as a molecular nexus of neuroinflammation in Alzheimer's disease and HIV-associated neurocognitive disorders.},
journal = {Journal of neuroinflammation},
volume = {23},
number = {1},
pages = {},
pmid = {41772634},
issn = {1742-2094},
support = {SC2GM139715//UTRGV internal funding/ ; R15NS108815 and R01AI147731//National Institute of Health, USA/ ; P30AG059305//NASA-MUREP, NASA-MOSAIC, UTRGV-Resource Centers for Minority Aging Research (RCMAR)/ ; U54MD019970//NIMHD grant/ ; },
abstract = {UNLABELLED: Alzheimer’s disease (AD) and HIV-associated neurocognitive disorder (HAND) are significant global health concerns characterized by cognitive impairment and shared pathological features, including chronic neuroinflammation, amyloid deposition, and immune dysregulation. However, the precise molecular connections between these disorders remain unclear. Here, we identify IFIT3 as a critical shared mediator of neuroinflammatory responses in both AD and HAND. Using complementary approaches, including neuronal and microglial cell cultures, the APP/PS1 mouse model, and human postmortem brain tissues, we demonstrate consistent IFIT3 upregulation in response to amyloid-beta (Aβ) and HIV-1 exposure, with notably enhanced expression under combined conditions. Treatment with combination antiretroviral therapy (cART) partially mitigated IFIT3 induction. Additionally, siRNA-mediated silencing of IFIT3 significantly reduced key inflammatory mediators, including mitochondrial antiviral signaling protein (MAVS), nuclear factor-κB, and proinflammatory cytokines. Clinically, elevated IFIT3 expression was associated with early HAND and progressively increased across advancing AD Braak stages. Together, these findings identify IFIT3 as a potential molecular bridge between HAND and AD, highlighting its promise as both a biomarker and a therapeutic target for inflammation-driven neurodegeneration.

GRAPHICAL ABSTRACT: [Image: see text]

SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s12974-026-03713-6.},
}

@article {pmid41776457,
year = {2026},
author = {Tang, Y and Yang, R and Zhang, M and Zhou, C and Chen, M and Pan, H and Qin, Y and Gui, Y and Fan, G},
title = {Classifying drug-related problems of neurodegenerative diseases in the physician-pharmacist joint clinic of neurology: an application of the PCNE method.},
journal = {BMC geriatrics},
volume = {26},
number = {1},
pages = {},
pmid = {41776457},
issn = {1471-2318},
support = {22QA1411400//Shanghai Science and Technology Development Funds/ ; 81973289//National Natural Science Foundation of China/ ; },
abstract = {BACKGROUND: The prevalence of neurodegenerative diseases (NDDs) is escalating, and complex medication regimens lead to a high incidence of drug-related problems (DRPs). This study analyzes DRPs in this population to identify their incidence and causes. The findings aim to provide a theoretical basis for clinical intervention strategies and outpatient pharmacy monitoring, ultimately ensuring rational drug use and enhancing patient safety.

METHOD: This study was conducted among patients with neurodegenerative diseases at a major hospital in Shanghai, China, between July 2023 and June 2024. The Pharmaceutical Care Network Europe (PCNE) classification system version 9.1 was used to identify DRPs. Data was entered and analyzed using SPSS software. Full model and stepwise logistic regression analyses were used to identify predictors of DRP occurrence in the total sample and Alzheimer’s disease (AD)/Parkinson’s disease (PD) subgroups. Outpatient medications were summarized. A p-value of less than 0.05 was considered statistically significant.

RESULT: A total of 254 patients (90 AD, 171 PD) were involved, resulting in 398 DRPs. The most commonly encountered type of DRP was treatment effectiveness (48.99%), and drug selection (46.73%) was the most common cause. The majority of clinical pharmacist interventions were provided at the drug level (98.99%), primarily involving dose adjustment and usage method adjustment. The acceptance level of interventions by prescribers was high (90.70%), with the acceptance rate in AD patients (92.96%) being higher than that in PD patients (90.07%). Through pharmacist intervention, over 70% of DRPs were completely resolved. Anti-Parkinson’s disease drugs, antianxiety or antidepressant drugs, and sedatives and hypnotics were the three main drug classes contributing to DRPs. Lifestyle habits (smoking, drinking), the number of comorbidities, and the dose of medication were factors associated with the development of DRPs.

CONCLUSION: This study finding revealed that DRPs were prevalent in patients with PD and AD. Medication care was a protective factor, whereas polypharmacy and the presence of multiple comorbidities were significantly associated with an elevated risk of DRPs. Based on the PCNE classification and the “PCIAO” process, clinical pharmacists’ involvement in precision management offers a robust evidence base and provides clear guidance for optimizing therapeutic regimens.

SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s12877-026-07234-y.},
}

@article {pmid41776637,
year = {2026},
author = {Wang, L and Wang, F and Wang, X and Chen, X and Li, C and Shan, K and Zhou, H and Wu, G and Xu, Z and Kong, X and Wei, P},
title = {The lung-brain axis: elucidating the mechanisms of pulmonary-driven neurological disorders.},
journal = {Journal of neuroinflammation},
volume = {23},
number = {1},
pages = {},
pmid = {41776637},
issn = {1742-2094},
support = {22201164//National Natural Science Foundation of China/ ; 82571352//National Natural Science Foundation of China/ ; QDZDZK-2025064//the Qingdao Key Health Discipline Development Fund/ ; ZR2024QH041//the Natural Science Foundation of Shandong Province/ ; QDKY2023ZD02//the Scientific Research Foundation of Qilu Hospital of Shandong University/ ; 2024M761822//China Postdoctoral Science Foundation/ ; },
abstract = {The brain and lungs represent two of the most vital organs in the human body. The conceptualization of the lung-brain axis has advanced our understanding of the bidirectional communication between the respiratory and central nervous systems. Accumulating evidence indicates that pulmonary diseases, including chronic obstructive pulmonary disease, asthma, acute respiratory distress syndrome and infections such as bacterial pneumonia, influenza and Coronavirus Disease 2019, along with airborne environmental exposures, constitute significant risk factors for various neurological disorders. The lung-brain axis is primarily mediated by microbial, immune, neural, metabolic and hormonal pathways. These mechanisms contribute to the disruption of blood-brain barrier integrity, the activation of neuroglial cells and the dysfunction of the cerebrovascular system, ultimately causing neuronal injury and diverse neurological conditions. Environmental factors, notably airborne particulate matter and chemical pollutants, further amplify the crosstalk among these mechanisms, extending the neurological risk. Here, we summarize the current knowledge regarding the association between pulmonary dysfunction and the development and progression of neurodegenerative diseases (such as Alzheimer’s disease and Parkinson’s disease), stroke, anxiety/depression, epilepsy, and migraine. Additionally, potential therapeutic strategies targeting the lung–brain axis are discussed to foster further research in this emerging field. Elucidating the complex interactions within the lung–brain axis will not only deepen our understanding of the shared pathophysiological mechanisms but also open novel avenues for the early diagnosis, prevention, and treatment of related neurological diseases.},
}

@article {pmid41776683,
year = {2026},
author = {Shin, H and Lee, S and Seo, W and Yoon, SH and Cho, I and Ye, S and Park, I and Yoon, S and Park, M and Kim, S and Lee, S and Kim, HY and Kim, I and Kim, Y},
title = {YIAD-0501 directly dissociates aggregates of full-length and N-terminal pyroglutamate-modified forms of Aβ.},
journal = {Alzheimer's research & therapy},
volume = {18},
number = {1},
pages = {},
pmid = {41776683},
issn = {1758-9193},
support = {RS-2018-NR031048//Basic Science Research Program, National Research Foundation of Korea (NRF), Ministry of Health & Welfare and Ministry of Science and ICT, Republic of Korea/ ; RS-2025-00523607//Mid-Career Researcher Program, Ministry of Health & Welfare and Ministry of Science and ICT, Republic of Korea/ ; RS-2021-NR059653//Mid-Career Researcher Program, Ministry of Health & Welfare and Ministry of Science and ICT, Republic of Korea/ ; RS-2024-00349158//Ministry of Health & Welfare and Ministry of Science and ICT, Republic of Korea/ ; RS-2024-00418203//Korea Institute for Advancement of Technology/ ; },
abstract = {BACKGROUND: Recent approvals of amyloid-β (Aβ) antibody drugs have established amyloid clearance as a viable therapeutic approach in Alzheimer’s disease (AD). However, despite substantial amyloid reduction, their cognitive benefits remain modest, potentially reflecting incomplete targeting of the structurally diverse pathogenic Aβ assemblies that drive AD progression. Given this molecular heterogeneity, a therapeutic strategy capable of targeting multiple toxic Aβ forms is required to achieve broader efficacy. To address this need, we investigated YIAD-0501, a small-molecule candidate designed to simultaneously engage multiple pathogenic Aβ species, including oligomeric and fibrillar forms of Aβ (1–42) and pyroglutamate Aβ(pE3–42).

METHODS: A series of 6H-furo[3,2-f]pyrrolo[1,2-d][1,4]diazepine derivatives was synthesized and screened by Thioflavin T fluorescence and A11 dot blot assays to identify compounds active against diverse pathogenic Aβ assemblies. The lead compound, YIAD-0501, was further characterized by transmission electron microscopy, circular dichroism, microscale thermophoresis, molecular docking, and amyloid plate mapping to define its Aβ interaction and structural effects. For in vivo evaluation, YIAD-0501 (10 mg/kg, daily for 4 weeks) was administered to 6-month-old male 5XFAD mice, followed by Y-maze testing for spatial working memory and contextual fear conditioning for hippocampal-dependent memory. Biochemical analyses, including immunoblotting, immunohistochemistry, and ELISA, were subsequently conducted to quantify Aβ plaque burden, soluble Aβ levels, and gliosis.

RESULTS: YIAD-0501 effectively reduced both oligomeric and fibrillar assemblies of Aβ (1–42) and Aβ(pE3–42) in vitro. Molecular docking and amyloid mapping analyses indicated interactions between YIAD-0501 and both the C-terminal hydrophobic region and the KLVFFA aggregation core of Aβ, consistent with the observed reduction in β-sheet content and direct binding. In 5XFAD mice, YIAD-0501 treatment decreased amyloid plaque burden, soluble Aβ levels, and neuroinflammation in the hippocampus, accompanied by improvements in spatial working and hippocampal-dependent memory.

CONCLUSIONS: Collectively, our findings identify YIAD-0501 as a small-molecule candidate that reduces multiple pathogenic Aβ assemblies and ameliorates hippocampal pathology and memory deficits in the 5XFAD mouse model. These findings highlight a chemically driven, multi-target mode of Aβ clearance, representing a strategy for broader intervention across the heterogeneous pathogenic landscape of AD.

SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s13195-026-01999-5.},
}

@article {pmid41862973,
year = {2026},
author = {Marei, HE},
title = {Enhancer-based gene therapy: a new path for precision medicine.},
journal = {Hereditas},
volume = {163},
number = {},
pages = {},
pmid = {41862973},
issn = {1601-5223},
abstract = {Enhancers are critical cis-regulatory elements that regulate gene expression in a context-dependent manner by integrating transcription factor binding, chromatin state, and the three-dimensional organization of the genome. Recent advances in functional genomics and synthetic biology have increased interest in harnessing enhancer activity to regulate the expression of therapeutic genes. Unlike traditional approaches that rely on promoter-driven gene regulation, enhancer-based approaches can bias transgene expression toward specific cellular states or disease contexts; however, this control remains probabilistic and highly dependent on the chromatin environment. This review summarizes current knowledge of enhancer biology, discusses new strategies for utilizing enhancer function directly, and examines the potential benefits and drawbacks of using enhancer-based strategies for gene therapy applications. Often delivered using adeno-associated virus (AAV) vectors with tailored capsids, enhancers in gene therapy can be included into expression cassettes. Astrocyte- or microglia-specific enhancers in the brain enable enriched or preferential distribution of neuroprotective or immunomodulatory genes, hence lowering unintentional expression in non-target cell types. It is important to control gene expression for specific cell types for the treatment of neurodegenerative conditions such as Alzheimer’s or Parkinson’s disease, were unintentional gene expression results in negative consequences. However, the uses of enhancer-guided gene therapy go beyond the central nervous system. In cancer, therapeutic constructs are designed to inhibit oncogenic expression or induce tumor suppression pathways, using enhancers in either malignant or immune cells as a target. Similarly, through the use of tissue-specific enhancers in cardiovascular and regenerative medicine, lineage-enriched genes can be used to promote repair of damaged tissues and enhance functional recovery. Enhancer-based systems that modulate the levels of gene expression (enhancer systems that adjust gene expression to levels that are physiologically appropriate for a given cell type) may also be useful in diseases caused by imbalances of gene dosage (e.g., haploinsufficiency and copy number variations). However, despite the potential promise of enhancer-driven gene therapy, many technical and translational hurdles remain. Mapping and validating the function of cell-type-specific enhancers is hampered by the dynamic, context-dependent regulation of chromatin. The identification of enhancers across a variety of developmental stages and clinical states is being accelerated through the combination of recent advances in single-cell epigenomic techniques (e.g., ATAC-seq, ChIP-seq, and multi-omic integration). Recent advances in non-viral delivery methods and AAV capsid engineering are improving the safety, efficacy, and scalability of enhancer-driven gene therapies. However, there must be careful regulatory oversight to avoid unintentional activation of enhancers and ensure continuing efficacy of enhancer-guided therapies. This paper provides an overview of the conceptual basis of enhancer-driven gene therapies, the currently available applications, and barriers to their clinical application. We show how the combination of delivery technology, synthetic biology, and genomics is enabling new possibilities for tailored gene therapy particular to cell- and disease-specific. Enhancer-driven gene therapy could become an important component of next-generation precision medicine by addressing current challenges and using creative technology.},
}

@article {pmid41865008,
year = {2026},
author = {Borgström Bolmsjö, B and Barbosa Djärf, J and van Westen, D and Schindler, SE and Fawad, A and Collij, L and Smith, R and Mattsson-Carlgren, N and Stomrud, E and Tideman, P and Hansson, O and Palmqvist, S},
title = {Eligibility for amyloid targeting therapies among primary care patients with cognitive symptoms.},
journal = {Alzheimer's research & therapy},
volume = {18},
number = {},
pages = {},
pmid = {41865008},
issn = {1758-9193},
abstract = {BACKGROUND: Alzheimer’s disease (AD) is the most common cause of dementia and a growing healthcare challenge. Amyloid-targeting therapies (ATT) may slow progression, but implementation is limited by logistical and economic barriers. As primary care is the first contact for most patients with cognitive concerns, quantifying treatment eligibility in this setting is essential. The purpose of this study was to estimate the proportion of primary care patients presenting with cognitive symptoms who are eligible for ATT.

