@article {pmid41974986,
year = {2026},
author = {Castroflorio, E and Cabot, J and Miralles, M and Suau-Fullana, M and Peter, M and Balogh, G and Torok, Z and Rodríguez, E and Sanchez-Juan, P and Férnandez-García, P and Llado, V and Escribá, PV and Torres, M},
title = {Lipidomic Analysis of Human Plasma and Hippocampus Across Alzheimer's Progression and Preclinical 5xFAD Mouse Model.},
journal = {Molecular neurobiology},
volume = {63},
number = {1},
pages = {},
pmid = {41974986},
issn = {1559-1182},
mesh = {*Alzheimer Disease/blood/metabolism/pathology ; Animals ; *Hippocampus/metabolism/pathology ; *Lipidomics/methods ; Mice, Transgenic ; Disease Models, Animal ; Humans ; *Disease Progression ; Male ; Female ; Aged ; *Lipids/blood ; Mice ; Cognitive Dysfunction/blood/metabolism/pathology ; Biomarkers/blood ; },
abstract = {Alzheimer's disease (AD) poses a significant global health burden, underscoring the need for early and accessible biomarkers to enable timely diagnosis and intervention. Lipids, which constitute over half of the brain's mass, play essential roles in numerous cellular processes, and their dysregulation has been increasingly implicated in AD pathophysiology. In this study, we performed lipidomic profiling of hippocampal samples derived from individuals at different Braak stages and plasma samples from patients with mild cognitive impairment (MCI), AD, and healthy controls. Parallel analyses were conducted in 5xFAD transgenic mice and wild-type littermates. Our results revealed lipid alterations across central and peripheral compartments in both human subjects and the 5xFAD mouse model. Notably, specific lipid changes identified in particular lipid species at early/mild Braak stages or in MCI persisted into advanced stages of the disease, highlighting the systemic nature of lipid dysregulation in AD and supporting the potential of these lipid signatures as diagnostic and prognostic biomarkers.},
}

*Alzheimer Disease/blood/metabolism/pathology
Animals
*Hippocampus/metabolism/pathology
*Lipidomics/methods
Mice, Transgenic
Disease Models, Animal
Humans
*Disease Progression
Male
Female
Aged
*Lipids/blood
Mice
Cognitive Dysfunction/blood/metabolism/pathology
Biomarkers/blood

@article {pmid41975027,
year = {2026},
author = {Zhang, W and Lukacsovich, D and Young, JI and Gomez, L and Schmidt, MA and Kunkle, BW and Chen, X and Martin, ER and Wang, L and , },
title = {The aging epigenome: integrative analyses reveal intersection with Alzheimer's disease.},
journal = {GeroScience},
volume = {},
number = {},
pages = {},
pmid = {41975027},
issn = {2509-2723},
support = {R01NS128145/NS/NINDS NIH HHS/United States ; R61NS135587/NS/NINDS NIH HHS/United States ; R01AG062634/AG/NIA NIH HHS/United States ; },
abstract = {Aging is the strongest risk factor for Alzheimer's disease (AD), yet the role of age-associated DNA methylation (DNAm) changes in blood and their relevance to AD remains poorly understood. We performed a meta-analysis of blood DNAm samples from 475 dementia-free subjects aged over 65 years across two independent cohorts, the Framingham Heart Study (FHS) at Exam 9 and the Alzheimer's Disease Neuroimaging Initiative (ADNI). We adjusted for sex and immune cell-type proportions and corrected batch effects and genomic inflation. Integrative analyses included pathway enrichment, mQTL analysis, colocalization with Alzheimer's disease and related dementia (ADRD) GWAS summary statistics, brain-blood DNAm correlations, and comparison to independent AD methylation studies. We identified 3758 CpGs and 556 differentially methylated regions (DMRs) consistently associated with chronological age in both cohorts at a 5% false discovery rate. Our pathway enrichment analyses highlighted metabolic regulation and synaptic signaling, processes previously implicated in Alzheimer's disease. Colocalization with ADRD GWAS summary statistics identified 32 genomic regions consistent with shared genetic signals for DNAm and ADRD risk. Roughly one-third of aging-associated CpGs overlapped CpGs associated with AD or AD neuropathology in external studies. Finally, we prioritized nine promoter CpGs (including those located in PDE1B, ELOVL2, and PODXL2) showing strong positive blood-to-brain methylation concordance and external AD associations, nominating them as candidate blood-based biomarkers. Our study demonstrated that late-life aging signatures in blood DNAm converge on processes implicated in AD and intersect with dementia genetics. A small set of CpGs with blood-brain concordance and external AD support offers promising candidate blood-based biomarkers for future validation.},
}

@article {pmid41975102,
year = {2026},
author = {Cavalcante, DP and Carvalho, GA and Nunes, AÍS and Quintanilha, AR and Nascimento, LRC and Caixeta, L and Ulrich, H and Gomez, RS and Pinto, MCX},
title = {GlyT1 (SLC6A9) inhibition in neurological and psychiatric disorders.},
journal = {Naunyn-Schmiedeberg's archives of pharmacology},
volume = {},
number = {},
pages = {},
pmid = {41975102},
issn = {1432-1912},
support = {APQ-04596-25//Fundação de Amparo à Pesquisa do Estado de Minas Gerais/ ; 406765/2021-9//Conselho Nacional de Desenvolvimento Científico e Tecnológico/ ; 407075/2018-6//Conselho Nacional de Desenvolvimento Científico e Tecnológico/ ; AUX2024361000034//Fundação de Amparo à Pesquisa do Estado de Goiás/ ; },
abstract = {Glycine is a fundamental neuroactive amino acid that serves dual roles in the central nervous system: acting as a primary inhibitory neurotransmitter via strychnine-sensitive glycine receptors and as an essential co-agonist at the N-methyl-D-aspartate (NMDA) receptor. This dual functionality is important for maintaining the excitation-inhibition balance, synaptic plasticity, and network stability. The spatial and temporal availability of glycine is strictly regulated by two high-affinity, Na[+]/Cl[-]-dependent transporters: GlyT1 (SLC6A9) and GlyT2 (SLC6A5). These transporters exhibit distinct cellular distributions and functional specializations. GlyT1 is predominantly expressed in astrocytes and specific neuronal populations, where it buffers ambient glycine levels to modulate NMDA receptor activity. In contrast, GlyT2 is primarily localized to presynaptic terminals of glycinergic neurons, where it facilitates vesicular refilling essential for inhibitory signaling. This review provides a comprehensive overview of glycine metabolism, the structural biology and transport cycles of SLC6 glycine transporters, and the neuroanatomical framework of GlyT1 function. We further synthesize pharmacological advances in GlyT1 inhibition, evaluating both sarcosine-derived and non-sarcosine inhibitors, such as NFPS (ALX-5407), bitopertin, and iclepertin. The clinical and preclinical evidence for GlyT1 as a therapeutic target in psychiatric, neurological, and neurodegenerative disorders is critically assessed. Finally, we address key translational challenges, including dosing constraints, compensatory mechanisms, and SLC6 family selectivity, while highlighting the potential of structure-guided design to refine GlyT1-targeted therapies.},
}

@article {pmid41975292,
year = {2026},
author = {Esmaeili, H and Mahdavi-Fikjvar, E and Poureshaghi, F and Moridi Farimani, M and Sonboli, A and Dastres, E and Behboudi, H and Mirjalili, MH},
title = {Variation in phytochemical profiles and anti-cholinesterase activity across wild Iranian populations of Leucojum aestivum L.: a conservation perspective.},
journal = {BMC plant biology},
volume = {},
number = {},
pages = {},
doi = {10.1186/s12870-026-08717-1},
pmid = {41975292},
issn = {1471-2229},
}

@article {pmid41975524,
year = {2026},
author = {More, SA and Mundke, RN and Agrawal, YO and Awathale, SN and Goyal, SN and Nakhate, KT and Rathod, SS},
title = {Intracerebroventricular streptozotocin-induced animal model of Alzheimer's disease: revealing dose optimization, administration regimen, and molecular pathways.},
journal = {Laboratory animal research},
volume = {42},
number = {1},
pages = {},
pmid = {41975524},
issn = {1738-6055},
}

@article {pmid41975535,
year = {2026},
author = {Life, BE and Navarro-Delgado, EI and Fornes, O and Friedman, JM and Wasserman, WW and Korthauer, K and Leavitt, BR},
title = {Progranulin genetic variant rs5848 displays ancestry-specific associations with Alzheimer's disease.},
journal = {Human genomics},
volume = {},
number = {},
pages = {},
doi = {10.1186/s40246-026-00958-3},
pmid = {41975535},
issn = {1479-7364},
}

@article {pmid41975550,
year = {2026},
author = {Falzarano, FB and Greenfield, A and Saviano, SC and Kolla, S and Korian, S and Osso, F and Miller, J and Maciejewski, PK and Whitson, HE and Prigerson, HG},
title = {Living Memory Home for Dementia Care Pairs (LMH-4-DCP): study protocol for a pilot randomized trial of a web-based reminiscence intervention for family caregivers and persons with dementia.},
journal = {Pilot and feasibility studies},
volume = {},
number = {},
pages = {},
doi = {10.1186/s40814-026-01781-2},
pmid = {41975550},
issn = {2055-5784},
support = {R21AG077144/AG/NIA NIH HHS/United States ; R00AG073509/AG/NIA NIH HHS/United States ; P30AG072958/AG/NIA NIH HHS/United States ; CA197730/CA/NCI NIH HHS/United States ; UL1TR002384/TR/NCATS NIH HHS/United States ; },
abstract = {BACKGROUND: Family caregivers provide most of the emotional, physical, and logistical support for people living with Alzheimer's disease and related dementias (ADRD). As the caregiving role intensifies with advancing illness, family caregivers navigate the cognitive and functional decline of the care recipient. They also must reconcile the shift from a mutual relationship to one of a primary caregiving role. The unique nature of ADRD makes pre-death grief highly prevalent among family caregivers. Reminiscence therapy, which uses memory prompts to evoke meaningful past experiences, has shown promise in improving psychosocial outcomes for individuals with dementia. Its potential to benefit caregivers through strengthened emotional connections, shared meaning, and mutual engagement among the dyad, however, has been largely underexplored. Guided by the Interdependence Model of Communal Coping and the Micro-Sociological Theory of Adjustment to Loss, the current study aims to assess the feasibility and acceptability of Living Memory Home for Dementia Care Pairs (LMH-4-DCP), a reminiscence-based online intervention for family caregivers and their care-recipients.

METHODS: This multisite pilot randomized controlled trial (RCT) will evaluate the feasibility, acceptability, and preliminary efficacy of LMH-4-DCP. Seventy ADRD family caregivers will be targeted for randomization to a 1:1 ratio to the intervention (n = 35) or attention control (n = 35) conditions and will participate for 2 weeks. Recruitment will be facilitated by the project's two study sites located in urban metropolitan areas of the USA. Primary feasibility outcomes include recruitment, retention, and completion rates, website usability (e.g., perceived usefulness and ease of use), and intervention satisfaction. Exploratory analyses will be conducted to assess the preliminary efficacy of LMH-4-DCP in reducing pre-death grief and improving relationship quality. Outcomes will be measured using validated questionnaires at baseline and 2-week follow-up, along with semi-structured interviews with LMH-4-DCP participants.

DISCUSSION: This pilot trial will offer foundational evidence regarding the feasibility and acceptability of the LMH-4-DCP intervention. Study findings will guide intervention refinements and inform the design of a larger-scale, fully powered RCT to evaluate its efficacy in reducing pre-death grief and enhancing relationship quality among ADRD family caregivers.

TRIAL REGISTRATION: Clinicaltrials.gov: NCT06225986, Registered: January 9, 2024, ClinicalTrials.gov; https://clinicaltrials.gov/study/NCT06225986?term=living%20memory%20home&rank=1.},
}

@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 {pmid41975595,
year = {2026},
author = {Tedeschi, V and Ciancio, R and Piccirillo, S and Preziuso, A and Serfilippi, T and Terenzi, V and Magi, S and Lariccia, V and Castaldo, P and Vinciguerra, A and Piccialli, I and Canzoniero, LMT and Pannaccione, A and Secondo, A},
title = {Organelles storing Ca2+ in the brain cells: New druggable targets in neurodegenerative diseases.},
journal = {Neural regeneration research},
volume = {},
number = {},
pages = {},
doi = {10.4103/NRR.NRR-D-25-01754},
pmid = {41975595},
issn = {1673-5374},
abstract = {Several lines of evidence suggest that targeting dysfunctional calcium (Ca2+)-storing organelles and their defective connections may represent a promising therapeutic strategy counteracting neurodegeneration. Dysfunction in these compartments converges to promote oxidative and endoplasmic reticulum stress, energy failure, autophagy blockade or hyperactivation, and progressive neurodegeneration. Within the intracellular scenario, several dysfunctional organelles have been characterized in terms of their capability to hijack Ca2+ signaling during neurodegeneration to deadly impact on neuronal tasks in amyotrophic lateral sclerosis, Alzheimer's disease, Parkinson's disease, Huntington's disease, brain ischemia, and neonatal hypoxic injury. This review has focused on the endoplasmic reticulum, mitochondria, and lysosomes, as well as their functional interconnection able to maintain the physiological processes such as lysosomal-dependent autophagy and function, lipid trafficking, and protein quality control. Clinically, looking ahead from the already existing therapies, drugs that enhance mitochondrial Ca2+ efflux or modulate mitochondrial Ca2+ uniporter regulation at mitochondria-associated membranes-endoplasmic reticulum sites represent innovative opportunities for next-generation strategies aimed at restoring mitochondrial homeostasis and protecting dopaminergic neurons in Parkinson's disease. Furthermore, functional stabilization of the lysosomal channel transient receptor potential mucolipin 1 by the lipid-based formulation of PI(3,5)P2 may extend the lifespan of amyotrophic lateral sclerosis mice by stimulating the nuclear translocation of the master regulator of autophagy activated by lysosomal Ca2+ release, namely transcription factor EB. Moreover, dysfunction of lysosomal-dependent autophagy can cause mutant huntingtin accumulation in Huntington's disease through the repression of transcription factor EB and lysophagy induction. Collectively, this growing focus may highlight a shift toward recognizing mitochondria, lysosomes, and endoplasmic reticulum, as well as their ionic machinery and interconnections, as a unifying strategy to maintain neuronal viability and mitigate the neurodegeneration progression in amyotrophic lateral sclerosis, Alzheimer's disease, Parkinson's disease, Huntington's disease, lysosomal storage diseases, brain ischemia, and neonatal hypoxic insult.},
}

@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 {pmid41975621,
year = {2026},
author = {Li Puma, DD and Boni, G and Puliatti, G and Bandiera, B and Rinaudo, M and Lerose, F and De Chiara, G and Palamara, AT and Piacentini, R and Grassi, C},
title = {Neuroinflammatory responses and synaptic impairment in a Herpes simplex virus type 1 model of sporadic Alzheimer's disease.},
journal = {Neural regeneration research},
volume = {},
number = {},
pages = {},
doi = {10.4103/NRR.NRR-D-25-01175},
pmid = {41975621},
issn = {1673-5374},
abstract = {Alzheimer's disease is a progressive neurodegenerative disorder in which neuroinflammation has emerged as a key contributor to early synaptic and cognitive dysfunction. In previous studies, we demonstrated that the spread of herpes simplex virus type 1 infection to the central nervous system and its reactivation induced by thermal stress, triggers the accumulation of Alzheimer's disease molecular hallmarks and the development of an Alzheimer's disease-like phenotype in wild-type C57BL/6 mice. In particular, two cycles of thermal stress-induced reactivation in wild-type mice induced a marked upregulation of the proinflammatory cytokine interleukin-1β, along with hippocampal synaptic and memory deficits, features reminiscent of an early stage of neurodegeneration. Notably, blocking interleukin-1β signaling with anakinra, a pharmacological interleukin-1 receptor antagonist, fully rescued all structural and functional indices of neurodegeneration, highlighting the central role of neuroinflammation in early phases of the disease. Here, we documented that, in addition to increased interleukin-1β levels, two cycles of thermal stress promoted the activation of glycogen synthase kinase 3β through phosphorylation of the tyrosine residue at position 216 (Tyr216), along with elevated phosphorylation of its direct substrates, amyloid precursor protein (APP) at threonine 668 and tau at Serine 199. To dissect the contribution of APP and tau to herpes simplex virus type 1-induced synaptic dysfunction, we employed APP-/- and Tau-/- mice. After two cycles of thermal stress, these knock-out mouse models exhibited lower increases in interleukin-1β levels and smaller synaptic deficits than infected wild-type mice, along with a distinct profile of microglial activation. To determine whether neuroinflammation remains the predominant pathological driver at later stages, we extended our analyses to herpes simplex virus type 1-infected wild-type mice subjected to six cycles of thermal stress (6TS), which recapitulate an advanced disease stage with features reminiscent of an Alzheimer's disease-like phenotype. Although interleukin- 1β levels remained persistently elevated in mice subjected to six cycles of thermal stress, anti-inflammatory treatments with either anakinra or dexamethasone failed to rescue synaptic and memory deficits, suggesting that neuroinflammation was no longer the primary pathological driver. Instead, synaptic failure correlated with a pronounced increase in glycogen synthase kinase 3β-induced APP cleavage products (e.g., amyloid-β) and hyperphosphorylated tau, indicating a stage-dependent shift in pathogenic mechanisms, whereby early neuroinflammatory responses are progressively replaced by other processes primarily mediated by glycogen synthase kinase 3β. These findings underscore the stage-specific contribution of interleukin-1β and glycogen synthase kinase 3β to herpes simplex virus type 1-induced Alzheimer's disease-like synaptic failure, highlighting the importance of a phase-specific therapeutic strategy.},
}

@article {pmid41975625,
year = {2026},
author = {Singh, S and Kumar, U},
title = {Somatostatinergic and dopaminergic systems in Alzheimer's disease: Mechanistic insights and therapeutic opportunities beyond plaques and tangles.},
journal = {Neural regeneration research},
volume = {},
number = {},
pages = {},
doi = {10.4103/NRR.NRR-D-25-01038},
pmid = {41975625},
issn = {1673-5374},
abstract = {Alzheimer's disease therapeutic development has largely focused on amyloid-β and tau pathologies, with limited clinical success. This review extends beyond the canonical amyloid/tau paradigm by examining the roles of somatostatin and dopamine neuromodulatory systems, which undergo early degeneration in Alzheimer's disease and contribute mechanistically to disease progression. Somatostatin deficiency impairs amyloid-β clearance by downregulating neprilysin activity and disrupts inhibitory network homeostasis. Somatostatin binds amyloid-β oligomers and attenuates tau hyperphosphorylation via kinase modulation and cytoskeletal stabilization. Dopaminergic deficits, particularly in ventral tegmental and cortical projections, disrupt synaptic plasticity, memory encoding, network oscillations, and neurogenesis. Dopamine receptor activation promotes amyloid-β clearance, enhances autophagy, and modulates tau phosphorylation. The intersection of somatostatin and dopamine pathways through receptor heteromerization and intersecting intracellular cascades delineates a promising therapeutic axis. Preclinical evidence demonstrates that somatostatin and dopamine receptor agonists mitigate amyloid and tau pathologies and preserve cognitive function, attesting the need for integrative therapeutic strategies targeting neural network dysfunction in Alzheimer's disease.},
}

@article {pmid41975761,
year = {2026},
author = {Prawiroharjo, P and Vidyanti, AN and Syafrita, Y and Yunus, RE and Fakhri, A and Martalia, V and Gabrielle, A and Rahmayani, SA and Marcel, G and Wijaya, VG and Tazkia, AA},
title = {Artificial Intelligence-Assisted Volumetric Brain Analysis Correlated with CSF Biomarkers in Alzheimer's Disease: A Pilot Study.},
journal = {Diagnostics (Basel, Switzerland)},
volume = {16},
number = {7},
pages = {},
pmid = {41975761},
issn = {2075-4418},
support = {//Riset Kolaborasi Indonesia (RKI) or Indonesian Research Collaboration Program/ ; },
abstract = {Background/Objectives: Alzheimer's disease (AD) is a leading cause of dementia globally, yet standard diagnostic markers like cerebrospinal fluid (CSF) analysis and molecular imaging are invasive and resource-intensive. While artificial intelligence (AI)-based volumetric magnetic resonance imaging (MRI) offers a scalable and non-invasive alternative, data correlating these structural metrics with fluid biomarkers and cognitive status in Southeast Asian populations are scarce. This study addresses this critical gap by examining the within-cohort relationship between CSF biomarkers and regional brain volumes derived from AI-assisted MRI in Indonesian patients with clinically diagnosed AD, providing novel data for an underrepresented population. Methods: Twenty-one AD patients from three national referral hospitals in Indonesia underwent lumbar puncture for CSF biomarker analysis and 3 Tesla structural brain MRI. Brain volumes were analyzed using United Imaging Intelligence software, focusing on AD-relevant regions (hippocampus, entorhinal cortex, parahippocampus, precuneus, and posterior cingulate cortex [PCC]). Results: Spearman's correlation revealed significant positive associations between CSF Aβ42 levels and several brain regions. Strong correlations were found with the right entorhinal volume indexed to intracranial volume (VICV) (r = 0.601, p = 0.004), right PCC VICV (r = 0.603, p = 0.004), right entorhinal volume (r = 0.533, p = 0.013), and right hippocampus VICV (r = 0.503, p = 0.020). Furthermore, MoCA-InA scores demonstrated highly significant positive correlations with CSF Aβ42 concentrations (r = 0.720, p < 0.001), right Hippocampus VICV (r = 0.703, p < 0.001), and right PCC VICV (r = 0.695, p < 0.001). No significant correlations were found between CSF pTau or the pTau/Aβ42 ratio and regional volumes. Conclusions: These results highlight the entorhinal cortex and PCC as early affected regions where CSF Aβ42 correlates with preserved volume, supporting their role as structural markers in early AD. The absence of pTau associations may reflect early-stage pathology or limitations of cross-sectional volumetry. In resource-limited settings, AI-assisted volumetric MRI demonstrates potential utility as a non-invasive tool for stratifying amyloid-associated brain atrophy and staging disease severity.},
}

@article {pmid41975824,
year = {2026},
author = {Al-Bakri, FH and Bejuri, WMYW and Al-Andoli, MN and Ikram, RRR and Khor, HM and Mispan, MS and Yunos, NM and Yusof, NFA and Fauadi, MHFM and Jaya, ASM and Moketar, NA and Yusop, N and Burhanudin, K and Marindah, TP and Bustamin, A and Zainuddin, Z and Wahyuni, D and Ariffin, UK},
title = {Correction: Al-bakri et al. A Hybrid Explainable AI Framework (HXAI) for Accurate and Interpretable Diagnosis of Alzheimer's Disease. Diagnostics 2025, 15, 3118.},
journal = {Diagnostics (Basel, Switzerland)},
volume = {16},
number = {7},
pages = {},
pmid = {41975824},
issn = {2075-4418},
abstract = {Removal of an Author [...].},
}

