@article {pmid40471467,
year = {2025},
author = {Angulo, MC},
title = {The Power of Neuroglia in Driving Brain Function.},
journal = {Neurochemical research},
volume = {50},
number = {3},
pages = {184},
pmid = {40471467},
issn = {1573-6903},
support = {EQU202103012626//Fondation pour la Recherche Médicale/ ; ANR-20-CE16-0001-01//Agence Nationale de la Recherche/ ; 00147199/WB-2023-50772//Fondation de France/ ; R24183KD//Fédération pour la Recherche sur le Cerveau/ ; R24190KK//France Sclérose en Plaques/ ; },
abstract = {Neuroglial cells are essential regulators of central nervous system (CNS) function in development, brain function, and disease. This mini-review summarizes recent advances that reveal how astrocytes, oligodendrocyte lineage cells, and microglia contribute to key brain processes. Astrocytes modulate synaptic plasticity and memory through gliotransmitter release, calcium signaling, and circuit-specific interactions, with dysfunctions implicated in disorders such as Alzheimer’s disease and depression. Oligodendrocytes and their precursors influence cognition through myelination, and disruptions in myelin plasticity and oligodendrogenesis can lead to significant cognitive deficits. Microglia, beyond their classical immune roles, are emerging as central sculptors of neural circuits, regulating synaptic pruning, neuronal survival, and extracellular matrix remodeling. Their dysfunction is increasingly associated with both neurodevelopmental and neurodegenerative disorders. Collectively, these findings highlight the powerful and multifaceted roles of neuroglial cells in shaping brain function and pathology. As tools to study and manipulate neuroglial activity continue to evolve, targeting neuroglial mechanisms offers exciting new therapeutic opportunities for a wide range of CNS disorders.},
}

@article {pmid40569486,
year = {2025},
author = {Singh, A and Tiwari, V and Roy, S},
title = {Multifaceted role of oxidative stress in neurological disorders.},
journal = {Molecular biology reports},
volume = {52},
number = {1},
pages = {640},
pmid = {40569486},
issn = {1573-4978},
abstract = {The intricate relationship between oxidative stress and neurological disorders stems from multiple factors inherent to central nervous system function. Neural tissue’s high oxygen consumption, elevated iron content, and hydrogen peroxide generation create conditions favorable for oxidative imbalance. The susceptibility of neuronal membranes to oxidative damage is particularly noteworthy due to their high polyunsaturated fatty acid composition. This vulnerability, coupled with disrupted redox homeostasis marked by excessive reactive oxygen species (ROS) and compromised antioxidant mechanisms, contributes to the pathogenesis of major neurodegenerative conditions, including Parkinson’s, Alzheimer’s, and Huntington’s diseases. The interplay between mitochondrial dysfunction, protein aggregation, and neuroinflammation further exacerbates oxidative damage, creating a self-perpetuating cycle of cellular stress. These processes trigger various cell death pathways, including apoptosis and necrosis, ultimately leading to progressive neuronal loss. Understanding the complex network of cellular and molecular mechanisms affected by oxidative stress is crucial for developing targeted therapeutic strategies. Current research focuses on both endogenous antioxidant systems and novel neuroprotective compounds that could potentially modulate these pathways. Future investigations into these biochemical pathways are essential for elucidating disease mechanisms, identifying biomarkers for early detection, and developing more effective therapeutic interventions in the field of neurodegeneration.},
}

@article {pmid40571761,
year = {2025},
author = {Richards, SEV and Yang, M and Deik, AA and Ricq, EL},
title = {APOE Genotype Impacts Polyunsaturated Neutral Lipid Storage and Ferroptosis Vulnerability in Astrocytes.},
journal = {Neurochemical research},
volume = {50},
number = {4},
pages = {211},
pmid = {40571761},
issn = {1573-6903},
support = {R21 AG068769-01/AG/NIA NIH HHS/United States ; },
abstract = {Astrocytes play a critical role in regulating the metabolism of cholesterol and other lipids in the brain. Increasing evidence suggests that dysfunctional lipid metabolism and lipid peroxide-mediated cell death, or ferroptosis, are involved in the pathophysiology of late-onset Alzheimer’s disease. The Alzheimer’s disease risk allele of APOE, APOE4, is expressed in astrocytes and is associated with increased accumulation of cholesterol as well as highly polyunsaturated and peroxidation-prone neutral lipids in lipid droplets. However, a direct connection between APOE4 genotype-dependent lipid dysregulation and sensitivity to ferroptotic cell death has not yet been explored. Here, we show that APOE4 and APOE knockout astrocytes accumulate cholesterol and polyunsaturated lipid-rich droplets in lysosomes and have increased vulnerability to ferroptotic cell death. APOE2 astrocytes are also enriched in polyunsaturated lipids but are less vulnerable to lipid peroxidation. Pharmacological manipulation of neutral lipid content modestly impacted ferroptosis sensitivity. In contrast, modulation of lysosomal lipid content via blockade of autophagy or promotion of cholesterol efflux with methyl-β-cyclodextrin strongly protects APOE4 cells from lipid-peroxide mediated cell death. In humanized APOE4 mice, reduction of brain lipid peroxidation selectively impacted cholesterol ester storage. Taken together, these findings suggest that correction of APOE4-mediated lipid trafficking defects may reduce risk for ferroptotic in astrocytes.},
}

@article {pmid40928715,
year = {2025},
author = {Mallahzadeh, A and Owjfard, M and Fereydoonnezhad, T and Karimi, F},
title = {Therapeutic spectrum of Piperine in ischemic stroke: a literature review.},
journal = {Molecular biology reports},
volume = {52},
number = {1},
pages = {885},
pmid = {40928715},
issn = {1573-4978},
abstract = {Ischemic stroke rate is increasing globally and causing a burden on society. The FDA- approved treatments (tissue plasminogen activator and mechanical thrombectomy) come with a series of limitations, such as a narrow therapeutic time window and failure to restore the dying neurons. The area around the ischemic core, known as the penumbra, can be saved and the number of dying neurons could be reduced. This goal can be achieved through reducing inflammation, oxidative stress, and cell apoptosis, All which result as secondary damage following cerebral ischemia. Therefore, identifying new pharmacological agents that possess neuroprotection are of significant interest. Piperine is an alkaloid from the Piperaceae family and has shown benefits for various neurological diseases including Alzheimer’s, Parkinson and epilepsy. Piperine has shown to inhibit inflammation, apoptosis, and oxidative stress, all of which contribute to worse stroke outcomes. Piperine’s impact on blood pressure is also noteworthy since controlling blood pressure, both before and after stroke management, is necessary. Few pre-clinical studies have demonstrated that piperine holds the potential to alleviate stroke severity. While the precise mechanism remains unclear, studies indicate that these beneficial effects are due to its immunomodulatory and neuroprotective mechanisms. Piperine has also been shown to enhance the bioavailability of various pharmacological agents and it could be used in combination with other neuroprotective agents to yield optimum results in stroke management. Despite the promising evidence, utilizing piperine in the stroke setting has not yet been established and future studies are required to shed light on its effects on stroke. This review explores the mechanisms by which piperine may impact stroke, highlighting its underlying mechanisms as supported by existing literature and laboratory findings.},
}

@article {pmid41160236,
year = {2025},
author = {Srivastava, R and Gupta, MK},
title = {Gut bacteria-derived metabolites and their implications in mental health and neurological diseases.},
journal = {World journal of microbiology & biotechnology},
volume = {41},
number = {11},
pages = {423},
pmid = {41160236},
issn = {1573-0972},
abstract = {Gut bacteria generate various metabolites that can significantly affect brain function and behavior through the microbiota–gut–brain axis. This article highlights the role of short-chain fatty acids, tryptophan derivatives, bile acids, and neurotransmitter-like metabolites in regulating neuroinflammation, synaptic plasticity, and neuronal signaling. The article also explores the potential mechanistic pathways through which these chemical signals act on the central nervous system, such as vagus nerve signaling, immune modulation, and blood–brain barrier integrity. The emerging studies suggested that the alterations to metabolites are linked to mental health disorders, including depression, anxiety, and autism spectrum disorders, and neurodegenerative diseases such as Alzheimer’s disease and Parkinson’s disease. Although preclinical and clinical studies provide early promise and insight into the relevance of metabolites in the brain, substantial gaps remain concerning the effects induced by metabolites at the mechanistic level, how the effect is dependent on the context, and how it varies between individuals. The article also highlights and focuses on the translational potential of clinical research, targeting the utilization of microbial metabolites for diagnostics and treatments, including methodological limitations on biomarkers, interventional reliability, and personalized interventions. The review illustrates both the potential and the shortcomings of metabolite-centric research in neuropsychiatric and neurological disorders. Future investigations should prioritize integrative approaches that combine metabolomics, neuroimaging, and clinical outcomes to infer causality and clinical relevance. Overall, metabolites derived from gut bacteria represent an attractive but underappreciated territory for advancing precision medicine for mental health and neurology.},
}

@article {pmid41212305,
year = {2026},
author = {Li, Z and Jia, L and Huai, S},
title = {Bidirectional causal association between cathepsins and neuropsychiatric disorders: univariate and multivariate Mendelian randomization study.},
journal = {European archives of psychiatry and clinical neuroscience},
volume = {276},
number = {4},
pages = {1775-1787},
pmid = {41212305},
issn = {1433-8491},
abstract = {BACKGROUND: Neuropsychiatric disorders are among the most common diseases worldwide and are characterized by complex pathogenic mechanisms. Cathepsins (CTS) are crucially involved in the pathogenesis and treatment of numerous diseases. Increasing evidence suggests a relationship between cathepsins and neuropsychiatric disorders. However, the causal associations remain unclear. METHODS: We performed a bidirectional two-sample Mendelian randomization (MR) analysis, applying univariable (UVMR) and multivariable MR (MVMR) to evaluate the causal association between nine cathepsins and five neuropsychiatric disorders. Data for this study were derived from genome-wide association studies (GWAS). The MR analysis primarily used five methods: Inverse Variance Weighted (IVW), Weighted Median Estimator (WME), MR-Egger regression, Simple mode, and Weighted mode. Additionally, sensitivity tests were employed to assess the robustness of the MR results. RESULTS: MR analyses indicated that CTSH is associated with an increased risk of Alzheimer’s disease (AD) (UVMR: OR, 1.041; 95% CI, 1.013–1.069; p = 0.004; MVMR: OR, 1.040; 95% CI, 1.014–1.066; p = 0.003; replication UVMR: OR, 1.046; 95% CI, 1.014–1.082; p = 0.011). Findings that were significant in only one MR approach, such as the putative causal effects of CTSF on AD and bipolar disorder (BIP), of CTSL2 on major depressive disorder (MDD), and of CTSH and CTSE on Parkinson’s disease (PD) should be interpreted with caution. CONCLUSION: CTSH can be considered a plasma biomarker for AD, offering new insights and potential directions for the prevention and treatment of AD. Additionally, during the treatment of BIP and PD, attention should be paid to CTSF and CTSE expression levels to maintain physiological homeostasis.},
}

@article {pmid41372737,
year = {2025},
author = {Shah, A and Doshi, G},
title = {Stress and neurodegeneration: mechanistic insights and therapeutic opportunities for preserving brain resilience.},
journal = {Acta neurologica Belgica},
volume = {},
number = {},
pages = {},
pmid = {41372737},
issn = {2240-2993},
abstract = {Neurodegenerative diseases such as Alzheimer’s disease, Parkinson’s disease, Huntington’s disease, and Amyotrophic Lateral Sclerosis are strongly influenced by persistent stress, which accelerates both their onset and progression. This review explores the intricate interplay between chronic stressors, oxidative and metabolic imbalances, protein misfolding, inflammatory responses, and psychosocial adversity, and their cumulative impact on the aging brain’s capacity for homeostasis. The loss of cellular resilience due to prolonged stress leads to maladaptive outcomes, including mitochondrial dysfunction, sustained neuroinflammation, breakdown in proteostasis, and disruption of hypothalamic-pituitary-adrenal axis signaling, all of which amplify neuronal vulnerability. The detailed molecular pathways that underlie these phenomena, the article identifies key mediators such as Reactive Oxygen species, mitochondrial regulators, heat shock proteins, and proinflammatory cytokines that drive neurodegeneration. A comprehensive literature search was conducted using PubMed, Scopus, Web of Science, and Google Scholar up to 2025. Eligible publications included original research articles, clinical studies, and systematic reviews focusing on stress-related molecular pathways, oxidative metabolism, proteostasis, neuroinflammation, and therapeutic interventions in aging and neurodegenerative diseases. A qualitative synthesis of these studies was performed to identify key mechanisms, biomarkers, and emerging treatment strategies relevant to stress-induced neurodegeneration. Further, the review evaluates both established and emerging interventions aimed at mitigating these stress-driven processes. Lifestyle modifications such as aerobic exercise, calorie restriction, and cognitive behavioural therapies complement pharmacological agents like antioxidants, chaperone modulators, and anti-inflammatory drugs to enhance brain resilience and delay disease onset. Recent advances in the field, including integrated multi-omics profiling, biomarker discovery, and medicine approaches, promise to refine our ability to satisfy patients and deliver targeted therapies based on individual stress profiles. Additionally, the article discusses the neuroimmune-gut axis and the potential for interventions targeting microbiome-related inflammation. Early detection of stress-related biomarkers and personalized strategies holds considerable promise for improving clinical outcomes, enabling earlier diagnosis, and fostering tailored therapies that preserve cognitive function and independence in aging populations.},
}

@article {pmid41417171,
year = {2026},
author = {Garnier-Villarreal, M and Johnson, DK},
title = {Bayesian multivariate longitudinal piecewise regression: detecting early onset of cognitive decline.},
journal = {Journal of behavioral medicine},
volume = {49},
number = {2},
pages = {225-238},
pmid = {41417171},
issn = {1573-3521},
support = {P30 AG066444/AG/NIA NIH HHS/United States ; P01 AG03991/AG/NIA NIH HHS/United States ; P01 AG003991/AG/NIA NIH HHS/United States ; P01 AG026276/AG/NIA NIH HHS/United States ; P30 AG072972/AA/NIAAA NIH HHS/United States ; P01 AG03991/AG/NIA NIH HHS/United States ; P30 AG066444/AG/NIA NIH HHS/United States ; P01 AG026276/AG/NIA NIH HHS/United States ; P30 AG072972/AA/NIAAA NIH HHS/United States ; },
abstract = {The current paper defines and tests a hierarchical multivariate change point model (HMLCP) to detect a random change point in longitudinal data (subject-specific). Given the large number of random effects that are estimated, we implemented the HMLCP using Bayesian methods. First, we present model parameterization and then applied it in a sample of older adults, to identify the onset of cognitive decline with neurocognitive data collected at the Knight Alzheimer Disease Center. These data presented an ideal case study to test a multivariate random change-point model with a diagnosed sample, to see if the model can detect the disease progression of AD. HMLCP model was sensitive to detect the presence of disease several years before clinical diagnosis. Further, the HMLCP allowed us to describe the sample disease progression, and predict change points at the level of the individual. We demonstrate HMLCP’s flexibility by comparing results from the whole sample with individual subjects and conclude that the HMLCP is a powerful model for estimating multivariate-multilevel unknown change point trajectories.},
}

@article {pmid41563458,
year = {2026},
author = {Jellinger, KA},
title = {The enigma of vascular dementia: current state and emerging perspectives.},
journal = {Journal of neural transmission (Vienna, Austria : 1996)},
volume = {},
number = {},
pages = {},
pmid = {41563458},
issn = {1435-1463},
abstract = {Vascular dementia (VaD) is a neurocognitive disorder attributed to different types of cerebrovascular disease (CVD) and characterized by complex and multifold pathophysiological mechanisms. The most common forms in the elderly brain are multi-infarct, subcortical and strategic infarct dementias caused by atherosclerosis, small vessel disease, and cerebral amyloid angiopathy (CAA), hereditary forms being rare. VaD prevalence, accounting for 5% to 20% of all dementias, in comparison to Alzheimer disease and mixed dementias declines due to recent improvement of cardiovascular risk factors. Its diagnosis relies on thorough clinical evaluations based on current classification criteria, neuroimaging, and fluid biomarkers. Epidemiological research has delineated multiple risk factors that contribute to the etiology of VaD. Its pathogenesis is complex and multifactorial, brain hypoperfusion and hypoxia being due to cerebrovascular pathologies. The lesions affect neuronal networks involved in many cognitive domains, e.g., thalamo-cortical, striato-subfrontal, and limbic systems. The sequence of events leading to VaD is defined by its clinical subtypes that are influenced by genetic disposition, aging, unhealthy lifestyle, and other factors, many of which are modifiable, highlighting the need for preventive measures and early intervention strategies. Newly developed biomarkers may help differentiate VaD from other dementias and unravel its pathomechanisms. Their integration into clinical practice and pathological assessment presents a prominent strategy for early assessment of VaD. Current treatments mainly target symptoms rather than slowing development and progression of VaD. This review will summarize recent findings about classification, epidemiology, risk factors, pathophysiology, biomarkers, and predictive and therapeutic strategies of VaD, in order to promote better clinical outcomes and enhanced quality of life for affected individuals.},
}