METHODS: This cohort study included patients presenting with cognitive symptoms in primary care across the region Skåne, in southern Sweden, recruited between January 2020 and April 2025. Stepwise exclusion criteria based on clinical diagnosis, comorbidities, and treatment contraindications were applied, in alignment with appropriate use recommendations for lecanemab and donanemab, respectively. Eligibility was further refined using CSF biomarkers (Aβ42/40 ratio), cognitive performance, and MRI findings.

RESULTS: In a full diagnostic work-up of 607 patients with sequential exclusions, 86 patients (14.2%) and 78 patients (12.8%) ultimately met the eligibility criteria for lecanemab and donanemab, respectively. Due to comorbidities, medication use, and age/BMI, around 1/3 of the original population was excluded. Most ineligible patients met more than one exclusion criterion. The eligible population was 63% female, mean age 77 years. Around 65% of the individuals had mild cognitive impairment (MCI), and 35% mild dementia.

CONCLUSIONS: About 13-14% of primary care patients evaluated for cognitive complaints were eligible for ATT. Compared with clinical trials, the eligible population was older and consisted of more women.

TRIAL REGISTRATION: BioFINDERPrimary Care study (NCT06120361, Registration date 2 November 2023 https//biofinder.se).

SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s13195-026-02019-2.},
}

@article {pmid41904593,
year = {2026},
author = {Merkel, J and Perneczky, R and Jessen, F and Frölich, L and Jansen, O and Peters, S and Berg, D and Schulz, JB and Bartsch, T},
title = {Amyloid-related imaging abnormalities (ARIA) in Alzheimer's disease: from pathophysiology to individualized risk assessment.},
journal = {Alzheimer's research & therapy},
volume = {18},
number = {},
pages = {},
pmid = {41904593},
issn = {1758-9193},
abstract = {UNLABELLED: Monoclonal antibodies targeting amyloid-β are the first approved disease-modifying treatment for Alzheimer’s disease. While amyloid-targeting therapies mitigate the progression of cognitive decline in early-stage Alzheimer’s disease, they are associated with amyloid-related imaging abnormalities (ARIA), an imaging phenomenon presenting as cerebral edema/effusion and/or hemorrhage. Redistribution of parenchymal amyloid-β to perivascular drainage pathways and direct antibody-amyloid interactions within the cerebral vasculature are considered key players in ARIA pathophysiology by promoting inflammation and vascular disruption, thus mirroring hallmarks of inflammatory cerebral amyloid angiopathy. Although ARIA is commonly regarded as an undesired side effect of amyloid-targeting therapies, its association with amyloid-β clearance from the brain opens up the possibility of an alternative interpretation as a physiological reaction to target engagement of anti-amyloid antibodies. Understanding risk factors that promote the occurrence of ARIA and its transformation from asymptomatic imaging phenomenon to its serious and severe form are of great importance to clinical practice. ARIA risk and severity are influenced by apolipoprotein E4 status, microvascular damage, and cerebral amyloid angiopathy, but may be further modulated by antibody binding preferences and comorbidities such as arterial hypertension and ischemic strokes. Identifying individual risk profiles based on deeper insights into pathophysiological pathways may improve patient safety and lead to personalized treatment concepts in Alzheimer’s disease. In this review, we provide a comprehensive summary of ARIA pathophysiology, highlight important risk factors and discuss their relevance in clinical risk management.

SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s13195-026-02022-7.},
}

@article {pmid41946775,
year = {2026},
author = {Phemphunananchai, K and Waiwut, P and Phetcharaburanin, J and Poonsawas, P and Boonyarat, C},
title = {Repurposing FDA-approved drugs as multi-target neuroprotective agents for Alzheimer's disease via computational screening and experimental validation.},
journal = {Scientific reports},
volume = {16},
number = {1},
pages = {},
pmid = {41946775},
issn = {2045-2322},
support = {67-2(7)/2567//Faculty of Pharmaceutical Sciences, Khon Kaen University, Thailand/ ; RA2567-M109//The Research Assistant Program, Khon Kaen University, Thailand/ ; },
abstract = {UNLABELLED: β-site APP-cleaving enzyme 1 (BACE1, a β-secretase) is a key aspartyl protease that initiates the proteolytic processing of the amyloid precursor protein (APP) to form the amyloid-β (Aβ) peptide. Given that Aβ aggregation and plaque formation are a central pathological feature of Alzheimer’s disease (AD), BACE1 remains a critical therapeutic target. Furthermore, the complexity of AD pathology necessitates the identification of novel multi-target agents. This study employed a structure-based virtual screening, targeting the BACE1 approach to identify the potential BACE1 inhibitors from FDA-approved drug scaffolds derived from the ZINC database. Top-ranked candidates were subsequently validated through extensive 500 ns molecular dynamics (MD) simulations and in vitro assays of BACE1 inhibition activity. Furthermore, multi-AD-related target profiling of candidates was conducted using molecular docking and a series of in vitro assays. Among them, ZINC000019796155 emerged as a promising multi-target compound. Biochemical analysis revealed that ZINC000019796155 exhibited moderate inhibitory effects against BACE1. Subsequent assays confirmed its capacity to inhibit butyrylcholinesterase (BuChE) action and Aβ aggregation, function as a free radical scavenger, and provide neuroprotection against H2O2-induced oxidative stress in cellular models. Furthermore, western blot analysis elucidated the mechanism of neuroprotection, indicating that ZINC000019796155 inhibits the apoptotic pathway while simultaneously suppressing the formation of Aβ plaques and neurofibrillary tangles (NFTs). These findings highlight ZINC000019796155 as a validated scaffold with a known safety profile for AD. While further structural optimization and preclinical in vivo studies are necessary, this study underscores the potential of ZINC000019796155 as a multi-target neuroprotective agent for AD treatment.

SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1038/s41598-026-46708-2.},
}

@article {pmid41950049,
year = {2026},
author = {Robb, WH and Kaur, G and Huang, S and Martinez, F and Nguyen, B and Shin, CH and Yang, M and Conyers, CT and Grilli, CB and Upjohn, DP and Ortega, VE and Hohman, TJ and Keegan, RM and Parent, EE and Cogswell, PM and Graff-Radford, J and Johnson, DR and Ramanan, VK and Koran, ME},
title = {Health system patterns of imaging and fluid biomarker testing in the era of anti-amyloid therapies.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {22},
number = {4},
pages = {e71343},
pmid = {41950049},
issn = {1552-5279},
support = {//Alzheimer's Association Clinician Scientist Fellowship (MEK)/ ; K76AG088554/AG/NIA NIH HHS/United States ; },
mesh = {Humans ; *Biomarkers/cerebrospinal fluid/blood ; Female ; *Alzheimer Disease/drug therapy/diagnostic imaging/cerebrospinal fluid/diagnosis ; Male ; *Amyloid beta-Peptides/cerebrospinal fluid/antagonists & inhibitors ; Retrospective Studies ; Aged ; Positron-Emission Tomography ; Apolipoproteins E/genetics ; Brain/diagnostic imaging ; Middle Aged ; tau Proteins/cerebrospinal fluid/blood ; Aged, 80 and over ; Electronic Health Records ; },
abstract = {INTRODUCTION: Anti-amyloid-β (Aβ) therapies are reshaping Alzheimer's disease (AD) management. Understanding changes in real-world patterns of diagnostic testing and infusion chair usage is essential for optimizing access to care.

METHODS: Retrospective analysis of Mayo Clinic enterprise electronic health records (Jan 2019-Mar 2025) assessed trends in AD-relevant brain imaging, fluid biomarkers, apolipoprotein E (APOE) testing, and lecanemab infusions. Rates of amyloid-beta (Aβ) positivity by sex and age, APOE genotype frequencies, and lecanemab treatment initiation and discontinuation were evaluated.

RESULTS: Following national insurance coverage changes, lecanemab infusions grew by 110 infusions per quarter to 605 in Q1 2025. Aβ positron emission tomography scans increased (+22/quarter), cerebrospinal fluid biomarker orders declined (-25/quarter), and plasma p-tau217 orders rapidly increased (+238/quarter). Females were more likely to be Aβ positive (p < 0.006). APOE-ε4 homozygotes were less likely to initiate lecanemab (HR = 0.11, p < 0.001).

DISCUSSION: The adoption of anti-Aβ therapies coincided with a rapid shift in diagnostic workflows.},
}

Humans
*Biomarkers/cerebrospinal fluid/blood
Female
*Alzheimer Disease/drug therapy/diagnostic imaging/cerebrospinal fluid/diagnosis
Male
*Amyloid beta-Peptides/cerebrospinal fluid/antagonists & inhibitors
Retrospective Studies
Aged
Positron-Emission Tomography
Apolipoproteins E/genetics
Brain/diagnostic imaging
Middle Aged
tau Proteins/cerebrospinal fluid/blood
Aged, 80 and over
Electronic Health Records

@article {pmid41951598,
year = {2026},
author = {Zhao, S and Ye, R and Tang, QY and Attaallah, B and Toniolo, S and Saleh, Y and Rouse, MA and Garrard, P and Broulidakis, MJ and Thompson, S and Manohar, SG and Irani, SR and Ang, YS and Lockwood, P and Apps, MAJ and Hu, P and Wang, K and Rowe, JB and Le Heron, C and Husain, M},
title = {The social dimension of apathy: evidence for a distinct domain from 11,243 individuals across health and neurocognitive disorders.},
journal = {Translational psychiatry},
volume = {},
number = {},
pages = {},
doi = {10.1038/s41398-026-04023-4},
pmid = {41951598},
issn = {2158-3188},
support = {226645/Z/22/Z//Wellcome Trust (Wellcome)/ ; 226645/Z/22/Z//Wellcome Trust (Wellcome)/ ; 226645/Z/22/Z//Wellcome Trust (Wellcome)/ ; 220258/WT_/Wellcome Trust/United Kingdom ; 226645/Z/22/Z//Wellcome Trust (Wellcome)/ ; 82171917//National Natural Science Foundation of China (National Science Foundation of China)/ ; 82471271//National Natural Science Foundation of China (National Science Foundation of China)/ ; MR/V007173/1//RCUK | Medical Research Council (MRC)/ ; MC_UU_00030/14//RCUK | Medical Research Council (MRC)/ ; SUAG/092 G116768//RCUK | Medical Research Council (MRC)/ ; 02/2019//Canterbury Medical Research Foundation (CMRF)/ ; },
abstract = {Apathy is a highly prevalent and disabling neuropsychiatric syndrome, but its multi-dimensional structure is a challenge for progress towards better identification and treatment. A crucial unresolved question is whether social disengagement reflects a distinct deficit in social motivation or a by-product of diminished initiative or emotional blunting. Previous studies have been constrained by modest sample sizes and limited use of apathy-specific instruments or phenotypically narrow cohorts. Here, we analysed item-level data from 11,243 individuals recruited across multiple centres, including 1154 neurological patients with Alzheimer's disease, Parkinson's disease, frontotemporal dementia, autoimmune encephalitis and small vessel disease, alongside people with depression and healthy adults. Across exploratory and confirmatory factor analyses, symptom-level network modelling, and lifespan analyses, social apathy consistently emerged as a coherent and separable dimension. This pattern was preserved across health, psychiatric, and neurocognitive cohorts, from adolescence through late life. Recognising social apathy as an independent domain reframes a central aspect of mental health-the motivation to connect, care, and act for others-and provides a foundation for more precise assessment and for interventions targeting both social and neurobiological mechanisms.},
}