@article {pmid41975901,
year = {2026},
author = {Risquez-Salgado, N and García-Bravo, S and Huertas-Hoyas, E and Pérez-Corrales, J and Salcedo-Perez-Juana, M and Donovan, M and Palacios-Ceña, D and Bullón-Benito, E and García-Bravo, C},
title = {Understanding the Lived Experience and Bereavement of Caregivers of People with Alzheimer's Disease: A Mixed-Methods Study Protocol.},
journal = {Healthcare (Basel, Switzerland)},
volume = {14},
number = {7},
pages = {},
pmid = {41975901},
issn = {2227-9032},
abstract = {Background: Alzheimer's disease (AD) is a progressive neurodegenerative disorder that severely affects cognitive, behavioral, and functional abilities, creating a substantial burden for family members who provide continuous care. Caregivers often experience role changes, occupational imbalance, emotional distress, and reduced quality of life, although some report personal growth. These experiences extend beyond active caregiving and include anticipatory grief during disease progression and grief after the relative's death. Despite this continuum, few studies have examined caregiving, loss, and bereavement from an integrative perspective. This protocol describes a mixed-methods study aimed at exploring the lived experiences of family caregivers of individuals with AD, focusing on how evolving relational, occupational, and identity-related losses influence their well-being and adaptation. Methods: A parallel convergent mixed-methods design will be used. The quantitative component consists of a cross-sectional observational study including 66 caregivers recruited through purposive sampling across kinship categories (spouse/partner, adult child, grandchild) and care settings (home care with day-center attendance vs. institutionalized care). Data will be collected using the Zarit Burden Interview, Role Checklist, Short Form-36 Health Survey, and Occupational Balance Questionnaire. Descriptive and subgroup analyses will be conducted using SPSS (version 27). The qualitative component comprises a multiple-case study with approximately 36 participants across three groups: caregivers living with individuals with AD, caregivers of institutionalized relatives, and bereaved family members. Semi-structured interviews (45-80 min) will be conducted online or in person, transcribed verbatim, and analyzed thematically using MAXQDA (version 26). Integration will follow a concurrent approach, combining quantitative and qualitative results through joint narratives and displays to produce a comprehensive interpretation. Discussion: This study aims to deepen understanding of the caregiving-grief continuum in families affected by AD by integrating quantitative indicators of burden, health status, and occupational balance with qualitative accounts of adaptation and meaning-making. Findings are expected to support the development of holistic, evidence-based interventions that promote caregiver well-being throughout the care trajectory and during bereavement. Ethics and Dissemination: Ethical approval was granted by the Research Ethics Committee of Universidad Rey Juan Carlos (Code: 041220246522024; 15 October 2025). ClinicalTrials.gov Identifier: NCT07251738. Registered November 2025. Protocol version: Version 2.},
}

@article {pmid41976093,
year = {2026},
author = {Dondi, M and Bianchi, E and Borghetti, P and Buffagni, V and Di Lecce, R and Gnudi, G and Guarnieri, C and Ravanetti, F and Saleri, R and Corradi, A},
title = {Evidence-Based Clinical Management of Canine Cognitive Dysfunction Syndrome: Diagnostic Algorithms, Practical Guidelines, Critical Appraisal of Biomarkers and Translational Limitations.},
journal = {Animals : an open access journal from MDPI},
volume = {16},
number = {7},
pages = {},
pmid = {41976093},
issn = {2076-2615},
abstract = {Canine Cognitive Dysfunction Syndrome (CCDS) is a progressive neurodegenerative disease affecting older dogs that shares many pathological mechanisms with human Alzheimer's disease (AD). Although it is common in geriatric dogs, CCDS is often underdiagnosed in veterinary medicine. Both CCDS and AD involve a gradual decline in cognitive functions such as memory, learning and executive abilities. From a pathological perspective, dogs with CCDS show brain changes similar to those seen in AD, including cerebral atrophy, loss of neurons and accumulation of amyloid-beta plaques. CCDS is diagnosed by exclusion, meaning that other medical or neurological conditions that could cause similar behavioural signs must first be ruled out. Clinical evaluation mainly relies on structured questionnaires completed by owners. Magnetic resonance imaging is used to confirm cerebral atrophy and, at the same time, to exclude other brain disorders, such as cerebrovascular accidents and neoplasia. Current research focuses on identifying fluid biomarkers, such as amyloid-beta, neurofilament light chain and glial fibrillary acidic protein, to support an early and objective diagnosis. The most effective management combines pharmacological therapy, targeted nutrition and non-pharmacological strategies, including environmental enrichment and behavioural support. Early intervention, ideally during mild cognitive impairment, is crucial to slow disease progression and maintain quality of life.},
}

@article {pmid41976156,
year = {2026},
author = {Phan, TQ and Huang, HT and Wang, SL and Nguyen, DS and Doan, MD and Pham, THT and Phan, TKT and Truong, BP and Nguyen, VB},
title = {Isolation, Identification and In Silico Evaluation of Novel Cholinesterase Inhibitors from Terminalia triptera Stapf.},
journal = {Molecules (Basel, Switzerland)},
volume = {31},
number = {7},
pages = {},
pmid = {41976156},
issn = {1420-3049},
support = {T2025-46CBTĐ//Tay Nguyen University/ ; },
mesh = {*Cholinesterase Inhibitors/chemistry/pharmacology/isolation & purification ; Molecular Docking Simulation ; Butyrylcholinesterase/chemistry/metabolism ; *Terminalia/chemistry ; Acetylcholinesterase/chemistry/metabolism ; Humans ; *Plant Extracts/chemistry/pharmacology ; Molecular Structure ; Computer Simulation ; Alzheimer Disease/drug therapy ; },
abstract = {Alzheimer's disease (AD) remains a significant global health challenge, highlighting the need for novel dual inhibitors targeting acetylcholinesterase (AChE) and butyrylcholinesterase (BChE). This study investigated the trunk bark of Terminalia triptera Stapf. as a potential source of bioactive secondary metabolites for AD management. Bioassay-guided isolation led to the identification of two flavan-3-ol derivatives, epicatechin-(4β→8)-ent-catechin (1) and (-)-catechin (2), reported here for the first time from this species. In vitro assays demonstrated that the dimeric compound 1 exhibited stronger dual inhibitory activity against AChE and BChE, with IC50 values of 4.41 × 10[-4] and 4.75 × 10[-4] mol/L, respectively, surpassing the reference compound berberine chloride. Molecular docking analysis revealed that compound 1 formed extensive interactions within both catalytic and peripheral anionic sites of the enzymes. Density Functional Theory (DFT) calculations indicated high kinetic stability, reflected by large HOMO-LUMO energy gaps (6.66-6.97 eV), while global reactivity descriptors suggested lower electrophilicity (ω = 2.19-2.34 eV), supporting a potentially favorable safety profile. Furthermore, 100 ns molecular dynamics simulations confirmed stable ligand-protein complexes stabilized by hydrogen-bond networks and deep binding within catalytic pockets. Overall, these findings highlight T. triptera and its dimeric proanthocyanidins as promising multi-target candidates for anti-Alzheimer drug development.},
}

*Cholinesterase Inhibitors/chemistry/pharmacology/isolation & purification
Molecular Docking Simulation
Butyrylcholinesterase/chemistry/metabolism
*Terminalia/chemistry
Acetylcholinesterase/chemistry/metabolism
Humans
*Plant Extracts/chemistry/pharmacology
Molecular Structure
Computer Simulation
Alzheimer Disease/drug therapy

@article {pmid41976241,
year = {2026},
author = {Shen, X and Ming, K and Shi, H and Li, J and Yang, Y and Zhang, W and Cui, X and Yang, X},
title = {Recent Progress in the Regioselective Biotransformation and Multitarget Therapeutic Potential of Ginsenoside Rd.},
journal = {Molecules (Basel, Switzerland)},
volume = {31},
number = {7},
pages = {},
pmid = {41976241},
issn = {1420-3049},
support = {32460114//National Natural Science Foundation of China/ ; KKXX202526073//Xingdian Talents Support Program of Yunnan Province/ ; },
mesh = {*Ginsenosides/pharmacology/chemistry/therapeutic use/metabolism ; Humans ; Biotransformation ; Animals ; *Neuroprotective Agents/pharmacology/chemistry/therapeutic use ; },
abstract = {Ginsenoside Rd, a protopanaxadiol (PPD)-type tetracyclic triterpenoid saponin, has emerged as a promising bioactive constituent for multitarget therapeutic interventions. However, its natural abundance in the source plant is extremely low, making direct extraction both costly and inefficient. This review systematically summarizes the latest research progress on regioselective biotransformation strategies for Rd production since 2022. Furthermore, it comprehensively reviews recent advances in the diverse pharmacological activities of Rd. Beyond its well-recognized neuroprotective effects against neurological disorders including Alzheimer's disease and Parkinson's disease, we also highlight its antitumor activity and multitarget protective effects in liver diseases. This review provides a theoretical basis for developing Rd as a high-value nutraceutical and therapeutic candidate for systemic health.},
}

*Ginsenosides/pharmacology/chemistry/therapeutic use/metabolism
Humans
Biotransformation
Animals
*Neuroprotective Agents/pharmacology/chemistry/therapeutic use

@article {pmid41976259,
year = {2026},
author = {Kukla, J and Olejnik, P and Kasarełło, K},
title = {Exploring the Evolving Role of Scopolamine in Pharmacotherapy: From Cognitive Impairment to Neuroplasticity?-A Narrative Review.},
journal = {Molecules (Basel, Switzerland)},
volume = {31},
number = {7},
pages = {},
pmid = {41976259},
issn = {1420-3049},
mesh = {*Scopolamine/pharmacology/therapeutic use/chemistry ; Humans ; *Neuronal Plasticity/drug effects ; *Cognitive Dysfunction/drug therapy/metabolism ; Animals ; },
abstract = {Scopolamine, also known as hyoscine, is a naturally occurring tropane alkaloid derived from plants of the Solanaceae family. Clinically, the compound has long been used for the prevention of motion sickness and postoperative nausea and vomiting, as well as for ophthalmological procedures requiring mydriasis and cycloplegia. However, beyond these established indications, increasing attention has been directed toward its broader neuropharmacological actions. This narrative review aims to summarise current knowledge regarding the pharmacological properties of scopolamine, with particular emphasis on its mechanisms of action and emerging implications in neuroscience and neuropsychiatric disorders. Scopolamine acts as a non-selective antagonist of muscarinic receptor subtypes M1-M5, interfering with cholinergic neurotransmission. Experimental and clinical studies demonstrate that scopolamine induces transient cognitive impairment. This property has led to its widespread use as a pharmacological model of Alzheimer's disease, enabling investigation of cholinergic contributions to cognitive decline. More recently, several early clinical studies suggested that intravenous administration may produce rapid reductions in depressive symptoms, possibly through modulation of glutamatergic neurotransmission and activation of mTORC1-dependent synaptic plasticity pathways in the prefrontal cortex. Nevertheless, subsequent trials have yielded inconsistent results, and the therapeutic relevance of these findings remains uncertain. Current evidence indicates that scopolamine's neuropsychiatric effects likely arise from complex interactions between cholinergic, glutamatergic, and neurotrophic signalling systems. Taken together, scopolamine represents both a valuable experimental tool for studying cholinergic function and a mechanistic framework for the development of novel therapeutics targeting rapid neuroplastic processes in neuropsychiatric disorders.},
}

*Scopolamine/pharmacology/therapeutic use/chemistry
Humans
*Neuronal Plasticity/drug effects
*Cognitive Dysfunction/drug therapy/metabolism
Animals

@article {pmid41976506,
year = {2026},
author = {Chen, T and Shahidin, and Zhu, Q and Wang, Y and Wu, Y and Wu, X and Yuan, W and Sheng, J and Zi, C},
title = {Phytochemical Diversity, Mechanistic Pharmacology, and Therapeutic Potential of Alpinia oxyphylla.},
journal = {Foods (Basel, Switzerland)},
volume = {15},
number = {7},
pages = {},
pmid = {41976506},
issn = {2304-8158},
support = {ZDYF2025SXLH005//Hainan Provincial Key Research and Development Program/ ; 202101BD070001-028//Yunnan Province Agricultural Basic Research Joint Foundation/ ; 31960075//National Natural Science Foundation of China/ ; YNWR-QNBJ-2020-178//Yunnan Ten Thousand Talents Plan Young & Elite Talents Project/ ; },
abstract = {Alpinia oxyphylla Miquel is a perennial medicinal plant widely cultivated in the provinces of Fujian, Guangdong, and Hainan in China. The dried mature fruit of A. oxyphylla, officially recorded as Alpiniae Oxyphyllae Fructus in the pharmacopoeia of the People's Republic of China (since 2012), is one of the four primary southern medicinal materials in traditional Chinese medicine (TCM). In TCM, the fruit is traditionally used to support kidney function, regulate urination, and alleviate gastrointestinal disorders such as diarrhea. Its continued use across Southeast Asia underscores its enduring ethnopharmacological relevance. The plant is rich in bioactive constituents, including terpenoids, flavonoids, diphenylheptanes, and sterols, which exhibit diverse biological activities, including antioxidant, anti-inflammatory, anticancer, neuroprotective, and gastrointestinal protective effects. Information on Alpinia oxyphylla was collected from multiple databases, including Web of Science, Google Scholar, PubMed, Baidu Scholar, ScienceDirect, CNKI, and the Pharmacopoeia of the People's Republic of China. The search strategy included keywords related to A. oxyphylla, its chemical constituents, biological activities, pharmacological effects, traditional medicinal uses, and safety. A bibliometric analysis of 217 English-language publications (2014-2025) using CiteSpace revealed a marked increase in global research interest, with keyword clustering and burst analyses highlighting oxidative stress, Alzheimer's disease, and cognitive enhancement as emerging research hotspots. Moreover, 692 patents were identified, demonstrating substantial technological innovation related to A. oxyphylla, particularly in essential oil formulations, functional foods, and health-promoting applications. Overall, this review integrates phytochemical, pharmacological, bibliometric, and patent perspectives to provide a holistic understanding of A. oxyphylla and its medicinal fruit, offering a solid scientific foundation for future research, standardization, and translational development.},
}

@article {pmid41977262,
year = {2026},
author = {Mîndreanu, R and Chiș, IC and Sevastre-Berghian, A and Login, C and Stan, A and Stan, T and Clichici, S and Suciu, Ș},
title = {N-Acetylcysteine in Neurological Disorders: A Systematic Review of Clinical and Translational Evidence Across Seven Disorders.},
journal = {International journal of molecular sciences},
volume = {27},
number = {7},
pages = {},
doi = {10.3390/ijms27073076},
pmid = {41977262},
issn = {1422-0067},
mesh = {*Acetylcysteine/therapeutic use/pharmacology ; Humans ; *Nervous System Diseases/drug therapy ; *Neuroprotective Agents/therapeutic use ; Parkinson Disease/drug therapy ; Translational Research, Biomedical ; Antioxidants/therapeutic use ; Alzheimer Disease/drug therapy ; Oxidative Stress/drug effects ; Amyotrophic Lateral Sclerosis/drug therapy ; Multiple Sclerosis/drug therapy ; Brain Injuries, Traumatic/drug therapy ; },
abstract = {N-acetylcysteine (NAC) is a glutathione precursor with established antioxidant and anti-inflammatory properties that has been investigated as a neuroprotective agent across multiple neurological conditions. This systematic review systematically mapped the clinical evidence for NAC across seven neurological disorders. PubMed and Cochrane Library were searched for studies published between 1 January 1995 and 31 December 2025. Twenty-three studies were included: traumatic brain injury (TBI, n = 6), Alzheimer's disease (AD, n = 5), Parkinson's disease (PD, n = 5), multiple sclerosis (n = 4), amyotrophic lateral sclerosis (n = 2), and migraine (n = 1); no eligible epilepsy studies were identified. The strongest evidence emerged for acute mild TBI, where early NAC administration significantly improved symptom resolution, and for PD, where combined intravenous/oral NAC improved dopamine transporter binding. In AD, nutraceutical formulations including NAC and other active compounds showed trends toward cognitive stabilization. Most included studies had a high or serious risk of bias, and only eight of 23 assessed oxidative stress biomarkers. NAC demonstrated a favorable safety profile across all conditions. Despite fragmented and heterogeneous evidence, the encouraging signals identified warrant large-scale randomized controlled trials with a standardized biomarker assessment.},
}

*Acetylcysteine/therapeutic use/pharmacology
Humans
*Nervous System Diseases/drug therapy
*Neuroprotective Agents/therapeutic use
Parkinson Disease/drug therapy
Translational Research, Biomedical
Antioxidants/therapeutic use
Alzheimer Disease/drug therapy
Oxidative Stress/drug effects
Amyotrophic Lateral Sclerosis/drug therapy
Multiple Sclerosis/drug therapy
Brain Injuries, Traumatic/drug therapy

@article {pmid41977275,
year = {2026},
author = {Zhu, Y and Zhao, L and Li, Y and Tian, M and Liao, Y and Huang, J and Guo, P and Xie, Y},
title = {Disruption of Synaptic Vesicle Trafficking in Alzheimer's and Parkinson's Disease: Mechanisms and Therapeutic Implication.},
journal = {International journal of molecular sciences},
volume = {27},
number = {7},
pages = {},
doi = {10.3390/ijms27073089},
pmid = {41977275},
issn = {1422-0067},
support = {82060823//National Natural Science Foundation of China/ ; 82074421//National Natural Science Foundation of China/ ; 202501AS070139//Natural Science Foundation of Yunnan Province/ ; 2024Y395//Yunnan Provincial Department of Education/ ; 202105AG070012XS25032//Yunnan Science and Technology Talent and Platform Program/ ; N/A//Yunnan Collaborative Innovation Center for the Application of Aromatic Chinese Medicine/ ; },
mesh = {*Synaptic Vesicles/metabolism/pathology ; Humans ; *Alzheimer Disease/metabolism/pathology/therapy ; *Parkinson Disease/metabolism/pathology/therapy ; Animals ; Endocytosis ; Protein Transport ; Amyloid beta-Peptides/metabolism ; alpha-Synuclein/metabolism ; },
abstract = {Alzheimer's (AD) and Parkinson's disease (PD) are prominent neurodegenerative disorders characterized by early synaptic loss, which correlates more closely with clinical symptoms than neuronal death. This synaptic impairment is primarily driven by disruptions in synaptic vesicle (SV) trafficking, a critical process for maintaining synaptic integrity through a tightly regulated cycle involving clustering, docking-priming, Ca[2+]-triggered fusion, and endocytosis. In AD, amyloid-β (Aβ) oligomers interfere with SNARE-mediated fusion and endocytosis, while hyperphosphorylated tau obstructs vesicle mobility and docking, resulting in cumulative toxicity that aggravates SV defects. Conversely, in PD, α-synuclein (α-syn) aggregation alters vesicle clustering, membrane fusion, and recycling, and these effects are further influenced by Leucine-rich repeat kinase 2 (LRRK2)-Rab-related trafficking defects and the selective vulnerability of dopaminergic terminals. Different from previous reviews that address synaptic dysfunction in a broader manner, the present review is specifically organized around the SV trafficking cycle and compares both shared presynaptic endpoints and disease-specific upstream mechanisms in AD and PD. In addition, recent mechanism-oriented therapeutic strategies are summarized. This vesicle-cycle-centered perspective may provide a clearer framework for understanding presynaptic pathology and for guiding the development of earlier and more targeted interventions.},
}

*Synaptic Vesicles/metabolism/pathology
Humans
*Alzheimer Disease/metabolism/pathology/therapy
*Parkinson Disease/metabolism/pathology/therapy
Animals
Endocytosis
Protein Transport
Amyloid beta-Peptides/metabolism
alpha-Synuclein/metabolism

@article {pmid41977297,
year = {2026},
author = {Kurma, SH and Adarvez-Feresin, C and Parravicini, O and Garro, A and Stepankova, S and Hosek, J and Pauk, K and Lisicic, J and Jampilek, J and Enriz, RD and Imramovsky, A},
title = {Structure-Based Design of New Series of Sulfonates with Potent and Specific BChE Inhibition and Anti-Inflammatory Effects.},
journal = {International journal of molecular sciences},
volume = {27},
number = {7},
pages = {},
doi = {10.3390/ijms27073109},
pmid = {41977297},
issn = {1422-0067},
support = {DKRVO RO0523//Ministry of Agriculture/ ; //Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET)/ ; //National University of San Luis/ ; APVV-24-0341//Slovak Research and Development Agency/ ; },
mesh = {*Butyrylcholinesterase/chemistry/metabolism ; *Cholinesterase Inhibitors/chemistry/pharmacology/chemical synthesis ; Molecular Docking Simulation ; Humans ; Molecular Dynamics Simulation ; *Anti-Inflammatory Agents/chemistry/pharmacology ; Drug Design ; *Sulfonic Acids/chemistry/pharmacology ; Structure-Activity Relationship ; Animals ; },
abstract = {In the present work, a novel series of eleven sulfonate derivatives with potent inhibitory activity against butyrylcholinesterase (BChE) is reported. Of these, compounds 2-[(E)-(2-Benzoylhydrazinylidene)methyl]phenyl 5-(dimethylamino)naphthalene-1-sulfonate (5c, IC50 = 1.11 µM) and tert-butyl (2E)-2-[(2-{[5-(dimethylamino)naphthalene-1-sulfonyl]oxy}p
henyl)methylidene]hydrazine-1-carboxylate (5b, IC50 = 11.51 µM) exhibit stronger inhibitory activity than rivastigmine, the reference compound, and exhibit high selectivity for BChE over AChE (e.g., selectivity index 57 for 5c). Interestingly, compound 5c also exhibited anti-inflammatory effects, which is important for potential therapeutic applications, especially in Alzheimer's disease. These new compounds were designed through a structure-based approach using molecular modeling techniques (docking, molecular dynamic (MD) simulations, and QTAIM (quantum theory of atoms in molecules) calculations). The most promising compounds show no detectable toxic effects and satisfy Lipinski's rule of five, indicating that they represent attractive starting structures for the design of new derivatives acting as specific BChE inhibitors. In addition, our results indicate that relatively simple computational techniques such as docking calculations and toxicity prediction programs can be valuable when properly used in the search of new candidates for this particular target. Docking calculations show that the more active compounds of this series reach the bottom region of the gorge interacting with residues within the active site of BChE. However, our data further suggest that the use of more precise techniques, such as MD simulations and QTAIM analysis, is necessary to obtain detailed insight into ligand-enzyme interactions. Regarding QTAIM calculations, they demonstrate that such computations are very useful to evaluate the molecular interactions of the different molecular complexes. In summary, we report a new series of sulfonate derivatives as promising starting structures for the development of new selective BChE inhibitors.},
}

*Butyrylcholinesterase/chemistry/metabolism
*Cholinesterase Inhibitors/chemistry/pharmacology/chemical synthesis
Molecular Docking Simulation
Humans
Molecular Dynamics Simulation
*Anti-Inflammatory Agents/chemistry/pharmacology
Drug Design
*Sulfonic Acids/chemistry/pharmacology
Structure-Activity Relationship
Animals

@article {pmid41977314,
year = {2026},
author = {Neamțu, M and Petreuș, T and Olinici, DT and Stoica, L and Arcan, OD and Stoica, BA and Moșoiu, C},
title = {The NLRP3 Inflammasome in Neuropsychiatric Disorders: Molecular Mechanisms and Emerging Therapeutic Strategies.},
journal = {International journal of molecular sciences},
volume = {27},
number = {7},
pages = {},
doi = {10.3390/ijms27073127},
pmid = {41977314},
issn = {1422-0067},
mesh = {Humans ; *Inflammasomes/metabolism/immunology ; *NLR Family, Pyrin Domain-Containing 3 Protein/metabolism ; *Mental Disorders/metabolism/immunology/therapy ; Animals ; },
abstract = {Inflammasomes are cytosolic multiprotein complexes that detect pathogens, cellular stress, and damage-associated molecular signals, thereby orchestrating innate immune responses. Increasing evidence suggests that dysregulated inflammasome activation contributes to persistent neuroinflammation and to a wide range of neuropsychiatric disorders, including mood disorders, schizophrenia, Alzheimer's disease, and autism spectrum disorders. Together, these findings emphasize the critical role of neuroimmune interactions in the pathophysiology of mental disorders. Recent molecular studies have substantially advanced our understanding of the crosstalk among neurons, microglia, astrocytes, and peripheral immune cells, uncovering complex regulatory networks mediated by cytokines, neurotrophins, and neurotransmitters. By examining key inflammatory mediators and cell type-specific mechanisms, this review consolidates current knowledge and proposes conceptual frameworks to guide future investigations and facilitate the development of targeted therapeutic strategies for neuropsychiatric disorders.},
}

Humans
*Inflammasomes/metabolism/immunology
*NLR Family, Pyrin Domain-Containing 3 Protein/metabolism
*Mental Disorders/metabolism/immunology/therapy
Animals