@article {pmid41575555,
year = {2026},
author = {Yu, S and Ye, Z and Zhao, W and Yu, X and Qiu, Y and Lin, K and Lu, T and Ge, L and Sun, J and Hua, R},
title = {Genetic evidence on chemical communication between gut microbiota and neurological and psychiatric disorders: a Mendelian randomization study.},
journal = {European archives of psychiatry and clinical neuroscience},
volume = {276},
number = {4},
pages = {1759-1773},
pmid = {41575555},
issn = {1433-8491},
support = {2019YFC1708601//the National Key Research and Development Program of China/ ; SZ2021ZZ14//the Specific Fund of State Key Laboratory of Dampness Syndrome of Chinese Medicine/ ; YN2018ZD04and2019-140//the Guangdong Provincial Key Laboratory of Research on Emergency in traditional Chinese medicine (TCM)/ ; },
abstract = {BACKGROUND: Accumulating evidence from clinical trials and preclinical studies revealed the importance of the microbiota-gut-brain axis (MGBA) in neurological and psychiatric disorders (NPDs). MGBA remains a blueprint for extended explorations. METHODS: We examine the bidirectional association between 5 NPDs (late-onset Alzheimer’s disease (AD), migraine, autism spectrum disorder (ASD), all anxiety disorder, depression) and gut microbiota (GM) via microbial-derived metabolites, neurotransmitter, and precursors including total branched-chain amino acids (BCAA), isoleucine, leucine, valine, acetate, tryptophan, kynurenine, glutamate, tyrosine, serotonin using two step Mendelian randomization. Five methods were performed, including inverse variance weighted, MR Egger regression, weighted median, weighted mode, and simple mode. The robustness of results was supported by Cochran’s Q test, the MR-Egger regression, the MR pleiotropy residual sum and outlier, and the leave-one-out method. RESULTS: After false discovery rate correction, we found elevated isoleucine in plasma as a risk factor for AD and elevated tyrosine in plasma as a risk factor for anxiety. Conversely, AD has genetically effect on a lower level of total BCAA, isoleucine, leucine, valine, glutamate, and tyrosine in plasma. We also found that Clostridia, Clostridiales, Sutterella, and Ruminococcus torques group were positively correlated with isoleucine. Elevated Sutterella abundance was found strongly positively correlated with ASD. Desulfovibrionales and Desulfovibrionaceae were found strongly positively correlated with AD. Pathways of Clostridia/Clostridiales/Ruminococcus torques group/Sutterella- isoleucine- AD were established with mediating percentages ranging from − 54.265% to 132.908%. CONCLUSION: Our study elucidates how chemical signalling bridges communication between GM and NPDs, paving avenues for microbiota-based treatment.},
}

@article {pmid41603981,
year = {2026},
author = {Raswanthiya, SP and Fernandes, OP and Mathew, MP and Balgote, PJ and Sivaraman, J},
title = {Decoding BDNF in neurodevelopmental, neurodegenerative, and neurological disorders: mechanisms and therapeutic perspectives.},
journal = {Molecular biology reports},
volume = {53},
number = {1},
pages = {330},
pmid = {41603981},
issn = {1573-4978},
abstract = {Brain-Derived Neurotrophic Factor (BDNF) is an essential neurotrophin involved in neuronal survival, synaptic plasticity, and neurogenesis, critical for normal brain function as well as the pathology of neurological and psychiatric disorders. It primarily functions by activating TrkB receptors, which subsequently modulate intracellular signalling pathways such as PI3K-Akt, Ras-MAPK, and PLC-γ1. The expression of BDNF is precisely controlled by genetic, epigenetic, and transcriptional mechanisms, with environmental and activity-dependent factors providing further modulation. However, it is worth noting that BDNF dysregulation has been linked to major diseases such as depression, schizophrenia, autism spectrum disorder, epilepsy, Alzheimer’s disease (AD), and Parkinson’s disease (PD), and depression, with growing evidence supporting its use as a biomarker for disease monitoring and treatment. This review provides a comprehensive overview of BDNF synthesis, regulation, and signalling mechanisms, highlighting its context-dependent roles in both health and disease. It also examines the role of BDNF in cerebellar development, specifically its effects on granule cells, Purkinje cells, and interneurons govern neuronal survival, migration, and synaptic refinement, and its disruption may predispose to neuropsychiatric vulnerability. While BDNF modulation correlates with clinical outcomes, it remains unclear whether BDNF upregulation directly contributes to therapeutic efficacy or is merely an associated response. BDNF shows promise as a diagnostic biomarker and therapeutic target, merging mechanistic and clinical insights, but requires further research for full potential in precision medicine.},
}

@article {pmid41636819,
year = {2026},
author = {Fu, H and Feng, J and Zhang, X and Tian, L and Sun, S and Bo, H and He, C and Wang, X},
title = {Memantine mitigates radiation-induced cognitive impairment by modulating AKT/GSK3β signaling.},
journal = {Radiation and environmental biophysics},
volume = {65},
number = {1},
pages = {257-269},
pmid = {41636819},
issn = {1432-2099},
support = {NO.HYZHXM02004//State Key Laboratory of Space Medicine Fundamentals and Application, China Astronaut Research and Training Center/ ; xcxjh20230610//Foundation of the Graduate Innovation Center, Nanjing University of Aeronautics and Astronautics/ ; },
abstract = {Memantine hydrochloride (MH), primarily employed in the clinical treatment of Alzheimer’s disease (AD), has been reported to exert beneficial effects on radiation-induced cognitive impairment; however, its underlying mechanisms have not been fully elucidated. In this study, a mouse model of radiation-induced injury was established. ICR(Institute of Cancer Research) mice were divided into six groups: control, 8 Gy irradiation, prophylactic 20 mg/kg + 8 Gy, prophylactic 40 mg/kg + 8 Gy, post-irradiation 8 Gy + 20 mg/kg, and post-irradiation 8 Gy + 40 mg/kg. Behavioral assessments indicated that ionizing radiation induced spatial cognitive deficits, which were ameliorated by MH administration. Morphological analyses revealed neuronal damage, synaptic injury, and demyelination in the hippocampal dentate gyrus (DG) region, which were markedly attenuated following MH treatment. Western blot analysis demonstrated that radiation upregulated dopamine D2 receptor (D2R) and β-arrestin 2 expression, suppressed PP2A expression, promoted AKT dephosphorylation, and led to GSK3β overactivation, along with increased expression of MBP and PLP1—potential mechanisms underlying radiation-induced cognitive impairment. MH administration downregulated D2R and β-arrestin 2, enhanced PP2A-AKT interaction, reduced GSK3β activity, and upregulated MBP and PLP1 expression. Notably, prophylactic administration conferred greater neuroprotection than post-irradiation treatment. These findings provide preliminary insight into the protective mechanisms of MH against radiation-induced cognitive impairment and offer a basis for future studies in radiation neuroprotection.},
}

@article {pmid41670842,
year = {2026},
author = {Majumder, D},
title = {Immune cell dynamics in neurological disorders: from inflammation to microgliopathy and Neuron-Glia crosstalk.},
journal = {Molecular biology reports},
volume = {53},
number = {1},
pages = {378},
pmid = {41670842},
issn = {1573-4978},
abstract = {The immune system is a complex network of cells and molecules that preserves homeostasis and provides defence against pathogens. Within the central nervous system (CNS), immune cells perform distinct yet integrated roles, balancing neuronal survival with inflammatory responses. Neuroinflammation is a hallmark of several neurological disorders, where immune activation may become maladaptive and drive neurodegeneration. Microglia, the resident macrophage-like immune cells of the brain, represent a unique interface between immune and neural function. They regulate synaptic pruning, release trophic factors, and respond to injury; however, their chronic or patchy activation leads to microgliopathy, an emerging pathological state underpinning diseases such as Alzheimer’s disease (AD), Parkinson’s disease (PD), multiple sclerosis (MS), and ischemic stroke. This review traces the evolution of immune involvement from peripheral to central contexts, examines microglial signalling mechanisms in health and disease, and highlights how dysregulated neuron–microglia communication contributes to disease pathology. This review also explores biomarkers, signalling cascades such as NF-κB, MAPK, JAK/STAT, and calcium-mediated pathways, and discuss future perspectives on targeting microglial states for therapeutic intervention.},
}

@article {pmid41677822,
year = {2026},
author = {Choi, S and Choi, Y and Cheon, DY and Lim, JS and Han, KD and Lee, M},
title = {Association between unhealthy lifestyles and young-onset dementia: a nationwide cohort study.},
journal = {European archives of psychiatry and clinical neuroscience},
volume = {},
number = {},
pages = {},
pmid = {41677822},
issn = {1433-8491},
support = {RS-2023-00223501//National Research Foundation of Korea/ ; },
abstract = {OBJECTIVES: The link between clusters of unhealthy lifestyle behaviors and the risk of young-onset dementia remains unclear. This study aimed to assess the impact of multiple unhealthy lifestyle behaviors on the risk of developing young-onset dementia, including all-cause dementia, Alzheimer’s disease, and vascular dementia. METHODS: We analyzed nationwide Korean National Health Insurance Service data from individuals aged 40–60 years who underwent health screening in 2009 and were followed until 2018 or age 65. The Unhealthy Lifestyle Behavior Score (ULBS) was derived from smoking, heavy drinking, and non-regular exercise (physical inactivity). Outcomes included all-cause young-onset dementia, Alzheimer’s disease, and vascular dementia. RESULTS: The study included 1,979,509 patients (average age 49.05 ± 5.96, 51.27% male), with distribution across ULBS categories as follows: 14.5% ULBS 0, 62.3% ULBS 1, 19.5% ULBS 2, and 3.7% ULBS 3. After adjusting for multiple variables, patients with ULBS 1, 2, and 3 showed a significantly increased risk of all-cause young-onset dementia compared to those with ULBS 0 in a dose-response relationship. (Adjusted hazard ratio [95% CI]: 1.147 [1.077–1.221], 1.486 [1.376–1.604], and 1.909 [1.704–2.138], respectively). INTERPRETATION: The accumulation of unhealthy lifestyle behaviors is significantly linked to a higher risk of all-cause young-onset dementia. These findings underscore the importance of promoting healthy lifestyle choices to mitigate the risk of developing young-onset dementia.},
}

@article {pmid41691358,
year = {2026},
author = {Scott, HM and Price, L and Ogden, M and Bharadia, T and Burke, P and Horne, R and Harding-Bell, A and Tonkin, A and Thomson, A},
title = {A rapid evaluation of the reporting and publishing practices of patient and public involvement and engagement in health research within a UK university institute.},
journal = {Research involvement and engagement},
volume = {12},
number = {1},
pages = {},
pmid = {41691358},
issn = {2056-7529},
abstract = {BACKGROUND: Patient and Public Involvement and Engagement is important to ensure research addresses the issues that matter most to patients and the public. However, reporting and publishing of these activities is variable and inconsistent. This rapid review aimed to assess how effectively, consistently, and transparently Patient and Public Involvement and Engagement is reported on in papers published by authors affiliated with a heath research institute at a UK Russell Group university. METHODS: A rapid review of all papers published by institute-affiliated authors (1st August 2021 to 31st December 2024) identified using PubMed. We also consulted with a group of patient co-authors to understand their experiences of being a Patient and Public Involvement and Engagement co-author in collaboration with researchers from the same institute. RESULTS: We retained and reviewed 523 papers for inclusion of Patient and Public Involvement and Engagement. There was significant variation in the reporting across the papers included. Overall, 21% of papers had reference to Patient and Public Involvement and Engagement activity in the main body of the paper, and 17% of papers included Patient and Public Involvement and Engagement in the acknowledgements. In terms of co-authorship, 5% of papers included an author with an affiliation to a charity/non-governmental organisation that represented Patient and Public Involvement and Engagement -related interested, e.g. Alzheimer’s Society, Caribbean and African Health Network and 1% of papers included a patient/lived-experience author. A total of 97% of papers were published open access but only 10% of articles included in this review had a plain English or lay summary. Only one paper included a published GRIPP2 form. The Patient and Public Involvement and Engagement group reviewed and contextualised our findings, supporting analysis and development of seven key recommendations to improve comprehensive, consistent, and transparent reporting of Patient and Public Involvement and Engagement in health research at an institute level. CONCLUSIONS: This work demonstrates the challenges that Patient and Public Involvement and Engagement faces and the importance of institutions reflecting on the practices of their academics, and the structures they put in place to encourage good and equitable practices of working with patents and the public.},
}

@article {pmid41708961,
year = {2026},
author = {Tahmasebi, F and Safarian, A and Asl, ER and Vahidinia, Z and Barati, S},
title = {The effect of astrocyte depletion and repopulation approaches in pathological condition of CNS.},
journal = {Acta neurologica Belgica},
volume = {},
number = {},
pages = {},
pmid = {41708961},
issn = {2240-2993},
abstract = {Astrocytes a highly diverse and functionally important class of glial cells in the central nervous system (CNS), are central to maintaining homeostasis, modulating synaptic activity, and supporting neuronal health. These cells exhibit remarkable heterogeneity, with distinct subtypes such as protoplasmic and fibrous astrocytes, each playing specialized roles in CNS physiology. Under pathological conditions, including neurodegenerative diseases such as Alzheimer’s, Parkinson’s, and multiple sclerosis (MS), astrocytes undergo reactive transformations, and adopt either neurotoxic (A1) or neuroprotective (A2) phenotypes. While A1-reactive astrocytes contribute to synaptic dysfunction and exacerbate neuroinflammation, A2-reactive astrocytes promote tissue repair and neuronal survival. Studies using astrocyte depletion models show that their absence disrupts extracellular matrix stability, compromises blood-brain barrier (BBB) integrity, and enhances neuroinflammatory responses, underscoring their dual role in disease progression. Pharmacological strategies such as L-AAA or ganciclovir-mediated depletion highlight the therapeutic potential of modulating astrocyte activity to influence disease outcomes. By unraveling the complexity of astrocyte diversity and its dynamic responses in health and disease, researchers can uncover novel therapeutic targets for a wide range of CNS disorders.},
}

@article {pmid41817635,
year = {2026},
author = {Luo, Z and Zhong, Y and Zhao, C and Ouyang, C and Ren, J and Peng, H},
title = {The correlation between olfactory bulb volume and T&T odor threshold: a systematic review and meta-analysis.},
journal = {Brain imaging and behavior},
volume = {20},
number = {2},
pages = {},
pmid = {41817635},
issn = {1931-7565},
support = {2023A1515010268//Natural Science Foundation of Guangdong Province/ ; },
abstract = {This meta-analysis aims to quantitatively assess the correlation between olfactory bulb (OB) volume measured by magnetic resonance imaging (MRI) and the T＆T olfactometer identification threshold, with subgroup analyses conducted in patients with neurodegenerative disorders and healthy individuals. We searched PubMed, Web of Science, Embase, Cochrane Library, China Biology Medicine Disc (CBM), China National Knowledge Infrastructure (CNKI), Wanfang, and VIP databases for relevant studies. The procedure was under the guidance of the Preferred Systematic Reviews and Meta-Analyses Reporting Items (PRISMA) checklist. English or Chinese cross-sectional studies concerned with OB volume and olfactory function published before January 31, 2025, were searched in the data sources mentioned above. After study selection, data extraction, and the assessment of study quality, this meta-analysis was performed independently performed by two reviewers. Correlation coefficients were pooled using Fisher’s z transformation. Random- or fixed-effects models were applied according to heterogeneity. Subgroup analyses were conducted for neurodegenerative disorder patients and healthy controls. Fifteen studies concerning 1289 subjects were qualified for the study, including 824 patients who suffered from olfactory deficiency and 465 healthy individuals. Fourteen studies were of high quality, and one study was of medium quality. An overall correlation between OB volume and T＆T olfactory test score (r=-0.64, P= 0.01) was detected. Further subgroup analysis showed significant correlations among cognitive syndrome patients (mild cognitive impairment (MCI) and Alzheimer’s disease (AD)) (r=-0.84,P=0.82), Parkinson’s disease patients (PD) (r=-0.70,P=0.01), healthy subjects (r=-0.61,P=0.97). According to meta-regression analysis, age was not a source of heterogeneity. The result supported a significant correlation between OB volume and T＆T odor identification threshold. OB volume measurement may be a potential alternative for the T＆T odor identification test, especially in neurodegenerative individuals.},
}

@article {pmid41832594,
year = {2026},
author = {Gasparre, D and Habich, A and Mulet-Pons, L and Yanez-Perez, R and Westman, E and Barroso, J and Vaque-Alcázar, L and Bartres-Faz, D and Taurisano, P and Ferreira, D and , },
title = {The cognitive connectome of men and women: a study on sex differences across three cohorts.},
journal = {Biology of sex differences},
volume = {17},
number = {1},
pages = {},
pmid = {41832594},
issn = {2042-6410},
abstract = {BACKGROUND: Cognitive processes are essential for efficient daily functioning. Demographic factors such as age and education influence cognitive performance. However, the impact of sex on cognition is less understood and previous research has reported inconsistent findings. We investigated sex differences in cognitively unimpaired adults in three cohorts, using two complimentary approaches: a univariate approach to compare direct performance across cognitive domains and the multivariate approach of graph theory to compare global and nodal features as well as the modular organization of cognitive connectomes. METHODS: We included 4,259 cognitively unimpaired participants (334 from the GENIC cohort, 3,703 from the National Alzheimer’s Coordinating Center [NACC], and 222 from the Alzheimer’s Disease Neuroimaging Initiative [ADNI]). Cognitive variables were corrected for age and education, and cognitive connectomes were constructed using Spearman correlation coefficients. Sex differences in cognitive performance were examined through ANCOVAs as well as global and nodal network measures. RESULTS: Univariate analyses showed significant sex differences in three out of five cognitive domains across cohorts, mainly of small effect sizes. Graph theory analyses revealed minimal sex differences in cognitive module organization and no significant differences on global network measures, except for a higher modularity observed in women compared to men in the NACC. In contrast, nodal analyses revealed sex differences in several network measures. CONCLUSIONS: Sex differences in cognition seem to be of small effect size and limited to specific cognitive domains or cognitive variables, while the overall organization and global features of cognitive connectomes were largely comparable between men and women. Future studies should clarify whether men and women may rely on slightly different cognitive strategies to approach cognitive tasks without overt differences in cognitive ability.},
}