@article {pmid41951832,
year = {2026},
author = {Islam, N and Akçesme, B},
title = {Single nucleotide polymorphisms affecting galantamine binding to acetylcholinesterase in Alzheimer's disease: a structural bioinformatics study.},
journal = {Journal of computer-aided molecular design},
volume = {40},
number = {1},
pages = {},
pmid = {41951832},
issn = {1573-4951},
mesh = {*Galantamine/chemistry/metabolism ; Humans ; *Alzheimer Disease/drug therapy/genetics/enzymology ; *Acetylcholinesterase/chemistry/genetics/metabolism ; *Cholinesterase Inhibitors/chemistry/metabolism/pharmacology ; Molecular Dynamics Simulation ; *Polymorphism, Single Nucleotide ; Molecular Docking Simulation ; Protein Binding ; Computational Biology ; Binding Sites ; Ligands ; Catalytic Domain ; Thermodynamics ; },
abstract = {Galantamine, an acetylcholinesterase (AChE) inhibitor used for symptomatic treatment of Alzheimer's disease (AD), shows substantial inter-individual variability in clinical response. Missense single nucleotide polymorphisms (SNPs) within the AChE active-site gorge may modulate inhibitor recognition. In this computational study, binding residues were defined from human AChE inhibitor co-crystal structures and cross-referenced with dbSNP missense variation, followed by in-silico predictions of variant impact, evolutionary conservation and folding stability, and assessment of ligand engagement by docking and molecular dynamics (MD) with MM/GBSA binding-energy estimation. Using complexes containing galantamine (GNT) and a donepezil-like ligand (E20), 11 of 807 AChE missense variants overlapped binding-site residues, highlighting Phe294 (UniProt Phe326) and His447 (UniProt His479). ConSurf classified His447 as highly conserved, and MUpro predicted decreased folding stability for His447 substitutions. SwissDock docking indicated that His447Gln retains a plausible GNT binding pose and yielded the least favourable docking score among the tested variants, consistent with a potential reduction in binding strength. MD simulations (200 ns) of wild-type and His447Gln AChE-GNT complexes supported preserved global structural integrity of the complex over the simulated timescale, while indicating local remodelling of the GNT binding microenvironment. MM/GBSA estimates from terminal snapshots suggested a modestly less favourable theoretical binding free energy for His447Gln relative to wild-type (approximately 2.0 kcal mol[-1]). Given that His447 is the catalytic triad histidine, such substitutions may have consequences for catalysis in addition to inhibitor binding; these in-silico findings require experimental validation using site-directed mutagenesis with kinetic and binding assays.},
}

*Galantamine/chemistry/metabolism
Humans
*Alzheimer Disease/drug therapy/genetics/enzymology
*Acetylcholinesterase/chemistry/genetics/metabolism
*Cholinesterase Inhibitors/chemistry/metabolism/pharmacology
Molecular Dynamics Simulation
*Polymorphism, Single Nucleotide
Molecular Docking Simulation
Protein Binding
Computational Biology
Binding Sites
Ligands
Catalytic Domain
Thermodynamics

@article {pmid41953054,
year = {2026},
author = {Zhuang, YY and Yan, JM and Wu, TC and Xu, WS and Wu, B and Xie, X and Wang, WJ and Lin, HW and Jian, JW and Wang, JZ and Jiang, T and Chen, LM and Qiu, YX and Hu, ZY and Zhou, YH and Yang, T and Yang, MG and Zhu, JF and Tao, J and Chen, LD and Li, WG and Yan, K and Liu, WL},
title = {tDCS improves early Alzheimer's disease by synaptic vesicle fusion and release.},
journal = {Military Medical Research},
volume = {13},
number = {1},
pages = {100003},
pmid = {41953054},
issn = {2054-9369},
mesh = {*Alzheimer Disease/therapy/physiopathology ; Animals ; Mice ; *Transcranial Direct Current Stimulation/methods/standards ; *Synaptic Vesicles/physiology/metabolism ; Mice, Transgenic ; Prefrontal Cortex/physiopathology ; Disease Models, Animal ; Male ; Memory, Short-Term ; Humans ; },
abstract = {BACKGROUND: Working memory deficits, one of the earliest hallmarks of Alzheimer's disease (AD), are closely linked to abnormal neural activity in the dorsolateral prefrontal cortex (DLPFC). Transcranial direct current stimulation (tDCS), a non-invasive neuromodulation therapy, has been shown to ameliorate early AD working memory deficits by modulating excitatory activity in the DLPFC, yet the underlying mechanisms remain incompletely understood.

METHODS: This investigation was structured around 3 experimental phases. We initially applied tDCS to stimulate the left prefrontal cortex (PFC) of transgenic mice with 5 familial AD (5×FAD) 5 d per week for 4 weeks. Subsequently, we employed optogenetic (Opt) techniques to modulate left PFC glutamatergic neurons. Finally, we inhibited soluble N-ethylmaleimide-sensitive factor attachment receptor (SNARE) expression in the left PFC to elucidate the essential function of SNARE complex assembly with chaperone molecules in orchestrating synaptic vesicle release.

RESULTS: tDCS treatment improved working memory deficits in early-stage AD mice. This was accompanied by increased cerebral blood flow, enhanced neuronal excitability, amelioration of neurochemical metabolic disorders, and reduced amyloid β-protein (Aβ) deposition in the left PFC. Opt stimulation of PFC glutamatergic neurons similarly improved working memory, indicating the association between tDCS's therapeutic effects and synaptic plasticity of excitatory neurons. Crucially, tDCS facilitated synaptic vesicle fusion and release, evidenced by increased vesicle numbers, enhanced release probability, improved synaptic transmission efficacy, and upregulation of the SNARE complex, Snap25, and Syt1. Inhibiting SNARE expression in the left PFC attenuated the tDCS-induced improvements in synaptic vesicle release and working memory.

CONCLUSION: These findings collectively demonstrate that left PFC-targeted tDCS modulates interactions between the SNARE complex and chaperone molecules, thereby promoting synaptic vesicle fusion and release. This mechanism underlies the amelioration of early AD-like working memory impairment by tDCS.},
}

*Alzheimer Disease/therapy/physiopathology
Animals
Mice
*Transcranial Direct Current Stimulation/methods/standards
*Synaptic Vesicles/physiology/metabolism
Mice, Transgenic
Prefrontal Cortex/physiopathology
Disease Models, Animal
Male
Memory, Short-Term
Humans

@article {pmid41954680,
year = {2026},
author = {Youssef, B and Ibrahim, EA and Moselhy, SS and ElShebiney, S and ELabd, WK},
title = {Nano-magnolol enhances the modulatory effects of magnolol on cognitive performance and BACE1-related biochemical changes in an STZ-induced rat model of Alzheimer's disease.},
journal = {Discover nano},
volume = {21},
number = {1},
pages = {},
pmid = {41954680},
issn = {2731-9229},
abstract = {BACKGROUND: The Late-onset Alzheimer's disease (LOAD) is progressive cognitive deficits associated with different abnormalities as cholinergic dysfunction, amyloid accumulation, inflammation, and oxidative stress. Magnolol is a polyphenolic compound that abrogated the neurodegenerative disease. The application of nanoparticles in medicine showed high bioavailability and low side effects for development of novel effective therapies. This study evaluated the neuroprotective potential of magnolol nanoparticles against streptozotocin (STZ) injected in intracerebroventricularly (ICV) induced Alzheimer's disease (AD) in rats.

METHODS: In current study, six groups of male Wister rats (10 rats/ group) were injected with STZ (2 mg/kg) in ICV bilaterally for induction of pathological features similar to AD. Rats were then treated with either magnolol or nano-magnolol or donepezil (p.o). Behavioral analysis was evaluated as the Morris Water Maze (MWM), Y-Maze, Novel Object Recognition (NOR), Passive Avoidance (PA), Elevated plus Maze (EPM), and Open Field Test (OFT). In addition, biochemical markers including brain acetylcholinesterase (AChE), glutathione-S-transferase (GST), B-secretase1 (BACE1) activities and nuclear factor kappa-B (NF-κB) were analyzed in hippocampal tissue.

RESULTS: Data obtained showed that nano-magnolol significantly showed a neuroprotective effect in LOAD rat model by restoring GST activity and effectively decreased the activities of AChE, BACE1 and level of NF-κB compared to both donepezil and magnolol. Molecular docking studies indicated strengthen the affinity of magnolol to the BACE-1 active site.

CONCLUSION: Nano-magnolol is promising in developing a new agent targeting cholinergic function, amyloidogenesis, neuro-inflammation, and oxidative stress reflecting its potent neuroprotective efficacy in AD treatment.},
}

@article {pmid41954847,
year = {2026},
author = {Ma, X and Wang, M and Yang, J and Li, G and Wang, Y and Fang, H and Zhang, S},
title = {Integrated Single-Cell and System Network Analysis: Exploring Cellular Communication Network Complexity and Signal Transmission Dysregulation in Down Syndrome Brain.},
journal = {Neuroinformatics},
volume = {24},
number = {2},
pages = {},
pmid = {41954847},
issn = {1559-0089},
support = {No. 2022D03052; No. XJNUBS202419; Grant Numbers. 82270417//This research was supported by the Special Natural Science Foundation of Xinjiang Uygur Autonomous Region Special Training Programme for Ethnic Minorities (No. 2022D03052), the Doctoral (Postdoctoral) Research Start-up Fund Project of Xinjiang Normal University (No. XJNUBS202419) and the National Natural Science Foundation of China (Grant Numbers. 82270417)./ ; No. 2022D03052; No. XJNUBS202419; Grant Numbers. 82270417//This research was supported by the Special Natural Science Foundation of Xinjiang Uygur Autonomous Region Special Training Programme for Ethnic Minorities (No. 2022D03052), the Doctoral (Postdoctoral) Research Start-up Fund Project of Xinjiang Normal University (No. XJNUBS202419) and the National Natural Science Foundation of China (Grant Numbers. 82270417)./ ; },
mesh = {*Down Syndrome/metabolism/pathology/genetics ; Humans ; *Cell Communication/physiology ; Middle Aged ; Male ; Female ; Adult ; *Brain/metabolism/pathology ; *Single-Cell Analysis/methods ; Neurons/metabolism ; Young Adult ; Signal Transduction/physiology ; Aged ; },
abstract = {Down syndrome (DS) is a widespread chromosomal disorder primarily associated with cognitive impairment and progressive neurodegenerative changes. Clinically, age 50 years is considered a pivotal turning point in the health trajectory of individuals with DS. Before this age, they primarily face developmental challenges including significant cognitive deficits and difficulties in social interaction. However, as they age, they increasingly exhibit more severe neurodegenerative changes, including Alzheimer's disease (AD)-like cognitive decline and dementia symptoms. This study aimed to dissect intricate gene expression patterns in key neuronal cell types within the DS cerebral cortex and to examine how these patterns evolve with age. We conducted a detailed gene expression analysis of key neuronal cells, including inhibitory neurons, excitatory neurons, microglia, and oligodendrocyte progenitor cells, in individuals with DS. Additionally, the bioinformatics tool NeuronChat was employed to investigate the intercellular communication networks in the DS brain. Individuals with DS were divided into younger and older groups, with age 50 years as the boundary. Through comparative analysis, our findings indicated that aging in DS is associated with exacerbated neuronal dysfunction, decreased energy metabolism in microglia, and increased neurodegenerative traits in oligodendrocyte progenitor cells. Notably, compared to the control group, the DS brain showed increased complexity in cellular communication networks, reflecting an effort to maintain adaptability during syndrome progression. However, this increased complexity does not translate into effective signal transmission, suggesting significant disruptions in the function and structure of the neural network. This study provides a deeper understanding of cell function abnormalities and signal transmission irregularities in DS. By integrating single-cell and systemic network analyses, we revealed complex pathophysiological mechanisms, laying a foundational framework for developing new treatment methods. Our comprehensive analysis emphasizes the necessity for targeted strategies to address the multifaceted nature of DS pathogenesis and improve treatment outcomes.},
}

*Down Syndrome/metabolism/pathology/genetics
Humans
*Cell Communication/physiology
Middle Aged
Male
Female
Adult
*Brain/metabolism/pathology
*Single-Cell Analysis/methods
Neurons/metabolism
Young Adult
Signal Transduction/physiology
Aged

@article {pmid41955600,
year = {2026},
author = {Krupa, J and Malinowski, M and Krasowski, M and Kalinowska, A and Pietras, W and Kozieł, A and Kurek, Z and Jentkiewicz, A and Obeid, EH and Ulrych, J},
title = {The role of the MIND diet in prevention and treatment of Alzheimer's disease: A literature review.},
journal = {Wiadomosci lekarskie (Warsaw, Poland : 1960)},
volume = {79},
number = {2},
pages = {390-398},
doi = {10.36740/WLek/217286},
pmid = {41955600},
issn = {0043-5147},
mesh = {Humans ; *Alzheimer Disease/prevention & control/diet therapy ; *Diet ; },
abstract = {OBJECTIVE: Aim: Recent research increasingly point to modifiable risk factors, especially dietary patterns, as potential tools to prevent or delay neurodegeneration. This review evaluates the impact of the MIND diet on the prevention and progression of AD and compares it with other dietary interventions.