@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 {pmid41977389,
year = {2026},
author = {Tiwari, S and Yadav, SK and Kumari, M and Dhakal, T and Puranik, N},
title = {Neuropeptides in the Management of Alzheimer's Disease: From Pathophysiology to Therapeutic Opportunities.},
journal = {International journal of molecular sciences},
volume = {27},
number = {7},
pages = {},
doi = {10.3390/ijms27073206},
pmid = {41977389},
issn = {1422-0067},
mesh = {Humans ; *Alzheimer Disease/drug therapy/metabolism/physiopathology ; *Neuropeptides/therapeutic use/metabolism/pharmacology ; Animals ; Vasoactive Intestinal Peptide/therapeutic use ; *Neuroprotective Agents/therapeutic use/pharmacology ; Pituitary Adenylate Cyclase-Activating Polypeptide/therapeutic use/metabolism ; Amyloid beta-Peptides/metabolism ; },
abstract = {Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by memory decline, cognitive impairment, and behavioral changes, ultimately leading to a loss of independence and reduced quality of life. Although understanding of the molecular basis of AD has advanced, effective disease-modifying therapies remain scarce. Neuropeptides are small protein-like signaling molecules that regulate diverse physiological processes, including mood, memory, and neuronal function. Growing evidence indicates that neuropeptides are promising therapeutic candidates for AD, particularly through modulation of neuroinflammation, synaptic plasticity, and amyloid-beta (Aβ) aggregation. Preclinical AD models show that neuroprotective neuropeptides, such as neuropeptide Y (NPY), vasoactive intestinal peptide (VIP), and pituitary adenylate cyclase-activating peptide (PACAP), exert neuroprotective effects, enhance memory, and attenuate cognitive decline. This review summarizes current research on neuropeptide-based therapies for AD, detailing their molecular mechanisms, therapeutic actions, and the barriers to their clinical translation. We specifically highlight neuropeptides whose clinical potential in AD remains comparatively underrecognized, discuss strategies for optimizing their delivery and overcoming pharmacokinetic limitations, and outline future perspectives for integrating neuropeptide-based interventions into AD therapy.},
}

Humans
*Alzheimer Disease/drug therapy/metabolism/physiopathology
*Neuropeptides/therapeutic use/metabolism/pharmacology
Animals
Vasoactive Intestinal Peptide/therapeutic use
*Neuroprotective Agents/therapeutic use/pharmacology
Pituitary Adenylate Cyclase-Activating Polypeptide/therapeutic use/metabolism
Amyloid beta-Peptides/metabolism

@article {pmid41977405,
year = {2026},
author = {Foncea-Bitrán, A and Barros-Osorio, C and Arriaza, F and Ramírez-López, C and Ruiz, LM and Barreto, M and Ortiz, FC and Cornejo, F and Gómez, GI},
title = {Connecting the Dots: Neurobiological Interplay Between Type 2 Diabetes and Alzheimer's Disease.},
journal = {International journal of molecular sciences},
volume = {27},
number = {7},
pages = {},
doi = {10.3390/ijms27073225},
pmid = {41977405},
issn = {1422-0067},
support = {1250485//Fondo Nacional de Desarrollo Científico y Tecnológico (FONDECYT)/ ; },
mesh = {Humans ; *Alzheimer Disease/metabolism/pathology/etiology ; *Diabetes Mellitus, Type 2/metabolism/complications/pathology ; Biomarkers/metabolism ; Animals ; tau Proteins/metabolism ; Insulin Resistance ; Amyloid beta-Peptides/metabolism ; Insulin/metabolism ; Cognitive Dysfunction/metabolism ; },
abstract = {Diabetes Mellitus is a chronic metabolic disorder characterized by impaired insulin production and/or action, leading to persistent hyperglycemia and insulin resistance. It has been associated with several comorbidities, including cognitive dysfunction, affecting functions such as attention, memory, and processing speed. Mounting evidence indicates a complex relationship between type 2 Diabetes Mellitus (DM2) and neurodegenerative disorders such as mild cognitive impairment and Alzheimer's disease (AD). Beyond the conventional hallmarks of each pathology, patients with DM2 face an increased risk of neuronal degeneration, while AD is characterized by a marked reduction in insulin receptor density. Although aging, neuroinflammation, and vascular dysfunction have been recognized as key risk factors in AD, the precise molecular mechanisms driving AD pathogenesis remain incompletely understood. Various studies have been conducted to identify reliable biomarkers that elucidate the connection between DM2 and AD, including insulin dysregulation, neuroinflammation, amyloid-β aggregation, and tau hyperphosphorylation. Investigation of these biomarkers is still ongoing, and they may serve not only as diagnostic tools but also as therapeutic targets. Here, we review the current evidence supporting a convergent biological framework between DM2 and AD. Clarifying these shared pathways may improve early detection and guide the development of targeted therapeutic strategies aimed at reducing neurodegeneration in metabolically vulnerable populations.},
}

Humans
*Alzheimer Disease/metabolism/pathology/etiology
*Diabetes Mellitus, Type 2/metabolism/complications/pathology
Biomarkers/metabolism
Animals
tau Proteins/metabolism
Insulin Resistance
Amyloid beta-Peptides/metabolism
Insulin/metabolism
Cognitive Dysfunction/metabolism

@article {pmid41977406,
year = {2026},
author = {Lin, L and Pratt, AE and Hoffman, DA},
title = {DPP6 Loss Causes Age-Dependent Sleep Dysregulation and Depression-like Phenotypes Linked to Neurodegeneration.},
journal = {International journal of molecular sciences},
volume = {27},
number = {7},
pages = {},
doi = {10.3390/ijms27073224},
pmid = {41977406},
issn = {1422-0067},
support = {ZIA HD008755/ImNIH/Intramural NIH HHS/United States ; },
mesh = {Animals ; Mice, Knockout ; Mice ; *Depression/genetics/metabolism ; Phenotype ; *Dipeptidyl-Peptidases and Tripeptidyl-Peptidases/genetics/deficiency/metabolism ; *Aging ; Sleep ; *Neurodegenerative Diseases/genetics ; Male ; *Sleep Wake Disorders/genetics/metabolism ; Circadian Rhythm ; Mice, Inbred C57BL ; Disease Models, Animal ; },
abstract = {Sleep disturbances are early hallmarks of Alzheimer's disease (AD) and other dementias, yet the molecular mechanisms remain poorly understood. We previously showed that dipeptidyl aminopeptidase-like protein 6-knockout (DPP6-KO) mice exhibit accelerated neurodegeneration with synaptic loss, neuronal death, and circadian dysfunction resembling AD pathology. Here, we investigate whether DPP6 deficiency directly causes sleep dysregulation and assess age-dependent effects using wireless EEG/EMG telemetry, behavioral monitoring, and body temperature recordings. We found striking age-dependent sleep phenotypes in DPP6-KO mice. Adult (3-month) DPP6-KO mice showed hyperactivity-driven REM sleep increases, while aged (12-month) DPP6-KO mice developed insomnia with fragmented sleep architecture. Critically, aged DPP6-KO mice exhibited decreased REM latency, a biomarker of depression, which we confirmed by behavioral assays. Conversely, DPP6 overexpression in aged wild-type mice increased NREM duration and reduced sleep fragmentation, demonstrating a protective effect. Throughout aging, DPP6-KO mice showed dysregulated locomotor activity and body temperature rhythms, suggesting broader disruption of circadian and metabolic homeostasis. These findings establish DPP6 as a critical regulator of sleep architecture whose loss recapitulates key sleep disturbances observed in AD/dementia. The progressive nature of sleep dysfunction in DPP6-KO mice, from REM abnormalities to insomnia, parallels human disease progression and positions DPP6 as a potential therapeutic target for sleep-related symptoms in neurodegenerative disorders.},
}

Animals
Mice, Knockout
Mice
*Depression/genetics/metabolism
Phenotype
*Dipeptidyl-Peptidases and Tripeptidyl-Peptidases/genetics/deficiency/metabolism
*Aging
Sleep
*Neurodegenerative Diseases/genetics
Male
*Sleep Wake Disorders/genetics/metabolism
Circadian Rhythm
Mice, Inbred C57BL
Disease Models, Animal

@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 {pmid41977467,
year = {2026},
author = {Nilewar, SS and Chavan, AD and Pradhan, AR and Tripathy, AA and Bandaru, N and Dudhe, PB and Kumar, PK and Lodha, S and Muteeb, G and Peredo-Valderrama, I and Naranjo-Redondo, AJ and Pawar, TJ},
title = {Dual-Site Acetylcholinesterase Inhibition and Multiscale Stability of Fused Quinoline Sulfonamides: A Chemoinformatic GA-MLR and Molecular Dynamics Study.},
journal = {International journal of molecular sciences},
volume = {27},
number = {7},
pages = {},
doi = {10.3390/ijms27073286},
pmid = {41977467},
issn = {1422-0067},
support = {UAG-CI-00001//Universidad Anáhuac Querétaro/ ; },
mesh = {*Cholinesterase Inhibitors/chemistry/pharmacology ; Molecular Dynamics Simulation ; *Quinolines/chemistry/pharmacology ; *Acetylcholinesterase/chemistry/metabolism ; Molecular Docking Simulation ; Quantitative Structure-Activity Relationship ; *Sulfonamides/chemistry/pharmacology ; Humans ; Catalytic Domain ; Cheminformatics/methods ; },
abstract = {Alzheimer's disease (AD) represents an escalating global neuropharmacological crisis, with prevalence in high-growth demographic regions such as India projected to exceed 14 million by 2040. This study addresses the urgent need for high-potency, dual-site acetylcholinesterase (AChE) inhibitors through an integrated computational pipeline. We address the failure of mono-target paradigms by designing scaffolds capable of simultaneously anchoring the Catalytic Active Site (CAS) and the Peripheral Anionic Site (PAS). A robust GA-MLR QSAR model was developed from 115 quinoline analogs using 11,135 descriptors. Lead candidates were prioritized via cavity directed molecular docking (7XN1) and 100 ns molecular dynamics (MD) simulations. The five-descriptor model (R[2] = 0.7569, QLOO2 = 0.7244) was validated by an external set of 8 experimental compounds (Rext2 = 0.8620). Lead Compound 19 emerged as a superior candidate (ΔG = -11.1 kcal/mol), exhibiting a stable MD trajectory (PL-RMSD ≈ 2.4 Å) and preserving essential Gly121-His447 catalytic anti-correlations. This study provides a statistically validated scaffold and computational mechanistic foundation for future in vitro experimental validation, advancing the high throughput screening of neuroprotective agents on a global scale.},
}

*Cholinesterase Inhibitors/chemistry/pharmacology
Molecular Dynamics Simulation
*Quinolines/chemistry/pharmacology
*Acetylcholinesterase/chemistry/metabolism
Molecular Docking Simulation
Quantitative Structure-Activity Relationship
*Sulfonamides/chemistry/pharmacology
Humans
Catalytic Domain
Cheminformatics/methods

@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 {pmid41977515,
year = {2026},
author = {Angelopoulou, E and Papatriantafyllou, J and Papageorgiou, S and Villa, C},
title = {Elucidating the Neurobiological Underpinnings of Mild Behavioral Impairment in Tauopathies: Clinical and Molecular Insights.},
journal = {International journal of molecular sciences},
volume = {27},
number = {7},
pages = {},
doi = {10.3390/ijms27073341},
pmid = {41977515},
issn = {1422-0067},
mesh = {Humans ; *Tauopathies/metabolism/pathology ; tau Proteins/metabolism ; Biomarkers ; Animals ; Alzheimer Disease/metabolism ; *Cognitive Dysfunction ; },
abstract = {Mild behavioral impairment (MBI) is a clinical syndrome characterized by the late-life onset and persistence of neuropsychiatric symptoms (NPSs), representing a change from longstanding behavior or personality and considered a potential prodrome of neurodegenerative disease. MBI is classified into five domains: decreased motivation, affective dysregulation, impulse dyscontrol, social inappropriateness, and psychotic symptoms. In this narrative review, we synthesize clinical, neuroanatomical, and molecular evidence linking MBI to the spectrum of tauopathies, including Alzheimer's disease (AD), frontotemporal spectrum disorders (FTSDs), and primary four-repeat tauopathies such as progressive supranuclear palsy (PSP) and corticobasal degeneration (CBD). Emerging evidence suggests that early behavioral symptoms associated with MBI may reflect the selective vulnerability of frontolimbic, salience, default mode, and frontostriatal networks to tau-mediated neurodegeneration. Mechanistically, converging findings support roles for tau-related synaptic dysfunction, including synaptotoxic soluble tau species, cytoskeletal and axonal transport disruption, monoaminergic neurotransmitter imbalance in brainstem systems, and neuroinflammatory and glial pathways. We also highlight genotype-related behavioral profiles in genetic frontotemporal lobar degeneration and discuss how scalable blood-based biomarkers, including neurofilament light chain, glial fibrillary acidic protein, and plasma phospho-tau species, may complement MBI-based phenotyping for differential diagnosis and prognostic stratification in clinical research.},
}

Humans
*Tauopathies/metabolism/pathology
tau Proteins/metabolism
Biomarkers
Animals
Alzheimer Disease/metabolism
*Cognitive Dysfunction

@article {pmid41977873,
year = {2026},
author = {Zinser, ALV and Zahrebelnei, F and Winiarski, JP and Picciani, PHS and Wohnrath, K and Pessôa, CA},
title = {Electrochemical Detection of miR-29a and miR-34a Using AuNPs Immobilized by a Silsesquioxane Polyelectrolyte: Potential Early Alzheimer's Disease Biomarkers Detection.},
journal = {Sensors (Basel, Switzerland)},
volume = {26},
number = {7},
pages = {},
doi = {10.3390/s26072089},
pmid = {41977873},
issn = {1424-8220},
support = {465572/2014-6//National Institute of Organic Electronics (INEO)/ ; 406008/2022-1//National Council for Scientific and Technological Development/ ; 22.027.260-5//Fundação Araucária/ ; },
mesh = {*MicroRNAs/isolation & purification/genetics ; *Alzheimer Disease/diagnosis/genetics ; Humans ; *Biosensing Techniques/methods ; *Gold/chemistry ; *Metal Nanoparticles/chemistry ; *Electrochemical Techniques/methods ; Biomarkers/blood ; Organosilicon Compounds/chemistry ; Polyelectrolytes/chemistry ; Electrodes ; Limit of Detection ; },
abstract = {Alzheimer's Disease (AD) is the leading cause of dementia worldwide, and early diagnosis is crucial to minimize neurological damage and loss of quality of life. Here, we report an electrochemical biosensor for detecting miRNAs 29a and 34a, potential non-invasive biomarkers associated with AD. The biosensor consisted of a glassy carbon electrode (GCE) modified with a novel nanohybrid of gold nanoparticles stabilized by 3-n-propyl(4-dimethylaminopyridinium) silsesquioxane chloride (AuNPs-Si4DMAP[+]Cl[-]). Thiolated anti-miRNA probes were immobilized separately on the GCE/AuNPs-Si4DMAP[+]Cl[-], followed by BSA blocking. Target miRNAs were detected via hybridization with complementary probes using electrochemical impedance spectroscopy. The nanohybrid, characterized by spectroscopic and morphological techniques, significantly enhanced the electrochemical response and was effective detecting both miRNAs, showing suspension stability over 600 days. LOD and LOQ were 1.79 pM and 5.87 pM for miRNA-29a, and 2.21 pM and 11.01 pM for miRNA-34a. These results highlight the platform's potential for electrochemical detection of these miRNAs in blood, supporting earlier detection of AD and other neurodegenerative diseases.},
}

*MicroRNAs/isolation & purification/genetics
*Alzheimer Disease/diagnosis/genetics
Humans
*Biosensing Techniques/methods
*Gold/chemistry
*Metal Nanoparticles/chemistry
*Electrochemical Techniques/methods
Biomarkers/blood
Organosilicon Compounds/chemistry
Polyelectrolytes/chemistry
Electrodes
Limit of Detection

@article {pmid41978186,
year = {2026},
author = {Castro, CB and Gardener, SL and Jahan, F and Chen, J and Brown, BM and Loo, RL and Taddei, K and Rainey-Smith, SR and Weinborn, M and Dos Reis, ACR and Verma, S and Carrigan, N and Inderjeeth, C and Doré, V and Garg, ML and Martins, RN and Sohrabi, HR},
title = {Dietary Patterns and Cerebral Glucose Metabolism in Older Adults: Findings from the Western Australian Memory Study.},
journal = {Nutrients},
volume = {18},
number = {7},
pages = {},
doi = {10.3390/nu18071136},
pmid = {41978186},
issn = {2072-6643},
support = {#324100; Molecular and Neuropsychological Predictive Markers of Cognitive Decline)//NHMRC/ ; },
mesh = {Humans ; Female ; Male ; Aged ; *Diet, Western/adverse effects ; *Glucose/metabolism ; Prospective Studies ; Longitudinal Studies ; Positron-Emission Tomography ; *Brain/metabolism/diagnostic imaging ; Aged, 80 and over ; Western Australia ; Alzheimer Disease/metabolism ; Fluorodeoxyglucose F18 ; *Diet ; },
abstract = {UNLABELLED: Alzheimer's disease (AD) is characterized by significant reductions in glucose metabolism, reflecting underlying synaptic dysfunction, correlating with cognitive decline. We aimed to explore the impact of dietary patterns on the change in glucose metabolism.

METHODS: This longitudinal, prospective study included 132 community-dwelling older adults without a diagnosed dementia history enrolled in the Western Australian Memory Study (WAMS). Participants completed a food frequency questionnaire at baseline and underwent [[18]F]-Fluorodeoxyglucose positron emission tomography (FDG-PET) imaging at baseline and at up to two follow-up assessments scheduled approximately 18 months apart, over a maximum follow-up period of 43 months. Principal component analysis yielded two dietary patterns-named Western Diet and Prudent Diet. Linear mixed-effect models evaluated the association between dietary adherence and glucose metabolism, including potential confounders. Analysis was repeated stratified by sex.

RESULTS: Adherence to a Western Diet, characterized by high sugars and saturated fats, was associated with faster decline in glucose metabolism in the left fusiform gyrus (β = -0.00062; SE = 0.00025; FDR-adjusted p = 0.043), neocortex (β = -0.00063; SE = 0.00026; FDR-adjusted p = 0.047), left ventrolateral prefrontal (β = -0.00083; SE = 0.00032; FDR-adjusted p = 0.045 and inferior parietal region (β = -0.00344; SE = 0.00129; FDR-adjusted p = 0.033) in females. A Prudent Diet, characterized by a high intake of fruits, vegetables, and whole grains, showed no significant effects.

CONCLUSIONS: Our study highlights the following: (a) The potential detrimental impact of a Western Diet on brain glucose metabolism, particularly for females, who are at higher risk for AD. The decline was observed in regions essential for cognitive functions, including visual processing and facial recognition, emphasizing the role of diet in brain health. (b) No significant associations were observed between adherence to a Prudent dietary pattern and changes in glucose metabolism.},
}

Humans
Female
Male
Aged
*Diet, Western/adverse effects
*Glucose/metabolism
Prospective Studies
Longitudinal Studies
Positron-Emission Tomography
*Brain/metabolism/diagnostic imaging
Aged, 80 and over
Western Australia
Alzheimer Disease/metabolism
Fluorodeoxyglucose F18
*Diet

@article {pmid41978265,
year = {2026},
author = {Lázaro, B and Tadeo, FJ and Rodríguez, A and Ayuso-Molina, L and Martínez-Láinez, JM and Quandt, E and Bernard, M and Borghi, F and Saiardi, A and Juan-Mateu, J and Jiménez, J and Clotet, J and Bru, S},
title = {Nuclear speckle dynamics are controlled by polyphosphate inhibition of CLK proteins.},
journal = {Nucleic acids research},
volume = {54},
number = {7},
pages = {},
doi = {10.1093/nar/gkag309},
pmid = {41978265},
issn = {1362-4962},
support = {//Ministerio de Ciencia e Innovación/ ; PID2021-127302NB-I00//Spanish Government/ ; PID2024-158824NB-I00//Spanish Government/ ; //Universitat Internacional de Catalunya/ ; },
mesh = {Humans ; *Polyphosphates/metabolism ; RNA Splicing/genetics ; *Cell Nucleus/metabolism/genetics ; *Protein Serine-Threonine Kinases/metabolism/antagonists & inhibitors/genetics ; *Protein-Tyrosine Kinases/metabolism/genetics ; Phosphorylation ; HeLa Cells ; Serine-Arginine Splicing Factors/metabolism/genetics ; RNA-Binding Proteins/metabolism ; HEK293 Cells ; },
abstract = {Nuclear speckles (NS) are membraneless nuclear organelles that act as critical hubs for pre-messenger RNA splicing. Defects in splicing are linked to several human diseases, including cancer, Alzheimer's disease, and dystrophies. While CLK kinases regulate the mobilization of splicing factors from NS, the molecular mechanisms underlying NS assembly and dissolution remain unclear. Using an adaptation of the Biotinylation by Antibody Recognition technique, we identified polyphosphate (polyP) as a novel and essential regulator of NS dynamics. Polyphosphate, a highly conserved polyanion composed of a chain of phosphate molecules, is involved in several functions in mammalian cells. Here, we show that polyP interacts with the NS core component SRRM2, and its depletion disrupts NS organization releasing splicing factors into the nucleoplasm. RNA-seq analysis reveals that polyP depletion increases exon exclusion, particularly in transcripts with multiple isoforms, highlighting its role in splicing regulation. Mechanistically, we demonstrate that polyP acts as a physiological inhibitor of CLK3 kinase, preventing the phosphorylation of SR proteins and thereby maintaining NS stability. Our findings not only expand our understanding of NS biology but also provide new insights into the polyP involvement in splicing-related diseases.},
}

Humans
*Polyphosphates/metabolism
RNA Splicing/genetics
*Cell Nucleus/metabolism/genetics
*Protein Serine-Threonine Kinases/metabolism/antagonists & inhibitors/genetics
*Protein-Tyrosine Kinases/metabolism/genetics
Phosphorylation
HeLa Cells
Serine-Arginine Splicing Factors/metabolism/genetics
RNA-Binding Proteins/metabolism
HEK293 Cells

@article {pmid41978701,
year = {2026},
author = {Long, S and Li, R and Yang, J and Cheng, R and Wang, Y and Dong, Y},
title = {SIRT1 decreases Aβ-induced IL-1β production by suppressing NLRP3 inflammasome activation and M1 microglial polarization.},
journal = {Cytotechnology},
volume = {78},
number = {3},
pages = {85},
pmid = {41978701},
issn = {0920-9069},
abstract = {Microglia polarize into the proinflammatory M1 phenotype drive Alzheimer's disease (AD) pathogenesis through NLRP3 inflammasome-dependent maturation of interleukin (IL)-1β. Silent information regulator-1 (SIRT1) regulates a large number of cellular pathways and is related to aging and age-associated diseases, however, there were limited studies investigated whether SIRT1 can affect NLRP3 inflammasome and microglial activation and subsequent IL-1β production in AD. Here, we identified SIRT1 over-expression attenuated the release of IL-1β in amyloid-β (Aβ) treated microglia. Furthermore, our findings also revealed that NLRP3 inflammasome were less activated while the SIRT1 has been up-regulated. In addition, SIRT1 considerably alleviated the polarization of microglia toward to M1 phenotype mediated by Aβ, and the inhibitory on M1 polarization accompanied with the up-regulation of phosphorylated AMPK. This study demonstrated that SIRT1 can reduce IL-1β production by inhibiting the activation of NLRP3 and microglial phenotype toward M1, which suggesting SIRT1 may represent a potential strategy for modulating neuroinflammation in AD.},
}

@article {pmid41978790,
year = {2026},
author = {Koenig, LN and Huber, H and Chongtham, A and Di Molfetta, G and Andrews, RD and Lukic, A and Shafiian, N and Fillit, HM and Blennow, K and Ashton, NJ and Zetterberg, H and Matthews, DC and Pereira, AC},
title = {Plasma p-tau217 and glucose metabolism correlate in neocortical association areas in Alzheimer's disease.},
journal = {Brain communications},
volume = {8},
number = {2},
pages = {fcag074},
pmid = {41978790},
issn = {2632-1297},
abstract = {While the biomarkers available for Alzheimer's disease are continually expanding, including clinically approved blood tests, not all of the relationships between various biomarkers have been fully elucidated. In this study, we explore how regional brain metabolism, as measured by fludeoxyglucose-18 (FDG)-PET, relates to plasma biomarkers such as p-tau217, Glial fibrillary acidic protein (GFAP), phosphorylated-tau (p-tau)217/beta-amyloid (Aβ) 42, and Aβ42/40 in a cohort of participants with early symptomatic Alzheimer's disease. P-tau217 showed a consistent pattern of participants with higher p-tau217 levels having increased hypometabolism in Alzheimer's disease-related regions in neocortical association areas such as the lateral temporal cortex, the precuneus and inferior parietal cortex and atrophy accompanied by greater cognitive impairment. GFAP also related to regional hypometabolism and atrophy in regions known to be affected in Alzheimer's disease, though with a slightly different regional pattern. We additionally observed that participants with equivalent biomarker levels still exhibited diverse patterns of FDG-PET and atrophy. This suggests that, despite the above correlations, imaging provides additional information. These findings support and extend our knowledge of how plasma p-tau217 relates to other Alzheimer's disease biomarkers and cerebral metabolism, helping to contextualize both the benefits and limitations of these plasma biomarkers.},
}

@article {pmid41978992,
year = {2026},
author = {Bouchoucha, K and Collin, L and Coquette, C and Colmant, L and Boyer, E and Huyghe, L and Quenon, L and Gerard, T and Salman, Y and Hox, V and Kienlen-Campard, P and Hanseeuw, B and Decottignies, A and Huart, C},
title = {Olfactory decline tracks central-to-peripheral spread of tau pathology in Alzheimer's disease.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {22},
number = {4},
pages = {e71402},
doi = {10.1002/alz.71402},
pmid = {41978992},
issn = {1552-5279},
support = {//Fondation Louvain/ ; //StopAlzheimer Foundation/ ; //FRFS-Welbio/ ; //Télévie-FNRS/ ; CCL40010417//Fonds De La Recherche Scientifique - FNRS/ ; //UCLouvain/ ; },
mesh = {Humans ; *Alzheimer Disease/pathology/complications/metabolism ; *tau Proteins/metabolism ; Male ; Female ; Aged ; *Olfactory Bulb/pathology/metabolism ; *Olfaction Disorders/pathology/etiology ; Aged, 80 and over ; Middle Aged ; Disease Progression ; },
abstract = {INTRODUCTION: Olfactory decline often precedes cognitive symptoms in Alzheimer's disease (AD) and is linked to tau pathology. Yet, whether tau aggregates start in peripheral olfactory structures or spread from central regions remains debated.