@article {pmid41863721,
year = {2026},
author = {Maidh, A and Kalra, P and Khan, H and Silakari, P and Grewal, AK},
title = {Circadian disruption as a driver and target in neurodegenerative diseases: from molecular mechanisms to chronotherapeutic strategies.},
journal = {Metabolic brain disease},
volume = {41},
number = {1},
pages = {},
pmid = {41863721},
issn = {1573-7365},
abstract = {The Circadian System is a complex network of coordinated clocks that regulates the organism’s internal clock in synchronisation with the outside world. These rhythms are controlled by genetically controlled positive and negative transcriptional-translational feedback loops (TTFL) that generate 24-hour oscillations in the protein level and mRNA of core circadian components. Circadian disruption is recognised as a significant contributor to the molecular pathogenesis of neurodegenerative illnesses, as disease-specific alterations in clock gene expression and melatoninergic signalling have been identified as possible early-stage molecular indicators. Emerging evidence suggests a link between dysregulated circadian rhythms and neurodegenerative diseases, implying that the changes in circadian function may play a critical role in the development and progression of neurodegenerative diseases. The correlation between circadian rhythm and neurodegeneration is highly promising for developing treatment and promoting healthy lifestyle measures. This review article primarily focuses on how abnormalities in circadian rhythms may increase the risk of neurodegenerative diseases, including Alzheimer’s disease (AD), Parkinson’s disease (PD), Huntington’s disease (HD), and Amyotrophic Lateral Sclerosis (ALS). Applying knowledge from pre-clinical and translational research on neurodegenerative diseases is crucial for lowering the risks of neurodegeneration and improving the symptoms and quality of life of people with neurodegenerative diseases through approaches that restore circadian rhythm in the context of precision medicine. Understanding this interaction holds promise for developing therapeutic approaches to support a healthy lifestyle.},
}

@article {pmid41894075,
year = {2026},
author = {Kuwar, OK and Tejpal, S and Sharma, V and Sharma, A and Rao, A and Attri, M and Pallavi, and Dhingra, MS},
title = {Therapeutic potential of sulforaphane in neurodegenerative diseases: mechanistic Insights into Nrf2, NF-κB, TrkB, SIRT1, MAPK, and JAK/STAT signalling pathways.},
journal = {Molecular biology reports},
volume = {53},
number = {1},
pages = {},
pmid = {41894075},
issn = {1573-4978},
abstract = {Neurodegenerative diseases, including Alzheimer’s, Parkinson’s, Huntington’s, and amyotrophic lateral sclerosis, are chronic and progressive disorders distinguished by neuronal dysfunction, oxidative stress, neuroinflammation, and abnormal protein aggregation. Due to the multifactorial nature of these disorders, current pharmacotherapies provide limited symptomatic relief without altering disease progression. Sulforaphane, a naturally occurring isothiocyanate abundant in cruciferous vegetables like broccoli, has emerged as a potent neuroprotective compound owing to its pleiotropic effects on key cellular signalling pathways. This review provides a thorough overview of the mechanistic insights underlying SFN’s neuroprotective potential, with a focus on the modulation of key signalling pathways such as Nrf2/ARE, NFĸB, BDNF/TrkB, SIRT1, MAPK, and JAK/STAT. Through the activation of antioxidant defenses and suppression of inflammatory cascades, SFN effectively mitigates neuronal damage and supports cellular homeostasis. Preclinical studies consistently demonstrate SFN’s ability to attenuate oxidative stress, inhibit apoptosis, preserve mitochondrial function, and improve neurobehavioral outcomes. While limited clinical evidence supports its safety and bioactivity, further investigations are needed to establish its therapeutic utility in human populations. Overall, SFN represents a promising natural compound with significant potential for the prevention and management of neurodegenerative diseases through multi-targeted pathway modulation.},
}

@article {pmid41920376,
year = {2026},
author = {Hussain, MA and Naheed, S and Saeed, K and Karim, A and Ahmad, F and Qaisar, R and Alkahtani, SA},
title = {Can Difficulty Standing from a Chair Signal Early Risk of Chronic Illness? Insights from a Multi-Wave European Cohort.},
journal = {Calcified tissue international},
volume = {117},
number = {1},
pages = {},
pmid = {41920376},
issn = {1432-0827},
support = {ORF2026 - 277//Deanship of Scientific Research, King Saud University/ ; },
abstract = {BACKGROUND: Difficulty rising from a chair may indicate early functional decline and vulnerability to adverse health outcomes. While widely used in geriatric assessments, its role in predicting diverse health domains using large-scale longitudinal data remains underexplored. METHODS: We analysed 52,541 adults aged ≥ 50 years from the Survey of Health, Ageing and Retirement in Europe (SHARE), Waves 5–9 (2013–2022). Chair-rise difficulty was assessed at baseline using a single self-reported item: “Getting up from a chair after sitting for long periods.” Responses were dichotomized (0 = no difficulty, 1 = difficulty). Incident outcomes included musculoskeletal, cardiometabolic, cardiovascular, neurological, and psychosocial conditions, as well as low handgrip strength (HGS) and low quality of life (QoL). Logistic regression models estimated odds ratios (OR) adjusted for baseline comorbidity, BMI, age, sex, and country. RESULTS: At baseline, 18.6% reported chair-rise difficulty. Adjusted models showed higher odds of low QoL (OR 1.46, 95% CI 1.28–1.64), elevated depressive symptoms (OR 1.27, 1.12–1.43), and osteoarthritis (OR 1.25, 1.12–1.38). Associations with HGS and rheumatoid arthritis were small and imprecise. Cardiometabolic and vascular outcomes were attenuated or inversely associated after adjustment (e.g., hypertension: OR 0.47; diabetes: OR 0.64). Alzheimer’s disease and stroke showed no clear association. CONCLUSION: Self-reported chair-rise difficulty is a simple, scalable indicator of psychosocial burden and musculoskeletal morbidity in older adults. Its feasibility for extensive surveys supports its use in population-level screening, although associations with cardiometabolic outcomes require cautious interpretation.},
}

@article {pmid41940962,
year = {2026},
author = {Buchinger, D and Aleksic, T and Brücke, C and Berger-Sieczkowski, E and Nakuz, T and Traub-Weidinger, T and Milenkovic, I},
title = {Longitudinal serum uric acid levels are not associated with dopamine transporter binding in progressive supranuclear palsy.},
journal = {Journal of neural transmission (Vienna, Austria : 1996)},
volume = {},
number = {},
pages = {},
pmid = {41940962},
issn = {1435-1463},
abstract = {Progressive supranuclear palsy (PSP) causes rapid motor decline and severe dopaminergic dysfunction. While uric acid (UA) may act as a neuroprotective antioxidant in some neurodegenerative disorders (like Parkinson’s disease), its role in PSP remains unclear. This study evaluated the relationship between serum UA levels, measured cross-sectionally and longitudinally, and striatal dopamine transporter binding in PSP. A total of 33 PSP patients with repeated pre-[123I]FP-CIT SPECT UA measurements, along with 30 healthy control individuals and 30 patients with Alzheimer’s disease (AD), were retrospectively analyzed. Group and sex effects were analyzed with t tests and ANOVA. Effects of mean UA and longitudinal UA trajectories on FP-CIT SPECT binding in PSP were modeled using linear mixed-effects models and regressed against binding in four regions (caudate and putamen), separated into more-affected and less-affected side for both sexes. A Bayesian two-stage measurement-error model provided sensitivity analysis. UA was significantly lower in PSP (4.98 mg/dl) and AD (4.69 mg/dl) compared to healthy controls (5.71 mg/dL; p = 0.001). Sex had a significant effect on UA (F(1, 89) = 9.38, p = 0.003, partial η2 = 0.10), however, this effect was significant only in PSP (p< 0.001). Within PSP, UA–[123I]FP-CIT SPECT correlations were weak and nonsignificant, and neither UA intercept nor slope predicted [123I]FP-CIT SPECT binding (all p > 0.7). Bayesian estimates corroborated the absence of a credible relationship. In the present cohort, serum UA is reduced in PSP, primarily in females, but neither mean levels nor longitudinal changes are related to striatal [123I]FP-CIT SPECT binding, suggesting no clear association with dopaminergic degeneration in PSP, without precluding a potential role of uric acid at other disease stages.},
}

@article {pmid41945111,
year = {2026},
author = {Lai, Z and Zhang, B and Fu, Z and Li, R and Qian, Y and Zhang, Y and Xu, P and Du, Y},
title = {Research advances on Cordyceps sinensis and its components in relation to omics biomarkers for the neurological disorders.},
journal = {Die Naturwissenschaften},
volume = {113},
number = {3},
pages = {},
pmid = {41945111},
issn = {1432-1904},
support = {2026ZL0010//Zhejiang Traditional Chinese Medicine Science and Technology Program of China/ ; 82202605//National Natural Science Foundation of China/ ; 2023, DU YAOQIANG//Zhejiang Provincial Special Support Program for Cultivation of High-Level Innovative Health Talents of China/ ; },
abstract = {Cordyceps is a traditional medicinal fungus belonging to the species Ophiocordyceps sinensis. It grows in the alpine ecological zone of the Tibetan Plateau and exhibits dual characteristics of both insects and fungi. The primary species include Cordyceps sinensis and Cordyceps militaris. Rich in bioactive components such as cordycepin, polysaccharides, adenosine, and peptides, cordyceps demonstrates broad applications in immune regulation, anti-tumor activity, anti-inflammatory, and neuroprotection. Cordyceps sinensis and its components show great therapeutic potential in neurological diseases such as epilepsy, Alzheimer’s disease and Parkinson’s disease through multi-level and multi-target actions However, current research faces challenges including unclear mechanisms of action and insufficient clinical translation. In this review, we analyze the molecular mechanisms underlying cordyceps’ neuroprotective effects, including the regulating of apoptosis, improvement of mitochondrial function, and promoting of nerve repair. Utilizing network pharmacology, we explore the multi-targeted actions of cordyceps and predict the key pathways. Further we summarize the research progress in the integrated multi-omics analyses (genomics, transcriptomics, proteomics and metabolomics), to reveal the synergistic roles of cordyceps components in treating neurological disorders and identify potential molecular biomarkers. Additionally, we highlight the findings from preclinical experiments and animal models on cordyceps-based drugs, discussing their advantages and challenges for clinical application. Future studies should prioritize systematic exploration of standardized drug development, advanced multi-omics integration, and rigorous clinical trials. This will provide a more robust scientific foundation and practical guidance for the treatment of neurological diseases with cordyceps.},
}

@article {pmid41945254,
year = {2026},
author = {Brahadeeswaran, S and Sreedhar, S and Ramesh, S and Tamizhselvi, R},
title = {Targeting ferroptosis mediated cell death: a novel strategy for mitigating acute pancreatitis.},
journal = {Molecular biology reports},
volume = {53},
number = {1},
pages = {},
pmid = {41945254},
issn = {1573-4978},
abstract = {Acute pancreatitis (AP) is a common and potentially fatal inflammatory disorder characterized by pancreatic tissue inflammation and necrosis. Though our understanding of its pathogenesis has advanced, effective therapeutic approaches remain elusive, with many potential strategies still unexplored. Ferroptosis, an iron-dependent form of regulated cell death marked by the accumulation of lipid peroxides, plays a crucial role in tissue damage and inflammation. It has been implicated in various disorders, including neurodegenerative diseases like Alzheimer and Parkinson, ischemia-reperfusion injury, cancer, and other metabolic diseases. In AP, ferroptosis exacerbates disease progression by promoting pancreatic inflammation and cellular damage, thereby worsening clinical outcomes. However, its role in AP remains insufficiently explored due to the complexity of its molecular mechanisms and the limited availability of targeted interventions. This comprehensive review summarizes the factors involved in ferroptosis, such as glutathione depletion, defective lipid peroxide detoxification, dysregulation of iron homeostasis, and discusses established and emerging biomarkers. Furthermore, we discuss the FDA approved drugs and other investigational compounds targeting ferroptosis, along with the role of pro-inflammatory mediators, lipid peroxidation products, glutathione peroxidase 4 (GPX4), and iron regulatory proteins. The influence of PAMPs and DAMPs on ferroptosis signaling along with the potential role of epigenetic regulation is also highlighted. Overall, this review provides an integrated perspective on the role of ferroptosis in AP and emphasizes its potential as a novel therapeutic approach to mitigate AP. The goal is to use these insights into clinical practice to reduce the burden of this difficult condition.},
}

@article {pmid41961418,
year = {2026},
author = {Priyadarshni, A and Sharma, R and Bora, KS and Dewangan, HK},
title = {Pharmacological insights into deoxyelephantopin: a multifunctional sesquiterpene with therapeutic promise in cancer and neurodegenerative disorders.},
journal = {Molecular biology reports},
volume = {53},
number = {1},
pages = {},
pmid = {41961418},
issn = {1573-4978},
abstract = {Deoxyelephantopin (DET), a sesquiterpene lactone predominantly isolated from Elephantopus scaber, has garnered attention for its emerging multifaceted potential bioactivity in both oncology and neurobiology. This review synthesizes current preclinical evidence on the pharmacological actions of DET and elucidates the pharmacological spectrum of DET, highlighting its potent anticancer, anti-inflammatory, hepatoprotective, and neuroprotective activities. DET demonstrates broad-spectrum cytotoxicity across various cancer cell lines, including breast, colon, pancreatic, and osteosarcoma, inducing apoptosis via mitochondrial pathways, generating reactive oxygen species (ROS), and modulating cell cycle regulators. Mechanistically, inhibits key oncogenic and inflammatory signalling cascades such as the NF-κB, PI3K/AKT/mTOR, MAPK, and STAT3 cascades, consequently inhibiting tumour proliferation, metastasis, and resistance to apoptosis. In preclinical models of neurodegeneration, DET exhibits pronounced neuroprotective effects against LPS-induced degeneration and associated cognitive decline. DET attenuates neuroinflammatory responses by diminishing pro-inflammatory mediators such as (iNOS, COX-2, TNF-α, IL-6) and increases anti-inflammatory cytokines (IL-4, IL-10) as well as maintains synaptic integrity with the upregulation of synaptic markers (PSD-95, SYP). Furthermore, DET mitigates neuronal apoptosis by inhibiting key apoptotic proteins (PARP-1, caspase 3), underscoring its preclinical potential for conditions like Alzheimer’s (AD) and Parkinson’s (PD) diseases. The review also discusses the translational potential of DET, emphasizing the need for dose optimization, clinical evaluation, and the exploration of synergistic therapies and analogue developments to overcome pharmacokinetic limitations. Collectively, the evidence positions DET as a versatile bioactive molecule with significant prospects for the development of novel therapeutics targeting various neurodegenerative diseases, warranting further investigation in clinical interventions. Nevertheless, no clinical data are available, and all existing evidence is based on in vitro and animal research. Rigorous pharmacokinetic, toxicological, and preclinical studies are needed before classifying deoxyelephantopin as a viable therapeutic agent.},
}

@article {pmid41964100,
year = {2026},
author = {Trigo-Alonso, P and Luengo, E and Fernández-Mendivíl, C and Viqueira, L and García-Magro, N and Del Sastre, E and Bernal, JA and Negredo, P and López, MG},
title = {Timing of microglial ablation determines protection from tau-mediated neurodegeneration and cognitive decline.},
journal = {Acta neuropathologica communications},
volume = {},
number = {},
pages = {},
doi = {10.1186/s40478-026-02291-1},
pmid = {41964100},
issn = {2051-5960},
support = {FPU16/03239//Ministerio de Ciencia, innovacion y universidades/ ; FPU20/03747//Ministerio de Ciencia, innovacion y universidades/ ; FPU18/00630//Ministerio de Ciencia, innovacion y universidades/ ; PID2023-151105OB-I00//Ministerio de Ciencia, innovacion y universidades/ ; PID2021-125039NB-I00//Ministerio de Ciencia, innovacion y universidades/ ; PDC2022-133809-I00 and PID2021-125986OB//Ministerio de Ciencia, innovacion y universidades/ ; P2022/BMD-7230//Comunidad de Madrid/ ; },
abstract = {Tauopathies comprise a diverse group of neurodegenerative diseases characterized by intracellular aggregation of the microtubule-associated protein tau, neuroinflammation, and neuronal loss. Since tau pathology shows the strongest correlation with cognitive decline in Alzheimer’s disease, understanding how microglia contribute to tau-mediated neurodegeneration remains a critical question. Here, we validated a tauopathy mouse model that progressively recapitulates key pathological features of tauopathy. Bilateral hippocampal injection of AAV-hTauP301L (AAV-hTau) resulted in widespread tau accumulation, early and sustained gliosis, complement component 1q (C1q) deposition, progressive reduction of hippocampal layer thickness and cognitive deficits. Notably, we observed marked activation of Cluster of Differentiation 68 (CD68+) microglia and the emergence of Complement 3 (C3+) reactive astrocytes, which developed in parallel over time. To dissect the role of microglia in tau-driven pathology, we depleted them at different stages using the colony-stimulating factor 1 receptor (CSF1R) inhibitor PLX5622. Microglial ablation conferred significant neuroprotection, with early depletion effectively mitigating cognitive decline and structural changes in hippocampal layers supporting an important role for microglial activation in tauopathy progression.Neuroprotection may result from decreased levels of insoluble p-tau oligomers, partial blockade of C3+ astrocyte induction and attenuation of microglial reactivity. Overall, our results support the potential of microglia-directed interventions as a promising therapeutic avenue for mitigating disease progression in tauopathies.},
}