PATIENTS AND METHODS: Materials and Methods: A literature search was conducted using the PubMed and Google Scholar databases for articles published from January 2015 to January 2025, focusing on the influence of the MIND diet, as well as other dietary patterns, on AD progression and cognitive performance.

CONCLUSION: Conclusions: While the MIND diet shows promise as a feasible non-pharmacological strategy, current evidence is largely observational and limited by population heterogeneity and inconsistent adherence definitions. Short-term randomized controlled trials are less conclusive. Long-term clinical trials are needed to establish causality. Despite these limitations, the MIND diet remains a practical and potentially effective approach to reducing cognitive decline and delaying the onset of AD.},
}

Humans
*Alzheimer Disease/prevention & control/diet therapy
*Diet

@article {pmid41956136,
year = {2026},
author = {More, PS and Rangari, SW and Lade, SN and Unidrwade, DS and Burle, SS and Umekar, MJ and Lohiya, RT and Zanwar, AS},
title = {Drug Repurposing in Alzheimer's Disease: Emerging Therapeutic Strategies and Promising Candidates.},
journal = {Ageing research reviews},
volume = {},
number = {},
pages = {103113},
doi = {10.1016/j.arr.2026.103113},
pmid = {41956136},
issn = {1872-9649},
abstract = {Alzheimer's disease is a progressive neurodegenerative disorder, and the most common cause of dementia, which causes 60 to 70 percent of the cases worldwide, and its prevalence is increasing by more than 55 million people globally, with an expected increase of 139 million cases by 2050. AD is characterized by Amyloid-β plaque deposition, tau hyperphosphorylation, synaptic dysfunction, neuroinflammation, and oxidative stress, which makes the pathophysiology multifactorial and complex in terms of the development of therapeutic treatment. Existing approved therapies, such as cholinesterase enzyme inhibitors and NMDA receptors antagonists, are merely symptomatic, whereas novel anti-amyloid monoclonal antibodies approved recently have low clinical efficacy with safety and cost issues. The dismal success rates of clinical trials highlight the necessity of alternative approaches. Repurposing of drugs has proved to be a prospective solution, which uses drugs with established safety profiles to speed up the discovery of therapeutic solutions. Repurposed agents are used targeting diverse pathologic pathways, including amyloid aggregation, tau pathology, neuroinflammation, and synaptic dysfunction, with antidiabetic agents (metformin, GLP-1 receptor agonists) and anti-hypertensives (candesartan), anti-inflammatory ones (NSAIDs, pioglitazone), and neuroprotective ones (minocycline, sildenafil). Notably, mitochondrial dysfunction is becoming a significant early and essential cause of AD development, and mitochondria-targeted therapeutics like SS-31, Mdivi-1, MitoQ, DDQ, and SkQ1 are currently considered promising disease-modifying options. The development of artificial intelligence, multi-omics, and precision medicine also improves drug repurposing plans. Overall possibility to integrate multi-target repurposed therapies with novel technologies is a promising prospect to overcome the available shortcomings and improve clinical outcomes in AD.},
}

@article {pmid41945082,
year = {2026},
author = {Falangola, MF and Voltin, J and Cole, M and Nietert, PJ and Liu, F and Iqbal, K and Jensen, JH},
title = {Corrigendum to Diffusion MRI measures detect brain microstructure changes due to early treatment with neurotrophic peptide mimetic P021 in the 3xTg-AD mouse model of Alzheimer's disease. Magn Reson Imaging. 2026 Jun;129:110641 Page: 9.},
journal = {Magnetic resonance imaging},
volume = {},
number = {},
pages = {110677},
doi = {10.1016/j.mri.2026.110677},
pmid = {41945082},
issn = {1873-5894},
}

@article {pmid41946054,
year = {2026},
author = {Tang, S and Peng, Y and Li, Y and Li, Y and Sun, H and Piao, S and Liu, Z and Wu, Y and Hou, Z and Liu, Z and Liu, S and Wang, R},
title = {Congming decoction alleviates Alzheimer's Disease induced by Aβ25-35 in rats via the microbiota-metabolism-inflammation axis, demonstrating its formulation advantages.},
journal = {Phytomedicine : international journal of phytotherapy and phytopharmacology},
volume = {155},
number = {},
pages = {158139},
doi = {10.1016/j.phymed.2026.158139},
pmid = {41946054},
issn = {1618-095X},
abstract = {BACKGROUND: Congming decoction (CMD) is a traditional Chinese herbal formulation traditionally employed for enhancing memory. Despite its historical use, the specific mechanisms and advantages of CMD in the context of Alzheimer's disease (AD) remain inadequately understood.

PURPOSE: This study seeks to elucidate the therapeutic effects of CMD on AD in rats induced by Aβ25-35 and to clarify its underlying process through a multi-perspective approach.

STUDY DESIGN AND METHODS: Cognitive function and pathological alterations were assessed using behavioral tests, hematoxylin and eosin (HE) staining, and immunohistochemistry. Fecal metabolomics analysis, conducted via ultra-high-performance liquid chromatography coupled with quadrupole Orbitrap mass spectrometry (UHPLC-Q-Orbitrap-MS), was utilized to investigate CMD's impact on metabolic disorders. The structure of the gut microbiota was analyzed through 16S rRNA sequencing. Short-chain fatty acids (SCFAs) and bile acids (BAs) in feces, serum, and brain tissue were quantified using gas chromatography-mass spectrometry (GC-MS) and ultra-high-performance liquid chromatography-tandem quadrupole mass spectrometry (UHPLC-TQ-MS). To establish causal relationships, experiments involving antibiotic-induced microbiota depletion (ABX) and fecal microbiota transplantation (FMT) were performed. Network pharmacology and molecular docking techniques were also employed to identify potential active components and targets. Inflammatory markers were evaluated using enzyme-linked immunosorbent assay (ELISA) kits, immunohistochemistry, and immunofluorescence in brain tissue.

RESULTS: CMD markedly enhanced learning and memory, mitigated pathological changes in the brain and colon, and reestablished gut microbiota equilibrium. It regulated 45 endogenous metabolites involved in BAs, α-linolenic acid, and linoleic acid metabolism. CMD also modulated the levels of SCFAs and BAs in fecal matter, serum, and brain tissue. Strong correlations were identified among gut microbiota, metabolites, and AD-related indicators. Antibiotic treatment inhibited the neuroprotective benefits of CMD, whereas FMT from CMD-treated donors successfully replicated its therapeutic benefits. Network pharmacology analysis indicated that the active components of CMD might target inflammatory pathways. Additionally, CMD exhibited a significant restorative impact on markers associated with the AKT/NF-κB signaling pathway.

CONCLUSION: CMD exerts anti-AD effects by modulating the microbiota-gut-brain axis through remodeling gut microbiota, regulating metabolic homeostasis, and reducing brain inflammation. Notably, CMD demonstrated superior efficacy compared to single herbs or herb pairs.},
}

@article {pmid41948063,
year = {2026},
author = {Yang, SO and Ahn, J and Jung, YH and Jang, H and Na, DL and Kim, H and Kim, JP and Seo, SW and Kwak, K},
title = {Deep learning-based detection of cerebral microbleeds on 2D T2*-weighted GRE MRI: toward ARIA-H risk assessment in Alzheimer's treatment.},
journal = {Frontiers in aging neuroscience},
volume = {18},
number = {},
pages = {1729422},
pmid = {41948063},
issn = {1663-4365},
abstract = {BACKGROUND: Amyloid-related imaging abnormalities with hemorrhage (ARIA-H) are a key safety concern in anti-amyloid therapies for Alzheimer's disease, as they are radiologically indistinguishable from cerebral microbleeds (CMBs). Accurate detection of CMBs is therefore essential for both treatment eligibility assessment and post-treatment safety monitoring. However, manual identification on 2D T2*-weighted gradient-recalled echo (GRE) MRI is labor-intensive and subject to variability.

OBJECTIVE: To develop and validate an artificial intelligence (AI)-based model for automated CMB detection using only 2D T2*-weighted GRE MRI, which is widely used in clinical settings.

METHODS: We implemented a YOLOv11-based deep learning model, preceded by a novel multi-channel preprocessing pipeline that enhances CMB visibility. The model was trained and tested using a dataset of 758 participants, with expert consensus used as the reference standard.

RESULTS: Using the optimized basic preprocessing with super-resolution (BP + SR) pipeline, the model achieved a lesion-level sensitivity of 0.694, precision of 0.705, and F1-score of 0.699. In patient-level analysis for detecting elevated CMB burden (≥4), the system demonstrated sensitivity of 0.933 and specificity of 0.935, supporting reliable stratification of CMB severity. Regional analysis showed sensitivity of 0.625 for lobar CMBs and 0.627 for deep structures.

CONCLUSION: This study demonstrates the feasibility of robust CMB detection using only 2D T2*-weighted GRE MRI. Based on current performance, we position this system as a decision-support tool for GRE-based CMB screening, in which lesion-level detections may be aggregated to inform patient-level CMB burden relevant to ARIA-H risk stratification, while final ARIA grading and clinical decisions require expert neuroradiological confirmation.},
}

@article {pmid41948065,
year = {2026},
author = {Oh, H and Kim, H and Kang, H and Kwon, D and French, L and Park, YH and Youn, YC and An, SS and Kim, S and Kang, S},
title = {Systemic proteomic and organ aging signatures associated with plasma Aβ oligomerization in a Korean cohort: a cross-sectional study.},
journal = {Frontiers in aging neuroscience},
volume = {18},
number = {},
pages = {1620991},
pmid = {41948065},
issn = {1663-4365},
abstract = {BACKGROUND: Alzheimer's disease (AD) is characterized by the accumulation of amyloid-beta (Aβ) in the brain, which begins decades before the appearance of clinical symptoms. Blood from AD patients, when spiked with synthetic Aβ, exhibited a higher Aβ oligomerization tendency (OAβT) than the non-AD subjects. OAβT reflected early pathological changes of AD and is considered as a promising blood-based biomarker. However, the mechanism underlying OAβT remained elusive. This study aimed to identify proteomic signatures associated with OAβT and explore its role in AD diagnosis.

METHODS: Forty AD and non-AD subjects from a Korean cohort were divided into four groups based on the disease diagnosis, OAβT values (thresholded at 0.78 ng/mL), and amyloid PET status (A-PET): A-PET-positive AD patients with high or low OAβT values, A-PET-negative non-AD subjects with high or low OAβT values. Using aptamer-based proteomics, 7,288 proteins from plasma samples were quantified, and the group differences were assessed in protein levels and the enrichment of gene sets associated with annotations from the Gene Ontology database. Further, we assessed whether OAβT-PET mismatched cases (A-PET-positive but OAβT-low or A-PET-negative but OAβT-high) exhibited distinct blood proteome signatures in comparison to typical AD cases. Aging signatures for 11 organs were analyzed to explore systemic factors linked to OAβT-PET discrepancies. Additionally, the pharmacological influences on the OAβT-related proteome were investigated by comparing OAβT-correlated proteins with a database of drug-induced proteomic changes.

RESULTS: Elevated OAβT values, regardless of AD diagnosis, correlated with increased immune response and decreased cellular metabolism. Dementia-predicting proteins were enriched in non-AD individuals with high OAβT. Accelerated muscle aging was associated with high OAβT values and worse cognitive function. Furthermore, several potential pharmacological modulators of OAβT, including Minocycline and Anamorelin, were identified.

CONCLUSION: Our findings demonstrated OAβT as a reflection of systemic changes linked to early AD pathology. Moreover, the influence of medications and systemic aging on OAβT values pointed to the potential avenues for intervention and emphasized the importance of considering systemic factors in AD pathogenesis and treatment.},
}

@article {pmid41948540,
year = {2026},
author = {Khorsand, B and Ghanbarian, E and Rabin, LA and Sajjadi, SA and Ezzati, A},
title = {Incremental value of plasma biomarkers in predicting clinical decline among cognitively unimpaired older adults: Results from the A4 trial.},
journal = {Alzheimer's & dementia (Amsterdam, Netherlands)},
volume = {18},
number = {2},
pages = {e70321},
pmid = {41948540},
issn = {2352-8729},
abstract = {INTRODUCTION: Alzheimer's disease (AD) heterogeneity complicates early detection and trial design. Scalable predictors may aid risk stratification. We assessed whether scalable baseline plasma biomarkers and neuropsychological measures predict 5‑year cognitive and functional decline in cognitively unimpaired older adults.