METHODS: We analyzed 34 post mortem human olfactory bulb (OB) and 2 neuroepithelium (ONE) samples across Braak stages, combined with ex vivo nasal swabs and standardized olfactory testing in 88 clinically characterized participants.

RESULTS: Tau aggregates appeared in the anterior olfactory nucleus layer of the OB from Braak stage III, spreading to peripheral layers only in late stages. Olfactory identification declined in the preclinical phase and was linked to central tau pathology. Discrimination worsened during the prodromal stage, while threshold impairment appeared only in dementia, reflecting the anatomical progression of tau pathology.

DISCUSSION: This anatomical-functional link supports a central-to-peripheral spread of tau pathology in the olfactory system, with stage-specific deficits suggesting targeted smell tests as early AD biomarkers.},
}

Humans
*Alzheimer Disease/pathology/complications/metabolism
*tau Proteins/metabolism
Male
Female
Aged
*Olfactory Bulb/pathology/metabolism
*Olfaction Disorders/pathology/etiology
Aged, 80 and over
Middle Aged
Disease Progression

@article {pmid41978994,
year = {2026},
author = {Li, J and Yi, Y and Gan, L and Bezgin, G and Chan, T and Rahmouni, N and Wang, YT and Aumont, E and Hosseini, SA and Hall, BJ and Trudel, L and Therriault, J and Macedo, AC and Socualaya, KMQ and Arias, JF and Zheng, Y and Olivia-Lopez, D and Hopewell, R and Hsiao, CH and Zou, T and Soucy, JP and Gauthier, S and Vitali, P and Pascoal, TA and Razlighi, QR and Montembeault, M and Li, R and Rosa-Neto, P},
title = {Elevation in network dynamics amplifies amyloid-dependent tau pathology.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {22},
number = {4},
pages = {e71354},
doi = {10.1002/alz.71354},
pmid = {41978994},
issn = {1552-5279},
support = {//Weston Brain Institute/ ; MOP-11-51-31/CAPMC/CIHR/Canada ; RFN 152985/CAPMC/CIHR/Canada ; 159815/CAPMC/CIHR/Canada ; 162303/CAPMC/CIHR/Canada ; MOP-11-51-31 -team 1//Canadian Consortium of Neurodegeneration and Aging/ ; NIRG-12-92090//the Alzheimer's Association/ ; NIRP-12-259245//the Alzheimer's Association/ ; CFI Project 34874//Brain Canada Foundation/ ; 33397//Brain Canada Foundation/ ; Chercheur Boursier 2020-VICO-279314//the Fonds de Recherche du Québec-Santé/ ; 2024-VICO-356138//the Fonds de Recherche du Québec-Santé/ ; 2022ZD0208903//Brain Science and Brain-like Intelligence Technology-National Science and Technology Major Project/ ; 823720853//National Natural Science Foundation of China/ ; LGL-1630-05//Lingang Laboratory/ ; //Fondation Brain Canada/ ; //Consortium canadien en neurodégénérescence associée au vieillissement/ ; },
mesh = {Humans ; Male ; *tau Proteins/metabolism ; Female ; Cross-Sectional Studies ; *Amyloid beta-Peptides/metabolism ; Magnetic Resonance Imaging ; Positron-Emission Tomography ; Aged ; *Brain/diagnostic imaging/metabolism/pathology ; *Alzheimer Disease/pathology/diagnostic imaging/metabolism ; Middle Aged ; *Nerve Net/diagnostic imaging ; Biomarkers ; },
abstract = {INTRODUCTION: The role of brain network dynamics in relation to amyloid beta (Aβ) and tau pathology across Braak stages remains unclear.

METHODS: In this cross-sectional study of 216 participants from Translational Biomarkers of Aging and Dementia (TRIAD) cohort, we analyzed resting-state functional magnetic resonance imaging using a multilayer modularity algorithm to assess brain network dynamics across 10 predefined functional networks, stratified by amyloid and tau positron emission tomography biomarkers and Braak stages.

RESULTS: Switching rates were significantly elevated in Aβ-positive/tau-positive individuals relative to Aβ-negative/tau-negative individuals, and increased progressively with advancing Braak stages. Elevated switching rates were strongly correlated with Aβ and tau burden in dorsal attention network and sensorimotor network, as well as with cognitive severity. Importantly, the interaction between network switching rate and Aβ burden synergistically contributed to accelerated tau accumulation in Braak stage III to V regions.

DISCUSSION: These findings support the framework that increased network switching may amplify Aβ-related tau load and cognitive deterioration in Alzheimer's disease.},
}

Humans
Male
*tau Proteins/metabolism
Female
Cross-Sectional Studies
*Amyloid beta-Peptides/metabolism
Magnetic Resonance Imaging
Positron-Emission Tomography
Aged
*Brain/diagnostic imaging/metabolism/pathology
*Alzheimer Disease/pathology/diagnostic imaging/metabolism
Middle Aged
*Nerve Net/diagnostic imaging
Biomarkers

@article {pmid41979006,
year = {2026},
author = {Caro, I and Pérez, G and Bize, JV and Ponferrada, J and Ferrante, FJ and Welford, AS and Gauder, L and Olavarría, L and Henríquez, F and Ramos, T and Besnier, C and Ferrer, L and Gorno-Tempini, ML and Slachevsky, A and Ibañez, A and García, AM},
title = {Benchmarking speech biomarkers of Alzheimer's against cognitive and neural measures.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {22},
number = {4},
pages = {e71365},
doi = {10.1002/alz.71365},
pmid = {41979006},
issn = {1552-5279},
support = {1231839//Fondecyt Regular/ ; ACT210096//PIA Anillos/ ; //NIH/ ; R01 AG057234/AG/NIA NIH HHS/United States ; R01 AG057234/AG/NIA NIH HHS/United States ; SG-20-725707/ALZ/Alzheimer's Association/United States ; //Rainwater Charitable Foundation - Tau Consortium, and Global Brain Health Institute/ ; //Fogarty International Center [FIC]/ ; R01 AG057234/AG/NIA NIH HHS/United States ; R01 AG057234/AG/NIA NIH HHS/United States ; 2P01AG019724/AG/NIA NIH HHS/United States ; R01 AG075775/AG/NIA NIH HHS/United States ; R01 AG21051/AG/NIA NIH HHS/United States ; R01 AG083799/AG/NIA NIH HHS/United States ; CARDS-NIH/AG/NIA NIH HHS/United States ; R01 AG057234/AG/NIA NIH HHS/United States ; //Rainwater Charitable Foundation - The Bluefield Project to Cure FTD/ ; //Global Brain Health Institute/ ; 1250091//ANID/FONDECYT Regular/ ; 1250317//ANID/FONDECYT Regular/ ; 1220995//ANID/FONDECYT Regular/ ; ACT210096//ANID/PIA/ANILLOS/ ; DISCeRN 2025//JPI JPND-Care/ ; //Health and Social Care Research with a Focus on the Moderate and Late Stages of Neurodegenerative Diseases/ ; ID20I10152//FONDEF/ ; 15150012//ANID/FONDAP/ ; /WT_/Wellcome Trust/United Kingdom ; 335293/Z/25/Z//BRAIN-CLIMA: Investigating the Combined Impact of Heat and Air Pollution on Blood-Brain Barrier Integrity and Brain Aging in Latin America/ ; CARE-2025-0883490149//Wellcome Leap CARE Program/ ; 101236426//Advancing Female-Specific Predictive Models and Risk Assessment Tools for Alzheimer's Disease in the US and Latin America, and the CliCBrain/ ; //Marie Skłodowska-Curie Actions - MSCA/ ; R01AG075775//NIA of the NIH/ ; R01AG083799//NIA of the NIH/ ; 2P01AG019724//NIA of the NIH/ ; FONDAP ID15150012//ANID/ ; FONDAP ID15150012//ANID/ ; FONDECYT Regular 1250317 1250091//ANID/ ; 01-PICTE-2022-05-00103//Agencia Nacional de Promoción Científica y Tecnológica/ ; /TW/FIC NIH HHS/United States ; //The Bluefield project to cure FTD/ ; //Rainwater Charitable Foundation/ ; //Tau Consortium/ ; R01 AG057234/AG/NIA NIH HHS/United States ; R01 AG057234/AG/NIA NIH HHS/United States ; R01 AG057234/AG/NIA NIH HHS/United States ; R01 AG057234/AG/NIA NIH HHS/United States ; 2P01AG019724/AG/NIA NIH HHS/United States ; FONDECYT Regular 1250091//Agencia Nacional de Investigación y Desarrollo/ ; },
mesh = {Humans ; *Alzheimer Disease/diagnosis/diagnostic imaging/physiopathology ; Male ; Female ; Magnetic Resonance Imaging ; Biomarkers ; Aged ; Neuropsychological Tests/statistics & numerical data ; *Benchmarking ; *Speech/physiology ; Executive Function/physiology ; Middle Aged ; Brain/diagnostic imaging ; *Cognition/physiology ; Machine Learning ; Hispanic or Latino ; Memory, Episodic ; White ; },
abstract = {INTRODUCTION: Digital speech biomarkers (DSBs) support the detection and monitoring of Alzheimer's disease (AD) in Latinos. However, they have not been benchmarked against standard cognitive and neuroimaging measures, missing a critical validation milestone.

METHODS: Thirty-three AD patients and 33 healthy controls completed verbal fluency tasks, episodic memory and executive tests, and magnetic resonance imaging (MRI) (volume) and functional MRI (fMRI) (connectivity) scans. Between-group machine learning classification was compared among fluency-derived DSBs, episodic and executive test scores, MRI, and fMRI measures.

RESULTS: The fluency classifier's performance (area under the curve [AUC] = 0.84) was comparable (p > 0.14) to the episodic (AUC = 0.90), executive (AUC = 0.79), and structural (AUC = 0.90) classifiers and superior to the functional classifier (AUC = 0.65, p = 0.002). Top discriminating features were word length and frequency, both associated with right (pre)frontal volume upon adjusting for sociodemographic factors.

DISCUSSION: DSBs appear non-inferior to standard cognitive and imaging measures, supporting scalable AD assessments in Latinos.

HIGHLIGHTS: We examined digital speech biomarkers (DSBs) for detecting AD in Latinos. DSBs were benchmarked against cognitive and neuroimaging features. DSB-based classifiers matched or outperformed cognitive and brain classifiers. Top DSBs included word length, phonological neighborhood, and frequency. Word length and frequency correlated with right (pre)frontal brain volume.},
}

Humans
*Alzheimer Disease/diagnosis/diagnostic imaging/physiopathology
Male
Female
Magnetic Resonance Imaging
Biomarkers
Aged
Neuropsychological Tests/statistics & numerical data
*Benchmarking
*Speech/physiology
Executive Function/physiology
Middle Aged
Brain/diagnostic imaging
*Cognition/physiology
Machine Learning
Hispanic or Latino
Memory, Episodic
White

@article {pmid41979010,
year = {2026},
author = {Crivelli, L and Fernandez, R and Corvalán, N and Sosa, AL and Acosta, D and Agnoletti, G and Surace, E and Acosta, I and Caramelli, P and Aguillón, D and Martelli, JL and Peñailillo, LD and Custodio, N and Charamelo, A and Damian, A and Llibre-Rodriguez, JJ and Allegri, R and Prina, M and Rogalski, E and Ibañez, L and Llibre-Guerra, JJ},
title = {A harmonized framework for studying exceptional cognitive aging in Latin America.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {22},
number = {4},
pages = {e71373},
doi = {10.1002/alz.71373},
pmid = {41979010},
issn = {1552-5279},
support = {ALZSI-25-1464205/ALZ/Alzheimer's Association/United States ; AARG-25-1485687/ALZ/Alzheimer's Association/United States ; 24HPE-1287320/ALZ/Alzheimer's Association/United States ; },
mesh = {Humans ; Latin America/epidemiology ; *Cognitive Aging/physiology/psychology ; Aged ; Female ; Male ; *Aging ; *Alzheimer Disease/epidemiology ; Neuropsychological Tests ; *Cognition/physiology ; },
abstract = {INTRODUCTION: Biological, genetic, and sociocultural factors underlying cognitive resilience and resistance to pathology remain unexplored in Latin America. The Life-Course Epidemiology of Aging, Resilience, and Neurodegeneration in Alzheimer's Disease (LEARN-AD) study and Latin American SuperAgers Study (LASAS) establish the first harmonized frameworks to characterize resilience and exceptional cognitive aging phenotypes in the region.

METHODS: The shared protocol integrates cognitive, neurological, psychosocial, and genetic data. SuperAgers are deeply phenotyped, while successful cognitive agers are identified through harmonized criteria applied to existing cohorts, ensuring regional adaptation and international comparability. Centralized training and shared procedures ensure cross-site consistency.

RESULTS: We define eligibility criteria and standardized assessments to classify successful cognitive agers and SuperAgers in Latin America and examine biological and psychosocial profiles supporting better-than-expected cognition.

DISCUSSION: LEARN-AD and LASAS represent the first Latin American infrastructure for studying cognitive resilience, resistance, and exceptional cognitive aging, which will generate unprecedented regional databases and grow into larger networks, providing foundations for research, prevention strategies, and precision approaches to promote brain health in Latin America.},
}

Humans
Latin America/epidemiology
*Cognitive Aging/physiology/psychology
Aged
Female
Male
*Aging
*Alzheimer Disease/epidemiology
Neuropsychological Tests
*Cognition/physiology

@article {pmid41979083,
year = {2026},
author = {Suzuki, M and Kamiya, M and Wakayama, S and Ueda, I and Suzuki, M and Osawa, A and Maeshima, S},
title = {Everyday Memory Failures as a Latent Risk Factor for Falls in Patients With Alzheimer's Disease.},
journal = {Geriatrics & gerontology international},
volume = {26},
number = {4},
pages = {e70489},
doi = {10.1111/ggi.70489},
pmid = {41979083},
issn = {1447-0594},
}

@article {pmid41979141,
year = {2026},
author = {Kaizi-Lutu, MA and Callow, DD and Rabinowitz, JA and Lucey, BP and An, Y and Wu, MN and Zipunnikov, V and Bakker, A and Davatzikos, C and Simonsick, EM and Walker, KA and Ferrucci, L and Resnick, SM and Spira, AP},
title = {Circadian rest/activity rhythms and change in MRI-derived brain volumes: Differences by age in a cognitively healthy sample.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {22},
number = {4},
pages = {e71190},
doi = {10.1002/alz.71190},
pmid = {41979141},
issn = {1552-5279},
support = {R01AG050507/AG/NIA NIH HHS/United States ; R01AG075883/AG/NIA NIH HHS/United States ; 5T32AG027668-19/AG/NIA NIH HHS/United States ; K01AG092954/AG/NIA NIH HHS/United States ; P30AG066507/AG/NIA NIH HHS/United States ; HHSN-260-2004-00012C//U.S. Department of Health and Human Services/ ; //Intramural Research Program of the National Institutes of Health/ ; },
mesh = {Humans ; Magnetic Resonance Imaging ; Male ; Female ; Aged ; *Brain/diagnostic imaging/pathology/anatomy & histology ; Cross-Sectional Studies ; Middle Aged ; *Circadian Rhythm/physiology ; *Rest/physiology ; Longitudinal Studies ; *Aging/physiology ; Aged, 80 and over ; Actigraphy ; Organ Size ; },
abstract = {INTRODUCTION: Circadian rest/activity rhythms (RARs) change across adulthood, and alterations in RARs have been associated with cognitive decline, Alzheimer's disease (AD), and dementia. Little is known, however, about associations of RARs with subsequent changes in brain structure.

METHODS: We investigated cross-sectional and longitudinal associations between RARs from wrist actigraphy and AD-relevant brain volumes from magnetic resonance imaging in cognitively unimpaired adults aged ≥ 50 and whether age moderated these associations.

RESULTS: In cross-sectional analyses, weaker and more fragmented RARs were associated with smaller medial temporal region volumes. Longitudinally, more regular and less fragmented RARs were associated with better maintenance of amygdala volume over time. Further, associations between RAR fragmentation and global atrophy were strongest among the oldest participants.

DISCUSSION: Results link RARs with medial temporal lobe and global brain volumes and indicate that these associations may differ by age. Research is needed on the effects of RAR-focused interventions on brain health.},
}

Humans
Magnetic Resonance Imaging
Male
Female
Aged
*Brain/diagnostic imaging/pathology/anatomy & histology
Cross-Sectional Studies
Middle Aged
*Circadian Rhythm/physiology
*Rest/physiology
Longitudinal Studies
*Aging/physiology
Aged, 80 and over
Actigraphy
Organ Size

@article {pmid41979157,
year = {2026},
author = {Chen, H and Ji, J and Liu, D and Yu, B},
title = {Unsupervised Sparse Multi-Task Learning With Application to Alzheimer's Disease.},
journal = {Statistics in medicine},
volume = {45},
number = {8-9},
pages = {e70526},
doi = {10.1002/sim.70526},
pmid = {41979157},
issn = {1097-0258},
support = {82404378//National Natural Science Foundation of China/ ; 82473738//National Natural Science Foundation of China/ ; T2341018//National Natural Science Foundation of China/ ; //Young Talent of Lifting Engineering for Science and Technology in Shandong, China/ ; //Young Scholars Program of Shandong University/ ; //Open Project of BGI-Shenzhen/ ; },
mesh = {*Alzheimer Disease/diagnostic imaging/physiopathology ; Humans ; Magnetic Resonance Imaging/methods ; Brain/physiopathology/diagnostic imaging ; *Unsupervised Machine Learning ; Disease Progression ; Biomarkers ; Computer Simulation ; Algorithms ; },
abstract = {This article is motivated by the challenge of identifying interpretable brain functional connectivity biomarkers for Alzheimer's disease (AD) progression using high-dimensional functional magnetic resonance imaging (fMRI) data, where predictors comprise both heterogeneous disease-stage activation patterns and strongly similar functional connections. We propose a unified statistical method, called Sparse Multi-task Adaptive Regularization Truncation (SMART), to simultaneously address three critical challenges: (1) High dimensionality is resolved through an ℓ 1 $$ {\ell}_
1 $$ -penalty (λ 1 $$ {\lambda}_
1 $$) that selects sparse, stage-distinct functional connections; (2) Disease-stage heterogeneity is accommodated via an ℓ 2 $$ {\ell}_
2 $$ -penalty (λ 2 $$ {\lambda}_
2 $$) that maintains stable activation patterns across tasks; (3) Connection collinearity is mitigated using a truncated ℓ 2 $$ {\ell}_
2 $$ penalty (TLP; λ 3 , τ $$ {\lambda}_
3,\tau $$) that adaptively groups edges with similar cross-task profiles without pre-specified structure. SMART offers key advantages over existing methods: Its joint regularization naturally handles smooth activation patterns across stages, while the TLP's dual parameters (τ $$ \tau $$ for adaptive grouping threshold, λ 3 $$ {\lambda}_
3 $$ for sparsity control) provide a principled trade-off between biological fidelity and model complexity. Computationally, we develop a DC-ADMM algorithm that transforms the optimization into tractable subproblems, establishing finite-step convergence to KKT points. Comprehensive simulation studies and real-data analysis of AD neuroimaging data demonstrate SMART's superior accuracy in connectivity biomarker identification, enhanced stability in feature selection, and improved interpretability for AD cohort studies. An accompanying R package, SMART, is available on GitHub (https://github.com/LDstat/SMART).},
}

*Alzheimer Disease/diagnostic imaging/physiopathology
Humans
Magnetic Resonance Imaging/methods
Brain/physiopathology/diagnostic imaging
*Unsupervised Machine Learning
Disease Progression
Biomarkers
Computer Simulation
Algorithms

@article {pmid41979288,
year = {2026},
author = {Sweeney, EM and Abate, G and Bakker, BRV and Mastinu, A and Lai, Y and Uberti, D and Nilsson, P and Tambaro, S},
title = {Cell Type-Specific Expression of p16, p21, and p53 Reveals Age-Dependent Glial Senescence in the App[NL-G-F] Mouse Model of Alzheimer's Disease.},
journal = {Aging cell},
volume = {25},
number = {4},
pages = {e70478},
doi = {10.1111/acel.70478},
pmid = {41979288},
issn = {1474-9726},
support = {24AARG-1244398/ALZ/Alzheimer's Association/United States ; 213-0295//Olle Engkvists Stiftelse/ ; 223087//Åhlén-stiftelsen/ ; //Gun & Bertil Stohnes Stiftelse/ ; //Demensfonden/ ; //Lindhés Advokatbyrå Stiftelse/ ; //Gamla tjänarinnor/ ; },
mesh = {Animals ; *Alzheimer Disease/pathology/genetics/metabolism ; Disease Models, Animal ; *Tumor Suppressor Protein p53/metabolism/genetics ; *Cellular Senescence/genetics ; Mice ; *Cyclin-Dependent Kinase Inhibitor p16/metabolism/genetics ; Female ; *Neuroglia/metabolism/pathology ; *Cyclin-Dependent Kinase Inhibitor p21/metabolism/genetics ; Mice, Transgenic ; *Aging ; },
abstract = {Cellular senescence, a state of irreversible cell cycle arrest, plays a key role in neurodegenerative diseases, including Alzheimer's disease (AD). While senescent cells are emerging as potential therapeutic targets, the dynamics of their occurrence over time and the specific cell types most affected by AD are still not well understood. This study investigates age- and pathology-dependent changes in senescence markers, specifically p16, p21, and p53, using the amyloidogenic App[NL-G-F] knock-in AD mouse model. Female App[NL-G-F] and wild-type (WT) mice were evaluated at 4, 12, and 24 months of age to capture disease progression changes from early to advanced AD stages. Immunofluorescence and qPCR were used to quantify p16, p21, and p53 expressions. Senescence-associated β-galactosidase (SA-β-Gal) activity, IL-1β and IL-6 levels, and CD68-p21 colocalization were assessed. At 4 months-of-age, only p21 levels in astrocytes differ between genotypes. By 12 months, App[NL-G-F] mice exhibited increased p16 and p21 expression in glial cells, along with elevated SA-β-Gal activity. IL-1β level increased in the cortex and hippocampus, while IL-6 only in the hippocampus. Most CD68-positive microglia co-expressed p21 in both hippocampus (73%) and cortex (82%), indicating a prevalent senescent phenotype among reactive microglia. p16 and p21 changes became more pronounced at 24 months. p53 expression followed a distinct pattern, increasing in astrocytes at 12 months and in microglia by 24 months. Neurons showed no genotype-dependent differences. These findings reveal a progressive, amyloid-linked glial senescence response, supporting the App[NL-G-F] model as a reliable platform for evaluating senotherapeutic strategies in AD.},
}

Animals
*Alzheimer Disease/pathology/genetics/metabolism
Disease Models, Animal
*Tumor Suppressor Protein p53/metabolism/genetics
*Cellular Senescence/genetics
Mice
*Cyclin-Dependent Kinase Inhibitor p16/metabolism/genetics
Female
*Neuroglia/metabolism/pathology
*Cyclin-Dependent Kinase Inhibitor p21/metabolism/genetics
Mice, Transgenic
*Aging

@article {pmid41979453,
year = {2026},
author = {Muñoz-Padros, J and Garolera, M and Puigoriol-Juvanteny, E and Bartés-Plans, A and Romero Mas, T and Roura-Poch, P and Foguet-Boreu, Q},
title = {Caregiver-Targeted Online Multicomponent Intervention and Quality of Life in Alzheimer's Disease: A Randomized Controlled Trial.},
journal = {Clinical gerontologist},
volume = {},
number = {},
pages = {1-15},
doi = {10.1080/07317115.2026.2659355},
pmid = {41979453},
issn = {1545-2301},
abstract = {OBJECTIVES: To examine whether a brief, fully online caregiver-targeted multicomponent psychological intervention improves self-reported quality of life (QoL) in people with Alzheimer's disease (AD).