@article {pmid41995815,
year = {2026},
author = {Pham, W and Jarema, A and Rim, D and Chen, Z and Khlif, M and Macefield, V and Henderson, L and Brodtmann, A},
title = {A comprehensive framework for automated segmentation of perivascular spaces in brain MRI with the nnU-Net.},
journal = {Neuroradiology},
volume = {},
number = {},
pages = {},
pmid = {41995815},
issn = {1432-1920},
abstract = {BACKGROUND: Enlargement of perivascular spaces (PVS) is common in cerebral small vessel disease, Alzheimer’s disease, and Parkinson’s disease, reflecting impaired clearance pathways. While MRI provides a means to quantify perivascular spaces, manual annotation remains time-consuming and labour-intensive. Thus, there is a need for accurate automated MRI-based PVS segmentation methods. AIM: To optimise the nnU-Net, a deep-learning framework, for PVS segmentation. METHODS: 30 T1-weighted (T1w) MRI images acquired on three different scanners were used. PVS in the white matter (WM) and basal ganglia (BG) were manually labelled via a sparse annotation strategy and used to optimise the nnU-Net for T1w PVS segmentation. The same pipeline was applied to T2-weighted (T2w) images. Additionally, we trained T1w+FLAIR and T2w+FLAIR models to simultaneously segment PVS and white matter hyperintensities (WMH). Performance was assessed with 5-fold cross validation using the Dice similarity coefficient (DSC). RESULTS: A voxel-spacing agnostic model (mean DSC = 64.3 ± 3.3%) outperformed models that resampled images to a common resolution (DSC = 40.5–55%). Training on PVS segmentations derived from preprocessed T1w images substantially improved performance (DSC = 78.3 ± 1.7%). The T2w model performed best overall (DSC = 84.7 ± 1.3%), especially for WM-PVS (DSC = 90.4 ± 0.9%) compared to BG-PVS (DSC = 79.1 ± 2%). Multimodal models achieved DSCs of 75.6 ± 3.4% (T1w+FLAIR) and 77.5 ± 2.7% (T2w+FLAIR). CONCLUSIONS: Our deep learning models provide a robust framework for automated PVS quantification across MRI modalities.},
}

@article {pmid42010038,
year = {2026},
author = {Nakatsuji, M and Shibano, M and Fujimori, K},
title = {Antioxidant Activity of Flavonoid Glabranin by Upregulating Antioxidant Gene Expression via MEK/ERK and PI3K/Akt Pathways in Human Neuroblastoma SH-SY5Y Cells.},
journal = {Neurochemical research},
volume = {51},
number = {3},
pages = {},
pmid = {42010038},
issn = {1573-6903},
support = {25ak0101219h0202//Japan Agency for Medical Research and Development/ ; },
abstract = {Oxidative stress is associated with neuronal cell death in neurodegenerative diseases, including Alzheimer’s disease and Parkinson’s disease. Glabranin, a flavonoid found in the stems and leaves of Glycyrrhiza glabra (licorice), exhibits antioxidant and anti-inflammatory properties. However, the effect of glabranin on the antioxidant response and the underlying mechanism including the specific signaling pathways, remain unclear. In the current study, we investigated the protective effect of glabranin on hydrogen peroxide (H2O2)-induced neurotoxicity in human neuroblastoma SH-SY5Y cells and its underlying mechanisms. H2O2-induced death of SH-SY5Y cells was restored by glabranin in a concentration-dependent manner. The number of H2O2-increased apoptotic cells was reduced by co-treatment with glabranin. Moreover, glabranin attenuated H2O2-induced cleaved caspase-3/7 levels. In addition, glabranin decreased H2O2-induced intracellular ROS levels via promoting the nuclear translocation of nuclear factor erythroid 2-related factor 2 and upregulating the antioxidant gene expression. Furthermore, glabranin enhanced the phosphorylation of extracellular signal-regulated kinase (ERK) and protein kinase B (Akt) following H2O2 treatment. Inhibition of mitogen-activated protein kinase kinase (MEK)/ERK and phosphoinositide 3-kinase (PI3K)/Akt pathways abrogated glabranin-mediated elevation of antioxidant gene expression and neuroprotective effects. These findings suggest that glabranin mitigated H2O2-induced apoptosis by increasing the expression of antioxidant genes through activation of the MEK/ERK and PI3K/Akt pathways in SH-SY5Y cells. Therefore, glabranin has the potential to prevent and treat neurodegenerative diseases as an antioxidant agent.},
}

@article {pmid42045964,
year = {2026},
author = {Jha, V and Kalia, LV},
title = {LRRK2 and GBA1 in Lewy body diseases: neuropathological subtypes at opposite ends of a spectrum?.},
journal = {Molecular neurodegeneration},
volume = {21},
number = {1},
pages = {},
pmid = {42045964},
issn = {1750-1326},
abstract = {Lewy body diseases (LBDs), including Parkinson’s disease (PD), are defined by the presence of pathological intraneuronal α-synuclein aggregates but exhibit considerable heterogeneity in clinical course, neuropathology, and underlying mechanisms. This review summarizes neuropathological findings in PD associated with pathogenic variants in GBA1 and LRRK2 – the two most common genetic risk factors for PD – and highlights how these genetic forms represent neuropathological subtypes at opposite ends of a spectrum. GBA1-associated PD typically shows widespread Lewy pathology with cortical involvement and relatively limited Alzheimer-type co-pathology, while LRRK2-associated PD may occur with or without Lewy bodies and displays variability in tau and TDP-43 aggregates. We also examine how these genetic forms may serve as models for subtypes within idiopathic PD, including the potential existence of Lewy body-negative idiopathic PD. We propose a conceptual framework in which idiopathic PD encompasses GBA1-like and LRRK2-like subtypes, as well as intermediate forms with mixed pathologies. This perspective supports a shift toward biomarker-informed, mechanism-based classification of PD, beyond genetic labels alone, that may ultimately enable broader application of targeted therapeutic strategies.},
}

@article {pmid42050692,
year = {2026},
author = {Rahbek, MT and Kildegaard, H and Hallas, J and Ernst, MT and Lund, LC},
title = {Acetylcholinesterase inhibitors and the risk of delirium - a Danish nationwide register-based cohort study.},
journal = {Alzheimer's research & therapy},
volume = {},
number = {},
pages = {},
doi = {10.1186/s13195-026-02060-1},
pmid = {42050692},
issn = {1758-9193},
abstract = {BACKGROUND: Delirium is frequent in people with dementia and is linked to adverse outcomes. Disturbed cholinergic neurotransmission is implicated in its pathophysiology. We examined whether continuous use of acetylcholinesterase inhibitors (AChEIs) is associated with a reduced risk of incident delirium in patients with dementia. METHODS: Using Danish nationwide registries (2005–2024), we identified individuals ≥ 50 years initiating AChEIs. Continuous users (second prescription within 90 days) were compared with early discontinuers. Follow-up started 90 days after initiation and continued for up to 3 years. The outcome was a hospital discharge diagnosis of delirium (ICD-10 F05). Confounding was addressed using high-dimensional propensity score (hdPS) fine-stratification weighting, and Cox regression yielded hazard ratios (HRs) with 95% confidence intervals (CIs). RESULTS: Among 45,651 patients, 311 delirium events occurred among continuous users and 84 among early discontinuers, corresponding to incidence rates of 66 and 112 events per 10,000 person-years, respectively. The hdPS-weighted HR for delirium was 0.72 (95% CI 0.54–0.96). Results were consistent across sensitivity analyses and in patients with Alzheimer’s disease HR 0.68 (95% CI 0.48–0.96). A negative control outcome showed no association. CONCLUSIONS: Continuous AChEI treatment was associated with a lower risk of delirium. Findings support a potential benefit of maintaining therapy in routine dementia care, and possibly even in patients with minor intolerance to acetylcholinesterase inhibitors.},
}

@article {pmid42076797,
year = {2026},
author = {Martineau, A and Conant, M and Myers Barnett, K and Norman, M and Lanza, E and Snowball, E and Forget, MF and Bruneau, MA and Couture, V and Nguyen, QD and Ducharme, S and Desmarais, P},
title = {Barriers to Clinical Care in Frontotemporal Dementia and Related Disorders: A Cross-Sectional Survey of Patients and Caregivers' Journey in the Canadian Healthcare System.},
journal = {The Canadian journal of neurological sciences. Le journal canadien des sciences neurologiques},
volume = {},
number = {},
pages = {1-13},
doi = {10.1017/cjn.2026.10609},
pmid = {42076797},
issn = {0317-1671},
abstract = {BACKGROUND: Frontotemporal dementia (FTD) and related disorders are major causes of young-onset dementia (YOD), yet caregivers often face delayed diagnosis and high distress. Data on the Canadian caregiving experience in FTD remain scarce. This study aimed to describe caregivers' profiles and experiences navigating diagnosis and care and to identify factors associated with diagnostic delay and caregiver burden.

METHODS: We conducted an online survey (June 2023-May 2024) of adults providing care to individuals with FTD. The survey captured sociodemographic characteristics, diagnostic journey, healthcare access and caregiver burden (Zarit Burden Interview, ZBI). Neuropsychiatric symptoms (NPS) were assessed using the Neuropsychiatric Inventory. Descriptive and multivariable analyses examined factors associated with delayed diagnosis and burden.

RESULTS: Ninety-seven caregivers participated (82.5% women; mean age 61.4 ± 13.1 years). Care recipients (58.8% men; mean age 72.9 ± 9.7 years) most commonly had behavioural-variant FTD (57.7%). Mean time to diagnosis was 3.1 ± 4.5 years and was longer for YOD, those without family history and those initially misdiagnosed. Nearly half were initially misdiagnosed as psychiatric disorders or Alzheimer. Women caregivers reported significantly longer diagnostic delays (+20 months, p = 0.005). Most caregivers reported substantial burden (mean ZBI = 23.1 ± 8.3) and severe distress related to NPS, especially disinhibition and irritability, which independently predicted higher burden.

CONCLUSION: Canadian FTD caregivers face prolonged diagnostic journeys, high neuropsychiatric-related distress and substantial unmet needs. Findings highlight gaps in awareness, access to specialized care and systematic assessment of caregiver burden, underscoring urgent priorities for improving diagnostic pathways and support services.},
}

@article {pmid42284682,
year = {2026},
author = {O'Brien, EK and Cox, T and Fernandez, S and Bourgeat, P and Porter, T and Goudey, B and Doecke, JD and Masters, CL and Fripp, J and Nho, K and Villemagne, VL and Cruchaga, C and Rowe, CC and Saykin, AJ and Doré, V and Laws, SM},
title = {Predicting accumulation and age at onset of amyloid-β from genetic risk and resilience for Alzheimer's disease.},
journal = {EBioMedicine},
volume = {129},
number = {},
pages = {106329},
doi = {10.1016/j.ebiom.2026.106329},
pmid = {42284682},
issn = {2352-3964},
abstract = {BACKGROUND: Accumulation of brain amyloid beta (Aβ), a key pathological hallmark of Alzheimer's disease (AD), begins decades before cognitive symptoms. Being able to predict the risk of Aβ accumulation, or the age at which Aβ exceeds a critical threshold, may enable intervention to delay or prevent onset of AD.

METHODS: Using published genome-wide association studies (GWASs), we developed polygenic scores (PGS) for AD risk (PGSrisk) and resilience (PGSresilience), and tested whether these predicted (i) if an individual is an Aβ accumulator ('Accumulator Status'), and (ii) in accumulators, the age at which brain Aβ exceeds a 20 centiloid (CL) threshold ('Age at onset of Aβ'; AAO-Aβ) in 2175 participants (1158 with AAO-Aβ) from the Alzheimer's Dementia Onset and Progression in International Cohorts (ADOPIC) study. We also performed GWASs on these traits to develop phenotype-specific PGSs.

FINDINGS: Higher genetic risk of AD predicted increased odds of Aβ accumulation (OR = 1.16; 95% CI = 1.05-1.29; p = 0.003) and younger AAO-Aβ (β = -1.32; SE = 0.31; p = 1.63 × 10[-5]). Higher genetic resilience to AD predicted later AAO-Aβ (β = 0.91; SE = 0.29; p = 0.002) but did not predict Aβ accumulation. These associations were independent of APOE ε4 status, the strongest genetic risk factor for AD. Phenotype-specific PGSs were not significantly associated with either trait.

INTERPRETATION: Polygenic scores, alongside other risk factors, may help identify individuals at risk of accumulating Aβ, and predict the age at which this exceeds a critical threshold. This could provide a window for administering disease-modifying treatment or lifestyle interventions to prevent or delay the onset of AD.

FUNDING: National Institutes of Health (R01-AG058676-01A1) and Australian National Health and Medical Research Council (GNT1161706; GNT2001320).},
}

@article {pmid42285026,
year = {2026},
author = {Bayram, E},
title = {Time to pay attention to sleep for Alzheimer's disease in women.},
journal = {The journal of prevention of Alzheimer's disease},
volume = {13},
number = {7},
pages = {100624},
doi = {10.1016/j.tjpad.2026.100624},
pmid = {42285026},
issn = {2426-0266},
}

@article {pmid42285404,
year = {2026},
author = {Xu, N and Xing, Y and Li, A and Liu, S and Gao, J and Liu, X and Xie, W and Guo, N and Chen, Y and Sun, X and Wu, J and Gong, W and Wang, D and Tang, Y and Liu, H},
title = {Personalized high-dose accelerated intermittent theta-burst stimulation improves cognitive function in mild Alzheimer's disease: A randomized sham-controlled trial.},
journal = {Brain stimulation},
volume = {},
number = {},
pages = {103142},
doi = {10.1016/j.brs.2026.103142},
pmid = {42285404},
issn = {1876-4754},
}

@article {pmid42285406,
year = {2026},
author = {Mendoza-Camacho, DM and Espinoza-Gutiérrez, HA and Viveros-Paredes, JM and Flores-Soto, ME and Tejeda-Martínez, AR},
title = {Recent advances in neurodegenerative diseases therapeutics: The inhibition of monoacylglycerol lipase strategy.},
journal = {Neuroscience},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.neuroscience.2026.06.011},
pmid = {42285406},
issn = {1873-7544},
abstract = {Neurodegenerative diseases share common pathophysiological mechanisms, including chronic neuroinflammation, glutamatergic excitotoxicity, oxidative stress, mitochondrial dysfunction, and disruptions in synaptic and lipid homeostasis. In this context, the endocannabinoid system has emerged as a key modulator of neuroimmune communication and neuronal survival. Within this system, Monoacylglycerol Lipase (MAGL) plays a central role by regulating the levels of the endocannabinoid 2-Arachidonoylglycerol (2-AG) while simultaneously contributing to the generation of arachidonic acid and pro-inflammatory eicosanoids. Pharmacological or genetic inhibition of MAGL increases 2-AG levels and concurrently reduces the biosynthesis of pro-inflammatory lipid mediators, thereby modulating microglial activation, astrocytic responses, and neuronal excitotoxicity. Preclinical studies in models of Alzheimer's disease, Parkinson's disease, multiple sclerosis, and amyotrophic lateral sclerosis consistently demonstrate that MAGL blockade attenuates neuroinflammation, preserves synaptic and neuronal integrity, improves motor and cognitive function, and, in some cases, delays disease progression. Although clinical evidence remains limited, the available data position MAGL as a metabolic convergence point between inflammation and neurodegeneration, suggesting that its modulation may represent a therapeutic strategy with disease-modifying potential.},
}

@article {pmid42285552,
year = {2026},
author = {},
title = {Correction: First presentation with neuropsychiatric symptoms in autosomal dominant Alzheimer's disease: the Dominantly Inherited Alzheimer's Network Study.},
journal = {Journal of neurology, neurosurgery, and psychiatry},
volume = {97},
number = {7},
pages = {e2},
doi = {10.1136/jnnp-2022-329843corr1},
pmid = {42285552},
issn = {1468-330X},
}

@article {pmid42285553,
year = {2026},
author = {},
title = {Correction: How well do plasma Alzheimer's disease biomarkers reflect the CSF amyloid status?.},
journal = {Journal of neurology, neurosurgery, and psychiatry},
volume = {97},
number = {7},
pages = {e1},
doi = {10.1136/jnnp-2024-334122corr1},
pmid = {42285553},
issn = {1468-330X},
}