METHODS: We analyzed 866 amyloid-positive participants from the Anti-Amyloid Treatment in Asymptomatic Alzheimer's Disease (A4) trial and 343 amyloid-negative individuals from the Longitudinal Evaluation of Amyloid Risk and Neurodegeneration (LEARN) study. Decline was defined as a ≥0.5 increase in Clinical Dementia Rating-Global Score over 240 weeks. The separate and joint value of demographics, apolipoprotein E (APOE) ε4, amyloid positron emission tomography (PET) standardized uptake value ratio (SUVR), plasma phosphorylated tau-217 (p-tau217), and Preclinical Alzheimer's Cognitive Composite (PACC) were assessed. A sub-study of 656 participants evaluated added value of plasma amyloid beta (Aβ)42/Aβ40, glial fibrillary acidic protein (GFAP), and neurofilament light chain (NfL).

RESULTS: The p-tau217 and PACC significantly improved prediction. Full models achieved areas under the curve (AUCs) of 0.78-0.80 across cohorts. Additional plasma biomarkers offered modest AUC gains (1%-3%).

DISCUSSION: The p-tau217 and PACC enhanced prediction of preclinical decline, supporting their utility in early identification and trial enrichment in AD.},
}

@article {pmid41948553,
year = {2026},
author = {Sólyomvári, C and Makkai, G and Capelo-Carrasco, N and Strac, DS and Zelena, D and Farkas, S},
title = {Time-dependent histological characterization of amyloid-β induced cholinergic and glial alterations and their modulation by dehydroepiandrosterone sulfate (DHEAS).},
journal = {Frontiers in endocrinology},
volume = {17},
number = {},
pages = {1764298},
pmid = {41948553},
issn = {1664-2392},
mesh = {Animals ; *Amyloid beta-Peptides/toxicity ; Male ; *Neuroglia/drug effects/pathology/metabolism ; Mice ; *Cholinergic Neurons/drug effects/pathology/metabolism ; Mice, Inbred C57BL ; *Dehydroepiandrosterone Sulfate/pharmacology ; *Alzheimer Disease/pathology/metabolism/drug therapy ; *Peptide Fragments/toxicity ; Microglia/drug effects/pathology/metabolism ; Time Factors ; *Basal Nucleus of Meynert/drug effects/pathology/metabolism ; },
abstract = {INTRODUCTION: Alzheimer's disease (AD) is a multifactorial neurodegenerative disorder characterized by predominant - but not exclusive - pathological accumulation of amyloid-β (Aβ) in the brain. This process affects not only neurons (particularly cholinergic) but also glial cells, contributing to progressive neuronal loss and neuroinflammation. Dehydroepiandrosterone (DHEA) and dehydroepiandrosterone sulfate (DHEAS) are endogenous steroids that are hypothesized to exert neuroprotective and anti-inflammatory effects. This study aims to histologically characterize the in vivo temporal progression of Aβ-induced alterations in cholinergic neurons and glial morphology. Our secondary aim was to evaluate whether DHEAS protects cholinergic integrity and, if so, whether this effect is mediated through glial activation.

METHODS: Aβ1-42 was injected into the cholinergic nucleus basalis magnocellularis (NBM) region of C57BL6/J male mice and one hour later 10 mg/kg DHEAS or vehicle (0.9% saline) was applied intraperitoneally. After 3, 12 or 33 days, the mice were transcardially perfused and immunohistochemical staining was used to investigate cholinergic cell (ChAT) and fiber (AChE) loss, as well as microglia (IBA1) and astrocyte (GFAP) morphology.

RESULTS: Our findings confirmed that Aβ peptide exerted neurotoxic effects on the cholinergic system and triggered time-dependent activation in both glia cell types. Microglial cells initiated their response by day 3, adopting an amoeboid morphology, whereas delayed astrocytic reactivity was observed between days 3 and 12, demonstrated by increased ramification. DHEAS treatment preserved cholinergic fiber density, without effecting the number of cell bodies and modulated the inflammatory responses of glia cells, by decreasing the area occupied and number of microglia in a time dependent manner.

DISCUSSION: Aβ toxicity exerts time-dependent effects on both cholinergic neurons and glia cells, while DHEAS shows therapeutic promise, though its efficacy and exact mechanism require further investigation.},
}

Animals
*Amyloid beta-Peptides/toxicity
Male
*Neuroglia/drug effects/pathology/metabolism
Mice
*Cholinergic Neurons/drug effects/pathology/metabolism
Mice, Inbred C57BL
*Dehydroepiandrosterone Sulfate/pharmacology
*Alzheimer Disease/pathology/metabolism/drug therapy
*Peptide Fragments/toxicity
Microglia/drug effects/pathology/metabolism
Time Factors
*Basal Nucleus of Meynert/drug effects/pathology/metabolism

@article {pmid41948610,
year = {2026},
author = {Naim, A and Farooqui, AM and Badruddeen, and Khan, MI and Akhtar, J and Ahmad, A and Ashique, S and Islam, A},
title = {Nanoengineered phytochemicals overcome blood-brain barrier constraints in neurodegenerative disorders.},
journal = {Frontiers in neurology},
volume = {17},
number = {},
pages = {1792829},
pmid = {41948610},
issn = {1664-2295},
abstract = {Neurodegenerative disorders represent a growing global health burden and remain largely incurable, with current therapies providing only symptomatic relief and limited disease modifications. A major obstacle to effective treatment is the inability of many neuroprotective agents to reach the brain at therapeutically relevant concentrations due to poor bioavailability and the restrictive nature of the blood-brain barrier. Plant-derived phytochemicals possess well-documented antioxidant, anti-inflammatory, anti-apoptotic, and neuromodulatory activities; however, their clinical translation has been hindered by physicochemical instability, rapid metabolism, and insufficient brain exposure. This review critically examines nanoengineered delivery systems as a strategy to overcome these limitations and enable the effective brain targeting of neuroprotective phytochemicals. By integrating mechanistic insights with preclinical and emerging clinical evidence, we compared lipid-based, polymeric, vesicular, and dendritic nanocarriers, highlighting how particle size, surface chemistry, and ligand functionalization govern blood-brain barrier transport and intracerebral distribution. Particular emphasis is placed on rational design principles that consistently enhance brain bioavailability and therapeutic efficacy across models of Alzheimer's disease, Parkinson's disease, multiple sclerosis, and related disorders. Beyond efficacy, we analyzed key translational challenges, including nanocarrier-associated neurotoxicity, standardization of herbal activities, and regulatory gaps unique to herbal nanomedicines. Collectively, this synthesis reframes nano-phytomedicine not as an incremental formulation upgrade but as a design-driven strategy capable of unlocking the therapeutic potential of phytochemicals for neurodegenerative disease management.},
}

@article {pmid41949026,
year = {2026},
author = {Boyd, RJ and Dong, D and Sagar, R and Iliuk, A and Ahmed, W and Androni, X and Porsteinsson, AP and Rosenberg, PB and Lyketsos, CG and Witwer, KW and Mahairaki, V},
title = {Proteomic profiling of brain organoids and extracellular vesicles identifies early Alzheimer's disease biomarkers and drug response heterogeneity.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {22},
number = {4},
pages = {e71273},
doi = {10.1002/alz.71273},
pmid = {41949026},
issn = {1552-5279},
support = {1RF1AG083801/GF/NIH HHS/United States ; AGR01054771/AG/NIA NIH HHS/United States ; AGR01050515/AG/NIA NIH HHS/United States ; AGR01046543/AG/NIA NIH HHS/United States ; AGR01071522/AG/NIA NIH HHS/United States ; //The Richman Family Precision Medicine Center of Excellence in Alzheimer's Disease/ ; },
mesh = {Humans ; *Alzheimer Disease/metabolism/drug therapy/pathology ; *Extracellular Vesicles/metabolism ; *Organoids/metabolism ; *Proteomics ; *Brain/metabolism/pathology ; Biomarkers/metabolism ; Induced Pluripotent Stem Cells/metabolism ; Male ; Female ; },
abstract = {INTRODUCTION: Alzheimer's disease (AD) exhibits high genetic and clinical heterogeneity that limits therapeutic success. Patient-derived brain organoids and their extracellular vesicles (EVs) provide physiologically relevant models to study disease mechanisms and individualized drug responses.

METHODS: We generated the largest brain organoid cohort to date, derived from 30 independent induced pluripotent stem cell (iPSC) lines from AD and control individuals. Comparative proteomic profiling was performed on both organoids and their secreted EVs to capture molecular diversity and treatment effects.

RESULTS: Organoids and EVs consistently recapitulated neuronal proteomic signatures and revealed early alterations in AD-related pathways, including synaptic and neurotransmitter dysfunction. Distinct proteomic responses mirrored individual variability in selective serotonin reuptake inhibitor sensitivity.

DISCUSSION: Integrating organoid and EV data provides a systems-level view of AD pathophysiology and treatment response, positioning this dual-platform model as a cost-effective tool for precision medicine and drug discovery.},
}

Humans
*Alzheimer Disease/metabolism/drug therapy/pathology
*Extracellular Vesicles/metabolism
*Organoids/metabolism
*Proteomics
*Brain/metabolism/pathology
Biomarkers/metabolism
Induced Pluripotent Stem Cells/metabolism
Male
Female

@article {pmid41942439,
year = {2026},
author = {Ohya, T and Arakawa, R and Sakayori, T and Nogami, T and Uchiyama, S and Tateno, A},
title = {Tau accumulation increases the susceptibility to effective seizures of electroconvulsive therapy.},
journal = {Translational psychiatry},
volume = {},
number = {},
pages = {},
doi = {10.1038/s41398-026-04016-3},
pmid = {41942439},
issn = {2158-3188},
abstract = {Electroconvulsive therapy (ECT) is a very valuable treatment for mood disorders. While previous studies have examined predictors of ECT responsiveness, there is a scarcity of neuroimaging studies examining these predictors. In previous studies, it has been reported that epilepsy is significantly more common in patients with Alzheimer's disease, and it has been suggested that tau accumulation is related to the susceptibility to seizures. Positron emission tomography (PET) with florzolotau (18 F) ([[18]F]PM-PBB3) allows accurate quantification of tau in the brain cortex. We therefore performed tau PET with florzolotau (18 F) in 14 patients with mood disorders undergoing ECT to determine whether there is a relationship between tau accumulation and susceptibility to ECT. As a result, we found that the more tau accumulates, the more likely it is to produce effective seizures in ECT. Although our study has some limitations, it is suggested that ECT would be the first choice for treatment of depression associated with degenerative pathology such as Alzheimer's disease because tau accumulation might enhance the therapeutic efficacy of ECT.},
}

@article {pmid41942585,
year = {2026},
author = {Jahanbani, P and Hosseinzadeh, L and Mahmoudi, M and Jalilian, F and Eftekhari, M and Modarresi, M},
title = {Beyond the root: licorice (Glycyrrhiza glabra L.) fruit extract modulates oxidative stress and apoptotic markers in PC12 cells.},
journal = {Scientific reports},
volume = {},
number = {},
pages = {},
doi = {10.1038/s41598-026-46382-4},
pmid = {41942585},
issn = {2045-2322},
support = {4020639//Kermanshah University of Medical Sciences/ ; },
abstract = {The rising global prevalence of neurodegenerative disorders underscores the urgent need for novel therapeutic strategies. Oxidative stress is a well-established central driver in the pathogenesis of conditions like Alzheimer's and Parkinson's disease. While the root of Glycyrrhiza glabra L. (licorice) is a renowned source of natural antioxidants, its fruit remains a largely unexplored reservoir of bioactive compounds with potential neuroprotective properties. This in vitro study aimed to systematically evaluate the neuroprotective potential of different licorice fruit extracts and elucidate the underlying mechanisms against hydrogen peroxide (H2O2)-induced oxidative damage in PC12 neuronal cells. Different licorice fruit extracts were prepared sequentially with n-hexane, chloroform, ethyl acetate, methanol, and water by the maceration method. The protective effects of these extracts against H2O2-induced cytotoxicity were assessed using the MTT assay. Phytochemical profiling of the active ethyl acetate extract (EA extract) was performed using TLC, total flavonoid assay, and HPLC-DAD. EA extract exhibited the strongest protective activity. Pre-treatment with non-toxic concentrations of EA extract (12.5 and 25 µg/mL) significantly increased cell viability against H2O2 (IC50 = 70 µg/mL approximately 2.06 mM) by 33% and 38%, respectively. This extract possessed the highest total flavonoid content (50.08 ± 0.31 mg of quercetin equivalents per gram of dry extract) among all extracts, and HPLC-DAD analysis confirmed the presence of glabridin 27.75 ± 0.01 mg per gram of dry EA extract. EA extract also notably restored mitochondrial membrane potential, reduced caspase-3 activity, and decreased ROS production in H2O2-stressed cells. Our findings indicate that the ethyl acetate extract of licorice fruit attenuates H2O2-induced oxidative stress in PC12 cells, and its neuroprotective effect is likely associated with its high flavonoid content. Further research on licorice fruit may facilitate the discovery of novel therapeutic agents for oxidative stress-related disorders.},
}