METHODS: In this randomized controlled trial, 56 people with AD and their informal caregivers were assigned to an intervention (n = 28) or usual-care control group (n = 28). Caregivers in the intervention group completed an 8-week online program combining psychoeducation and mindfulness. Outcomes were assessed at baseline and post-intervention by blinded assessors. The primary outcome was QoL assessed with the QoL-AD. Group-by-time effects were analyzed using linear mixed-effects models.

RESULTS: Compared with controls, people with AD in the intervention group showed greater improvement in QoL-AD (p < .001). Neuropsychiatric symptoms worsened in the control group but remained stable in the intervention group (group × time p = .039). No significant effects were observed for cognitive performance.

CONCLUSIONS: A brief caregiver-targeted online intervention was associated with improved QoL and stabilization of neuropsychiatric symptoms in people with AD.

CLINICAL IMPLICATIONS: Trial registration: ClinicalTrials.gov, NCT04280861 (registered 17 February 2020).},
}

@article {pmid41979757,
year = {2026},
author = {Sunnetci, KM and Balci, M and Ekersular, MN and Oguz, FE and Alkan, A},
title = {Alzheimer's and Parkinson's Detection with Video-Based Hybrid Deep Learning from Brain MRI.},
journal = {Journal of imaging informatics in medicine},
volume = {},
number = {},
pages = {},
pmid = {41979757},
issn = {2948-2933},
abstract = {Dementia, which refers to disorders related to human memory, significantly affects the human brain, and a person with it can experience certain difficulties in physical and mental activities. The most common and fatal types of dementia are Alzheimer's Disease (AD) and Parkinson's Disease (PD). Therefore, AD, PD, and control labels are detected in this study from videos created using brain Magnetic Resonance Imaging (MRI). A public dataset including these three classes is used in this study. After preprocessing this dataset, a video is created for each class. Afterward, short video clips are randomly obtained from these videos. These video clips are randomly split into 50% training and 50% validation sets. Herein, features are extracted for training and validation using a Convolutional Neural Network (CNN)-based architecture. Long Short-Term Memory (LSTM), LSTM + Gated Recurrent Units (GRU), and Deeper LSTM architectures are trained using these extracted features. In addition, a user-friendly Graphical User Interface (GUI) application including all three models developed in the study is designed for AD, PD, and control detection. It is noted that these video-based architectures can achieve high performance with fewer short video clips, although 50% of the training data is used in the study. The maximum accuracy and specificity values achievable by the models developed in the study are 99.67% and 99.83%, respectively.},
}

@article {pmid41979943,
year = {2026},
author = {Rogers, AH and Roach, A and Lopez, RP},
title = {The role of spirituality among nursing home staff caring for residents with advanced dementia: a qualitative descriptive study.},
journal = {International journal of palliative nursing},
volume = {32},
number = {4},
pages = {177-183},
doi = {10.12968/ijpn.2023.0035},
pmid = {41979943},
issn = {2052-286X},
mesh = {Humans ; *Spirituality ; *Nursing Homes ; Qualitative Research ; *Dementia/nursing ; Female ; Male ; *Nursing Staff/psychology ; Middle Aged ; Adult ; Attitude of Health Personnel ; },
abstract = {BACKGROUND: Experts recommend that people with advanced dementia receive palliative care focused on comfort and quality of life and including spiritual care. While expected to provide this care, the role of spirituality in the work of staff is not known.

AIMS: To explore the role of spirituality in the work of nursing home staff caring for residents with advanced dementia.

METHODS: A qualitative descriptive study was conducted using interview data generated from by a parent study, Assessment of Disparities and Variation for Alzheimer's Disease Nursing Home Care at End of Life (ADVANCE) and analysed using thematic analysis.

FINDINGS: Four themes described how staff perceived spirituality to influence their work to comfort, guide, protect and make meaning.

CONCLUSIONS: Understanding the role of spirituality in caring for nursing home residents with advanced dementia could help identify strategies that help staff draw on their spiritual resources.},
}

Humans
*Spirituality
*Nursing Homes
Qualitative Research
*Dementia/nursing
Female
Male
*Nursing Staff/psychology
Middle Aged
Adult
Attitude of Health Personnel

@article {pmid41979952,
year = {2026},
author = {Tang, Y and Kong, H and Jiang, H and Lei, B and Liu, F and Ng, MK and Wang, S},
title = {Structural-Functional Connectome Generation via Diffusion-Guided Graph Transformer for Alzheimer's Disease Analysis.},
journal = {IEEE transactions on neural systems and rehabilitation engineering : a publication of the IEEE Engineering in Medicine and Biology Society},
volume = {PP},
number = {},
pages = {},
doi = {10.1109/TNSRE.2026.3683861},
pmid = {41979952},
issn = {1558-0210},
abstract = {Brain networks can reveal abnormal structural and functional connection patterns induced by Alzheimer's Disease (AD), providing critical insights for early diagnosis and intervention. However, current brain network computation tools can only construct unimodal brain networks, overlooking the complementarity between structural and functional brain connections, and suffer from limitations such as time-consuming processes and subjective parameter settings. To address these issues, we propose a structural-functional connectome generation paradigm called DiffusionBrain and apply it to the diagnosis and analysis of AD. Firstly, a Graph Prompt Fusion Module (GPFM) is designed to extract complementary structural and functional features from multimodal brain images and perform interleaved fusion as conditional prompts. Subsequently, a Dual Diffusion-guided Graph Transformer (DDGT) is developed to efficiently generate structural and functional brain networks from Gaussian noise under the guidance of conditional prompts. Lastly, a Graph Alignment Module (GAM) deeply fuses the structural and functional brain networks to obtain the structural-functional connectome. Experimental results on the ADNI dataset demonstrate that DiffusionBrain can better capture the complex interaction mechanisms of structural and functional brain networks and effectively reveal abnormal connection patterns in AD. More importantly, the proposed DiffusionBrain provides a multimodal brain network modeling paradigm, supporting further exploration of AD biomarkers and pathological mechanisms.},
}

@article {pmid41980178,
year = {2026},
author = {Li, Q and Liao, Y and Zhao, YB and Wu, H and Jin, T and Li, S and Liu, Y and Li, P and Ouyang, S and Li, Z and Xia, Y and Hua, Q and Pan, RY and Yuan, Z},
title = {Kinsenoside Targets IDH1 to Restore Microglial Immune-Metabolic Homeostasis for Alzheimer's Disease Therapy.},
journal = {Advanced science (Weinheim, Baden-Wurttemberg, Germany)},
volume = {},
number = {},
pages = {e75125},
doi = {10.1002/advs.75125},
pmid = {41980178},
issn = {2198-3844},
support = {82230042//National Natural Science Foundation of China/ ; 81930029//National Natural Science Foundation of China/ ; 82522028//National Natural Science Foundation of China/ ; 82471452//National Natural Science Foundation of China/ ; 82301373//National Natural Science Foundation of China/ ; 82505057//National Natural Science Foundation of China/ ; U21A20414//National Natural Science Foundation of China/ ; 82271236//National Natural Science Foundation of China/ ; 2024YFA1802600//National Key R&D Program of China/ ; 2025B1515020005//Natural Science Foundation of Guangdong Province/ ; 2022RC1219//Science and Technology Innovation Program of Hunan Province/ ; 2023SK4050//Clinical Medical Research Center of Hunan Province/ ; },
abstract = {Dysregulated tricarboxylic acid (TCA) cycle activity is increasingly recognized as a contributor to Alzheimer's disease (AD) pathogenesis, yet the mechanistic underpinnings of the relationship remain unclear. Here, we identify isocitrate dehydrogenase 1 (IDH1), a key enzyme in the TCA cycle, as a critical pathogenic driver of AD in microglia. IDH1 expression was markedly upregulated in microglia from both AD patients and 5×FAD mice. Elevated IDH1 promoted excessive cytosolic citrate consumption, which restricted citrate shuttling into mitochondria and impaired mitochondrial TCA cycle function. This citrate metabolic imbalance further disrupted epigenetic regulation, thereby exacerbating AD-related pathological processes. Using structure-based screening and co-crystallization analysis, we identified Kinsenoside (KIN), a natural small molecule, as a selective competitive inhibitor of IDH1 that binds to its isocitrate-binding pocket. Targeting IDH1 with KIN inhibited its activity, which restored intracellular citrate distribution, reactivated mitochondrial TCA cycle flux, and reestablished metabolic homeostasis. Notably, this intervention not only attenuated neuroinflammation but also reduced β-amyloid (Aβ) deposition and significantly improved cognitive performance in 5×FAD mice. Collectively, our findings establish IDH1-mediated metabolic dysregulation as a pivotal pathogenic mechanism in AD and highlight KIN as a promising therapeutic candidate by targeting microglial IDH1 to restore metabolic and functional homeostasis.},
}

@article {pmid41980207,
year = {2026},
author = {Lafon, PA and Tsitokana, ME and Alenda, UG and Lian, YL and Philibert, CE and Oosterlaken, M and Cimadevila, M and Dudon, G and Monnic, J and Roux, S and Bessié, J and Diem, S and Vandermoere, F and Prézeau, L and Chames, P and Kniazeff, J and Claeysen, S and Menny, A and Pin, JP and Perrier, V and Liu, J and Rondard, P},
title = {Divergent Roles of mGlu2 and mGlu3 Receptors in Amyloid-β Production and Cognitive Dysfunctions in Alzheimer's Disease.},
journal = {Advanced science (Weinheim, Baden-Wurttemberg, Germany)},
volume = {},
number = {},
pages = {e23791},
doi = {10.1002/advs.202523791},
pmid = {41980207},
issn = {2198-3844},
support = {2022YFE0116600//National Key R&D Program of China/ ; 2021ZD0203302//National Key R&D Program of China/ ; 32421003//National Natural Science Foundation of China/ ; 32330049//National Natural Science Foundation of China/ ; 82320108021//National Natural Science Foundation of China/ ; ANR-22-CE18-0003//Agence Nationale de la Recherche/ ; ANR-10-LABX-5301//Agence Nationale de la Recherche/ ; EQU202303016470//Fondation pour la Recherche Médicale/ ; ERC-2023-STG-101116944/ERC_/European Research Council/International ; },
abstract = {Immunotherapy is a promising avenue for reducing amyloid-β (Aβ) accumulation, a hallmark of Alzheimer's disease (AD) pathology. Camelid single domain antibodies, called nanobodies, offer several advantages over conventional monoclonal antibodies, including improved brain penetration and fine-tuning of the targeted neuroreceptors, and may represent an effective strategy to modulate Aβ production. Among potential therapeutic targets, group II metabotropic glutamate receptors (mGluR2 and mGluR3) have been implicated in Aβ regulation, though their individual contributions remain unclear. Here, we showed that activation of mGluR2 significantly increases Aβ peptides and sAPPβ production in a cellular model, by enhancing the internalization of amyloid precursor protein (APP) and its subsequent amyloidogenic processing. In contrast, mGluR3 directly interacts with APP, protecting it from amyloidogenic cleavage and favoring its non-amyloidogenic processing. We used a brain-penetrant nanobody acting as a selective positive allosteric modulator of mGluR2 to validate its role in Aβ dynamics in vivo. Chronic administration of this nanobody in 5xFAD mice accelerated amyloid plaque deposition and worsened cognitive deficits. These findings establish mGluR2 as a target in AD and demonstrate that its selective modulation by nanobodies influences Aβ pathology. This also highlights the potential of nanobodies as next-generation therapeutic agents for modulating neuroreceptors activity in AD.},
}

@article {pmid41980211,
year = {2026},
author = {Izquierdo, JM},
title = {InflammAging and Human Diversity: Expanding Horizons in Age-Related Chronic Disease.},
journal = {Aging and disease},
volume = {},
number = {},
pages = {},
doi = {10.14336/AD.2026.0077},
pmid = {41980211},
issn = {2152-5250},
abstract = {InflammAging (IA) is a sterile, low-grade systemic inflammation characterizing human aging. This chronic inflammatory state, combining "inflammation" and "aging", drives the aging trajectory and associated pathology even in the absence of acute clinical signs. IA is a key etiological factor for numerous age-associated diseases, including neurodegeneration (e.g., Alzheimer's disease), cardiovascular disorders, diabetes, sarcopenia, cancer, frailty, and multimorbidity, by exacerbating tissue/organ damage and impairing endogenous repair. Historically viewed as a universal hallmark of aging, this concept is now being refined. Current research highlights how human diversity-encompassing genetic, ethnic, gender, sex, environmental, socioeconomic, and lifestyle variations-could modulate the expression and severity of IA. This interplay, as emerging hypotheses, represents a new horizon in gerontology and chronic diseases, necessitating a potential paradigm shift from a one-size-fits-all model to personalized, population-specific approaches. This evolving nuanced understanding might be crucial for the successful implementation of precision medicine and for advancing global health strategies targeting age-related chronic diseases.},
}

@article {pmid41980212,
year = {2026},
author = {Rimal, S and Lee, JH and He, Y and Lu, B},
title = {Extension of Lifespan and Amelioration of Alzheimer's Disease Phenotypes by Genetic Manipulation of Mitochondrial NAD[+]/NADH Ratio.},
journal = {Aging and disease},
volume = {},
number = {},
pages = {},
doi = {10.14336/AD.2026.0011},
pmid = {41980212},
issn = {2152-5250},
abstract = {Aging remains the most significant risk factor for common neurodegenerative diseases including Alzheimer's disease (AD). According to the geroscience hypothesis, aging is malleable and that by targeting basic aging physiology, we can alleviate many of the age-related chronic diseases. The common mechanisms driving aging and age-related diseases remain poorly defined. Mitochondrial dysfunction is recognized as a fundamental hallmark of aging, and recent studies implicate mitochondrial reverse electron transport (RET) as a driver of aging. The key outcomes of RET, increased ROS and decreased NAD[+]/NADH ratio, have both been associated with aging and age-related disease, but the causal relationship remains uncertain. Here we applied causal metabolism to test the role of mitochondrial NAD[+]/NADH in aging and AD, using Drosophila as a model system. By using a mitochondrial targeted version of Lactobacillus brevis NADH oxidase (LbNox) to boost mitochondrial NAD[+]/NADH ratio independent of the energy state of the cell, we found that increasing mitochondrial NAD[+]/NADH ratio in neuronal or muscle tissues is sufficient to extend lifespan. Moreover, boosting mitochondrial NAD[+]/NADH ratio is beneficial in two independent models of AD, rescuing the proteostasis failure, locomotor and cognitive deficits, and lifespan shortening in these models. Our results identify altered mitochondrial NAD[+]/NADH ratio as a major contributor to the biological effects of RET on aging and age-related diseases and a potential therapeutic target.},
}

@article {pmid41980215,
year = {2026},
author = {Zhang, L and Dove, A and Du, J and Yang, D and Su, Q and Huang, X and Wang, J and Yue, J},
title = {The Lung-Brain Axis in Cognitive Impairment and Dementia: Mechanisms and Therapeutic Prospects.},
journal = {Aging and disease},
volume = {},
number = {},
pages = {},
doi = {10.14336/AD.2026.0095},
pmid = {41980215},
issn = {2152-5250},
abstract = {The lung-brain axis has been recognized as a critical interface linking lung health to cognitive disorders, including cognitive impairment, Alzheimer's disease, and dementia. Epidemiological and clinical evidence shows a close association between compromised lung health-including chronic obstructive pulmonary disease (COPD), asthma, obstructive sleep apnea (OSA), and pulmonary infections-and cognitive impairment and dementia. Potential mechanisms include established factors (systemic inflammation and immune crosstalk, hypoxic injury, and air-pollutant-induced neurotoxicity) and exploratory mechanisms (lung microbiome dysregulation). Notably, lung-centric strategies targeting the lung-brain axis involve repurposing pulmonary medications, intervening in shared mechanisms, and employing non-pharmacological strategies. Furthermore, realizing this promise will require future randomized controlled trials (RCTs) to develop comprehensive management strategies and alleviate the global burden of cognitive impairment and dementia.},
}

@article {pmid41980216,
year = {2026},
author = {Ma, L and Gong, Z and Gao, R and Zhu, L and Wu, L and Zhang, M and Ba, L},
title = {Clock and the Cleaner: Circadian Rhythms and Autophagy Coupling in Alzheimer's Disease.},
journal = {Aging and disease},
volume = {},
number = {},
pages = {},
doi = {10.14336/AD.2025.1496},
pmid = {41980216},
issn = {2152-5250},
abstract = {Alzheimer's disease (AD) continues to progress despite decades of research on protein aggregation, highlighting the need to understand upstream homeostatic failures. Among the earliest alterations in AD are disruptions of circadian rhythms and autophagy, which are mechanistically intertwined. Although circadian dysfunction and autophagic failure have been studied separately, the stage-dependent, region-specific, and cell-type-specific interplay between these systems remains poorly integrated, limiting the development of targeted interventions. In a healthy brain, the circadian clock and autophagy mutually interact, maintaining proteostasis, neuronal function, and rhythmic metabolic and immune processes. In early-stage AD, circadian rhythms show mild disruption and autophagy initiation remains active, but downstream autophagosome-lysosome fusion and lysosomal degradation are impaired, leading to the accumulation of AD pathological proteins. Dysregulation is cell-type-specific: neuronal clocks remain relatively intact, whereas astrocytic and microglial clocks exhibit altered metabolic and immune rhythms, contributing to early pathogenic events. In late-stage AD, severe circadian disruption likely uncouples circadian control from autophagy, and these dysfunctions mutually exacerbate each other, driving neuroinflammation, neuronal dysfunction, and further accumulation of pathological proteins. This review synthesizes current evidence on the circadian-autophagy axis, highlighting mechanistic insights and therapeutic opportunities, and emphasizes the importance of integrating stage-, region-, and cell-type-specific dynamics for the development of precise interventions in AD.},
}

@article {pmid41980219,
year = {2026},
author = {Galizzi, G},
title = {MAMs as a promising therapeutic strategy for age-related neurodegenerative diseases.},
journal = {Aging and disease},
volume = {},
number = {},
pages = {},
doi = {10.14336/AD.2025.1342},
pmid = {41980219},
issn = {2152-5250},
abstract = {Aging is a natural process leading to the slow and progressive deterioration of numerous physiological functions. It is the main risk factor for several neurodegenerative diseases. Mitochondria-associated membranes (MAMs) or mitochondria-ER contacts (MERCs) are essential and dynamic sites of contact between mitochondria and the endoplasmic reticulum (ER) and are involved in numerous cellular processes, such as calcium (Ca[2+]) homeostasis, reactive oxygen species (ROS) production, autophagy, inflammation, mitochondrial dynamics, apoptosis, lipid biosynthesis, and trafficking. As a result, they play a significant role in maintaining cellular functionality regulating metabolism and ensuring proper stress responses. Recently, MAMs have been widely investigated to understand their critical role in cell physiology as well as in different pathological conditions. Increasing evidence indicates that alterations in ER-mitochondria communication contribute to aging and the development of age-related diseases. However, the cellular mechanisms underlying this link remain unclear. Understanding how these interactions change with age could provide further insights into the aging process and the mechanisms underlying age-related diseases, suggesting potential new therapeutic strategies. This review summarizes the current knowledge on MAM biology, focusing on their role in the pathogenesis of age-related brain disorders. Their therapeutic potential in limiting the progression of some neurodegenerative disorders such as Alzheimer's disease, Parkinson's disease and amyotrophic lateral sclerosis, and slowing the physiological aging process are also explored.},
}

@article {pmid41980229,
year = {2026},
author = {Sewell, KR and Solis-Urra, P and Huang, H and Karikari, TK and Grove, G and Kramer, AF and McAuley, E and Burns, JM and Hillman, CH and Vidoni, ED and Morris, JK and Marsland, AL and Kang, C and Sutton, BP and Wan, L and Kamboh, MI and Gianaros, PJ and Drake, JA and Stern, Y and Oberlin, LE and Erickson, KI},
title = {Cognitive and Brain Reserve as Modifiers of Early Alzheimer Disease-Related Cognitive Vulnerability.},
journal = {Neurology},
volume = {106},
number = {9},
pages = {e214833},
doi = {10.1212/WNL.0000000000214833},
pmid = {41980229},
issn = {1526-632X},
mesh = {Humans ; *Alzheimer Disease/psychology/diagnostic imaging/pathology ; *Cognitive Reserve/physiology ; Female ; Male ; Aged ; *Brain/diagnostic imaging/pathology ; Cross-Sectional Studies ; tau Proteins/blood ; Magnetic Resonance Imaging ; Middle Aged ; Amyloid beta-Peptides/metabolism ; Aged, 80 and over ; *Cognition/physiology ; Positron-Emission Tomography ; Neuropsychological Tests ; Educational Status ; Social Class ; },
abstract = {BACKGROUND AND OBJECTIVES: Maintaining cognitive function despite the presence of Alzheimer disease (AD) pathology is the foundation of cognitive reserve. Although the theory of cognitive reserve is strongly supported by empirical research, the field lacks standardized, validated methods for quantifying cognitive and brain reserve. We tested whether associations between AD pathology and cognitive function were modified by proxy measures of cognitive reserve (years of education, socioeconomic status; SES) and brain reserve (brain-predicted age difference, and a volumetric AD signature). We hypothesized that greater structural brain integrity, higher education, and higher SES would attenuate the association between greater AD pathology and poorer cognitive performance.

METHODS: This cross-sectional study analyzed baseline data from a multisite randomized clinical trial, which was conducted at 3 US universities and enrolled cognitively unimpaired, physically inactive, community-dwelling adults. AD pathology was measured via plasma assays for phosphorylated tau (p-tau)-217 in the whole cohort, and PET for β-amyloid (Aβ) in a subset of participants as a secondary analysis. The primary outcome of cognitive function was evaluated by a comprehensive cognitive assessment. SES was measured via the MacArthur Socioeconomic Status Index, and magnetic resonance imaging was used to calculate brain-predicted age difference (brain-PAD) and a volumetric AD signature. Data were analyzed using linear regression models with interaction terms for moderation analyses.

RESULTS: A total of 621 participants (aged 69.9 ± 3.8, 71% female) had available data for the main analyses and 355 had PET Centiloid data available. Brain-PAD moderated the association between AD pathology (measured by p-tau217) and multiple cognitive domains, including episodic memory (β = -0.09 [-0.16 to -0.02]), processing speed (β = -0.08 [-0.15 to -0.01]), working memory (β = -0.10 [-0.18 to -0.03]), and executive function/attentional control (β = -0.08 [-0.15 to -0.01]). Specifically, the negative association of greater AD pathology with poorer cognition was weakest in individuals with younger appearing brains. A latent SES score also moderated the relationship between p-tau217 and episodic memory (β = 0.08 [0.01-0.16]), but this did not survive correction for multiple comparisons. Neither years of education nor the volumetric AD signature moderated pathology-cognition associations.