@article {pmid42285687,
year = {2026},
author = {Zheng, M and Wang, C and Liu, J and Xia, Y and Zhang, X and Gu, L},
title = {Nuciferine ameliorates cognitive impairment and insulin resistance in T2DM by targeting the insulin receptor and activating PI3K/AKT signaling.},
journal = {Chinese journal of natural medicines},
volume = {24},
number = {7},
pages = {819-831},
doi = {10.1016/S1875-5364(26)61190-9},
pmid = {42285687},
issn = {1875-5364},
mesh = {Animals ; *Insulin Resistance ; *Phosphatidylinositol 3-Kinases/metabolism/genetics ; *Receptor, Insulin/metabolism/genetics ; *Proto-Oncogene Proteins c-akt/metabolism/genetics ; Signal Transduction/drug effects ; *Diabetes Mellitus, Type 2/drug therapy/metabolism/complications ; *Aporphines/administration & dosage/pharmacology ; Mice ; *Cognitive Dysfunction/drug therapy/metabolism/etiology ; Male ; Humans ; Mice, Inbred C57BL ; },
abstract = {Insulin resistance is a hallmark of type 2 diabetes (T2DM) and can increase the risk of cognitive impairment, including Alzheimer's disease. Nuciferine, an alkaloid derived from lotus leaves, shows neuroprotective effects. This study investigated nuciferine's protective role in T2DM-induced cognitive impairment (T2DM-CI) and its mechanisms. Mouse models were created using high-fat diets and streptozotocin, along with high glucose-induced HT-22 cells. Nuciferine reduced blood glucose, improved cognitive function, and mitigated glial cell activation, neuron and synapse loss in T2DM mice. It enhanced insulin signaling by increasing protein levels of IR, IRS1, and IGF-1R, reversing PI3K and AKT phosphorylation, inhibiting GSK3β activity, and reducing hyperphosphorylated Tau in HT-22 cells and T2DM mice. mRNA levels of these molecules matched their protein levels. Further studies revealed that nuciferine directly interacts with IR, knocking out IR abolished its effects on the PI3K/AKT pathway. Thus, nuciferine activates the PI3K/AKT pathway via IR, improving insulin resistance and slowing T2DM-CI progression.},
}

Animals
*Insulin Resistance
*Phosphatidylinositol 3-Kinases/metabolism/genetics
*Receptor, Insulin/metabolism/genetics
*Proto-Oncogene Proteins c-akt/metabolism/genetics
Signal Transduction/drug effects
*Diabetes Mellitus, Type 2/drug therapy/metabolism/complications
*Aporphines/administration & dosage/pharmacology
Mice
*Cognitive Dysfunction/drug therapy/metabolism/etiology
Male
Humans
Mice, Inbred C57BL

@article {pmid42286062,
year = {2026},
author = {Mahmoud, E and Elshennawy, NM and Elkholy, A},
title = {Hybrid deep learning model for brain age prediction using time-distributed convolutional and bidirectional LSTM networks.},
journal = {Scientific reports},
volume = {16},
number = {1},
pages = {},
pmid = {42286062},
issn = {2045-2322},
mesh = {Humans ; *Brain/diagnostic imaging/physiology ; *Deep Learning ; Magnetic Resonance Imaging/methods ; Long Short Term Memory ; *Aging/physiology ; Convolutional Neural Networks ; Predictive Learning Models ; Image Processing, Computer-Assisted/methods ; },
abstract = {Brain age prediction has gained significant attention due to its strong correlation with neurological and cognitive disorders. The discrepancy between an individual's chronological age and their predicted brain age-known as the Brain Age Gap-has been linked to conditions such as schizophrenia, Alzheimer's disease, cognitive decline, and lifestyle factors like stress and poor health. A positive Brain Age Gap is often associated with accelerated aging and neurodegeneration, highlighting the need for precise and reliable estimation methods. In this study, we propose a novel deep learning model that incorporates time-distributed, convolutional and bidirectional LSTM layers for brain age estimation. Using MRI data from the OpenBHB dataset, processed through Voxel-Based Morphometry (VBM), our model undergoes rigorous preprocessing, including outlier detection, data augmentation, and MRI slice selection, to enhance learning efficiency. The model is optimized with the Adam optimizer with a scheduled learning-rate decay and evaluated using Mean Absolute Error (MAE) and [Formula: see text] Score. Experimental results demonstrate that our model achieves an MAE of 3.1573 years, outperforming previous methods and improving brain age prediction accuracy. These findings underscore the importance of advances in deep learning and data preprocessing in enhancing brain age estimation.},
}

Humans
*Brain/diagnostic imaging/physiology
*Deep Learning
Magnetic Resonance Imaging/methods
Long Short Term Memory
*Aging/physiology
Convolutional Neural Networks
Predictive Learning Models
Image Processing, Computer-Assisted/methods

@article {pmid42286187,
year = {2026},
author = {Heikkinen, S and Julkunen, V and Martiskainen, H and Takalo, M and Solje, E and Leinonen, V and Haapasalo, A and Lipponen, A and Hiltunen, M},
title = {Biobank-based genetic characterization of neurodegenerative diseases and idiopathic normal pressure hydrocephalus: insights and lessons learned from FinnGen.},
journal = {Molecular psychiatry},
volume = {},
number = {},
pages = {},
pmid = {42286187},
issn = {1476-5578},
abstract = {Brain disorders characterized by progressive neurodegeneration, such as Alzheimer's disease (AD) and frontotemporal dementia (FTD), represent an increasing medical and societal challenge. While genome‑wide studies have uncovered numerous susceptibility loci, these efforts have largely focused on common variants and leave a substantial portion of genetic liability unresolved. Variants of low frequency, often associated with stronger biological effects, remain insufficiently characterized, particularly in heterogeneous populations. Genetically isolated populations offer an effective strategy to overcome these limitations. Finland, shaped by historical demographic events, harbors a distinctive spectrum of enriched rare variants that can facilitate gene discovery. The FinnGen initiative capitalizes on this setting by combining extensive genotyping with nationwide health registry data through a coordinated network of Finnish biobanks. With half a million participants analyzed, FinnGen supports highly powered analyses across a broad array of clinical outcomes and registry data. Recent comprehensive analyses have reported thousands of significant genotype-phenotype associations, including novel protein‑altering variants. Importantly, the FinnGen cohort structure favors older individuals and hospital‑derived samples, increasing representation of brain disorders, such as AD and idiopathic normal pressure hydrocephalus (iNPH), a disorder frequently accompanied by AD‑like pathological features. In this expert review, we summarize FinnGen‑based investigations relevant to neurodegenerative diseases and iNPH, highlighting insights into genetic susceptibility, disease overlap, and protective factors, and discuss how integration with recall studies as well as biomarker and clinical data accelerates translational applications in brain disorders.},
}

@article {pmid42286188,
year = {2026},
author = {Long, RA and Ballard, S and Shah, S and Bianchi, O and Jones, L and Koretsky, MJ and Kuznetsov, N and Marsan, E and Jen, B and Chiang, P and Mukherjee, A and Blauwendraat, C and Leonard, H and Vitale, D and Levine, K and Bandres-Ciga, S and Jarreau, P and Brannelly, P and Phatak, M and Pantazis, C and Screven, L and Andersh, K and Kapasi, A and Crary, JF and Gutman, D and Dugger, BN and Biber, S and Hohman, T and Faghri, F and Griswold, M and Sargent, L and Keuren-Jensen, KV and Singleton, AB and Fann, Y and Nalls, MA and Iwaki, H},
title = {A new AI assisted approach aligns data standards and accelerates interoperability in biomedical research.},
journal = {NPJ digital medicine},
volume = {},
number = {},
pages = {},
doi = {10.1038/s41746-026-02795-z},
pmid = {42286188},
issn = {2398-6352},
abstract = {We demonstrate how Large Language Models (LLMs) accelerate biomedical data harmonization through automated Common Data Element (CDE) generation. We processed 31 datasets including clinical taxonomies and research data dictionaries through OpenAI's Generative Pre-trained Transformer - 4 (API Model gpt-4-0613), generating comprehensive metadata for each element using a template-based system. Subject-matter experts validated outputs, finding 94% of generated metadata fields required no revision overall, with an unweighted accuracy of 83.8%, unweighted, for semi-structured sources. Dramatically faster than manual approaches. Our system uses ElasticSearch with weighted field matching to identify semantic equivalences between variables, avoiding duplicate CDEs while building a standardized repository. Testing with Alzheimer's Disease Neuroimaging Initiative (ADNI) and Global Parkinson's Genetic Program (GP2) datasets showed 32.4% of previously unseen headers successfully mapped to our CDEs, with interoperability scores averaging 53.8/100 based on matching, completeness, and compliance metrics. This approach automates the most tedious aspects of data integration, reducing barriers to cross-study collaboration in biomedical research.},
}

@article {pmid42286377,
year = {2026},
author = {Lin, J and Shao, X and Shi, T and Wang, H and Zhang, P and Zhou, Y and Liu, N and He, Y and Fang, D and Shi, Y and Ma, Y and Liu, B and Gong, W and Wu, W and Peng, R and Wang, C and Shen, T and Jiang, Z and Ben, Y and Qin, J and Xu, Z and Chen, X and Jiang, Q and Guo, B},
title = {Author Correction: Exercise alleviates cognitive dysfunction in Alzheimer's disease mice via skeletal muscle-derived extracellular vesicles that enhance plaque clearance by microglia.},
journal = {Nature aging},
volume = {},
number = {},
pages = {},
doi = {10.1038/s43587-026-01156-5},
pmid = {42286377},
issn = {2662-8465},
}

@article {pmid42286514,
year = {2026},
author = {Javed, A and Kumar, S and Iftekhar, M and Siddiqui, HT and Khan, A and Faisal, F and Ali, M and Sohail, F and Khan, MH},
title = {Trends in both Alzheimer's disease and Diabetes mellitus related mortality among middle-aged and older adults in the United States, 1999 to 2023: a CDC WONDER database analysis.},
journal = {BMC neurology},
volume = {},
number = {},
pages = {},
doi = {10.1186/s12883-026-05058-2},
pmid = {42286514},
issn = {1471-2377},
abstract = {OBJECTIVE: To analyze the temporal trends of both Alzheimer's disease and Diabetes mellitus-related mortality in adults aged > 45years in the United States between 1999 and 2023, and to evaluate the changes in mortality patterns over time.

BACKGROUND: Alzheimer's Disease and Diabetes Mellitus are two different diseases that have diverse underlying pathophysiology, but they often coexist, having common pathways. There is a high prevalence of concurrence between these two conditions, yet their combined mortality trend is underexplored.

METHODS: We utilize mortality data from the CDC Wide-Ranging Online Data for Epidemiologic Research (WONDER). Individuals aged > 45 were included who had both Alzheimer's disease (G30) and Diabetes mellitus(E10-14). Age-adjusted mortality rates (AAMRs) and crude mortality rates (CMRs) per 100,000 were calculated and were standardized to the 2000 U.S population. Joint point regression models were used to identify the temporal variations and to calculate Annual Percentage Change (APC) and Average Annual Percentage Change (AAPC) with 95% confidence intervals.

RESULTS: Overall, a total of 224,082 deaths occurred in patients of both Alzheimer's disease and Diabetes mellitus, in the age group ≥ 45 years, from 1999 to 2023. There is an upward trajectory noted from 2.82 in 1999 to 4.42 in 2023, with the highest incidence between 2017 and 2020, followed by a decline. Mortality rose in both sexes, with a persistently higher rate in females. The mortality rise from 1999 to 2023 in middle-aged people (45-64 years), and there was a rise in the trend of around 41% among adults ≥ 65 years. White individuals show higher deaths (78.9%), yet higher AAMR is observed in Black and Hispanic populations, showing racial disparities. Regionally, the West shows the highest AAMR, while non-metropolitan areas show higher mortality than metropolitan areas.

CONCLUSION: The trend of mortality in individuals with both Alzheimer's disease and Diabetes Mellitus has increased in the past two decades, but there is a sharp rise observed after 2020 that may show the impact of the COVID-19 pandemic. These findings emphasized public health strategies.},
}

@article {pmid42286647,
year = {2026},
author = {Rauchmann, BS and Hamet, J and Lai, J and Kafi, H and Rexwinkle, J and Brendel, M and Franzmeier, N and Kurz, C and Pogarell, O and Levin, J and Höglinger, G and Perneczky, R},
title = {Estimation of positron emission tomography amyloid load and related biomarkers in Alzheimer's disease using evoked potential tomography EEG: development and internal validation in a cross-sectional cohort.},
journal = {Alzheimer's research & therapy},
volume = {},
number = {},
pages = {},
doi = {10.1186/s13195-026-02076-7},
pmid = {42286647},
issn = {1758-9193},
abstract = {BACKGROUND: Dementia affects over 50 million individuals globally, predominantly due to Alzheimer's disease (AD). Effective early detection and intervention remain clinical challenges, as there is a lack of unified, portable solutions to assess multiple biomarkers.

METHODS: We evaluated Evoked Potential Tomography (EPT), an EEG-based method using a novel visual evoked potential protocol. An automated pipeline for EEG preprocessing, ERP extraction, feature selection, optimization, and regression modeling was developed to estimate key AD biomarkers: PET-amyloid standardized uptake value ratio (SUVR), CSF phosphorylated tau (p-tau181), Free and Cued Selective Reminding Test (FCSRT), and Mini-Mental State Examination (MMSE) scores.

RESULTS: Regression models using ERP features from dementia participants demonstrated strong correlations (r = 0.8-0.94, p < 0.01) between predicted and true PET-amyloid SUVR, p-tau181, FCSRT, and MMSE values. In an independent external cohort, PET-amyloid SUVR predictions remained significantly associated with true values (r = 0.60, p < 0.01).

DISCUSSION: Despite limitations, these preliminary results support EPT's potential as a sensitive and non-invasive method for estimating AD-related biomarkers in a clinically enriched AD cohort. Further validation studies are ongoing.},
}

@article {pmid42286794,
year = {2026},
author = {Qi, X and Ruan, JY and Zhong, J and Wan, Y and Wei, DH and Ko, E and Yang, S and Shen, L and Wu, B},
title = {The landscape of knowledge graph and LLM-augmented knowledge graph applications in dementia caregiving support: a scoping review.},
journal = {The Gerontologist},
volume = {},
number = {},
pages = {},
doi = {10.1093/geront/gnag125},
pmid = {42286794},
issn = {1758-5341},
abstract = {BACKGROUND AND OBJECTIVES: Dementia's rising prevalence places an immense burden on caregivers. Knowledge Graphs (KGs) and Large Language Model (LLM)-augmented KGs are emerging AI approaches that organize complex dementia care knowledge and enable personalized, context-aware support, yet this field remains nascent. We aimed to map and synthesize research on KGs and LLM-augmented KGs in dementia caregiving, identifying system types, applications, outcomes, challenges, and ethical considerations.

RESEARCH DESIGN AND METHODS: Following the JBI framework, a comprehensive search was conducted across six academic databases (PubMed, Scopus, Web of Science, IEEE Xplore, PsycINFO, CINAHL) and grey literature. Eligibility criteria included studies detailing the design, development, or evaluation of KGs or LLM-augmented KGs for dementia caregiving.

RESULTS: Twelve articles representing 11 unique studies met the inclusion criteria. All 11 studies used KG or ontology components; eight were KG-only systems, often supporting personalized meal planning, care plan recommendations, knowledge management, robotic assistance, or virtual assistants. Three studies described LLM-augmented KGs (3/11), primarily using retrieval-augmented generation to enhance conversational AI for caregivers or persons with dementia. Reported benefits included improved usability, personalized support, more accurate or relevant recommendations, and potential improvements in quality of life and independence. Key challenges involved technical complexity, KG maintenance, data quality, limited real-world evaluation, and underdeveloped ethical analysis.

DISCUSSION AND IMPLICATIONS: Integrating KGs with LLMs for dementia caregiving is a promising yet nascent interdisciplinary field. While early systems demonstrate potential, significant gaps remain in clinical validation, comprehensive ethical guidelines development, and responses to caregivers' diverse and evolving needs.},
}

@article {pmid42286801,
year = {2026},
author = {Yi Wong, KL and Hung, L and Wong, J and Adekoya, A and Yee Wong, JO and Young, E and Acosta, C and Vasarhelyi, K},
title = {Implementing Antipsychotic Reduction in Long-Term Care: Interdisciplinary and Lived-Experience Insights into System-Level Barriers and Facilitators.},
journal = {The Gerontologist},
volume = {},
number = {},
pages = {},
doi = {10.1093/geront/gnag126},
pmid = {42286801},
issn = {1758-5341},
abstract = {BACKGROUND AND OBJECTIVES: Despite the availability of evidence-based antipsychotic reduction strategies, implementation of these strategies in long-term care (LTC) often stalls. Understanding how change occurs in real-world practice requires perspectives from interdisciplinary team members. This study interviewed interdisciplinary team members, a family caregiver, and a person living with dementia in LTC in Vancouver, Canada, to explore how they operationalize antipsychotic reduction in LTC homes and examine their perceived barriers and facilitators to implementation.

RESEARCH DESIGN AND METHODS: Semi-structured interviews were conducted with 20 participants: 18 interdisciplinary healthcare providers, one dementia advocate, and one family caregiver. Data were analyzed using reflexive thematic analysis. To preserve inductive insights, the Consolidated Framework for Implementation Research (CFIR) was applied post hoc to the emergent themes. We examined the extent to which the findings were aligned with the CFIR, thereby deepening the analysis.