@article {pmid41944296,
year = {2026},
author = {Gong, W and Hui, W and Qiao, S and Ji, Q and Liu, M and Zhang, B and Liu, D and Wu, Y and Zhou, S},
title = {Brain and Liver Dual-Targeting Oridonin Nanoparticles to Enhance Aβ Clearance for Alzheimer's Disease Therapy.},
journal = {Advanced science (Weinheim, Baden-Wurttemberg, Germany)},
volume = {},
number = {},
pages = {e23458},
doi = {10.1002/advs.202523458},
pmid = {41944296},
issn = {2198-3844},
support = {2023-ZDYJSY-001//Shaanxi Administration of Traditional Chinese Medicine/ ; 2023JSYX16//Research Project from Air Force Medical University/ ; //Key Laboratory of New Drug Delivery System and New Technology for Formulation/ ; 82073775//National Natural Science Foundation of China/ ; 82071515//National Natural Science Foundation of China/ ; SZY-KJCYC-2025-ZY-013//Scientific Research Project of Shaanxi Administration of Traditional Chinese Medicine/ ; },
abstract = {The brain and liver are both critical organs involved in the pathogenesis of Alzheimer's disease (AD), particularly in the modulation of amyloid-beta (Aβ) metabolism and neuroinflammation. Based on this, a multifunctional nanodrug delivery system, termed OAF, was developed by encapsulating oridonin (ORI) into apoferritin (ApoFn), enabling simultaneous targeting of both brain and the liver through transferrin receptor 1 (TfR1). OAF upregulated the expression of low-density lipoprotein receptor-related protein 1 (LRP1) in cerebral capillary endothelial cells and hepatic parenchymal cells to promote Aβ clearance from the brain and subsequent hepatic degradation. In AD mice, OAF treatment markedly reduced Aβ deposition, neuroinflammation, and cognitive impairment, while ameliorating inflammation, oxidative stress, and mitochondrial dysfunction in both brain and liver. Overall, OAF synergistically combined Aβ clearance, anti-inflammatory, and antioxidant mechanisms, offering a novel therapeutic strategy for AD.},
}

@article {pmid41936874,
year = {2026},
author = {Wang, YX and Zhou, XW and Du, WR and Qin, SH and Zhang, CY and Ma, ZY},
title = {Novel 2-aminopyrimidine carboxamide derivatives as potential anti-Alzheimer's disease agents: Design, synthesis, biological activity and computational simulation evaluation.},
journal = {Bioorganic & medicinal chemistry letters},
volume = {},
number = {},
pages = {130650},
doi = {10.1016/j.bmcl.2026.130650},
pmid = {41936874},
issn = {1464-3405},
abstract = {In this study, a series of 2-amino-5-formamidopyrimidine derivatives were designed and synthesized. Their potential as cholinesterase inhibitors (ChEIs) for the treatment of Alzheimer's disease (AD) were evaluated by the Ellman method. Meanwhile, the antioxidant activity of these compounds were assessed by the DPPH (2,2-diphen-yl-1-picrylhydrazyl) free radical scavenging assay. The cholinesterase (ChE) inhibition test showed that most compounds exhibited excellent to moderate inhibitory effects on acetylcholinesterase (AChE), while most of them did not show significant inhibitory effects on butyrylcholinesterase (BuChE), demonstrating significant selectivity. Among them, compound 9 s (AChE: IC50 = 1.60 μM) whose AChE inhibitory activity is superior to the positive control galantamine (AChE: IC50 = 5.10 μM) is the most promising representative compound. Meanwhile, compound 9 s has high selectivity with a SI (IC50 ratio of BuChE to AChE) value of 29.85. The results of enzyme kinetics study determined that compound 9 s was a mixed-type inhibitor. Additionally, the molecular docking studies results indicated that compound 9 s could simultaneously interact with the catalytic active site (CAS) and the peripheral anionic site (PAS) of AChE, which was consistent with the results of the enzyme kinetics experiments. Molecular dynamics (MD) simulation study further verified the stability of the 9 s-AChE complex. In addition, the DPPH radical scavenging assay indicated that these compounds also possessed relatively weak antioxidant activities. Among them, compound 9p exhibited the best antioxidant activity with an IC50 value of 113.93 μM, which was lower than that of the positive control ascorbic acid (IC50 = 41.17 μM). Overall, these experimental results suggested that compound 9 s as AChE inhibitor had potential value for further research.},
}

@article {pmid41936993,
year = {2026},
author = {Lizard, G and Sassi, K and Mackrill, JJ and Ghzaiel, I and Meziane, S and Hassen, E and Abdelkarim, M and Masmoudi-Kouki, O and Ghrairi, T and Brahmi, F and Gargouri, A and Rezig, L and Benkalifa, R and Khallouki, F and El Midaoui, A and Pincemail, J and Atanasov, AG and Vejux, A and Millot, N},
title = {7-ketocholesterol as a theranostic target: potential applications and future perspectives.},
journal = {Chemistry and physics of lipids},
volume = {},
number = {},
pages = {105588},
doi = {10.1016/j.chemphyslip.2026.105588},
pmid = {41936993},
issn = {1873-2941},
abstract = {7-Ketocholesterol (7KC) is mainly formed by cholesterol autoxidation and is a pro-oxidant and pro-inflammatory bioactive lipid that also induces different types of cell death, including oxiapoptophagy. It is frequently associated with major age-related diseases, such as cardiovascular diseases, age-related macular degeneration, and Alzheimer's disease. 7KC can therefore be considered a biomarker for these diseases, offering the possibility of developing theranostic strategies combining diagnosis and treatment. Currently, all the elements are in place to develop tools for the design of theranostic therapies targeting 7KC in diseased organs: antibodies, nanoparticles used as nanoplatforms, molecules that neutralize 7KC such as enzymes which degrade it, as well as natural or synthetic compounds that inhibit the cytotoxic signaling pathways associated with oxidative stress, inflammation and cell death activated by 7KC. Identifying and neutralizing 7KC biological activities using a theranostic approach could also be of interest for growing medical fields such as space medicine widely concerned by oxidative stress, aging and age-related diseases, driven by microgravity. This review supports that most of key tools are now available to develop theranostic treatments targeting 7KC in age-related pathologies, especially in cardiovascular diseases associated with atheroma, but also in age-related macular degeneration and Alzheimer's disease. Discovery of effective treatments for these diseases is a major challenge and will answer an important need for both patients and caregivers.},
}

@article {pmid41937403,
year = {2026},
author = {Borda, MG and O'Hara-Veintimilla, K and Aarsland, D},
title = {Older Adults, Anti-Amyloid Therapy, and Frailty: What Oncology Can Teach Us.},
journal = {European journal of neurology},
volume = {33},
number = {4},
pages = {e70567},
doi = {10.1111/ene.70567},
pmid = {41937403},
issn = {1468-1331},
support = {//Helse Vest/ ; //Nasjonalforeningen for Folkehelsen/ ; },
mesh = {Humans ; *Frailty/diagnosis ; Aged ; *Geriatric Assessment/methods ; *Alzheimer Disease/drug therapy ; *Medical Oncology/methods ; Clinical Decision-Making ; Frail Elderly ; },
abstract = {BACKGROUND: Anti-amyloid therapies, such as lecanemab or donanemab, represent the first disease-modifying treatments approved for early Alzheimer's disease (AD) in individuals with confirmed amyloid pathology. Their implementation in routine care raises important challenges, particularly in older adults with heterogeneous functional reserve and multimorbidity. We address the role of frailty in refining clinical decision-making for anti-amyloid therapies.

METHODS: This short communication presents a conceptual discussion informed by geriatric oncology, where frailty assessment and comprehensive geriatric assessment (CGA) are routinely used to individualize treatment in heterogeneous older populations. We describe how similar principles may be applied to anti-amyloid monoclonal antibodies once regulatory eligibility has been established, and outline a frailty-informed conceptual framework to support clinical decision-making in routine care.

RESULTS: This conceptual analysis proposes a stepwise, frailty-informed clinical framework that integrates regulatory eligibility assessment with brief frailty screening and targeted comprehensive geriatric assessment. The framework defines differentiated clinical pathways for robust, pre-frail, and frail individuals, linking frailty status to specific decisions regarding treatment initiation, need for prehabilitation, intensity of monitoring, and consideration of treatment deferral. By embedding frailty assessment within routine clinical workflows, the framework operationalizes evaluation of physiological reserve, anticipates treatment burden and monitoring feasibility, and provides a structured approach to individualized risk-benefit appraisal for anti-amyloid therapies.

CONCLUSIONS: Frailty-informed frameworks may offer a pragmatic and ethically grounded approach to support real-world implementation of anti-amyloid therapies, guiding treatment selection as well as longitudinal decisions on monitoring, continuation, and reassessment over time.},
}

Humans
*Frailty/diagnosis
Aged
*Geriatric Assessment/methods
*Alzheimer Disease/drug therapy
*Medical Oncology/methods
Clinical Decision-Making
Frail Elderly

@article {pmid41937689,
year = {2026},
author = {Helphrey, JH and Hart, J and McClintock, SM and Peters, ME and Thakkar, VJ and LoBue, C},
title = {A scoping review of frontal cortex tDCS on neuropsychological functioning in older adults with mild cognitive impairment and Alzheimer's Clinical Syndrome.},
journal = {International review of psychiatry (Abingdon, England)},
volume = {},
number = {},
pages = {1-17},
doi = {10.1080/09540261.2026.2647921},
pmid = {41937689},
issn = {1369-1627},
abstract = {Mild cognitive impairment (MCI) and Alzheimer's Clinical Syndrome (ACS) are prevalent, incurable, and are expected to increase in incidence over the next 30 years. Finding new treatments to address the cognitive and behavioral problems in MCI and ACS represent an urgent need. Brain circuitry disruption can cause cognitive dysfunction and neuropsychiatric symptoms (NPS) in both MCI and ACS. Therefore, one promising avenue of treatment is non-invasive brain stimulation through transcranial direct current stimulation (tDCS). This scoping review examined the current knowledge base for the potential neuropsychological and neuropsychiatric effects of frontal cortex tDCS in older adults with MCI and ACS. Of the 17 randomized controlled trials reviewed, treatment parameters such as session length, current intensity, number of treatments, and time between treatments varied widely across studies, which restricted identification of optimal tDCS treatment protocols. Mixed findings on neuropsychological outcomes were observed, though significant improvements were most commonly seen in studies measuring global cognition (10) followed by executive function (6). Only three studies yielded clinically significant cognitive improvement, and few studies assessed NPS outcomes. Additional rigorous research is indicated to enhance our understanding of tDCS as a treatment for cognitive and neuropsychiatric symptoms in older adults with MCI and ACS.},
}

@article {pmid41937703,
year = {2026},
author = {Salim, MW and Zhang, W and Collins-Praino, L and Wang, Y and Care, A},
title = {Small Extracellular Vesicles from Neural Cells: Physiological and Pathological Roles, and Potential in Neurodegenerative Therapy.},
journal = {Advanced healthcare materials},
volume = {},
number = {},
pages = {e04608},
doi = {10.1002/adhm.202504608},
pmid = {41937703},
issn = {2192-2659},
support = {//Higher Education Commission/ ; //International Macquarie University Research Excellence Scholarship/ ; FT210100737//ARC Future Fellowship/ ; //Dementia Australia Research Foundation/ ; //Mason Foundation/ ; //National Foundation for Medical Research & Innovation/ ; },
abstract = {Small extracellular vesicles (sEVs) have emerged as central mediators of intercellular communication in the central nervous system (CNS) and are increasingly recognized for their dual roles in the pathogenesis and treatment of neurodegenerative diseases (NDDs). In disease contexts, sEVs facilitate the intercellular dissemination of pathogenic proteins and nucleic acids, thereby contributing to the propagation of Alzheimer's disease (AD) and Parkinson's disease (PD) pathology. Conversely, their intrinsic biocompatibility, capacity to traverse brain barriers, and inherent organotropic properties position sEVs as highly promising nanocarriers for CNS drug delivery. While mesenchymal stem cell-derived sEVs have been widely investigated in preclinical NDD models, accumulating evidence suggests that sEVs derived from neural cells, including neural stem cells, neurons, astrocytes, microglia, oligodendrocytes, and brain endothelial cells may offer superior brain targeting, disease relevance, and functional efficacy. This review provides a comprehensive and critical analysis of current knowledge on neural cell-derived sEVs, encompassing their physiological roles in brain homeostasis, their involvement in AD and PD pathogenesis, and their emerging therapeutic applications. We discuss cell-type-specific sEV cargo profiles, mechanisms underlying blood-brain and blood-cerebrospinal fluid barrier traversal, and recent advances in endogenous and exogenous engineering strategies that enhance cargo loading, targeting precision, and therapeutic performance. Importantly, we address key translational challenges that currently limit clinical implementation. By integrating mechanistic insights with therapeutic and engineering perspectives, this review highlights neural cell-derived sEVs as a biologically informed and versatile platform, underscoring their potential to advance next-generation neuro-nanomedicine for NDDs.},
}

@article {pmid41940797,
year = {2026},
author = {Rus Prelog, P and Kores Plesničar, B and Zupan, M and Frol, S and Kramberger, MG},
title = {The value and risks of antidepressant therapy in Alzheimer's disease: a field update and its clinical implications.},
journal = {Expert review of neurotherapeutics},
volume = {},
number = {},
pages = {1-15},
doi = {10.1080/14737175.2026.2653170},
pmid = {41940797},
issn = {1744-8360},
abstract = {INTRODUCTION: Depression is one of the most frequent and disabling neuropsychiatric syndromes in Alzheimer's disease (AD), yet antidepressant use is still largely extrapolated from late‑life depression and is poorly aligned with emerging evidence on 'neurodegenerative depression' and disease‑modifying therapies. This article critically re‑examines the clinical value and risks of antidepressants in AD.