DISCUSSION: These results support the hypothesis that higher cognitive and brain reserve may help buffer the cognitive consequences of AD pathology. Strategies to increase both cognitive and brain reserve could help to boost resilience against emerging AD pathology; however, longitudinal studies are needed to confirm these conclusions.},
}

Humans
*Alzheimer Disease/psychology/diagnostic imaging/pathology
*Cognitive Reserve/physiology
Female
Male
Aged
*Brain/diagnostic imaging/pathology
Cross-Sectional Studies
tau Proteins/blood
Magnetic Resonance Imaging
Middle Aged
Amyloid beta-Peptides/metabolism
Aged, 80 and over
*Cognition/physiology
Positron-Emission Tomography
Neuropsychological Tests
Educational Status
Social Class

@article {pmid41980231,
year = {2026},
author = {Carrigan, M and Groot, C},
title = {Can a "Youthful" Brain Moderate Vulnerability to Alzheimer Disease?.},
journal = {Neurology},
volume = {106},
number = {9},
pages = {e214927},
doi = {10.1212/WNL.0000000000214927},
pmid = {41980231},
issn = {1526-632X},
}

@article {pmid41980232,
year = {2026},
author = {Bender, AC and Berezuk, C and Pellerin, KR and You, JC and Sarkis, RA and Lam, AD},
title = {Association of Sleep Spindle Activity With Cognitive Decline in Early Clinical Stages of Alzheimer Disease.},
journal = {Neurology},
volume = {106},
number = {9},
pages = {e214839},
doi = {10.1212/WNL.0000000000214839},
pmid = {41980232},
issn = {1526-632X},
}

@article {pmid41980296,
year = {2026},
author = {Song, X and Zhang, S and Du, C and Chai, L and Zhang, J},
title = {Connection density affects the behavior of functional brain network metrics.},
journal = {Computer methods and programs in biomedicine},
volume = {281},
number = {},
pages = {109366},
doi = {10.1016/j.cmpb.2026.109366},
pmid = {41980296},
issn = {1872-7565},
abstract = {BACKGROUND AND OBJECTIVE: Many neuropsychiatric disorders are associated with alterations in functional brain network (FBN) connectivity. Functional network metrics reveal alterations in FBNs by quantifying changes in network segregation and integration. In general, calculating functional network metrics requires a reasonable thresholding or binarization of the network, which is a challenging task. We observe that the same functional network metric yields conflicting conclusions across different studies: some report higher values in patient groups compared to healthy groups, while others report lower values in patient groups. This paper postulates the hypothesis that arbitrary choices of connection density are responsible for the inconsistency of experimental results.

METHODS: We investigate the behavior of 16 functional network metrics using three independent datasets that include patients with Alzheimer's disease (AD), mild cognitive impairment (MCI), and schizophrenia (SZ). Our analysis covers connection densities from 1% to 99% (in 1% intervals) and examines both binary and weighted networks in time and wavelet domains.

RESULTS: Our results reveal a "reversal phenomenon" in many functional network metrics, where the difference between patient and healthy groups reverses as connection density increases. This provides a plausible explanation for the inconsistent conclusions reported in the literature. We further find that the metrics showing significant differences vary across analytical modes (domain and network type). Moreover, the significant metrics differ across diseases, reflecting disease-related heterogeneity.

CONCLUSION: To avoid the "reversal phenomenon" and maximize the inter-group differences, we establish optimal connection density ranges for FBN analyses across various neuropsychiatric disorders, thereby improving the consistency and comparability of research results. In addition, we identify a set of metrics that demonstrate robustness across multiple datasets, providing a reliable reference for subsequent analyses. Our work sheds new light into the widespread use of functional network metrics and emphasizes that standardized connection density selection is crucial for achieving consistent results.},
}

@article {pmid41980314,
year = {2026},
author = {Liao, Y and Shen, C and Sun, L and Ding, P and Luo, L and Luo, J},
title = {MRDGNN: A multi-relational reasoning framework for predicting drug indications via relational digraphs.},
journal = {Computational biology and chemistry},
volume = {123},
number = {},
pages = {109065},
doi = {10.1016/j.compbiolchem.2026.109065},
pmid = {41980314},
issn = {1476-928X},
abstract = {Predicting drug indications is a fundamental task in biomedical research and drug repurposing. In addition to known therapeutic associations, clinically relevant but opposite signals, such as contraindications, may provide complementary evidence for identifying novel indications. In this work, we propose MRDGNN (Multi-Relational Digraph-based Graph Neural Network), a framework for drug-disease association prediction that performs multi-hop reasoning over recursively constructed relational digraphs (r-digraphs). MRDGNN incorporates a query-conditioned relation-aware attention mechanism to distinguish clinically opposite drug-disease relations and employs layer-wise attention to adaptively integrate evidence from different reasoning depths. To provide biologically informed initialization, we further adopt a pretraining-fine-tuning strategy on PrimeKG, where drug-disease associations are excluded during pretraining to avoid direct information leakage while preserving rich auxiliary biomedical knowledge. Experiments on PrimeKG show that MRDGNN consistently outperforms competitive baselines on indication prediction across both discrimination and ranking metrics. Additional evaluations under held-out-drug cold-start and sparse-relation settings further show that the model remains reasonably effective under less favorable conditions, although its performance is still positively associated with the availability of relational evidence. A case study on Alzheimer's disease further demonstrates the utility of MRDGNN by identifying plausible candidate drugs and providing interpretable relational evidence for its predictions.},
}

@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 {pmid41980468,
year = {2026},
author = {Li, Z and Luo, C and Wen, P and Zou, T and Jin, Z and Jiang, S},
title = {Systematic Review: Porphyromonas gingivalis Outer Membrane Vesicles From Pathogenesis to Therapeutic Implications.},
journal = {International dental journal},
volume = {76},
number = {3},
pages = {109548},
doi = {10.1016/j.identj.2026.109548},
pmid = {41980468},
issn = {1875-595X},
abstract = {BACKGROUND: Outer membrane vesicles (OMVs) from Gram-negative bacteria are spherical lipid bilayer nanostructures with diameters of 20 to 250 nm. Porphyromonas gingivalis (P. gingivalis), a keystone periodontal pathogen, releases OMVs that mediate its virulence and systemic pathological effects.

METHODS: This systematic review followed PRISMA guidelines and included studies from PubMed, Scopus, and Web of Science up to 2025.

RESULTS: A total of 62 articles were incorporated into the analysis. Generally, OMVs of P. gingivalis play a role in mediating interbacterial communication and are involved in pathogen-host interactions. These processes contribute to periodontal tissue destruction and systemic dissemination via blood vessels, thereby being associated with multiple systemic diseases. Key findings are as follows: (1) Periodontal destruction: OMVs inhibit endothelial cells (ECs)-mediated osteogenesis via the cGAS-STING-TBK1 pathway and induce apoptosis in human periodontal ligament stem cells (hPDLSCs) through the msRNA45033-CBX5-p53 methylation axis. Moreover, OMVs induce ferroptosis in BMSCs via the Hippo-YAP pathway. (2) Oral squamous cell carcinoma (OSCC) progression: OMVs promote the development of OSCC by inducing NF-κB-regulated ferroptosis. Additionally, sRNA23392 within OMVs downregulates desmocollin-2, which impairs the invasion and migration of OSCC cells. (3) Systemic dissemination: OMVs can cross the blood-brain barrier (BBB) to transport bacterial components to distant organs, which is associated with Alzheimer's disease, cardiovascular disease, and diabetes mellitus. (4) Immune modulation: OMVs interact with macrophages and dendritic cells to trigger robust immune responses, inducing the secretion of pro-inflammatory cytokines.

CONCLUSIONS: P. gingivalis OMVs act as key mediators of virulence dissemination and significantly modulate host-microbe interactions along the oral-systemic axis. This systematic review consolidates recent advancements in the research on P. gingivalis OMVs, emphasizing their roles in immunoregulation, pathogenic mechanisms, and associations with both periodontal and systemic diseases. Gaps in existing literature include strain-specific heterogeneity of OMVs and the dose-response relationships within systemic disease contexts. Future studies should employ multi-omics approaches and standardized methodologies to elucidate their heterogeneity and dose-response relationships, facilitating targeted therapies.},
}

@article {pmid41980534,
year = {2026},
author = {Li, CX and Cheng, GR and Liu, XC and Chen, M and Dong, H and Meng, H and Peng, YY and Liu, N and Che, JW and Zhang, YY and Wang, ZM and Zhou, W and Luo, Y and Liu, L and Lu, JY and Liu, AQ and Liu, D and Hu, FF and Xie, XY and Cheng, YF and Wang, X and Xu, L and Tan, W and Zeng, Y},
title = {Serum homocysteine, hemoglobin, and Alzheimer's biomarkers involved in the relationship of folate and vitamin B12 with cognitive function: Findings from the Hubei Memory and Aging Cohort Study.},
journal = {Nutrition research (New York, N.Y.)},
volume = {149},
number = {},
pages = {178-188},
doi = {10.1016/j.nutres.2026.03.008},
pmid = {41980534},
issn = {1879-0739},
abstract = {Vitamin B12 and folate deficiency are significant risk factors for cognitive impairment (CI), although the underlying biological mechanisms remain incompletely characterized. We hypothesized that anemia, hyperhomocysteinemia, and plasma Alzheimer's disease biomarkers mediate the relationship between vitamin B12/folate status and CI. Data were analyzed from the Hubei Memory and Aging Cohort Study (2023-2024), which included 1614 community-dwelling older adults in Wuhan, China (mean age 68.52 ± 8.36 years; 58.43% female). Both cross-sectional (n = 1614) and 1-year longitudinal (n = 510) analyses were conducted. Cognitive status was determined through clinical adjudication. Mediation models assessed the roles of hemoglobin (Hb), homocysteine (Hcy), and plasma Alzheimer's disease biomarkers (Aβ40, Aβ42, p-Tau181, p-Tau217, GFAP, NFL). Lower concentrations of folate, vitamin B12, and Hb, and higher concentrations of Hcy, NFL, and GFAP were associated with increased CI risk. Elevated Hcy was correlated with higher concentrations of p-Tau181, GFAP, and NFL, while lower Hb was correlated with higher concentrations of p-Tau181, p-Tau217, GFAP, and NFL. Chain mediation analyses revealed that folate (indirect effect = -0.007, 95% confidence interval: -0.033 to -0.002) and vitamin B12 (indirect effect = -0.009, 95% confidence interval: -0.016 to -0.002) were associated with CI risk sequentially through Hcy and NFL. The folate-Hcy-CI pathway was further supported by longitudinal analysis. Findings suggest that folate and vitamin B12 deficiencies may relate to CI risk through distinct pathways that converge on NFL. Monitoring Hcy and NFL could help identify at-risk individuals, though further validation in intervention studies is warranted.},
}

@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 {pmid41980611,
year = {2026},
author = {Li, S and Xu, J and Yue, H and Yin, J and Yuan, Y and Ni, S and Wang, H and Zhang, Y and Liao, X and Tao, J and Yang, Y},
title = {Disruption of circadian rhythms is associated with cognitive impairment during gestation.},
journal = {Journal of neuroendocrinology},
volume = {38},
number = {4},
pages = {e70178},
doi = {10.1111/jne.70178},
pmid = {41980611},
issn = {1365-2826},
support = {2024ZD0523200//National Major Science and Technology Projects of China/ ; },
mesh = {Female ; Animals ; Pregnancy ; *Circadian Rhythm/physiology ; *Cognitive Dysfunction/physiopathology/metabolism ; Hippocampus/metabolism ; Mice ; Humans ; Aspartic Acid Endopeptidases/metabolism ; *Pregnancy Complications/physiopathology/metabolism ; Mice, Inbred C57BL ; Amyloid Precursor Protein Secretases/metabolism ; Adult ; Postpartum Period ; *Chronobiology Disorders/complications/physiopathology ; },
abstract = {Disruption of circadian rhythms is increasingly recognized as a contributor to cognitive dysfunction, but its role in gestation-associated cognitive changes remains unexplored. Here we combine human cognitive screening with a comprehensive longitudinal mouse model to investigate whether gestational cognitive impairment and postpartum recovery are coupled with disruption and restoration of hippocampal circadian rhythms. Cognitive function was assessed in pregnant and postpartum women using the Montreal Cognitive Assessment (MoCA) and Mini-Mental State Examination (MMSE). In mice, four reproductive stages were compared: control, gestation, 1 month postpartum, and 3 months postpartum. Serum gonadotropins and sex hormones levels were quantified using ELISA. Home-cage locomotor activity was recorded over 48 h under a 12 h:12 h light-dark cycle. Hippocampal-dependent memory was evaluated using the novel object recognition test and Barnes maze at Zeitgeber times ZT6 (day) and ZT18 (night). Hippocampal amyloid β (Aβ) deposition was visualized via immunofluorescence; protein expression of amyloid precursor protein (APP), β-site amyloid precursor protein cleaving enzyme-1 (BACE1), and phosphorylated tau was measured by Western blots. Hippocampal clock gene expression was quantified by RT-qPCR at six time points; circadian parameters (mesor, amplitude, acrophase) were derived by cosinor analysis and compared between groups. Human cognitive screening confirmed modest gestational decline with postpartum recovery. In mice, gestation disrupted daily locomotor activity rhythms and reduced nocturnal preference; both partially recovered by 1 month and fully by 3 months postpartum. Behaviourally, pregnancy impaired the normal day-night difference and performance in novel object exploration and Barnes maze, which recovered progressively. At the molecular level, gestation increased hippocampal APP and BACE1 expression, elevated Aβ42 deposition, and induced tau hyperphosphorylation at multiple sites-hallmarks of Alzheimer's disease-related pathology. These alterations partially reversed by 1 month postpartum and normalized by 3 months. Hippocampal clock genes maintained 24 h rhythmicity, but gestation induced gene-specific phase shifts, amplitude reductions, and mesor alterations. These parameters showed gradual, gene-dependent normalization postpartum. Gestational cognitive impairment and postpartum recovery are associated with reversible disruption and restoration of both hippocampal circadian rhythms and Alzheimer's disease-related molecular pathology. These findings are correlational in nature and provide a foundation for future causal investigations.},
}

Female
Animals
Pregnancy
*Circadian Rhythm/physiology
*Cognitive Dysfunction/physiopathology/metabolism
Hippocampus/metabolism
Mice
Humans
Aspartic Acid Endopeptidases/metabolism
*Pregnancy Complications/physiopathology/metabolism
Mice, Inbred C57BL
Amyloid Precursor Protein Secretases/metabolism
Adult
Postpartum Period
*Chronobiology Disorders/complications/physiopathology

@article {pmid41980622,
year = {2026},
author = {Liu, KZ and Zhou, X and Dong, YF and Luo, XY and Tan, L and Tan, CC and Xu, W},
title = {The moderation and mediation roles of white matter insults in relationship of APOE ε4 genotype with Alzheimer's disease and related phenotypes: two longitudinal studies.},
journal = {Journal of advanced research},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.jare.2026.04.030},
pmid = {41980622},
issn = {2090-1224},
abstract = {INTRODUCTION: The Apolipoprotein E ε4 (APOE ε4) allele and white matter hyperintensities (WMH) have been implicated in the pathogenesis of Alzheimer's disease (AD).

OBJECTIVES: To investigate the dual roles of WMH in statistically moderating and mediating the relationship of APOE ε4 with AD and related phenotypes, as well as the potential biological correlates.

METHODS: Data were derived from 34,783 non-demented participants in the UK Biobank (UKB; mean age = 55 years; follow-up = 4.3 years) and 863 in the Alzheimer's disease Neuroimaging Initiative (ADNI; mean age = 71.9 years; follow-up = 3.8 years). Multivariable models evaluated associations of APOE ε4 status, WMH, and their interaction with cognition, neurodegeneration, core pathologies, and AD risk. Mediation analyses were performed to quantify the extent to which WMH statistically explained ε4-outcome associations. Cerebrospinal fluid proteomic and bioinformatic analyses were used to explore biological clues in a subsample of ADNI (n = 708).

RESULTS: APOE ε4 carriers exhibited larger WMH volumes (p < 0.001, UKB) and faster WMH change rates (p = 0.019, ADNI). In UKB, WMH statistically mediated a small proportion of associations between APOE ε4 and poorer numeric memory performance, smaller hippocampal volume, increased incident AD and all-cause dementia (ACD). In ADNI, WMH showed statistical mediation signals in the associations of APOE ε4 with faster rates of cognitive decline, amyloid-β (Aβ) deposition, and neurodegeneration. Notably, WMH interacted with APOE ε4 to exacerbate cognitive decline, hippocampal atrophy, and Aβ deposition. Proteomic analyses suggested that neuroinflammatory and axonal injury pathways may be associated with the observed mediating and moderating patterns.

CONCLUSION: WMH mediates and enhanced the associations of APOE ε4 with AD-related phenotypes. These findings warrant further studies to clarify the underlying mechanisms and clinical implications.},
}

@article {pmid41980636,
year = {2026},
author = {Yang, Z and Hao, J and Nash, H and Chen, W and Qiu, C and Karim, R and Chen, Z},
title = {Polychlorinated Biphenyl (PCB) Exposure and Cognitive Function in Adults: A Systematic Review of Epidemiologic Evidence and Risk of Bias Assessment.},
journal = {Neurotoxicology},
volume = {},
number = {},
pages = {103447},
doi = {10.1016/j.neuro.2026.103447},
pmid = {41980636},
issn = {1872-9711},
abstract = {BACKGROUND: Polychlorinated biphenyls (PCBs) are persistent organic pollutants known for their environmental longevity and neurotoxicity. Although developmental exposure has been extensively studied, the cognitive impacts of PCB exposure in adult and aging populations remain less understood.

OBJECTIVES: This systematic review evaluates the epidemiologic evidence linking PCB exposure to cognitive function, with an emphasis on neurocognitive decline and dementia risk in adults.

METHODS: Following PRISMA guidelines, we searched PubMed and Web of Science for human epidemiological studies published in English up to November 2024. Inclusion criteria focused on empirical studies investigating associations between PCB exposure and cognitive outcomes in elderly population. Data were synthesized narratively, and a domain-based risk of bias assessment was conducted using the Navigation Guide methodology.

RESULTS: Twenty-four studies were included in the final analysis, spanning diverse populations and exposure contexts (occupational, environmental and dietary). Six studies examined the association between PCB exposure and dementia or Alzheimer's disease, with overall mixed findings. Some studies reported associations in specific subgroups, particularly among individuals with higher exposure levels or among women, while others reported null relationships. For cognitive outcomes, memory, processing speed and executive functions were the frequently assessed domain; however, findings across studies were inconsistent and did not demonstrate a clear pattern of association. A smaller number of studies assessed cognitive decline, with similarly heterogeneous results. Risk of bias was generally low for exposure and outcome assessment but higher for confounding and other validity domains. Notably, inconsistent cognitive testing methods and limited longitudinal data constrained causal inference.

CONCLUSION: Current epidemiologic evidence is insufficient to support a consistent association between PCB exposure and dementia or cognitive performance in aging populations. Further well-designed longitudinal studies using standardized cognitive assessments are needed to clarify potential relationships.

PROSPERO REGISTRATION NUMBER: CRD420251003803.},
}

@article {pmid41980665,
year = {2026},
author = {Hoyt, KR and Kyhl, T and Halloy, NR and Obrietan, K},
title = {Cellular- and systems-level profiling of amyloid-beta effects on circadian timing.},
journal = {Neurobiology of disease},
volume = {},
number = {},
pages = {107389},
doi = {10.1016/j.nbd.2026.107389},
pmid = {41980665},
issn = {1095-953X},
abstract = {Disruption of the circadian timing system has been reported in the preclinical phase of Alzheimer's disease (AD) and is a well-characterized component of mid- and late-stage AD. Given the distributed nature of the body's clock, with a central pacemaker in the suprachiasmatic nucleus (SCN) and peripheral clocks throughout the brain, understanding how AD affects this system has been challenging. To investigate how AD may disrupt circadian physiology, we focused on the amyloid-beta (Aβ) peptide, a key contributor to familial early-onset AD. Using the 5xFAD mouse model and ex vivo single-cell profiling, we examined how Aβ influences clock timing in both SCN neurons and hippocampal neuronal populations. Circadian profiling of 5xFAD mice (4- and 8-months-old) showed only modest changes in key clock timing properties, including a shortening of the SCN rhythm. Interestingly, the mice showed enhanced rates of re-entrainment to changes in the light cycle, suggesting that elevated Aβ levels increase the clock's sensitivity to light. Further, using both in vitro SCN slice explant and dispersed SCN culture models, the exogenous administration of oligomerized Aβ had no significant effect on inherent clock timing capacity. In contrast, the timing properties of cultured hippocampal neurons showed a dose-dependent sensitivity to Aβ. This included an elevated mesor and an increased rhythm amplitude. These findings reveal a divergence in Aβ sensitivity between the central SCN clock and peripheral oscillators. This raises the possibility that circadian disruptions in AD may stem from both the destabilization and decoupling of peripheral oscillators from the SCN's central timing properties.},
}

@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 {pmid41980907,
year = {2026},
author = {Holper, S and Barnham, KJ and Churilov, L and Yates, P and Brodtmann, A and Johns, S and Li, QX and Bhalala, O and Chin, KS and Loveland, P and Yu, JJ and Masters, CL and Watson, R and Yassi, N},
title = {A phase 2, randomized, multicenter, double-blind, placebo-controlled trial of S-adenosyl methionine in participants with mild cognitive impairment or dementia due to Alzheimer's disease.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {22},
number = {4},
pages = {e71381},
doi = {10.1002/alz.71381},
pmid = {41980907},
issn = {1552-5279},
support = {//National Health and Medical Research Council/ ; /ALZ/Alzheimer's Association/United States ; },
mesh = {Humans ; Double-Blind Method ; *S-Adenosylmethionine/therapeutic use ; Male ; *Alzheimer Disease/complications/drug therapy ; Female ; Aged ; *Cognitive Dysfunction/drug therapy/etiology/blood ; tau Proteins/blood ; Treatment Outcome ; Middle Aged ; Aged, 80 and over ; },
abstract = {INTRODUCTION: S-adenosyl methionine (SAMe) is a pivotal metabolite in multiple neuronal pathways, including tau dephosphorylation. Reduced SAMe availability has been reported in the Alzheimer's disease (AD) brain, prompting interest in supplementation as a potential therapeutic strategy.

METHODS: This multicenter, randomized, double-blind, placebo-controlled phase 2 study recruited people (n = 63) with a clinical AD diagnosis. Participants received 180 days of SAMe (400 mg daily) or placebo. Primary outcome was change in plasma phosphorylated tau (p-tau)217 concentration. Secondary endpoints included safety, tolerability, and cognitive outcomes.

RESULTS: Mean percentage change in plasma p-tau217 in the SAMe group was an increase of 53.22 (standard deviation [SD] 159.19) compared to 25.34 (SD 94.83) in the placebo group (standardized mean difference 37.58, 95% confidence interval -32.61, 107.76; p = 0.288). No significant differences were observed in safety or other secondary endpoints.

DISCUSSION: SAMe did not demonstrate disease-modifying efficacy at the dose and duration studied; however it was safe and well tolerated.