RESULTS: Identified strategies included person-centred care planning, non-pharmacological interventions, medication review with behaviour monitoring, and education. Barriers were: (1) challenging work environments, (2) safety concerns and unconscious dismissive attitudes, and (3) communication gaps. Facilitators included: (1) supportive leadership and frontline champions, (2) team communication, and (3) persistence. Each factor aligns with different CFIR constructs and domains to varying degrees.

DISCUSSION AND IMPLICATIONS: The main contribution of this study is that, drawing on CRIF, it found barriers to antipsychotic reduction in LTC are not merely individual but also systemic. Sustained improvement depends on policies that enable and resource effective interdisciplinary teamwork. This includes adequate staffing, education, team communication, and culture change.},
}

@article {pmid42286894,
year = {2026},
author = {Evers, MJAP and Krom, BP and de Jongh, CA},
title = {A mechanistic framework linking the oral microbiome to Alzheimer's disease through neuroinflammation.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261456324},
doi = {10.1177/13872877261456324},
pmid = {42286894},
issn = {1875-8908},
abstract = {Alzheimer's disease (AD) is a growing problem in our society and the most common form of dementia. This neurodegenerative disease is characterized by neuroinflammation and the accumulation of amyloid-β (Aβ) and tau. Previous studies have found associations between the oral microbiome and AD. This review aims to elucidate the role of the oral microbiome in AD, through neuroinflammation, and reviews the relationship between AD and bacteria and fungi. Studies have found bacteria (e.g., Porphyromonas gingivalis) and fungi (e.g., Candida albicans) in postmortem AD brains. Moreover, mice models have shown that oral microbes are able to cross the blood-brain barrier (BBB), and were correlated with activated microglia, neuroinflammation, and Aβ load. This review introduces a mechanistic framework that describes how oral microbes cause an inflammatory response resulting in AD pathology. Specifically, oral dysbiosis causes oral pathogens to disseminate into the bloodstream, this triggers an inflammatory response, subsequently activating microglia, ultimately resulting in AD pathology. This process can follow two pathways: First, there is a direct response of the immune system in the brain to oral pathogens that migrate through the bloodstream and cross the BBB, which causes neuroinflammation and activates microglia, leading to AD pathology. Second, an early-life systemic inflammation causes microglia to get into a "hyperactive" state, in which they respond in an exaggerated way to normal stimuli triggering immune responses throughout a person's life that result in AD pathology. This mechanistic framework provides new line of thought for future research on the question of causality of AD.},
}

@article {pmid42286895,
year = {2026},
author = {Ghiasvand, S and Tegegne, GT and Tabatabaei-Jafari, H and Mazumdar, S and Ambikairajah, A and Bagheri, N},
title = {Social and environmental determinants of dementia risk: An umbrella review.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261456777},
doi = {10.1177/13872877261456777},
pmid = {42286895},
issn = {1875-8908},
abstract = {BackgroundGrowing evidence suggests that dementia risk is influenced not only by genetic factors but also by social and environmental determinants. Understanding these modifiable factors is critical for informing prevention strategies.ObjectiveTo synthesize existing evidence from systematic reviews on the associations between social and environmental determinants and the risk of dementia, including Alzheimer's disease, vascular dementia, and frontotemporal dementia.MethodsAn umbrella review was conducted by systematically searching five major databases for systematic reviews published between 2004 and 2024. Eligible reviews examined the relationship between at least one social or environmental determinant and dementia outcomes.ResultsThe review found strong associations between environmental exposures and increased dementia risk. Exposure to fine particulate matter (PM2.5) was consistently linked to elevated dementia risk, with estimates ranging from 3% to 226% per 10 μg/m[3] increase. Occupational exposures to toxic metals, pesticides, and electromagnetic fields were also associated with higher neurodegeneration risk. Conversely, protective environmental factors included residential greenness and walkable neighborhoods. Among social determinants, higher education, socioeconomic status, and social engagement were found to promote cognitive resilience. In contrast, social disadvantage and limited access to healthcare contributed to increased dementia risk, likely through cumulative psychosocial stress.ConclusionsThis umbrella review underscores the significant role of social and environmental determinants in dementia risk. Targeted public health policies aimed at reducing environmental hazards and addressing social inequalities are essential for mitigating dementia risk and promoting cognitive health at the population level.},
}

@article {pmid42287135,
year = {2026},
author = {Abdel-Rasol, MA and El-Sayed, WM},
title = {Saponarin: Therapeutic Potential, Pharmacological Insights, and Future Directions.},
journal = {Chemical biology & drug design},
volume = {107},
number = {6},
pages = {e70339},
doi = {10.1111/cbdd.70339},
pmid = {42287135},
issn = {1747-0285},
mesh = {Animals ; Humans ; Antioxidants/chemistry/pharmacology ; Cardiovascular Diseases/drug therapy ; Neoplasms/drug therapy ; Neurodegenerative Diseases/drug therapy ; Oxidative Stress/drug effects ; Signal Transduction/drug effects ; *Glucosides/chemistry/pharmacology ; Apigenin ; },
abstract = {Saponarin, a flavonoid glycoside, has demonstrated various pharmacological effects in preclinical systems, including antioxidant, anti-inflammatory, hepatoprotective, neuroprotective, anticancer, and cardioprotective properties. These effects are attributed to its modulation of key signaling pathways such as Nrf2, NF-κB, PI3K/Akt, MAPK, and TGF-β. However, the translational relevance of these interactions remains unestablished in human subjects. This review consolidates findings on saponarin's mechanisms of action and therapeutic potential, focusing primarily on in vitro and animal model evidence, while highlighting gaps that limit its clinical applicability across liver diseases, neurodegenerative conditions, cancer, diabetes, and cardiovascular diseases. In hepatic disease models, saponarin has shown potential in reducing oxidative stress markers, attenuating liver fibrosis, and improving mitochondrial function, indicating its relevance to non-alcoholic fatty liver disease, alcoholic liver disease, and drug-induced liver injury. However, these findings have not been confirmed in human trials, and the translation of rodent hepatoprotective data to humans remains uncertain. In neurodegenerative models, saponarin reduced β-amyloid deposition and tau hyperphosphorylation. However, poor blood-brain barrier penetration and the lack of human validation limit the therapeutic relevance for Alzheimer's and Parkinson's diseases. In cancer models, saponarin inhibited proliferation, induced apoptosis, suppressed metastatic markers, and reduced angiogenic signaling. However, cancer cell line sensitivity often fails to predict in vivo efficacy, and no clinical evidence supports its use as adjunctive cancer therapy. Limited preclinical evidence also suggests potential effects on insulin sensitivity, glycemic regulation, and cardiovascular parameters, but human studies are absent. Despite these promising findings, saponarin lacks clinical validation. Most effects come from in vitro and animal models, which exhibit variability in experimental conditions, doses, and formulations, limiting definitive conclusions. Saponarin's poor oral bioavailability, absence of standardized formulations, restricted blood-brain barrier penetration, and lack of long-term safety data present significant barriers to development. Although novel delivery methods such as nanoparticles and liposomal formulations have been proposed to improve pharmacokinetics, they remain experimental and unvalidated in humans. Future research should focus on rigorous clinical trials to assess whether preclinical findings translate to clinically meaningful outcomes, alongside comprehensive pharmacokinetic and safety evaluations in humans. Until then, saponarin should be regarded as an experimental compound with preliminary preclinical findings, rather than a clinically recommended therapeutic agent.},
}

Animals
Humans
Antioxidants/chemistry/pharmacology
Cardiovascular Diseases/drug therapy
Neoplasms/drug therapy
Neurodegenerative Diseases/drug therapy
Oxidative Stress/drug effects
Signal Transduction/drug effects
*Glucosides/chemistry/pharmacology
Apigenin

@article {pmid42287242,
year = {2026},
author = {Del Chicca, M and Mignani, G and Iannaccone, F and Piccarducci, R and Giannini, N and Tognoni, G and Masi, S and Ceravolo, R and Siciliano, G and Mancuso, M and Baldacci, F},
title = {Fluid biomarkers in Cerebral amyloid angiopathy: current limitations and future directions.},
journal = {Expert review of molecular diagnostics},
volume = {},
number = {},
pages = {},
doi = {10.1080/14737159.2026.2687501},
pmid = {42287242},
issn = {1744-8352},
abstract = {INTRODUCTION: Cerebral amyloid angiopathy (CAA) is the leading cause of lobar intracerebral hemorrhage in older adults and an independent contributor to cognitive decline. Current diagnostic criteria are based on neuroimaging, lacking pathophysiological specificity.

AREAS COVERED: This narrative review evaluated studies assessing cerebrospinal fluid (CSF) and plasma biomarkers in sporadic CAA compared with Alzheimer disease (AD), other small vessel diseases, and healthy controls (HC). CSF profiles show reduced beta-amyloid 1-42 and beta-amyloid 1-42/ beta-amyloid 1-40 ratio in CAA, although a similar pattern is observed in AD, limiting the specificity of these markers. Beta-amyloid 1-40 is decreased in CAA versus HC and AD, reflecting vascular amyloid deposition, yet this alteration alone does not provide sufficient discriminatory power. Plasma studies have reported heterogeneous results, influenced by variability in methods and populations studied. Nevertheless, amyloid isoforms and phosphorylated tau appear promising. Neurofilament light chain has been linked to imaging markers and disease burden, though prognostic data remain scarce.Given the frequent coexistence of CAA and AD, the limited pathophysiological specificity of current neuroimaging criteria, and the growing therapeutic implications of accurate diagnosis, interest in fluid biomarkers has increased substantially in recent years.

EXPERT OPINION: Currently, fluid biomarkers lack both specificity and validation required for clinical implementation in CAA, largely due to substantial overlap with AD pathology. Their clinical utility remains unproven, and large longitudinal real-world studies are needed to assess their reliability and incremental diagnostic value.},
}

@article {pmid42287259,
year = {2026},
author = {Kerwash, E and Butler, AS and Malamatari, M and Cole, S},
title = {Quantitative Medicine to Support Drug Development and Regulatory Decisions: A UK Regulatory Approach Informed by ICH M15.},
journal = {Clinical and translational science},
volume = {19},
number = {6},
pages = {e70636},
doi = {10.1111/cts.70636},
pmid = {42287259},
issn = {1752-8062},
mesh = {Humans ; United Kingdom ; *Drug Development/legislation & jurisprudence/standards/methods/organization & administration ; Risk Assessment ; Alzheimer Disease/drug therapy ; Antibodies, Monoclonal, Humanized/pharmacokinetics/administration & dosage/therapeutic use ; Drug Approval/legislation & jurisprudence ; Decision Making ; },
abstract = {Quantitative medicine supports modern drug development and regulatory decision-making by integrating non-clinical and clinical data to inform dose selection, trial optimization, and extrapolation across populations and benefit-risk assessment. The Medicines and Healthcare products Regulatory Agency (MHRA) has adopted quantitative approaches across the product lifecycle within a risk-proportionate regulatory framework. Internationally, the ICH M15 guideline provides a harmonized framework for planning, evaluation and documentation of model-informed drug development (MIDD) evidence which is aligned with MHRA practice. This perspective describes the application of quantitative medicine to UK regulatory decision-making using two case studies: sugemalimab (Eqjubi) in oncology and lecanemab (Leqembi) in Alzheimer's disease. The case studies are assessed using ICH M15 concepts, including context of use, model influence, and consequence of a wrong decision. For sugemalimab, quantitative pharmacokinetic modeling supported a high-impact dosing decision with clinically meaningful consequences of a wrong decision requiring proportionate scrutiny and mitigation of uncertainty. For lecanemab, multiple quantitative models with lower individual influence supported interpretation of pharmacokinetic variability, biomarkers, and clinical outcomes within the overall benefit-risk assessment. These case studies demonstrate how quantitative models can support decisions with differential impact ranging from critical dosing decisions to interpretation of complex data. Regulatory policy that is aligned with ICH M15 can be used to support the use of quantitative medicine to link complex modeling approaches with regulatory decision-making and enable patient access to medicines.},
}

Humans
United Kingdom
*Drug Development/legislation & jurisprudence/standards/methods/organization & administration
Risk Assessment
Alzheimer Disease/drug therapy
Antibodies, Monoclonal, Humanized/pharmacokinetics/administration & dosage/therapeutic use
Drug Approval/legislation & jurisprudence
Decision Making

@article {pmid42287388,
year = {2026},
author = {Hu, TW and Prince, J and Zhou, L and Wang, XH and Tanzi, EB and Khalafi, M and Nehmeh, SA and Pahlajani, SS and Hojjati, H and Glodzik, L and Butler, T and Chiang, GC and Li, Y},
title = {Evaluating early vs. late static SUVR windows of [[18]F]MK-6240 tau PET in Alzheimer disease: a head-to-head comparison study.},
journal = {European journal of nuclear medicine and molecular imaging},
volume = {},
number = {},
pages = {},
pmid = {42287388},
issn = {1619-7089},
support = {AG077576/AG/NIA NIH HHS/United States ; AG057848/AG/NIA NIH HHS/United States ; },
abstract = {PURPOSE: [[18]F]MK-6240 is a widely used second-generation tau PET tracer in Alzheimer disease (AD) and is under FDA review, making it important to refine practical static imaging windows for clinical use. Prior dynamic studies have supported late static windows (~ 90-110 min) because they improve agreement between standard uptake value ratios (SUVR) and kinetic models in high-binding regions, but extracerebral skull and meningeal uptake becomes more prominent at later times and may confound visual interpretation and SUVR quantification. In this study, we aim to determine whether an earlier static window (40-60 min) provides comparable discrimination of tau burden while reducing extracerebral spill-in and SUVR instability.

METHODS: In this retrospective within-subject study, 67 participants across the AD spectrum (normal controls (cognitively unimpaired) [NL], mild cognitive impairment [MCI], and AD) underwent [¹⁸F]MK-6240 PET with early (40-60 min) and late (90-120 min) frames. SUVRs were computed in the cerebral cortex (CTX) and Braak ROIs using cerebellar cortex as reference. Early-late agreement was assessed using correlation, regression, and Kolmogorov-Smirnov (KS) tests. Diagnostic and tau-status classification performance was evaluated with ROC analyses. Skull/meningeal uptake was graded visually and quantified, and PET-MRI misregistration simulations assessed SUVR robustness. Time-resolved analyses (30-120 min) evaluated temporal changes in stability and discrimination.

RESULTS: Early and late SUVRs were highly correlated (r ≥ 0.97; p < 0.01) and showed similar cohort-level distributions (CTX KS D = 0.060; p > 0.99). Discrimination was comparable for diagnosis and tau status (e.g., CTX AUC 0.88 vs. 0.85 for NL vs. MCI/AD). Late frames showed greater skull/meningeal uptake with increased spill-in and reference-region sensitivity; in tau-negative participants, skull SUVR exceeded entorhinal SUVR after ~ 60 min. Misregistration simulations showed greater variability for late versus early entorhinal SUVR (σ = 0.071 vs. 0.017). Time-resolved analyses showed that in this cohort, later acquisition did not materially improve diagnostic discrimination and was associated with more extracerebral contamination and instability.