AREAS COVERED: Drawing on a narrative search of PubMed/MEDLINE and Embase (January 2000-December 2025) and targeted review of recent guidelines and anti‑amyloid trials, the article synthesizes randomized and observational data on efficacy and safety across antidepressant classes, highlighting modest and inconsistent benefits alongside adverse outcomes such as falls, hyponatremia, bleeding, mortality and possible acceleration of cognitive decline. It integrates mechanistic work on synaptic loss, neuroinflammation and network disruption, discusses the exclusion of depressed patients from anti‑amyloid trials, and reviews rapid‑acting, neuromodulatory and psychosocial strategies within a proposed precision‑prescribing framework based on biomarkers, vascular burden and symptom dimensions.

EXPERT OPINION: Monoaminergic antidepressants in AD should not be abandoned but repositioned as time‑limited, closely monitored options for clearly defined, functionally impairing depressive syndromes, embedded in multimodal care rather than used as default, long‑term treatment for non‑specific distress. Future priorities include biomarker‑stratified AD depression trials, evaluation of interactions with anti‑amyloid therapies and rigorous testing of non‑monoaminergic interventions.},
}

@article {pmid41940869,
year = {2026},
author = {Sharif-Askari, Z and Atoui, K and El Zein, W and Rizk, M and Sharif Askari, E},
title = {From periodontitis to neurodegeneration: Can probiotics modulate the P. gingivalis-amyloid pathway in Alzheimer's disease?.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261432686},
doi = {10.1177/13872877261432686},
pmid = {41940869},
issn = {1875-8908},
abstract = {Alzheimer's disease (AD) is a neurodegenerative disorder characterized by the gradual destruction of cognitive and behavioral functions. Despite the continuous research efforts, there is still no cure for this disease. In recent years, researchers have investigated Porphyromonas gingivalis (P. gingivalis) as a potential cause of AD. P. gingivalis-lipopolysaccharides (LPS) and gingipains have been implicated in neuroinflammatory cascades relevant to AD. The gut-brain axis provides a pathway for microbial migration, immune activation, and regulation of the central nervous system function. Emerging evidence suggests that selected probiotics may modulate these pathways by restoring microbial balance, reinforcing epithelial barrier function, and regulating innate and adaptive immunity. Importantly, much of the evidence and mechanistic support for these effects derives from preclinical and animal studies, whereas human data remain limited to associative findings and early-stage clinical trials. Early clinical trials report modest improvements in cognitive scores and systemic inflammatory markers. Strain selection, dose, and treatment duration make direct comparisons challenging. This review integrates the literature on the links between P. gingivalis and AD, suggesting that probiotics may be used as neuroprotective agents. Taken together, current preclinical signals are consistent with the potential of probiotics as feasible adjuncts, pending confirmatory trials with standardized formulations.},
}

@article {pmid41941206,
year = {2026},
author = {Andrews, SJ and Yaffe, K},
title = {Advancing Precision Dementia Care With Genetic-Exposome Risk Assessment.},
journal = {JAMA neurology},
volume = {},
number = {},
pages = {},
doi = {10.1001/jamaneurol.2026.0573},
pmid = {41941206},
issn = {2168-6157},
}

@article {pmid41941234,
year = {2026},
author = {Oo, WJ and Sia, WT and Lee, JY and Chen, CH and Chang, WL and Chye, SM},
title = {The Role of Presynaptic Cytomatrix Protein Bassoon (BSN) in Tau Pathology and Propagation.},
journal = {CNS & neurological disorders drug targets},
volume = {},
number = {},
pages = {},
doi = {10.2174/0118715273400895251129055504},
pmid = {41941234},
issn = {1996-3181},
abstract = {Neurodegenerative disorders have become a global health threat following a prolonged lifespan, with the majority involving the accumulation and propagation of pathological tau. Tau oligomers can migrate to presynaptic terminals and interact with surrounding proteins, among which Bassoon (BSN) is one that selectively binds to and colocalises with misfolded tau. Studies have reported numerous implications of BSN mutations in tau pathology, including promoting tau seeding activity, hyperphosphorylation, misfolding, and aggregation. These eventually lead to the formation of neurofibrillary tangles in tauopathies. Given the BSN's physiological role in maintaining synapses, its mutation also impairs synaptic integrity. These abnormalities are consistently attenuated by downregulating BSN levels. However, BSN downregulation can lead to tau hyperphosphorylation via an alternative pathway, CDK5 hyperactivity. Current findings hypothesize that BSN reduces tau clearance by inhibiting proteasome activity. It is also suggested that BSN can impair dopaminergic pathways prior to the detection of tau pathological features. Tunnelling nanotubes also emerge as a potential interneuronal route for BSN-mediated tau spread. Despite a lack of clinical evidence, findings from postmortem samples, in vitro, and preclinical models highlight BSN as a potential candidate for tau-targeting therapies, indicating its role in the pathological development of tau. The involvement of BSN in tau seeding might also resolve challenges posed by tau-targeting drugs during clinical trials. Hence, this article aims to provide new insights into recent findings on BSN and tau with reference to previous studies. We will discuss the possible mechanisms involved, along with the future therapeutic value of BSN in the treatment of tauopathies.},
}

@article {pmid41941239,
year = {2026},
author = {Wang, N and Wen, H and Sun, Y and Xu, W and Shen, X and Wang, R},
title = {Effects of Hesperetin Early Intervention on Brain Neurons and Microglia in APPswe/PS1dE9 Mice.},
journal = {CNS & neurological disorders drug targets},
volume = {},
number = {},
pages = {},
doi = {10.2174/0118715273418623251203072424},
pmid = {41941239},
issn = {1996-3181},
abstract = {INTRODUCTION: Neuroinflammation and microglial dysfunction play central roles in the pathogenesis of Alzheimer's disease (AD). This study investigated whether early intervention with hesperetin, a citrus flavonoid, could attenuate neuroinflammation and modulate microglial polarization in both wild-type (WT) and APPswe/PS1dE9 transgenic (TG) mice.

METHODS: Three-month-old male C57BL/6J WT and APPswe/PS1dE9 TG mice were administered hesperetin (10 or 20 mg/kg/day for WT; 20, 40, or 80 mg/kg/day for TG) or vehicle for six months. Neuronal morphology was assessed using thionine staining. Microglial polarization was evaluated via CD11b/iNOS and CD11b/Arginase-1 immunofluorescence. Protein expression of CD11b, iNOS, Arginase-1, and TREM2 was measured by Western blot, and cytokine levels (TNF-α, IL-10) were quantified by ELISA.

RESULTS: In WT mice, hesperetin improved neuronal integrity, reduced M1 markers (CD11b⁺/ iNOS⁺ cells, iNOS, TNF-α), and enhanced M2 markers (CD11b⁺/Arginase-1⁺ cells, Arginase-1, TREM2). TG mice exhibited exacerbated neuroinflammation and neuronal loss compared to WT controls, which was significantly mitigated by hesperetin treatment. All hesperetin doses in TG groups reduced pro-inflammatory markers and increased anti-inflammatory and repair-associated factors.

DISCUSSION: These results indicate that hesperetin shifts microglial polarization toward the protective M2 phenotype, potentially via TREM2 upregulation, thereby reducing neuroinflammation and neuronal damage. This effect was observed in both age-related and Aβ-driven pathology, suggesting a dual role for hesperetin in immunomodulation and neuroprotection.

CONCLUSION: Early hesperetin intervention exerts neuroprotective effects by rebalancing microglial polarization and enhancing TREM2 expression, highlighting its potential as a preventive strategy against AD-related neuroinflammation.},
}

@article {pmid41941282,
year = {2026},
author = {Agrawal, MM and Mittal, P},
title = {Emerging Therapies and Research in Alzheimer's Disease: A Critical Review.},
journal = {Central nervous system agents in medicinal chemistry},
volume = {},
number = {},
pages = {},
doi = {10.2174/0118715249403872251208145159},
pmid = {41941282},
issn = {1875-6166},
abstract = {Alzheimer's disease, an extremely prevalent neurological illness and the leading cause of dementia globally, is an extremely prevalent neurological illness and is the leading cause of dementia globally. There are a few treatment options for AD, and those that do exist only slightly reduce symptoms, even after several clinical studies. The formation of Aβ plaques, neuroinflammation, and hyperphosphorylated tau neurofibrillary tangles are the characteristics of AD. While monoclonal antibodies such as lecanemab, donanemab, and aducanumab have demonstrated potential in addressing Aβ, their clinical efficacy and safety over an extended period of time remain uncertain. Novel avenues for tackling the underlying genetic causes of AD have been made possible by developments in genome editing tools, most notably CRISPR-Cas9. In preclinical animals, CRISPR-Cas9 has effectively edited genes relevant to AD, such as APP and PSEN1, leading to decreased levels of Aβ and enhanced cognitive function. Additionally, base and prime editing, two precision gene-editing techniques, have increased the medicines' selectivity and decreased their offtarget effects. However, before clinical applications are deployed, challenges related to technology, ethics, and safety must be resolved. This review highlights how monoclonal antibodies, neuroinflammation research, and CRISPR-Cas9 have the potential to revolutionize therapy choices for AD by examining the most current developments in the field.},
}

@article {pmid41941989,
year = {2026},
author = {Sun, Z and Peng, Q and Qiu, C and Jia, X and Wang, H and Wu, S and Tao, W},
title = {A specific Pilose antler peptide LVLVEAELRE ameliorates cognitive deficits in SAMP8 mice via Celsr2.},
journal = {Journal of ethnopharmacology},
volume = {},
number = {},
pages = {121649},
doi = {10.1016/j.jep.2026.121649},
pmid = {41941989},
issn = {1872-7573},
abstract = {Pilose antler peptide (PAP), an extract derived from the traditional Chinese medicinal material Pilose antler, has shown promise in the treatment of neurodegenerative diseases. However, the precise molecular mechanisms underlying its anti-Alzheimer's disease (AD) effects remain to be fully elucidated.

AIM OF THE STUDY: This study focuses on a specific PAP monomer with a defined sequence (LVLVEAELRE), herein referred to as PAP, to explore its potential role and molecular mechanisms in AD treatment.

MATERIALS AND METHODS: Senescence-accelerated mouse prone 8 (SAMP8) mice were employed to evaluate the effects of PAP on cognitive function, classical AD pathologies (Aβ and p-Tau), and synaptic plasticity. To further elucidate the causal role of Cadherin EGF LAG seven-pass G-type receptor 2 (Celsr2), bidirectional viral manipulations (AAV-shCelsr2 for knockdown and AAV-OECelsr2 for overexpression) were performed in vivo. Furthermore, cellular thermal shift assays (CETSA), molecular docking, and microscale thermophoresis (MST) were utilized to validate the direct interaction between PAP and Celsr2.

RESULTS: PAP administration significantly improved cognitive impairment, mitigated Aβ deposition and Tau hyperphosphorylation, and enhanced synaptic plasticity in SAMP8 mice. Mechanistically, PAP upregulated Celsr2 expression, restored AMPA receptor subunits, and inhibited neuronal senescence. Crucially, Celsr2 knockdown abolished these neuroprotective benefits, whereas Celsr2 overexpression synergistically amplified the therapeutic efficacy of PAP. Finally, MST and docking analyses confirmed that PAP possesses a high and specific binding affinity for WT Celsr2.