TRIAL REGISTRATION: ACTRN12620000506998. Registered on the Australian New Zealand Clinical Trials Registry (http://www.anzctr.org.au).},
}

Humans
Double-Blind Method
*S-Adenosylmethionine/therapeutic use
Male
*Alzheimer Disease/complications/drug therapy
Female
Aged
*Cognitive Dysfunction/drug therapy/etiology/blood
tau Proteins/blood
Treatment Outcome
Middle Aged
Aged, 80 and over

@article {pmid41980911,
year = {2026},
author = {Wang, M and Buthut, M and Meinhardt, J and Otto, C and Gallaccio, G and Fernández-Zapata, C and Teves, M and Samol, C and Dettmer, K and Heckscher, S and Kamboj, S and Bahar, Y and Conrad, C and Böttcher, C and Kunkel, D and Ruprecht, K and Paul, F and Oefner, PJ and Radbruch, H and Gronwald, W and Prüß, H and Böttcher, C},
title = {Immune-proteo-metabolomic changes link to Aβ and tau pathology in Alzheimer disease.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {22},
number = {4},
pages = {e71359},
doi = {10.1002/alz.71359},
pmid = {41980911},
issn = {1552-5279},
support = {//the Federal Ministry of Education and Research/ ; ID 259373024 - CRC/TRR 167 (B05)//Deutsche Forschungsgemeinschaft/ ; },
mesh = {Humans ; *Alzheimer Disease/metabolism/cerebrospinal fluid/pathology/immunology ; *tau Proteins/cerebrospinal fluid/metabolism ; Female ; Male ; *Amyloid beta-Peptides/cerebrospinal fluid/metabolism ; Aged ; Tryptophan/metabolism ; Metabolomics ; Proteomics ; Brain/metabolism ; Biomarkers/cerebrospinal fluid ; },
abstract = {INTRODUCTION: Tryptophan metabolism is increasingly implicated in Alzheimer's disease (AD), particularly through aryl hydrocarbon receptor (AhR) ligands that influence neuroinflammation. However, their relationships with core AD pathology-amyloid-β (A) and tau (T) deposition-and associated immune-proteomic alterations remain unclear.

METHODS: We performed integrative multi-omics/high-dimensional profiling of cerebrospinal fluid (CSF) and peripheral blood from A-T- (n = 19) and A+T+ (n = 35) individuals, classified based on CSF Aβ and pTau181 levels. Analyses included targeted metabolomics, mass cytometry, and NULISA-based proteomics, and inter-compartmental correlation analysis. Brain-derived tryptophan catabolism was investigated using single-nucleus RNA sequencing (snRNA-seq).

RESULTS: Thirteen differentially expressed CSF proteins in A+T+ individuals correlated positively with tryptophan metabolites and pyroglutamate, and negatively with regulatory T cells, isobutyrate, and dendritic cells. Similar patterns were observed in blood. snRNA-seq suggested partial brain origin of metabolites.

DISCUSSION: Our findings highlight conserved immune-metabolic-proteomic signatures in AD and implicate tryptophan metabolism as a cross-compartmental factor relevant for biomarker and therapeutic development.

HIGHLIGHTS: Thirteen cerebrospinal fluid (CSF) proteins involved in metabolism and neuronal function link to Alzheimer's disease (AD) pathology Intergrative analysis reveals shared and compartment-specific AD signatures Tryptophan-kynurenine metabolites correlate with AD pathology Indole metabolites show CSF-plasma coupling in A+T+ individuals Immune signatures diverge across CSF (regulatory T cells [Tregs], dendritic cells [DCs]) and blood (B and myeloid cells).},
}

Humans
*Alzheimer Disease/metabolism/cerebrospinal fluid/pathology/immunology
*tau Proteins/cerebrospinal fluid/metabolism
Female
Male
*Amyloid beta-Peptides/cerebrospinal fluid/metabolism
Aged
Tryptophan/metabolism
Metabolomics
Proteomics
Brain/metabolism
Biomarkers/cerebrospinal fluid

@article {pmid41980948,
year = {2026},
author = {Yang, HS and Anzai, JAU and Yau, WW and Healy, BC and Román Viera, AM and Maa, C and Kirn, D and Properzi, MJ and Bellier, JP and Schultz, AP and Farrell, ME and Jacobs, HIL and Buckley, RF and Papp, KV and Marshall, GA and Amariglio, RE and Rentz, DM and Liu, L and Selkoe, DJ and Verghese, PB and Braunstein, JB and Johnson, KA and Sperling, RA and Chhatwal, JP},
title = {Plasma phosphorylated tau 217 and longitudinal trajectories of Aβ, tau, and cognition in cognitively unimpaired older adults.},
journal = {Nature communications},
volume = {17},
number = {1},
pages = {},
pmid = {41980948},
issn = {2041-1723},
support = {K23 AG062750/AG/NIA NIH HHS/United States ; K23 AG084868/AG/NIA NIH HHS/United States ; P01 AG036694/AG/NIA NIH HHS/United States ; P01 AG036694/AG/NIA NIH HHS/United States ; R01 AG071865/AG/NIA NIH HHS/United States ; },
mesh = {Humans ; *tau Proteins/blood ; *Amyloid beta-Peptides/blood/metabolism ; Aged ; Male ; Female ; Positron-Emission Tomography ; *Cognition/physiology ; Phosphorylation ; *Alzheimer Disease/blood/diagnostic imaging ; Biomarkers/blood ; Aged, 80 and over ; Longitudinal Studies ; Cognitive Dysfunction/blood/diagnostic imaging ; Prospective Studies ; Brain/diagnostic imaging/metabolism ; },
abstract = {Plasma phosphorylated tau 217 (pTau217) is an excellent biomarker of Alzheimer's disease (AD) pathology, but it remains uncertain whether pTau217 can predict amyloid-β (Aβ) and tau accumulation prior to Aβ positron emission tomography (PET) positivity. Here, we leverage data from a well-characterized prospective cohort of cognitively unimpaired older adults to examine mass spectrometry-based plasma %pTau217 (pTau217/non-phosphorylated-Tau217×100) relative to changes in Aβ/tau PET and cognition. A higher baseline %pTau217 was associated with faster Aβ and tau accumulation on PET, which then led to greater cognitive decline. Among individuals Aβ PET-negative at baseline, higher %pTau217 levels presaged increases in Aβ and tau PET signals. Together, our results suggest that very low %pTau217 in cognitively unimpaired older adults is associated with a minimal risk of AD pathology accumulation and cognitive decline.},
}

Humans
*tau Proteins/blood
*Amyloid beta-Peptides/blood/metabolism
Aged
Male
Female
Positron-Emission Tomography
*Cognition/physiology
Phosphorylation
*Alzheimer Disease/blood/diagnostic imaging
Biomarkers/blood
Aged, 80 and over
Longitudinal Studies
Cognitive Dysfunction/blood/diagnostic imaging
Prospective Studies
Brain/diagnostic imaging/metabolism

@article {pmid41980951,
year = {2026},
author = {Poulot-Becq-Giraudon, Y and Guillemaud, O and Degl'Innocenti, E and Letenneur, V and Bascarane, K and Barbay, T and Møller Clausen, M and Derbois, C and Guillermier, M and Juricek, L and Riquelme-Perez, M and Lakomy, T and Benhaim, L and Dufour, N and Gipchtein, P and Petit, F and Siron, L and Aurégan, G and Dechamps, N and Gaillard, MC and Bemelmans, AP and Bos, R and Carrillo-de Sauvage, MA and Milior, G and Rouach, N and Brohard, S and Muret, K and Bonnet, E and Escartin, C},
title = {Signaling cascades shape functional subpopulations of cortical astrocytes in male wild-type mice and APP/PS1dE9 Alzheimer's disease model.},
journal = {Nature communications},
volume = {},
number = {},
pages = {},
doi = {10.1038/s41467-026-71826-w},
pmid = {41980951},
issn = {2041-1723},
support = {6173//Association France Alzheimer (French Alzheimer's Association)/ ; 6173//Association France Alzheimer (French Alzheimer's Association)/ ; ANR-16-TERC-0016-01 and ANR21-CE17-0047-02//Agence Nationale de la Recherche (French National Research Agency)/ ; ANR-10-IDEX-0001//Agence Nationale de la Recherche (French National Research Agency)/ ; EQU202303016285//Fondation pour la Recherche Médicale (Foundation for Medical Research in France)/ ; },
abstract = {Astrocytes are key partners for neurons and can impact diseases such as Alzheimer's disease (AD), as they exhibit multiple reactive changes. Recent single cell/nucleus genomics analyses evidence astrocyte subpopulations coexisting in normal and AD brains. However, the signaling cascades controlling them, their functional characteristics and roles in AD are still unknown. Here, thanks to astrocyte-specific reporters for STAT3 and NF-kB signaling pathways, two regulators of astrocyte reactivity, we report the presence of three astrocyte subpopulations defined by their signaling activity, in the prefrontal cortex of male APP/PS1dE9 mice. These subpopulations are not triggered by amyloid deposition and are also observed in wild-type mice. They show distinct morphologies, molecular signatures and functional profiles. While NF-kB+ astrocytes have larger territories and higher lysosomal activity, STAT3+ astrocytes display enhanced hemichannel activity. Specific inhibition of these subpopulations reduces amyloid plaque size and impacts anxiety, social preference and social memory in AD but not wild-type mice. Our results show how innate signaling shapes astrocyte subpopulations in the mouse cortex, with distinct functions in health and disease.},
}

@article {pmid41981142,
year = {2026},
author = {Bansal, A and Kaushik, S and Kubíček, J and Garg, S and Slovák, J},
title = {Finsler fractional anisotropy (FFA): a directionally sensitive descriptor for multi-fiber white matter characterization in HARDI.},
journal = {Scientific reports},
volume = {},
number = {},
pages = {},
doi = {10.1038/s41598-026-48225-8},
pmid = {41981142},
issn = {2045-2322},
support = {CZ.10.03.01/00/22_003/0000003//European Union under the LERCO Project/ ; 10108612//HORIZON-MSCA-SE Project, CaLIGOLA/ ; 101119552//HORIZON-MSCA-DN Project, CaLiForNIA/ ; },
}

@article {pmid41981180,
year = {2026},
author = {Wang, K and Bu, G},
title = {Alzheimer disease protection from the periphery.},
journal = {Nature reviews. Neurology},
volume = {},
number = {},
pages = {},
pmid = {41981180},
issn = {1759-4766},
}

@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 {pmid41981185,
year = {2026},
author = {Bjørnholm, KD and Butler, PM and Francis, AE and Varma, C and Spooner, ET and Grenon, MB and Xu, YR and Tao, Y and Meunier, AL and Anderson, AK and Hennessey, EL and Miller, MB and Selkoe, DJ and Lemere, CA and Stern, AM},
title = {Anti-amyloid antibody equilibrium binding to Aβ aggregates from human Alzheimer's disease brain.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {22},
number = {4},
pages = {e71350},
doi = {10.1002/alz.71350},
pmid = {41981185},
issn = {1552-5279},
support = {K08NS128329/NH/NIH HHS/United States ; R01NS136122/NH/NIH HHS/United States ; R01AG084531/NH/NIH HHS/United States ; R01AG082346/NH/NIH HHS/United States ; },
mesh = {Humans ; *Alzheimer Disease/metabolism/genetics/pathology ; *Amyloid beta-Peptides/metabolism/immunology ; Plaque, Amyloid/metabolism ; *Brain/metabolism/pathology ; *Antibodies, Monoclonal, Humanized/metabolism ; Female ; Male ; Aged ; Apolipoprotein E4/genetics ; Aged, 80 and over ; Protein Binding ; Cerebral Amyloid Angiopathy/metabolism ; },
abstract = {INTRODUCTION: Lecanemab binds "protofibrils," which are poorly characterized in human brain. It is unknown why lecanemab caused fewer amyloid-related imaging abnormalities (ARIAs) than other antibodies in trials. The apolipoprotein E (APOE) ε4 allele increases ARIA risk through unknown mechanisms.

METHODS: Equilibrium binding constants (KD) and total amyloid beta (Aβ) binding (Bmax) of aducanumab, lecanemab, and donanemab equivalents to soluble and insoluble amyloid plaque-enriched and cerebral amyloid angiopathy (CAA)-enriched Aβ were compared across 17 Alzheimer's disease (AD) cases by mixed models. Titrated immunofluorescence (IF) staining compared antibody binding.

RESULTS: Lecanemab and aducanumab had indistinguishable preference for "protofibrils." Antibody preference for plaque-enriched versus CAA-enriched Aβ did not differ in soluble extracts or by IF staining but differed slightly in insoluble extracts. The APOE ε4 allele was associated with more soluble antibody-accessible Aβ.

DISCUSSION: Lecanemab's binding target is similar to other antibodies'. Differences in antibody preference for plaque versus CAA Aβ may not explain differences in ARIA with edema rates.},
}

Humans
*Alzheimer Disease/metabolism/genetics/pathology
*Amyloid beta-Peptides/metabolism/immunology
Plaque, Amyloid/metabolism
*Brain/metabolism/pathology
*Antibodies, Monoclonal, Humanized/metabolism
Female
Male
Aged
Apolipoprotein E4/genetics
Aged, 80 and over
Protein Binding
Cerebral Amyloid Angiopathy/metabolism

@article {pmid41981211,
year = {2026},
author = {Zhu, TT and Liu, PM and Hashimoto, K and Yang, JJ},
title = {Clinical innovations and future directions of nanoparticles in the treatment of psychiatric and neurological disorders.},
journal = {Molecular psychiatry},
volume = {},
number = {},
pages = {},
pmid = {41981211},
issn = {1476-5578},
support = {82171189//National Natural Science Foundation of China (National Science Foundation of China)/ ; 81971020//National Natural Science Foundation of China (National Science Foundation of China)/ ; },
abstract = {Nanoparticles (NPs) provide a versatile toolkit for psychiatry and neurology by leveraging tunable size, surface chemistry, and payload control to overcome long-standing barriers in central nervous system (CNS) therapy. Lipid, polymeric, inorganic, and hybrid NPs can be engineered to traverse the blood-brain barrier (BBB) via receptor/transporter pathways, target specific cell types, and deliver sustained or stimuli-responsive release. Beyond drug delivery, NPs improve imaging, enable gene/RNA therapeutics, and support anti-inflammatory and neuroprotective strategies, advancing precision medicine. Preclinical studies in depression, schizophrenia, Alzheimer's disease, and Parkinson's disease show superior exposure, target engagement, and behavioral or cognitive benefits versus free drugs, including photothermal/photodynamic and nanobody-based approaches. Clinically, translation remains early: a handful of CNS-directed candidates (e.g., gold-based bioenergetic agents, intranasal lipid formulations, liposomal modulators) are in trials, while approvals largely lie outside CNS indications. Key hurdles include variable BBB integrity, immunogenicity and protein-corona effects, manufacturing and stability constraints, and limited effect-site exposure-response data in humans. This review outlines a translational playbook: model-informed development linking formulation to brain interstitial exposure; Quality-by-Design chemistry, manufacturing, and controls (CMC); stratified, adaptive trials with population PK/PD and harmonized biomarkers; and proactive safety monitoring with long-term registries. We also highlight NP strategies targeting the gut-brain axis-delivering probiotics, metabolites, or antimicrobials-as complementary routes to modulate neuroinflammation and circuit function. With rigorous clinical science, manufacturing quality, and safety governance embedded from the outset, nanotechnology is positioned to deliver safer, more effective, and potentially disease-modifying therapies for CNS disorders.},
}

@article {pmid41981256,
year = {2026},
author = {Shao, B and Zeng, Y and Ju, J},
title = {Dynamic collaboration between mitochondria and organelles: mechanisms, functions, and disease implications.},
journal = {Apoptosis : an international journal on programmed cell death},
volume = {31},
number = {4},
pages = {},
pmid = {41981256},
issn = {1573-675X},
support = {32572715//The National Natural Science Foundation of China/ ; },
mesh = {Humans ; *Mitochondria/metabolism ; Neurodegenerative Diseases/metabolism/pathology ; Neoplasms/metabolism/pathology/genetics ; Animals ; *Organelles/metabolism ; Alzheimer Disease/metabolism ; Endoplasmic Reticulum/metabolism ; Oxidative Stress ; },
abstract = {In recent years, numerous studies have revealed that dysregulation of mitochondria-organelle interactions is a common feature underlying various pathological processes and pathogen infections. For instance, in Alzheimer's disease (AD), dysfunction of mitochondrial-associated ER membranes (MAMs) leads to calcium overload and oxidative stress, while cancer cells enhance glycolysis by remodeling mitochondria-Golgi interactions. Targeting these key interacting nodes has shown significant therapeutic potential. Although technological advances have uncovered some underlying mechanisms, the spatiotemporal dynamics, tissue specificity, and causal role of organelle interactions in diseases remain unclear. In-depth understanding of these collaborative networks will provide new targets for the treatment of cancer, metabolic syndrome, and neurodegenerative diseases, and also create novel possibilities for elucidating pathogen-host interaction mechanisms and developing anti-infective therapies. Given the importance of dynamic mitochondria-organelle collaboration in disease treatment, this review first focuses on analyzing the molecular mechanisms underlying this crosstalk. Building on this, the dysregulation of mitochondria-organelle collaboration in diseases is discussed in depth, with a particular focus on cancer, cardiovascular diseases, metabolic syndrome, and neurodegenerative diseases. Finally, the potential therapeutic strategies targeting organelle interactions are summarized and analyzed. In conclusion, the information in this manuscript offers a new way to think about and treat several serious illnesses.},
}

Humans
*Mitochondria/metabolism
Neurodegenerative Diseases/metabolism/pathology
Neoplasms/metabolism/pathology/genetics
Animals
*Organelles/metabolism
Alzheimer Disease/metabolism
Endoplasmic Reticulum/metabolism
Oxidative Stress

@article {pmid41981266,
year = {2026},
author = {Cavaillès, C and Carnethon, MR and Knutson, KL and Thomas, SJ and Yaffe, K},
title = {Midlife sleep characteristics and Alzheimer's disease biomarkers 20 years later.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {22},
number = {4},
pages = {e71342},
doi = {10.1002/alz.71342},
pmid = {41981266},
issn = {1552-5279},
support = {//Coronary Artery Risk Development in Young Adults Study (CARDIA)/ ; //National Heart, Lung, and Blood Institute (NHLBI)/ ; 75N92023D00002/HL/NHLBI NIH HHS/United States ; 75N92023D00005/HL/NHLBI NIH HHS/United States ; 75N92023D00004/HL/NHLBI NIH HHS/United States ; 75N92023D00006/HL/NHLBI NIH HHS/United States ; 75N92023D00003/HL/NHLBI NIH HHS/United States ; R35AG071916/AG/NIA NIH HHS/United States ; R01AG063887/AG/NIA NIH HHS/United States ; },
mesh = {Humans ; *Alzheimer Disease/blood/diagnostic imaging ; Male ; Biomarkers/blood ; Female ; *Amyloid beta-Peptides/blood ; tau Proteins/blood ; Magnetic Resonance Imaging ; Middle Aged ; Neurofilament Proteins/blood ; Adult ; *Sleep/physiology ; Peptide Fragments/blood ; Brain/pathology/diagnostic imaging ; *Sleep Wake Disorders ; },
abstract = {INTRODUCTION: Poor sleep characteristics are associated with Alzheimer's disease (AD) among older adults; however, this relationship remains underexplored earlier in life. We investigated how early midlife sleep relates to AD-related biomarkers in late midlife.

METHODS: A total of 1325 adults (mean age = 40.3 years) self-reported sleep quality, sleep duration, daytime sleepiness, and insomnia symptoms. Twenty years later, we assessed plasma amyloid beta (Aβ)42/40, tau phosphorylated at threonine 217 (p-tau217), neurofilament light chain (NfL), and magnetic resonance imaging (MRI)-derived Spatial Pattern of Abnormality for Recognition of Early AD (SPARE-AD), characterizing AD-like brain atrophy.

RESULTS: After multivariable adjustment, longer sleep duration was associated with lower Aβ42/40, poor sleep quality with higher NfL, daytime sleepiness with both lower Aβ42/40 and higher NfL, and insomnia symptoms with higher SPARE-AD. No associations were observed with sleep and p-tau217.

DISCUSSION: Poor sleep in early midlife was associated with unfavorable AD biomarker levels 20 years later, supporting the idea of sleep as a potential modifiable AD risk factor.},
}

Humans
*Alzheimer Disease/blood/diagnostic imaging
Male
Biomarkers/blood
Female
*Amyloid beta-Peptides/blood
tau Proteins/blood
Magnetic Resonance Imaging
Middle Aged
Neurofilament Proteins/blood
Adult
*Sleep/physiology
Peptide Fragments/blood
Brain/pathology/diagnostic imaging
*Sleep Wake Disorders

@article {pmid41981294,
year = {2026},
author = {Malviya, M and Baniya, S and Wong, E and Jain, T and Manoranjan, B and Vogt, KC and Kehs, Z and Silberman, PC and Dao, T and Li, Y and Scheinberg, DA},
title = {Targeted cellular micropharmacies deliver therapeutic agents to the brain.},
journal = {EMBO molecular medicine},
volume = {},
number = {},
pages = {},
pmid = {41981294},
issn = {1757-4684},
support = {R35CA241894//HHS | NIH | NCI | Center for Cancer Research (CCR)/ ; R01AG061350//HHS | National Institutes of Health (NIH)/ ; R01AG061350//HHS | National Institutes of Health (NIH)/ ; R35CA241894//HHS | National Institutes of Health (NIH)/ ; RO1 CA55349//HHS | National Institutes of Health (NIH)/ ; PO1 CA23766//HHS | National Institutes of Health (NIH)/ ; R01AG080684//HHS | National Institutes of Health (NIH)/ ; T32 grants GM115327 & GM136640//HHS | National Institutes of Health (NIH)/ ; Grant P30 CA008748//Memorial Sloan-Kettering Cancer Center (MSK)/ ; Experimental Therapeutics Center of MSKCC//Memorial Sloan-Kettering Cancer Center (MSK)/ ; 1746886//NSF | National Science Foundation Graduate Research Fellowship Program (GRFP)/ ; },
abstract = {The systemic administration of therapeutic agents, particularly large, charged molecules such as antibodies, has limited efficacy in treating central nervous system (CNS) disorders. In addition, the slow progression of neurodegenerative diseases makes repeated intrathecal injections unfeasible. Alzheimer's disease is characterized by the accumulation of Aβ amyloid plaques. Microglia contribute to the clearance of Aβ, but are inhibited by the expression of CD33. Therefore, antibody blocking of CD33 may enhance the phagocytosis of Aβ by microglial cells, slowing AD progression. Here, we use cells as "targeted cellular micropharmacies" that are retained in the CNS to deliver therapeutic proteins directly into the brain. To achieve this, we genetically engineered CD4 T-cells to express: (1) a chimeric antigen receptor against GD2 to retain the cells in the brain, (2) ectopic FoxP3 to reduce inflammation, (3) secreted IL-2 to promote cell longevity, and (4) secreted anti-CD33 scFv antibody. Our proof-of-concept demonstrates that therapeutic antibodies can be delivered to the brain for at least 8 weeks to treat neurological disorders. Other agents could be similarly delivered into the brain by this platform.},
}

@article {pmid41981333,
year = {2026},
author = {Papatriantafyllou, M},
title = {Astrocyte-based CAR immunotherapy against Alzheimer's disease.},
journal = {Nature aging},
volume = {},
number = {},
pages = {},
doi = {10.1038/s43587-026-01115-0},
pmid = {41981333},
issn = {2662-8465},
}

@article {pmid41981347,
year = {2026},
author = {Sengupta, P and Mukhopadhyay, D},
title = {Nuclear Translocation of IGF1R Induces Cell Cycle Re-entry via Cyclin D1 Regulation in an Aβ-Driven Alzheimer's Disease Model.},
journal = {Molecular neurobiology},
volume = {63},
number = {1},
pages = {},
pmid = {41981347},
issn = {1559-1182},
mesh = {*Alzheimer Disease/metabolism/pathology/genetics ; Humans ; *Amyloid beta-Peptides/toxicity ; *Cell Nucleus/metabolism/drug effects ; *Receptor, IGF Type 1/metabolism ; *Cyclin D1/metabolism ; Cell Line, Tumor ; *Cell Cycle/drug effects ; Active Transport, Cell Nucleus/drug effects ; Phosphorylation/drug effects ; Neurons/metabolism/drug effects ; Models, Biological ; Protein Transport/drug effects ; },
abstract = {Alzheimer's disease (AD) involves progressive neurodegeneration, with abnormal receptor signaling and disrupted cell-cycle activity leading to neuronal loss. Here, we identify a previously unknown mechanism linking β-amyloid (Aβ) exposure to the nuclear translocation of the Insulin-like Growth Factor 1 Receptor (IGF1R) in differentiated SH-SY5Y neuronal cells. The differentiated cholinergic model induced by retinoic acid and BDNF expresses acetylcholinesterase (AChE) and indicates that under amyloidogenic stress, IGF1R may transition from homeostatic membrane and vesicular signaling to a nuclear-centric function. We show that prolonged Aβ treatment causes phosphorylation-dependent nuclear import of IGF1R, confirmed by confocal imaging and biochemical fractionation. IGF1R is conventionally located in the membrane and vesicular membranes; however, under amyloidogenic stress, we show here that it is imported to the nucleus and exerts transcriptional control. The buildup of nuclear IGF1R coincided with increased Cyclin D1 levels and redistribution of neurons into S and G2 phases, indicating abnormal cell-cycle re-entry. Chromatin immunoprecipitation demonstrated increased IGF1R binding at the CCND1 and JUN promoters after Aβ exposure, suggesting a direct role in gene transcription. Pharmacological blockade of IGF1R phosphorylation by PPP or SUMOylation by Ginkgolic acid significantly reduced Cyclin D1 elevation, implying that both post-translational modifications are involved in receptor nuclear trafficking. Co-immunoprecipitation and confocal imaging identified Nucleophosmin (NPM1) as a putative IGF1R interacting partner, potentially contributing to its nuclear transport and stabilizing receptor-chromatin complexes. These results establish IGF1R as a signaling-transcription connector linking extracellular amyloid stress to nuclear gene regulation, providing a mechanistic explanation for faulty neuronal cell-cycle re-entry in AD. We suggest that abnormal IGF1R-NPM1 interactions contribute to receptor mislocalization and cell-cycle failure, highlighting new targets for therapeutic intervention aimed at receptor trafficking and neuroprotection in Alzheimer's disease.},
}