CONCLUSION: The 40-60-minute window provides discrimination comparable to 90-120 min while reducing extracerebral contamination and improving robustness, supporting shorter static [¹⁸F]MK-6240 protocols for clinical and research applications.},
}

@article {pmid42287757,
year = {2026},
author = {Jaberi, KR and Haghighi, MR and Aligholi, H and Takallu, S and Asadi, P and Mirzaei, E and Jaberi, AR and Sahraian, A},
title = {Focused ultrasound-mediated nanocarrier delivery across the blood-brain barrier for neurodegenerative diseases.},
journal = {Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie},
volume = {201},
number = {},
pages = {119622},
doi = {10.1016/j.biopha.2026.119622},
pmid = {42287757},
issn = {1950-6007},
abstract = {The development of effective therapies for neurodegenerative disorders such as Alzheimer's disease, Parkinson's disease, Huntington's disease, and amyotrophic lateral sclerosis remains a major challenge due to the restrictive nature of the blood-brain barrier (BBB). Conventional systemic drug delivery strategies often fail to achieve sufficient central nervous system (CNS) penetration while avoiding peripheral toxicity. Focused ultrasound (FUS), particularly when combined with microbubbles or nanocarriers, has emerged as a non-invasive approach to transiently and precisely open the BBB, enabling targeted delivery of therapeutics to the brain parenchyma. This review provides a comprehensive overview of the mechanisms by which FUS enhances CNS drug delivery, with a dedicated focus on its integration with nanoparticle-based systems, including liposomes, polymeric nanoparticles, dendrimers, metallic nanoparticles, and exosomes. We discuss how these nanocarriers can be engineered for improved stability, targeting specificity, and stimulus-responsive release upon FUS exposure. Recent advances in ultrasound technology, image guidance (particularly MRI), and therapeutic formulations are summarized, along with preclinical and clinical evidence across key neurodegenerative conditions. Despite promising results, several challenges remain, including long-term BBB stability, regulatory standardization, and scalability for broad clinical application. By integrating principles from acoustics, pharmacology, and nanotechnology, FUS-mediated drug delivery, especially in combination with smart nano systems, represents a significant advancement in precision neurotherapeutics, offering new hope for previously untreatable CNS diseases.},
}

@article {pmid42287769,
year = {2026},
author = {Kjaergaard, D and Nielsen, TR and Stomrud, E and Bali, D and Clemmensen, FK and Frederiksen, KS and Gleerup, HS and Hasselbalch, SG and Janelidze, S and Hansson, O and Waldemar, G and Simonsen, AH},
title = {Plasma phosphorylated tau217 discordance with amyloid status in an ethnically diverse mixed memory clinic cohort.},
journal = {Journal of the neurological sciences},
volume = {488},
number = {},
pages = {126057},
doi = {10.1016/j.jns.2026.126057},
pmid = {42287769},
issn = {1878-5883},
abstract = {We characterized patients with discordant plasma p-tau217 results and amyloid status determined by the Aβ42/p-tau181 CSF ratio or Aβ-PET biomarkers in an ethnically diverse mixed memory clinic cohort. Among 539 patients, 83.9% had concordant biomarker profiles, while 13.4% were amyloid negative and plasma p-tau217 positive discordant, and 2.8% were amyloid positive and plasma p-tau217 negative discordant. Discordant groups differed in cognitive syndrome severity and etiological diagnosis, but no other variables reached significance. However, analyses indicated small effects of BMI, kidney function, and certain neurological conditions. Amyloid negativity and plasma p-tau217 positivity discordance may reflect plasma p-tau217 detecting early amyloid pathology not detected by CSF or Aβ-PET. Further research is needed to clarify mechanisms underlying discordant biomarker profiles.},
}

@article {pmid42287775,
year = {2026},
author = {Grill, JD and Gillen, DL},
title = {Eligibility of men vs. women in Alzheimer's trials: Inclusive vs. representative.},
journal = {The journal of prevention of Alzheimer's disease},
volume = {13},
number = {7},
pages = {100625},
doi = {10.1016/j.tjpad.2026.100625},
pmid = {42287775},
issn = {2426-0266},
}

@article {pmid42287840,
year = {2026},
author = {Kim, T and Jia, Q and de Leon, MJ and Shu, H and , },
title = {A false discovery rate control method using a fully connected hidden Markov random field for neuroimaging data.},
journal = {Medical image analysis},
volume = {113},
number = {},
pages = {104158},
doi = {10.1016/j.media.2026.104158},
pmid = {42287840},
issn = {1361-8423},
abstract = {False discovery rate (FDR) control methods are essential for voxel-wise multiple testing in neuroimaging data analysis, where hundreds of thousands or even millions of tests are conducted to detect brain regions associated with disease-related changes. Classical FDR control methods (e.g., BH, q-value, and LocalFDR) assume independence among tests and often lead to high false non-discovery rates (FNR). Although various spatial FDR control methods have been developed to improve power, they still fall short of jointly addressing three major challenges in neuroimaging applications: capturing complex spatial dependencies, maintaining low variability in both false discovery proportion (FDP) and false non-discovery proportion (FNP) across replications, and achieving computational scalability for high-resolution data. To address these challenges, we propose fcHMRF-LIS, a powerful, stable, and scalable spatial FDR control method for voxel-wise multiple testing. It integrates the local index of significance (LIS)-based testing procedure with a novel fully connected hidden Markov random field (fcHMRF) designed to model complex spatial structures using a parsimonious parameterization. We develop an efficient expectation-maximization algorithm incorporating mean-field approximation, the Conditional Random Fields as Recurrent Neural Networks (CRF-RNN) technique, and permutohedral lattice filtering, reducing the time complexity from quadratic to linear in the number of tests. Extensive simulations demonstrate that fcHMRF-LIS achieves accurate FDR control, lower FNR, reduced variability in FDP and FNP, and a higher number of true positives compared to existing methods. Applied to an FDG-PET dataset from the Alzheimer's Disease Neuroimaging Initiative, fcHMRF-LIS identifies neurobiologically relevant brain regions and offers notable advantages in computational efficiency.},
}

@article {pmid42287941,
year = {2026},
author = {Ye, X and Jing, X and Li, Z and Jia, L and Zhong, F and Luo, XG},
title = {Dynamic dual roles of gut microbial metabolites in Alzheimer's disease: Translational insights for gut-brain axis interventions.},
journal = {Microbiological research},
volume = {311},
number = {},
pages = {128587},
doi = {10.1016/j.micres.2026.128587},
pmid = {42287941},
issn = {1618-0623},
abstract = {Alzheimer's disease (AD) is a complex neurodegenerative disorder in which the microbiome-gut-brain axis (MGBA) plays a crucial regulatory role through microbial metabolites. This review analyzes the concentration trajectories of representative metabolites across different disease stages and compartments, and synthesizes current preclinical evidence on how these metabolites influence AD pathogenesis, with particular attention to the mechanisms underlying their dual roles. We integrate evidence for bidirectional pathological crosstalk: gut dysbiosis accelerates central neurodegeneration through altered metabolite signaling, while AD-related neuropathology concurrently disrupts gut homeostasis. The review also evaluates MGBA-targeted intervention strategies and critically identifies key limitations that hinder clinical translation, including unclear dose-response relationships and insufficient patient stratification. We note that brain-to-gut mechanistic evidence remains considerably less developed than that for the gut-to-brain direction, and that signaling crosstalk among multiple metabolites is poorly characterized. Future studies should prioritize the neuroendocrine and immune pathways linking central pathology to gut dysbiosis, the dose-response relationships of individual metabolites, and standardized multi-metabolite profiling within prospective longitudinal cohorts. Addressing these gaps will advance mechanism-guided, precision-targeted interventions that mitigate the prevalent gut dysfunction in AD and confer global therapeutic benefits.},
}

@article {pmid42287971,
year = {2026},
author = {Zhou, S and Sudeshna, P and Trotti, LM and Bliwise, D and Pak, V},
title = {Vitamin D supplement intake is associated with better cognition in persons with sleep disturbance and mild cognitive impairment.},
journal = {Sleep medicine},
volume = {146},
number = {},
pages = {108960},
doi = {10.1016/j.sleep.2026.108960},
pmid = {42287971},
issn = {1878-5506},
abstract = {INTRODUCTION: Sleep disturbances affect nearly half of individuals with mild cognitive impairment (MCI), a population at elevated risk of progressing to Alzheimer's disease (AD). Vitamin D's role in cognitive outcomes, particularly among individuals with sleep disturbance and MCI, remains unclear. This study explored associations between cognitive function and vitamin D supplement intake in individuals with MCI and sleep disturbance-a high-risk group that may be more vulnerable to progression toward AD.

METHODS: This cross-sectional study included 54 participants with diagnosed or suspected mild cognitive impairment (MCI) and disturbed sleep (as determined by validated sleep questionnaires). We administered the MoCA (Montreal Cognitive Assessment) to assess cognition. Disturbed sleep was defined using the Pittsburgh Sleep Quality Index (PSQI ≥ 5) or the Epworth Sleepiness Scale (ESS ≥ 10). Vitamin D supplement intake was assessed by self-reported questionnaire. A multiple linear regression model was utilized to examine the association between vitamin D supplement intake and cognitive impairment (MoCA score), controlling for covariates of age, sex, body mass index (BMI), vitamin D type, and education.

RESULTS: Participants had a mean age of 67.2±8.9, a mean BMI of 29.5±7.2 kg/m[2], and 46% were male. Participants who took a daily dosage of 5000+ IU of vitamin D showed a marginally significant association with total MoCA score (adjusted mean (SE) = 3.78 (1.77); p = 0.039) in comparison to individuals who did not take daily vitamin D. Having a college degree was significantly associated with a higher total MoCA score (adjusted mean (SE) = 3.14 (1.38); p = 0.031. Individuals who were overweight also demonstrated higher total MoCA scores (adjusted mean (SE) = 3.59 (1.36); p = 0.013. No significant differences were found between individuals who regularly took vitamin D3 versus D2. Lower doses of Vitamin D did not significantly impact total MoCA score.

CONCLUSION: To our knowledge, this is the first study to evaluate the relationship between vitamin D supplemention and overall global cognition in individuals with both sleep disturbance and MCI. Our findings suggest that taking higher doses of daily vitamin D supplementation is associated with better overall cognitive performance in this population.},
}

@article {pmid42288030,
year = {2026},
author = {Zhi, J and Feng, H and Xue, Q and Pang, Z and Shen, R and Yang, A and Kou, X},
title = {Cu[2+]-selective porphyrin probes with multifunctional anti-AD activities and the structural-activity insights from X-ray single crystal analysis.},
journal = {European journal of medicinal chemistry},
volume = {316},
number = {},
pages = {119050},
doi = {10.1016/j.ejmech.2026.119050},
pmid = {42288030},
issn = {1768-3254},
abstract = {Metal ions play an important role in the pathogenesis of Alzheimer's disease (AD). The aggregation of β-amyloid and oxidative stress caused by metal dyshomeostasis are important reasons for the progression of AD. Therefore, metal therapeutics have received increasing attention. In this work, two multifunctional near-infrared porphyrin probes (1 and 2) were designed and synthesized, and the single crystals of their Cu[2+] complexes (1-Cu and 2-Cu) were obtained. Comprehensive biological activity evaluations demonstrated that 1, 2 possessed strong multifunctional anti-AD activities, including metal chelating, self-/Cu[2+]- induced Aβ1-42 aggregation inhibition, and in vitro/in vivo reactive oxygen species (ROS) elimination. Especially after coordination with copper, the cholinesterase inhibition and ROS elimination abilities were significantly increased. Notably, X-ray single crystal diffraction of 1, 1-Cu and 2-Cu provided crucial molecular-level structural information. Combined with molecular docking, density functional theory (DFT) calculations, and molecular dynamics simulations, these crystallographic data fully elucidated the precise structure-activity relationships, revealing that the larger conjugated plane structure, differences in intermolecular forces and the picket-fence architecture significantly influenced the activities. Meanwhile, both probes exhibited highly selective fluorescence quenching responses to Cu[2+] with very low cytotoxicity, indicating their promising potential as both therapeutic and diagnostic agents for AD.},
}

@article {pmid42288063,
year = {2026},
author = {Zhao, H and Qian, S and Wang, Y and Yang, W},
title = {Information quality of Alzheimer's disease treatment videos on TikTok and related factors: A cross-sectional study.},
journal = {Journal of clinical neuroscience : official journal of the Neurosurgical Society of Australasia},
volume = {152},
number = {},
pages = {112144},
doi = {10.1016/j.jocn.2026.112144},
pmid = {42288063},
issn = {1532-2653},
abstract = {BACKGROUND: The increasing reliance on mobile internet for health information necessitates a critical evaluation of content quality. This study aimed to systematically assess the quality of Alzheimer's Disease (AD) treatment-related short videos on TikTok, a leading platform for health information dissemination.

METHOD: A total of 100 CE treatment videos from TikTok, retrieved on December 20, 2025, were comprehensively evaluated using established assessment tools. Specifically, the Journal of American Medical Association (JAMA) benchmark criteriaand themodified Decision-making Information Support Criteria for Evaluating the Reliability of Non-randomised Studies (mDIS) scorewere used to evaluate thereliabilityof the video content. TheGlobal Quality Score (GQS) was used to assess theoverall quality, and the Patient Education Materials Assessment Tool for Audio Visual Content (PEMAT-A/U)was used to evaluate understandability and actionability.

RESULTS: Neurologists were identified as primary contributors of high-quality content, while videos on experimental treatments like deep cervical lymphovenous anastomosis (LVA) generally exhibited lower quality. Videos from emerging first-tier cities and those uploaded by top-tier creators demonstrated superior audience engagement and often higher content quality. A significant positive correlation was found between video duration, audience engagement metrics, and content quality scores.

CONCLUSIONS: Neurologists play a crucial role in providing reliable AD treatment information on short video platforms. There is an urgent need to improve the quality of content on experimental treatments and to encourage longer, well-referenced videos. Platforms should enhance content moderation and explicitly label experimental therapies to ensure accurate and trustworthy public health education regarding AD.},
}

@article {pmid42288107,
year = {2026},
author = {Fandrich, M and Schulte, C and Jakobi, M and Roeben, B and Wurster, I and Lerche, S and Zimmermann, S and Deuschle, C and Schneiderhan-Marra, N and Joos, TO and Gasser, T and Brockmann, K and Zimmermann, M},
title = {Impact of genetic variants in the longevity gene PPARGC1A and cerebrospinal fluid PPARγ levels on clinical trajectories in Parkinson's disease: Potential biomarkers for neurodegeneration and ageing.},
journal = {Parkinsonism & related disorders},
volume = {149},
number = {},
pages = {108380},
doi = {10.1016/j.parkreldis.2026.108380},
pmid = {42288107},
issn = {1873-5126},
abstract = {INTRODUCTION: Parkinson's disease (PD) is characterized by marked phenotypic heterogeneity particularly with regard to cognitive decline, which may be partly driven by ageing-related molecular pathways. Peroxisome Proliferator-Activated Receptor γ (PPARγ) represents a key downstream component of such pathways, while genetic variation in its coactivator gene peroxisome proliferator-activated receptor γ coactivator-1-α (PPARGC1A) may further modulate disease trajectories. We aimed to investigate the association of cerebrospinal fluid (CSF) PPARγ levels and PPARGC1A single nucleotide polymorphisms (SNPs) with clinical outcomes in PD, METHODS: CSF PPARγ levels were measured in a cohort of 446 with PD, 61 patients with dementia with Lewy Bodies (DLB), and 13 control participants. Associations with clinical parameters were analyzed using cross-sectional and longitudinal approaches. In addition, three PPARGC1A SNPs (rs4697447, rs7659588, rs4697455) were examined for their relationship with cognitive and motor outcomes.

RESULTS: Higher CSF PPARγ levels were associated with older age at examination and lower Montreal Cognitive Assessment (MOCA) scores. PPARγ levels differed across diagnostic groups, with highest levels observed in DLB, followed by PD and controls. Elevated PPARγ levels were associated with a higher incidence of cognitive impairment; these associations were largely attenuated after adjustment for age. In exploratory analyses, PPARGC1A variants were associated with cognitive trajectories.

CONCLUSION: CSF PPARγ levels are primarily associated with ageing-related processes rather than reflecting disease-specific effects. Genetic variation in PPARGC1A may contribute to interindividual differences in cognitive progression. Together, these findings support a role of ageing-related pathways in shaping clinical heterogeneity in PD.},
}

@article {pmid42288169,
year = {2026},
author = {Santerre, M and Shcherbik, N and Sawaya, BE},
title = {AQP4-Mediated Glymphatic Clearance: Sleep, Neurodegeneration, and the Translational Gap.},
journal = {Neuroscience and biobehavioral reviews},
volume = {},
number = {},
pages = {106819},
doi = {10.1016/j.neubiorev.2026.106819},
pmid = {42288169},
issn = {1873-7528},
abstract = {One-third of adults in industrialized societies are chronically sleep-deprived. If current evidence linking sleep disruption to glymphatic failure extends to human populations, this may represent not merely a productivity concern but a significant and underappreciated risk factor for neurodegeneration at the population scale. The glymphatic system, a brain-wide perivascular network that clears soluble amyloid-beta, tau, alpha-synuclein, and other neurotoxic metabolites through astrocytic aquaporin-4 water channels, operates predominantly during slow-wave sleep and is impaired when sleep is disrupted. Glymphatic dysfunction has been documented across Alzheimer's disease, Parkinson's disease, traumatic brain injury, and normal aging, with evidence from animal models and post-mortem and neuroimaging studies suggesting self-amplifying cycles in which impaired clearance may accelerate protein accumulation, though causal directionality in humans remains to be established prospectively. This review synthesizes the current mechanistic understanding of glymphatic biology, the bidirectional relationship between sleep disruption and neurotoxic protein accumulation, and emerging evidence that chronic conditions that suppress slow-wave sleep, including obstructive sleep apnea, chronic obstructive pulmonary disease, and tinnitus, represent plausible but largely untested glymphatic risk factors for neurodegeneration that warrant prospective investigation. We critically evaluate therapeutic strategies targeting glymphatic enhancement, including slow-wave sleep augmentation, aquaporin-4 restoration, noradrenergic tone reduction, and cerebrospinal fluid flow augmentation, and argue that the absence of validated non-invasive glymphatic biomarkers remains a major translational limitation that warrants systematic prioritization.},
}

@article {pmid42288184,
year = {2026},
author = {Ren, L and Luo, XQ and Mi, FY and Yu, CY},
title = {Current status and challenges in targeting circulating amyloid-β carriers for Alzheimer's disease therapy.},
journal = {Neuroscience},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.neuroscience.2026.06.009},
pmid = {42288184},
issn = {1873-7544},
abstract = {Amyloid-β (Aβ) accumulation in the brain is a defining pathological feature of Alzheimer's disease (AD). Cerebral Aβ burden is regulated not only by central production and degradation but also by its transport and clearance in the peripheral circulation. Blood-borne Aβ carriers provide a potential peripheral route for reducing brain Aβ levels by strengthening the brain-to-blood concentration gradient, representing a therapeutic strategy that does not require direct penetration of the blood-brain barrier. This review summarizes advances in blood-borne Aβ carriers and discusses their potential therapeutic applications in AD. Key carriers include human serum albumin (HSA), transthyretin (TTR), α2-macroglobulin (α2M), soluble low-density lipoprotein receptor-related protein 1 (sLRP1), apolipoproteins, red blood cells (RBC), monocytes and platelets, all of which participate in Aβ binding, transport from the brain to peripheral organs, and subsequent clearance. Structural abnormalities or functional dysregulation of these carriers may impair peripheral Aβ metabolism and promote cerebral Aβ deposition. Because blood-based therapeutic strategies are clinically feasible, may improve patient compliance, and do not require direct blood-brain barrier penetration, targeting circulating Aβ carriers has attracted increasing attention as a potential therapeutic approach for AD. This review further summarizes the classification and functional mechanisms of major blood-borne Aβ carriers, analyzes related intervention strategies and current limitations, and highlights future directions, including multi-target combination therapy and precision medicine. These discussions may provide a theoretical basis for developing AD treatments that target blood-borne Aβ transport and clearance.},
}