CONCLUSIONS: This study demonstrates that PAP ameliorates AD-like pathology by regulating Celsr2, highlighting its potential as a promising preclinical drug candidate. The research findings provide a theoretical basis for the development of PAP-based therapeutic strategies for Alzheimer's disease.},
}

@article {pmid41934929,
year = {2026},
author = {Yao, M and Guo, H and Fang, Y and Chen, Y and Liu, Y and Liu, S and Guo, J and Guo, Z and Qian, J and Ma, Q},
title = {Microplastics released from dental materials induce oral inflammatory bone resorption and apoptosis via mitochondrial dysfunction.},
journal = {Environment international},
volume = {210},
number = {},
pages = {110226},
doi = {10.1016/j.envint.2026.110226},
pmid = {41934929},
issn = {1873-6750},
abstract = {Microplastics (MPs) are emerging pollutants that are associated with many diseases including atherosclerosis, inflammatory bowel disease (IBD), and Alzheimer's. The oral cavity is the primary point for the uptake of MPs by human, where MPs could pose risks to oral and even system health. Various polymer-based materials have been used as dental materials in oral treatment, however, the assessment of MPs in dental treatments remains limited and the processes and mechanisms by which MPs affect human health through the oral route are elusive. Here, we report the assessment of the risks and sources of MPs in dental clinics, the establishment of the relationship between MPs and oral inflammatory disorders, and also the elucidation of underlying mechanisms. Our results showed that commonly used therapeutic dental materials could generate MPs in dental clinics with proportions significantly higher than those in office areas and outdoors. As a representative, polymethyl methacrylate (PMMA) MPs showed significant toxicity to human oral keratinocytes (HOK), human periodontal ligament stem cells (hPDLCs), and THP-1-derived macrophages. Mechanistic investigations of apoptosis and inflammation processes revealed that MPs could lead to mitochondrial stress and autophagy and trigger the Notch signaling pathway and the JAK-STAT signaling pathway. Mice experiments showed that prolonged high-dose MPs exposure induced periodontal inflammatory reactions and even led to inflammatory bone resorption. This study provides a scientific basis for the oral health risks by MPs in dental practice and addresses the need for the development of dental materials with higher biocompatibility and environmentally sustainability.},
}

@article {pmid41935066,
year = {2026},
author = {Shou, R and Wang, Z and Han, Z and Li, A and Shang, J and Lou, H and Zhang, F and Zhan, Y and Shen, G and Lu, X and Jiang, H and Fan, X},
title = {Dietary silver nanoparticle supplementation induces Alzheimer-like lesions through Bifidobacterium deficiency-dominated gut microbiota dysbiosis and neuroinflammation.},
journal = {NPJ science of food},
volume = {},
number = {},
pages = {},
doi = {10.1038/s41538-026-00820-9},
pmid = {41935066},
issn = {2396-8370},
support = {No. LY23B070004//Zhejiang Provincial Natural Science Foundation of China/ ; No. 82374136//National Natural Science Foundation of China/ ; No.2024SDXT001-7//Key R&D Program of Zhejiang/ ; },
abstract = {Dietary supplement silver nanoparticles have recently drawn attention following reports of hazards associated with long-term use. However, their biosafety, especially their effects on the gut-brain axis, remains largely unexplored. This study demonstrated that dietary supplement silver nanoparticles can accumulate in the intestines, brain, and liver of mice. Chronic exposure to these nanoparticles leads to Alzheimer-like lesions, primarily by disrupting gut microbiota balance. Specifically, this exposure depletes Bifidobacterium and Ruminococcaceae, resulting in reduced intestinal metabolites such as sphingomyelin (d18:1/20:0), tryptophan, and indole. Consequently, this disruption causes neuroinflammation, cognitive impairment, and amyloid-β deposition in mice. Moreover, Bifidobacterium was identified as a key microbial group contributing to Alzheimer-like lesions after exposure, whereas supplementation with Bifidobacterium breve MCC1274 effectively alleviated these lesions. Therefore, the potential risks of silver nanoparticles in dietary supplements should be carefully evaluated. This study provides a promising new direction for the prevention and treatment of Alzheimer-like lesions through microbial interventions.},
}

@article {pmid41935801,
year = {2026},
author = {Kong, L and Wu, Y and Zeng, H and Wu, R and Xu, X and Lu, Z and Zhang, W and Ma, C},
title = {The preclinical evidence and clinical translational prospects of medicarpin.},
journal = {Pharmacological research},
volume = {},
number = {},
pages = {108183},
doi = {10.1016/j.phrs.2026.108183},
pmid = {41935801},
issn = {1096-1186},
abstract = {Medicarpin (MED) is an isoflavonoid compound derived from traditional Chinese medicine (TCM). Numerous preliminary experimental studies have shown that MED has significant pharmacological effects in the treatment of cancer, osteoporosis, osteoarthritis, Alzheimer's disease (AD), arthritis, and other diseases. However, the clinical application of MED has not yet been reported. Summarizing the preclinical drug research of MED is helpful for clarifying its pharmacological activities and evaluating its research prospects. In this review, we search for the preliminary experimental research of MED, encompassing pharmaceutics, pharmacodynamics, pharmacology, pharmacokinetics, clinical studies, and toxicology. A comprehensive review of the chemical synthesis and biosynthesis, biological activities, mechanisms, bioavailability, and clinical research of MED is conducted to systematically evaluate its safety, efficacy, and druggability. Ultimately, our work promotes the understanding of MED and facilitates its clinical translation and application.},
}

@article {pmid41936348,
year = {2026},
author = {Shimasaki, R and Kurihara, M and Bannai, T and Hatano, K and Suzuki, F and Tokumaru, AM and Ishii, K and Ihara, R and Iwata, A},
title = {Amyloid-related imaging abnormalities in Japanese patients with Alzheimer's disease treated with Lecanemab: A real-world study.},
journal = {The journal of prevention of Alzheimer's disease},
volume = {13},
number = {6},
pages = {100562},
doi = {10.1016/j.tjpad.2026.100562},
pmid = {41936348},
issn = {2426-0266},
abstract = {BACKGROUND: Although clinical trials have suggested a lower incidence of adverse events associated with Lecanemab in Asian populations compared to global cohorts, longitudinal real-world data across broader clinical indications are necessary to confirm these findings in routine practice.

OBJECTIVES: This study aimed to provide real-world evidence regarding the safety profile of Lecanemab in Japanese patients in a clinical setting.

DESIGN: A real-world observational study with a follow-up period of up to 18 months.

SETTING: A single center in Japan.

PARTICIPANTS: We included 120 Japanese patients who received Lecanemab between December 2023 and November 2025 and underwent at least one brain MRI before the fifth infusion.

MEASUREMENTS: Safety outcomes included amyloid-related imaging abnormalities (ARIA), infusion-related reactions (IRRs), and treatment discontinuation.

RESULTS: The mean age was 74.2 ± 7.9 years, and 89 (74%) were female. The majority of patients (88%) had a baseline CDR global score of 0.5. During follow-up, 81 patients completed the 12-month assessment. ARIA occurred in 24 patients (20%); ARIA-E with or without ARIA-H occurred in 5 patients (4%), and isolated ARIA-H occurred in 19 patients (16%). Crucially, no patients experienced symptomatic ARIA. All patients with ARIA-E who had available APOE data were ε4 carriers. Patients with ARIA had significantly lower baseline MMSE scores (p = 0.04), alongside non-significant trends toward higher plasma GFAP levels (p = 0.11) and higher deep white matter Fazekas scores (p = 0.05). IRRs occurred in 34 patients (28%), all of which were mild. Treatment was discontinued in 19 patients (16%), mainly due to disease progression (n = 8).

CONCLUSION: In this Japanese AD cohort, Lecanemab demonstrated a manageable safety profile in a real-world setting. In exploratory analyses, potential trends toward a higher frequency of ARIA were observed in patients with lower MMSE scores, higher plasma GFAP levels, and higher Fazekas scores, underscoring the importance of individualized risk assessment prior to therapy.},
}

@article {pmid41933174,
year = {2026},
author = {Cummings, JL and Agadjanyan, MG and Barry, M and Corey, L and Doody, R and Hendrix, S and Mattke, S and Mattsson-Carlgren, N and McDade, E and Menetski, JP and Mohs, RC and Partrick, KA and Petrovsky, N and Selkoe, DJ and Silva, D and Sperling, RA and Tiede, B and Vradenburg, G},
title = {Target product profiles for treatments to delay or prevent symptomatic Alzheimer's disease.},
journal = {Nature medicine},
volume = {},
number = {},
pages = {},
pmid = {41933174},
issn = {1546-170X},
abstract = {Despite advances in understanding the mechanisms, risk factors and treatment strategies for Alzheimer's disease (AD), no approved therapies exist to prevent or delay onset in at-risk individuals or those with elevated biomarkers who do not yet show symptoms. Multiple candidate interventions are now being evaluated in clinical trials in these settings, raising key questions around which populations are most appropriate and what criteria should guide regulatory and clinical decision-making. Data are expected within 1-2 years, underscoring the need for stakeholder alignment on clinically meaningful and acceptable characteristics of preventative therapies or other products. To address this need, the Global CEO Initiative on Alzheimer's Disease convened an international group of experts to develop target product profiles for therapies designed to delay or prevent the onset of clinical symptoms in AD. These target product profiles outline minimum and preferred characteristics, including intended use, target populations, safety expectations and efficacy benchmarks. This effort provides a foundational framework to accelerate therapeutic development and guide researchers, regulators and patients in the evaluation of emerging therapies for preventing symptomatic AD.},
}

@article {pmid41933339,
year = {2026},
author = {Huang, N and Hong, R and Cui, X and Cao, L and Shi, L and Chen, B and Su, Y and Xu, X and Hua, C and Ying, T},
title = {Targeting the HDAC4-NHE6-endosomal pH axis restores amyloid-β clearance and cognitive function in Alzheimer's disease mice.},
journal = {Journal of nanobiotechnology},
volume = {},
number = {},
pages = {},
doi = {10.1186/s12951-026-04297-2},
pmid = {41933339},
issn = {1477-3155},
support = {82272018//the National Natural Science Foundation of China/ ; ynnkxzd202404//Shanghai Sixth People's Hospital Institutional Brain Science and Brain-Inspired Research Project/ ; },
abstract = {BACKGROUND: Impaired clearance of amyloid-β (Aβ) is a major pathological hallmark of Alzheimer's disease (AD). Although histone deacetylase (HDAC) inhibitors show therapeutic potential, their clinical translation for AD is hampered by poor blood brain barrier (BBB) penetration and an incomplete understanding of their mechanism in Aβ clearance. Here, angiopep2-conjugated nanoparticles (SAHA@LIPO-ANG2) for efficient BBB translocation and delivery of the HDAC inhibitor vorinostat (SAHA) was developed and its underlying mechanisms were validated.

RESULTS: Our result demonstrates that SAHA@LIPO-ANG2 potently inhibits HDAC4 nuclear translocation, which was identified as a key upstream event responsible for the transcriptional repression of sodium-hydrogen exchanger 6 (NHE6). Restoration of NHE6 expression rectifies endosomal hyperacidification, thereby rescuing the trafficking and plasma membrane expression of the Aβ clearance receptor, low-density lipoprotein receptor-related protein 1 (LRP1). Furthermore, this HDAC4-NHE6-pH axis modulates the neuroimmune microenvironment to enhance Aβ clearance through multiple synergistic mechanisms: it upregulates phagocytic receptors and recruit microglial to phagocytize Aβ plaques, while concurrently reactivating autophagy-lysosomal function in astrocytes by increasing LAMP2 expression. Consequently, treatment with SAHA@LIPO-ANG2 in 5xFAD mice significantly reduced Aβ burden, suppressed neuroinflammation, rescued synaptic loss, and ultimately reversed cognitive deficits.

CONCLUSIONS: Our study not only elucidates a HDAC4-NHE6-pH regulatory axis in AD pathogenesis but also establishes a multifaceted nanotherapeutic strategy for restoring Aβ homeostasis. Our findings may provide therapeutic strategies for treating amyloid-related diseases.},
}

@article {pmid41933799,
year = {2026},
author = {Huang, Q and Lv, Y and Ye, X and Xia, X and Chen, Y and Wang, X and Tong, F and Yang, W and Bozorov, K and Shevtsov, M and Li, H and Gao, H and Ye, B},
title = {Engineered microglial membrane-coated polydopamine-based nanomedicine for precise treatment of Alzheimer's disease.},
journal = {Journal of controlled release : official journal of the Controlled Release Society},
volume = {},
number = {},
pages = {114896},
doi = {10.1016/j.jconrel.2026.114896},
pmid = {41933799},
issn = {1873-4995},
abstract = {Multimodal treatment for Alzheimer's disease (AD) is a pivotal option because of its complex pathogenesis. The major challenge of pharmacotherapies is effective drug delivery to the diseased brain and reduction of associated toxicity. Here, we propose a dual-target nanomedicine (PDA@R@M/K) for the management of AD by coating engineered microglial cell membrane (M/K) onto polydopamine (PDA) cores encapsulated with rivastigmine. M/K conferred nanoparticles (NPs) with reduced circulation clearance, pathological blood-brain barrier recognition, and enhanced brain inflammation chemotaxis. PDA cores not only acted as potent ROS scavengers to alleviate neuroinflammation but also piggybacked rivastigmine and implemented responsive release. After applying PDA@R@M/K in preclinical transgenic mouse models, amyloid plaque deposition, neurologic changes, and cognitive decline were largely rescued. These results provide the possibility of directly using NPs as therapeutics rather than merely as nanocarriers, and demonstrate the feasibility of engineered microglia membrane-coated NPs to improve the pharmacokinetics and efficacy of anti-AD drugs.},
}