*Alzheimer Disease/metabolism/pathology/genetics
Humans
*Amyloid beta-Peptides/toxicity
*Cell Nucleus/metabolism/drug effects
*Receptor, IGF Type 1/metabolism
*Cyclin D1/metabolism
Cell Line, Tumor
*Cell Cycle/drug effects
Active Transport, Cell Nucleus/drug effects
Phosphorylation/drug effects
Neurons/metabolism/drug effects
Models, Biological
Protein Transport/drug effects

@article {pmid41981348,
year = {2026},
author = {Abdellatif, AI and Elsharab, A and Moubarak, ES and Alsaadany, KR and Ayad, YW},
title = {Focused and unfocused transcranial ultrasound stimulation in Alzheimer's disease: a systematic review and meta-analysis of randomized controlled trials.},
journal = {Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology},
volume = {47},
number = {5},
pages = {},
pmid = {41981348},
issn = {1590-3478},
}

@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 {pmid41968260,
year = {2026},
author = {Zhan, M and Liu, G and Liu, YM and Wang, B},
title = {Up-regulation of miR-548 m Leading to Neuroinflammation to Promote the Progression of Alzheimer's Disease.},
journal = {Molecular neurobiology},
volume = {63},
number = {1},
pages = {},
pmid = {41968260},
issn = {1559-1182},
mesh = {*MicroRNAs/genetics/metabolism ; Animals ; *Alzheimer Disease/genetics/pathology/metabolism ; Male ; *Up-Regulation/genetics ; Microglia/metabolism/pathology ; *Neuroinflammatory Diseases/genetics/pathology/metabolism ; *Disease Progression ; Mice, Transgenic ; Mice ; Mice, Inbred C57BL ; Cytokines/metabolism ; },
abstract = {Neuroinflammation mediated by microglia is recognized as a critical contributor to Alzheimer's disease (AD) pathogenesis, and P2RY12 maintains microglial homeostasis. MicroRNAs regulate gene expression post-transcriptionally and have been implicated in modulating microglial activation states during AD by affecting inflammatory pathways. This study aimed to investigate the role of miR-548 m in regulating microglial polarization and neuroinflammation in Alzheimer's disease. Male APP/PS1 transgenic and wild-type mice were utilized as animal models alongside cultured microglial cells for in vitro studies. Behavioral assessments, including contextual fear Morris water maze (MWM) and fear conditioning (FC), evaluated cognitive function. Molecular analyses comprised RT-qPCR western blot, and ELISA, as well as dual-luciferase reporter assays to validate miR-548 m and P2RY12 interactions. In vivo modulation of miR-548 m expression was achieved via stereotaxic intracerebral injections of agomir or antagomir oligonucleotides targeting the dentate gyrus. MiR-548 m was significantly upregulated in AD. Overexpression of miR-548 m promoted microglial M1 polarization characterized by increased pro-inflammatory cytokines (TNF-α, IL-6, iNOS, IL-1β) and reduction in M2 anti-inflammatory markers (Arg1, CD206, IL-4, TGF-β). Inhibition of miR-548 m improved spatial learning and memory performance while attenuating microglial activation in vivo. Luciferase reporter assays confirmed that P2RY12 is a direct downstream target suppressed by miR-548 m. And overexpression of miR‑548 m reversed the inflammatory effects induced by P2RY12 overexpression. These findings demonstrate that elevated miR‑548 m exacerbates neuroinflammation through negative regulation of P2RY12 expression, leading to enhanced microglial M1 polarization during AD progression. Targeting the miR‑548 m/P2RY12 axis may provide a novel therapeutic for mitigating AD.},
}

*MicroRNAs/genetics/metabolism
Animals
*Alzheimer Disease/genetics/pathology/metabolism
Male
*Up-Regulation/genetics
Microglia/metabolism/pathology
*Neuroinflammatory Diseases/genetics/pathology/metabolism
*Disease Progression
Mice, Transgenic
Mice
Mice, Inbred C57BL
Cytokines/metabolism

@article {pmid41968275,
year = {2026},
author = {Moon, J and Kim, S and Chung, H and Jang, I and , },
title = {Cyclic 2.5D Perceptual Loss for Cross-Modal 3D Medical Image Synthesis: T1w MRI to Tau PET.},
journal = {Human brain mapping},
volume = {47},
number = {5},
pages = {e70508},
doi = {10.1002/hbm.70508},
pmid = {41968275},
issn = {1097-0193},
support = {RS-2024-00455720//National Research Foundation of Korea (NRF), Ministry of Science and ICT (MSIT)/ ; RS-2024-00414119//National Research Foundation of Korea (NRF), Ministry of Science and ICT (MSIT)/ ; RS-2024-00338048//National Research Foundation of Korea (NRF), Ministry of Science and ICT (MSIT)/ ; 2024ER040700//Korea National Institute of Health (KNIH)/ ; 2025ER040300//Korea National Institute of Health (KNIH)/ ; RS-2025-13002970//Ministry of Trade, Industry and Energy (MOTIE)/ ; RS-2025-02220534//Korea Health Industry Development Institute (KHIDI), Ministry of Health & Welfare (MOHW)/ ; //Hankuk University of Foreign Studies Research Fund of 2025/ ; RS-2024-00412644//Institute for Information & Communication Technology Planning & Evaluation (IITP), Ministry of Science and ICT (MSIT)/ ; IITP-(2025)-RS-2023-00253914//Institute for Information & Communication Technology Planning & Evaluation (IITP), Ministry of Science and ICT (MSIT)/ ; RS-2024-00332210//Korea Creative Content Agency (KOCCA), Ministry of Culture, Sports and Tourism (MCST)/ ; RS-2020-II201373//Artificial Intelligence Graduate School Program (Hanyang University), Ministry of Science and ICT (MSIT)/ ; RS-2023-00261368//Artificial Intelligence Graduate School Program (Hanyang University), Ministry of Science and ICT (MSIT)/ ; KSC-2025-CRE-0065//National Supercomputing Center, Korea Institute of Science and Technology Information/ ; KSC-2024-CRE-0021//National Supercomputing Center, Korea Institute of Science and Technology Information/ ; },
mesh = {Humans ; *Positron-Emission Tomography/methods/standards ; *Magnetic Resonance Imaging/methods/standards ; *tau Proteins/metabolism ; *Imaging, Three-Dimensional/methods/standards ; *Alzheimer Disease/diagnostic imaging/metabolism ; *Neuroimaging/methods/standards ; Male ; Female ; Aged ; *Brain/diagnostic imaging/metabolism ; },
abstract = {Positron emission tomography (PET) provides an in vivo molecular marker for various diseases, including Alzheimer's disease and related dementias (ADRD). PET has become increasingly integrated into diagnostic decision-making, disease staging, and clinical trial enrichment. However, its widespread use remains constrained by high costs, government regulations, and the invasiveness of radiotracer injection. Modern diagnostic frameworks emphasize the importance of multimodal biomarker assessment, such as the "amyloid/tau/neurodegeneration" (A/T/N) framework for Alzheimer's disease; however, they are constrained by these barriers. Medical image synthesis or translation offers a potential solution by enabling the reconstruction of unavailable modalities. The clinical utility of PET depends on accurately capturing regional uptake patterns rather than exact voxel-wise intensities, motivating the use of perceptual loss functions to assess higher-level semantic features in generative models. While 2D, 3D, and 2.5D perceptual losses are utilized in 3D synthesis, each encounters challenges, including limited volumetric context, the scarcity of pretrained 3D models, and difficulty balancing optimization across anatomical planes. In this work, we address cross-modal synthesis of tau PET from structural magnetic resonance imaging (MRI), generating 3D pseudo-[[18]F]flortaucipir standardized uptake value ratio (SUVR) maps from 3D T1-weighted MR images. We propose a cyclic 2.5D perceptual loss that cyclically optimizes the axial, coronal, and sagittal planes over training phases, thereby enhancing volumetric consistency. Furthermore, we standardize PET SUVRs by scanner manufacturer, reducing inter-manufacturer variability and better preserving high-uptake regions. We evaluate the proposed approach on cohorts spanning the ADRD spectrum using data from the Alzheimer's Disease Neuroimaging Initiative and the Standardized Centralized Alzheimer's Disease and Related Dementias Neuroimaging cohort. Our approach is broadly applicable across various generative frameworks and achieves high quantitative and qualitative performance on diverse architectures, including U-Net, UNETR, SwinUNETR, CycleGAN, and Pix2Pix. Notably, it achieves better agreement between synthesized SUVRs and measured PET scans in key brain regions relevant to Alzheimer-type tau pathology. The code is publicly available at https://github.com/labhai/Cyclic-2.5D-Perceptual-Loss.},
}

Humans
*Positron-Emission Tomography/methods/standards
*Magnetic Resonance Imaging/methods/standards
*tau Proteins/metabolism
*Imaging, Three-Dimensional/methods/standards
*Alzheimer Disease/diagnostic imaging/metabolism
*Neuroimaging/methods/standards
Male
Female
Aged
*Brain/diagnostic imaging/metabolism

@article {pmid41968284,
year = {2026},
author = {Kim, Y and Lee, BH and Ahn, B and Ko, EA and Kang, D},
title = {Microglia-Specific K2P Channel THIK-1: Structure, Function, and Therapeutic Potential.},
journal = {Acta physiologica (Oxford, England)},
volume = {242},
number = {5},
pages = {e70224},
doi = {10.1111/apha.70224},
pmid = {41968284},
issn = {1748-1716},
mesh = {Humans ; *Microglia/metabolism ; *Potassium Channels, Tandem Pore Domain/metabolism/chemistry ; Animals ; Potassium Channels ; },
abstract = {BACKGROUND: The tandem pore domain halothane-inhibited potassium (THIK-1) channel is a member of the two-pore domain potassium (K2P) channel family and plays a critical role in maintaining the resting membrane potential. THIK-1 has emerged as a key regulator of microglial physiology and neuroimmune signaling. With the rapid accumulation of structural, electrophysiological, and functional evidence, there is an increasing need for an integrated understanding of THIK-1 in the context of microglial biology and disease.

AIMS: This review provides a comprehensive synthesis of the structural, regulatory, and functional properties of THIK-1, with a particular focus on its roles in microglial physiology, neuroimmune signaling, and central nervous system (CNS) pathologies.

MATERIALS AND METHODS: We conducted a comprehensive review of recent literature, including electrophysiological, molecular, and structural studies, with particular emphasis on cryo-electron microscopy findings, pharmacological modulation, and disease-associated functional analyses.

RESULTS: THIK-1 is selectively enriched in microglia and contributes to essential cellular processes, including surveillance motility, synaptic pruning, and inflammasome activation. Its high constitutive activity makes it a dominant determinant of the microglial membrane potential. Structural studies have identified key features, including a lipid-interacting pocket and a cytoplasmic gate, which underlie lipid- and anesthetic-mediated regulation. Functionally, THIK-1-mediated K⁺ efflux is required for NOD-like receptor pyrin domain-containing protein 3 (NLRP3) inflammasome activation and pyroptosis. Accumulating evidence links THIK-1 to major CNS disorders, including neuroinflammation, neurodegeneration (e.g., Alzheimer's and Parkinson's diseases), and psychiatric disorders.

DISCUSSION: The convergence of structural, electrophysiological, and immunological findings positions THIK-1 as a central regulator of neuroimmune signaling. Integration of these findings provides new insights into how ion channel activity shapes microglial function and disease processes.

CONCLUSION: THIK-1 represents a critical nexus between ion channel biophysics and neuroimmune dysfunction. A comprehensive understanding of its regulation and function supports its potential as a microglia-specific therapeutic target in neuroinflammatory and neurodegenerative disorders.},
}

Humans
*Microglia/metabolism
*Potassium Channels, Tandem Pore Domain/metabolism/chemistry
Animals
Potassium Channels

@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 {pmid41968642,
year = {2026},
author = {Winford, ED and Huber, BD and Seblova, D and Pyne, J and Avila-Rieger, JF and Turney, IC and Mazen, JA and Brickman, AM and Manly, JJ},
title = {Associations between parental history of dementia and plasma markers of inflammation in a multi-ethnic middle-aged community of adults.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {22},
number = {4},
pages = {e71355},
doi = {10.1002/alz.71355},
pmid = {41968642},
issn = {1552-5279},
support = {R01AG054070/AG/NIA NIH HHS/United States ; //Burroughs Wellcome Fund Postdoctoral Diversity Enrichment Program (PEDP)/ ; AARF-21-848200/ALZ/Alzheimer's Association/United States ; 22/MED/012//PRIMUS Research Programme/ ; UL1R001873//National Center for Advancing Translational Sciences, National Institutes of Health/ ; },
mesh = {Humans ; Female ; Male ; *Dementia/genetics/blood/ethnology ; Middle Aged ; Biomarkers/blood ; *Inflammation/blood/genetics/ethnology ; *Cytokines/blood ; *Parents ; Ethnicity ; Aged ; },
abstract = {INTRODUCTION: Parental history of dementia is associated with increased dementia risk. We investigated whether having a parent with dementia is associated with increased peripheral inflammation in middle-aged adults.

METHODS: Participants were from the Offspring Study (n = 1204). Parental dementia status was determined by a diagnostic consensus conference. Plasma chemokine and cytokine concentrations were assayed with Luminex technology.

RESULTS: Parental history of dementia was associated with higher levels of eotaxin and lower levels of granulocyte colony-stimulating factor, vascular endothelial growth factor A, and interleukin (IL)-27. IL-18 and epidermal growth factor levels were higher in Black individuals with a parental history of dementia compared to Hispanic individuals with the same history. Women with a parental history of dementia had higher levels of interferon-alpha 2, IL-12p70, soluble CD40 ligand, and IL-18 compared to men with the same history.

DISCUSSION: Parental history of dementia is associated with elevated markers of peripheral inflammation. These associations vary across sex, race, and ethnicity.},
}

Humans
Female
Male
*Dementia/genetics/blood/ethnology
Middle Aged
Biomarkers/blood
*Inflammation/blood/genetics/ethnology
*Cytokines/blood
*Parents
Ethnicity
Aged

@article {pmid41968685,
year = {2026},
author = {Zeng, J and Wang, P and Fan, Z and Wang, G and Zhou, J and Zhang, F},
title = {Chlorogenic Acid: Characteristics, Neuroprotective Effects, and Potential Mechanisms.},
journal = {Current neuropharmacology},
volume = {},
number = {},
pages = {},
doi = {10.2174/011570159X459115260204170117},
pmid = {41968685},
issn = {1875-6190},
abstract = {In this review, we explore recent evidence connecting chlorogenic acid (CGA) to neuropsychiatric disorders and critically discuss the biological mechanisms underlying these effects. CGA is a natural polyphenol that usually exists in fruits and vegetables. CGA has long been recommended for its broad pharmacological activities. Increasing evidence from animal studies has revealed that dietary CGA supplementation may confer protective effects on the nervous system. Here, we summarize multiple findings on CGA in animal models of neuropsychiatric disorders, including Parkinson's disease, Alzheimer's disease, stroke, depression, epilepsy, and other neuropsychiatric disorders. We place equal emphasis on chemical features, natural sources, bioavailability, and pharmacological properties of CGA; all of these can have a critical impact on CGA's intervention. Current experimental evidences suggest that the neuroprotective effects of CGA are driven by the convergence of several processes, including suppression of neuroinflammation, attenuation of oxidative stress, and context-dependent effects on synaptic and cellular homeostasis. In some models, CGA has also been associated with changes in autophagic activity and reduced accumulation of misfolded or aggregated proteins. Despite these advances, the field still lacks a coherent molecular framework that links CGA exposure to specific neural outcomes. Therefore, resolving this gap will be essential for the clinical application of CGA.},
}

@article {pmid41968748,
year = {2026},
author = {Hilpert, K},
title = {Peptidomics: A New Dimension in Microbiome Research.},
journal = {Protein and peptide letters},
volume = {},
number = {},
pages = {},
doi = {10.2174/0109298665436241260327111926},
pmid = {41968748},
issn = {1875-5305},
abstract = {The human gut microbiome is now recognised as a major determinant of health, with roles extending beyond digestion to influence neurodegeneration, metabolism, immunity, and pharmacological responses. Clinical studies link microbial imbalances to Alzheimer's disease, Parkinson's disease, depression, and cardiovascular disorders, yet the underlying mechanisms remain only partly understood. Methodological advances have progressively deepened our insight. DNA-based sequencing (metagenomics) catalogues microbial genes but reveals only potential functions. RNA-based sequencing (metatranscriptomics) highlights active gene expression, but instability of transcripts and poor correlation with protein activity limit its predictive value. Metabolomics measures small-molecule end products, providing direct evidence of microbial biochemistry and identifying disease-linked metabolites such as urolithin A, trimethylamine N-oxide, and equol. These approaches together have transformed microbiome science, but they remain incomplete. A critical and underutilised dimension is peptidomics: the systematic analysis of endogenous peptides in the gut and circulation. Enabled by peptide-enriching, protease-inhibiting workflows and high-resolution liquid chromatography-tandem mass spectrometry (LC-MS/MS), peptidomics directly captures unstable signaling peptides and proteolytic fragments that are often invisible to conventional proteomics. Coupled with emerging gut-specific peptide databases, such as MetaPep, and Artificial Intelligence (AI) assisted de novo sequencing and spectral prediction for non-human peptides, this provides a concrete technical route to reading out the functional peptide layer of the microbiome. Peptidomics can capture functional signals of host-microbiome interaction, reveal context-specific biomarkers, and provide mechanistic insight into disease. Recent studies demonstrate that peptide-level resolution uncovers microbial contributions to gut inflammation, modulates the gut-brain axis, and enables peptide-based disease stratification in conditions such as inflammatory bowel disease. However, despite these promising examples, peptidomics remains largely absent from mainstream microbiome research, which needs to be changed. Integrating peptidomics with existing genomic, transcriptomic, and metabolomic approaches will generate a more complete and functional picture of the microbiome. This shift will accelerate biomarker discovery, refine diagnostics, and expand the search for peptide-based therapeutics, positioning peptidomics as an essential next step in microbiome science.},
}

@article {pmid41968970,
year = {2026},
author = {Massons, M and Guillen, N and Sarto, J and Falgàs, N and Borrego-Écija, S and Esteller-Gauxax, D and Castellví, M and Tort-Merino, A and Pérez-Millan, A and Antonell, A and Augè Fradera, JM and Piñol, G and Riba, I and Carnes-Vendrell, A and Cullell, M and Osuna, MT and Bajo, L and Romero, T and Bonjoch, E and Bello, J and Fernández, S and Balagué, M and Gómez-Ruiz, I and Boltes, A and Pont, C and Cuevas, R and Carrillo, S and Iglesias, L and Casadevall Codina, TM and Guinea, LG and Espada, FJ and Sánchez-Valle, R and Balasa, M and Lladó, A},
title = {Predictive Ability of Plasma p-tau217 for β-Amyloid Status: A Prospective Multicenter Study.},
journal = {Annals of clinical and translational neurology},
volume = {},
number = {},
pages = {},
doi = {10.1002/acn3.70387},
pmid = {41968970},
issn = {2328-9503},
support = {CM23/00137//Instituto de Salud Carlos III/ ; JR22/00014//Instituto de Salud Carlos III/ ; AGAUR (SGR 2021-01126)//Fundació Societat Catalana de Neurologia, Generalitat de Catalunya/ ; },
abstract = {OBJECTIVE: Plasma tau phosphorylated at threonine 217 (p-tau217) measured with fully automated platforms has shown high accuracy for Alzheimer's disease (AD) diagnosis, but real-world multicenter data remain limited. We aimed to validate the diagnostic performance of p-tau217 for identifying AD pathology in a real-world multicenter cohort across seven memory clinics in Catalonia (Spain), with only one tertiary hospital with prior experience in AD blood-based biomarkers.

METHODS: In this prospective multicenter study, consecutive patients with cognitive impairment undergoing routine cerebrospinal fluid (CSF) biomarker testing were included. Plasma samples were collected following a standardized pre-analytical protocol and analyzed centrally using the Lumipulse G p-tau217 assay (Fujirebio). Diagnostic accuracy for Aβ status was assessed overall and across sites.

RESULTS: A total of 185 participants were included. Plasma p-tau217 showed excellent accuracy for CSF-defined Aβ status (AUC 0.916) with consistent performance across centers. Using a single cut-off, diagnostic accuracy reached 84.9%, which prompted the use of a dual-threshold strategy to improve overall performance and to classify p-tau217 values into low, intermediate, and high probability categories of Aβ positivity. When applying a strict model with 97.5% sensitivity and specificity (cut-offs 0.146/0.486 pg/mL), 42.7% of participants fell within the intermediate zone, whereas the remaining 57.3% were confidently classified with 95.3% accuracy.

INTERPRETATION: In a real-world multicenter memory-clinic cohort, plasma p-tau217 measured on a fully automated platform accurately discriminated CSF Aβ status and enabled reliable rule-in/rule-out classification in over half of patients. These findings support its broader clinical use as an initial diagnostic tool for AD.},
}

@article {pmid41969021,
year = {2026},
author = {Tran, D and Georgiadis, M and DiGiacomo, P and Nirschl, J and Cobos, I and Rosenberg, J and Edwards, N and Bone, S and Webb, S and Zeineh, M},
title = {Characterizing ferrous versus ferric iron in Alzheimer's disease using X-ray fluorescence imaging and XANES spectroscopy.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261435561},
doi = {10.1177/13872877261435561},
pmid = {41969021},
issn = {1875-8908},
abstract = {BackgroundThe accumulation of iron, such as ferrous Fe[2+], in the Alzheimer's disease (AD) brain may contribute to neurodegeneration by driving oxidative stress. While elevated iron in AD has been shown, the oxidation state of iron and its regional distribution in AD, particularly in the hippocampus, is unclear.ObjectiveTo characterize the oxidation state and spatial distribution of iron in the hippocampus of AD and control brains, and to assess the effect of tissue thawing on ferrous iron measurements.MethodsWe utilized X-ray fluorescence imaging and X-ray absorption near edge structure spectroscopy to localize and analyze iron deposition in fresh-frozen human hippocampal specimens stratified by AD disease stage. To assess the effect of thawing on iron oxidation, we used a cryo-chamber to keep three specimens frozen while their respective deposits were being scanned. These specimens were then allowed to thaw and their same deposits were rescanned for comparison.ResultsCompared to control brains, AD specimens exhibited elevated levels of ferrous iron (Fe[2][+]) in the cornu ammonis 1 (CA1)-subiculum subfields-regions known to degenerate early in AD. We also measured a decrease in Fe[2+] levels in AD and control specimens scanned after being thawed.ConclusionsOur findings support the association between elevated Fe[2+] and AD, consistent with existing hypotheses linking redox-active iron to oxidative stress and neuroinflammation. The observed reduction in Fe[2+] levels following thawing suggests that studies using thawed brain samples may underestimate Fe[2+] levels.},
}