@article {pmid42288287,
year = {2026},
author = {Lietzke, EE and Saeb, D and Aldrich, EC and de Menezes, RF and Bruce, KD and Sprenger, KG},
title = {Uncovering the Biological Mechanisms of TREM2 with Molecular Simulations: A Comprehensive Review and Perspective.},
journal = {Progress in biophysics and molecular biology},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.pbiomolbio.2026.06.002},
pmid = {42288287},
issn = {1873-1732},
abstract = {Triggering receptor expressed on myeloid cells 2 (TREM2) is a central regulator of microglia activation and lipid metabolism, linking immune signaling to neurodegenerative and metabolic disease. While experimental and clinical studies have greatly expanded our understanding of TREM2 biology, the molecular principles governing its conformational plasticity, interactions with membranes and ligands, and the behavior of disease-associated variants remain unresolved. Recent molecular dynamics (MD) simulations of TREM2 have provided an atomistic view of these mechanisms, revealing novel structural, dynamic, and energetic features inaccessible to experimental methods alone. In this Review, we comprehensively assess these MD studies, integrating mechanistic insights across protein domains and modeling approaches. We critically evaluate simulations that describe how missense mutations uniquely perturb TREM2's complementarity-determining region (CDR) ligand-binding sites, transmembrane domain signaling motifs, and multimerization interfaces. We further elucidate how simulations capture novel CDR2 dynamics that cannot be resolved using traditional experimental methods, and how in silico findings align with data from experimental binding assays and crystallographic studies. Finally, we outline how rigorously designed simulations-performed with sufficient replicates and timescales-can guide rational engineering of small-molecule and peptide modulators targeting TREM2, advancing therapeutic strategies that can restore TREM2-mediated lipid sensing and signaling in metabolic and neurodegenerative diseases.},
}

@article {pmid42288508,
year = {2026},
author = {Liu, HH and Chen, TI and Chen, YC and Wang, V and Yip, PK and Lee, FJ and Hsu, WL and Lan, YC},
title = {Proton pump inhibitor use and risk of dementia in a population-based cohort study.},
journal = {Scientific reports},
volume = {},
number = {},
pages = {},
doi = {10.1038/s41598-026-55683-7},
pmid = {42288508},
issn = {2045-2322},
support = {Grant No. A1113251//Fu Jen Catholic University/ ; Grant No. A1113251//Fu Jen Catholic University/ ; Grant No. A1113251//Fu Jen Catholic University/ ; Grant No. A1113251//Fu Jen Catholic University/ ; Grant No. A1113251//Fu Jen Catholic University/ ; Grant No. A1113251//Fu Jen Catholic University/ ; Grant No. A1113251//Fu Jen Catholic University/ ; Grant No. A1113251//Fu Jen Catholic University/ ; },
abstract = {Understanding the effect of long-term medication exposure in middle-aged to older adults is crucial for dementia prevention. Proton pump inhibitors (PPIs), widely used for gastrointestinal conditions, have shown inconsistent associations with dementia risk. We conducted a retrospective cohort study using the Taiwan Adult Preventive Health Services and National Health Insurance databases. The study included 2,444,999 adults aged ≥ 40 years without baseline dementia. Incident dementia and cumulative PPI use, calculated as cumulative defined daily doses, were tracked. Multivariate Cox proportional hazards models estimated hazard ratios (HRs), adjusting for age, sex, BMI, lifestyle factors, and comorbidities like hypertension and diabetes. During follow-up, 137,126 participants (5.6%) developed dementia (mean age: 72.7 years; 58.6% females). PPI use was associated with an increased dementia risk in a dose-response manner (HR 1.66; 95% CI, 1.64-1.69 for the high-exposure category). The strongest associations were observed in the younger cohort: individuals aged < 65 years with high-exposure exhibited a significantly higher risk (HR 1.97; 95% CI, 1.89-2.06) compared to older groups. PPI use is associated with an elevated, dose-dependent risk of all-cause dementia in this observational cohort. While this association attenuates with advancing age, potential causal mechanisms remain to be fully elucidated.},
}

@article {pmid42288956,
year = {2026},
author = {Judge, K and Grant, C and Stratton, L and Yaroslavsky, I and Moreno, M and Elliott, K and Fazio, S},
title = {Evaluating the Efficacy and Acceptability of the Empowered Caregiver Program on Caregivers of People Living with Dementia.},
journal = {Clinical gerontologist},
volume = {},
number = {},
pages = {1-20},
doi = {10.1080/07317115.2026.2684972},
pmid = {42288956},
issn = {1545-2301},
abstract = {OBJECTIVES: Evaluate the efficacy and acceptability of a two-session online program, The Empowered Caregiver, for caregivers of people living with dementia.

METHODS: A randomized controlled trial (RCT) research design was used to examine efficacy with caregivers randomly assigned to the program (n = 219) or wait-list control (n = 219) conditions. Self-reported data were collected at three timepoints: baseline, after program completion, and 45 days post-completion. Program content areas included: caregiving supports, independence, communication, and dementia behaviors. Acceptability data was collected by program participants.

RESULTS: Significant improvements after completing the program and short-term maintenance 45 days post-program completion were found for self-efficacy, emotional health strain, role captivity, mastery, personal gain, unmet needs distress, symptoms of anxiety and depression, behavioral intentions and actions. The majority of participants (55%) attended both sessions; 74% attended one session; and 26% did not attend either session. Participants evaluated the program as highly acceptable.

CONCLUSIONS: Results indicated that The Empowered Caregiver was efficacious in improving outcomes along with short-term maintenance across outcomes and was viewed as a very acceptable approach.

CLINICAL IMPLICATIONS: The two-session protocol delivered online by volunteer community educators serves as a model for developing and implementing pragmatic and scalable educational and skill-building programs.},
}

@article {pmid42288958,
year = {2026},
author = {Braga, SS and Santos, NE and Almeida-Santos, M and Figueira, FF and Almeida Paz, FA},
title = {Phosphonates as Modulators of Brain Chemistry.},
journal = {Medicinal research reviews},
volume = {},
number = {},
pages = {},
doi = {10.1002/med.70070},
pmid = {42288958},
issn = {1098-1128},
abstract = {The present review describes the current knowledge on phosphonates designed for brain disease therapeutics, a less explored aspect of the studies on their medicinal chemistry. Because of their structural similarity with phosphates and of the ubiquitous presence of phosphate-dependent processes in the brain, phosphonate compounds are able to influence brain chemistry, interfering with neurotransmission and phosphorous-dependent bioprocesses. One of the main applications for phosphonates in the brain is Alzheimer's disease, for which they can be new drug candidates and/or afford innovative strategies for diagnostics. Such applications are described in the first section of this review, which includes a large number of reports on phosphonates with cholinesterase-inhibiting activity, some recent studies exploring phosphonates for inhibiting the interaction between amyloid-β protein and alcohol dehydrogenases, and phosphonate-based materials used in proteomics-based investigative and diagnosis platforms for the different stages of development of Alzheimer's disease. The second section of the review is dedicated to ischemic brain injury and to the development of phosphonates for active against NMDA and AMPA receptors with the purpose of reducing brain damage caused by glutamate excitotoxicity. Furthermore, agonists targeting the mGlu-4 receptor suggest potential for promoting neuroregeneration. The review concludes by emphasizing the relevance of phosphonate stability, versatility, and ability to mimic natural phosphate groups in the development of new therapeutic agents for brain disorders, weighing the advantages against the gaps in knowledge in order to set future directions of research in brain health.},
}

@article {pmid42288974,
year = {2026},
author = {Ghahremani, M and Guan, DX and Ballard, C and Creese, B and Corbett, A and Pickering, E and Smith, EE and Ismail, Z},
title = {Mild Behavioural Impairment and Everyday Functioning in Cognitively Unimpaired Older Adults: Evidence From the CAN-PROTECT Study.},
journal = {Journal of geriatric psychiatry and neurology},
volume = {},
number = {},
pages = {8919887261457447},
doi = {10.1177/08919887261457447},
pmid = {42288974},
issn = {1552-5708},
abstract = {BackgroundRecognizing early clinical signs of dementia is key to optimizing emerging therapies, including monoclonal antibodies. Mild behavioural impairment (MBI) characterizes later-life emergent and persistent nropsychiatric symptoms linked to greater dementia risk, representing a behavioural manifestation of the underlying neurodegenerative disease for some. The association of MBI with functional ability may therefore reveal subtle functional decline as an additional early risk marker in cognitively unimpaired (CU) older adults.MethodsBaseline data from 1714 CU participants from the CAN-PROTECT study were analyzed. MBI was assessed using the MBI Checklist (MBI-C) (continuous and dichotomized, MBI+ ≥8). Functional ability was assessed using the SAGEA scale capturing instrumental and basic activities. Negative binomial models examined associations between MBI and function, adjusting for demographics, cognition, and physical/sensory limitations.ResultsHigher MBI-C scores (count ratio [CR] = 1.07; 95%CI: 1.06-1.07) and MBI+ status (CR = 2.64; 95%CI: 2.36-2.95) were associated with greater global and domain-specific functional impairments.ConclusionFindings highlight the importance of assessing both behavioural and functional changes in CU adults to identify at-risk individuals for timely interventions.},
}

@article {pmid42289203,
year = {2026},
author = {Wang, J and Han, T and Hu, P and Hu, S and Song, J and Li, S and Zhou, Q and Luo, A and Zeng, L},
title = {Current advances in PDGF isoform specificity and variable functions in aging-associated neurological disorders.},
journal = {Neurobiology of disease},
volume = {227},
number = {},
pages = {107488},
doi = {10.1016/j.nbd.2026.107488},
pmid = {42289203},
issn = {1095-953X},
abstract = {Among the signaling molecules that influence the health and pathology of central nervous system (CNS), Platelet-derived growth factor (PDGF) has emerged as a pivotal regulator of neurogenesis, neuroinflammation, and neuronal survival. However, the isoform-specific signaling of PDGF in aging-related neurological disorders remains under-characterized, and the interplay between PDGF and cellular senescence in CNS is inadequately understood. Additionally, the dual role of PDGFs signaling remains underexplored, especially in aging-related neurological disorders. This review aims to address these gaps by analyzing the roles of five PDGF isoforms in CNS functions, PDGFs downstream signaling in the nervous system, PDGF's modulation of neural components, and its role in aging-related diseases including Stroke, Alzheimer's Disease (AD), Parkinson's Disease (PD), and Glioblastoma (GBM). In this review, we highlight the effects of PDGF isoforms in the CNS vary with experimental conditions, dosage, cellular microenvironment and aging status. This review provides a comparative analysis of PDGF isoform-specific functions, emphasizing age-dependent signaling shifts and potential therapeutic implications.},
}

@article {pmid42289359,
year = {2026},
author = {Li, XY and Lu, JY and Shen, Q and Zhao, YX and Chan, KW and Liu, W and Ge, JJ and Zhao, J and Sun, YM and Yen, TC and Wu, JJ and Zuo, CT and Wang, J and Liu, FT and , },
title = {Brain Metabolic Signatures of Amyloid-β and Tau Pathology in Corticobasal Syndrome: A Multimodal Biomarker Study.},
journal = {Movement disorders : official journal of the Movement Disorder Society},
volume = {},
number = {},
pages = {},
doi = {10.1002/mds.70395},
pmid = {42289359},
issn = {1531-8257},
support = {2025ZD0214800//Brain Science and Brain-like Intelligence Technology-National Science and Technology Major Project/ ; 82171421//National Natural Science Foundation of China/ ; 82371432//National Natural Science Foundation of China/ ; 82371266//National Natural Science Foundation of China/ ; 82171252//National Natural Science Foundation of China/ ; 82501508//National Natural Science Foundation of China/ ; 82272039//National Natural Science Foundation of China/ ; 82021002//National Natural Science Foundation of China/ ; 82394434//National Natural Science Foundation of China/ ; //Shanghai Municipal Science and Technology Major Project/ ; 2023-YN008//Clinical Research Project of Huashan Hospital, Fudan University/ ; 2024JC055//Huashan Hospital Seed Project/ ; 2022ZD0211606//STI2030-Major Project/ ; 25TS1405000//Shanghai Science and Technology Program Project/ ; 24PJD010//Shanghai Magnolia Talent Program Pujiang Project/ ; },
abstract = {BACKGROUND: Corticobasal syndrome (CBS) may arise from heterogeneous neuropathological substrates, including corticobasal degeneration (CBD), progressive supranuclear palsy (PSP), and Alzheimer's disease (AD), and biomarker-based stratification has therefore become central to its characterization in vivo. In a large CBS cohort, we examined whether [18]F-fluorodeoxyglucose (FDG) positron emission tomography (PET) metabolic patterns reflect underlying amyloid-β deposition and tau topography, and how these patterns relate to the clinical phenotype.

METHODS: We conducted a cross-sectional study of consecutive patients with CBS and were enrolled at Huashan Hospital, Fudan University, between December 2019 and February 2025. Each patient underwent [18]F-FDG PET for cerebral glucose metabolism, amyloid status assessment using amyloid PET or cerebrospinal fluid biomarkers, and florzolotau([18]F) PET for tau topography.

RESULTS: Among 113 patients, [18]F-FDG PET identified five distinct metabolic subgroups: AD type (n = 20), CBD type I (n = 45), CBD type II (n = 18), PSP type (n = 26), and frontotemporal dementia type (n = 4). The AD metabolic pattern showed high specificity for amyloid-β positivity (98.5%) and for combined AD pathology (amyloid-β plus tau, 98.6%), with correspondingly lower sensitivity (54.2% and 72.2%). [18]F-FDG PET patterns further showed high specificity for the PSP tau profile (96.2%) and high sensitivity for the CBD tau profile (97.7%). On spatial analysis, amyloid-β deposition significantly mediated the regional coupling between tau accumulation and cerebral glucose hypometabolism.

CONCLUSIONS: [18]F-FDG PET identifies metabolic patterns that correspond to specific proteinopathies underlying CBS with high specificity but requires integration within multimodal biomarker frameworks for comprehensive patient stratification. © 2026 International Parkinson and Movement Disorder Society.},
}

@article {pmid42289414,
year = {2026},
author = {Park, S and Ahn, J and Na, DL and Kim, HJ and Jang, H and Kim, JP and Kang, SH and Yun, J and Chun, MY and Seo, SW and Kwak, K},
title = {Scalable CT-based prognostic modeling of dementia conversion in mild cognitive impairment.},
journal = {Scientific reports},
volume = {16},
number = {1},
pages = {},
pmid = {42289414},
issn = {2045-2322},
support = {RS2020-KH106434//Ministry of Science and ICT, South Korea/ ; RS-2025-02223212//Korea Health Industry Development Institute/Republic of Korea ; RS-2019-NR040057//National Research Foundation of Korea/ ; SMX1250081//Samsung Medical Center, Sungkyunkwan University/ ; 2024ER1003-01//Korea National Institute of Health/ ; },
}

@article {pmid42289425,
year = {2026},
author = {Sajjad, TB and Zahid, A and Rehman, H and Nadeem, S and Nasir, MA and Rauf, S and Mazhar, MW and Raza, A and Okon, II},
title = {Serum Aβ42 and hemoglobin as independent predictors of post-stroke cognitive impairment: a comparative biomarker study.},
journal = {Scientific reports},
volume = {},
number = {},
pages = {},
doi = {10.1038/s41598-026-56327-6},
pmid = {42289425},
issn = {2045-2322},
abstract = {Stroke is a devastating medical condition, and one of its side effects is post-stroke cognitive impairment (PSCI). The objective of this study is to investigate and analyse the potential indicators for post-stroke cognitive decline (PSCI), with a particular emphasis on the biomarkers Aβ42 (beta-amyloid 42) and haemoglobin (Hb) levels. Based on clinical diagnosis, 120 participants were divided into three groups: PSCI (n = 40), PSCN (n = 40), and AD (n = 40): Alzheimer's disease (AD), post-stroke cognitive impairment (PSCI), and post-stroke cognitively normal (PSCN). The first data set was documented. The study examined the relationship between Aβ42 and Hb and cognitive score. Finally, ROC curve and logistic regression analysis were used to analyze the aforementioned indicators' PSCI prediction abilities. Compared to the AD group (104.00 ± 64.43 pg/ml, 112.4 ± 19.05 g/L) and the PSCN group (87.38 ± 66.69 pg/ml, 134.8 ± 13.28 g/L), the PSCI group had lower levels of Aβ42 (69.20 ± 49.36 pg/ml) and Hb (110.53 ± 22.73 g/L) (P < 0.05). The study identified Hb, age, and hypertension as the main risk factors for PSCI, while Aβ42 was noted as a pertinent risk factor. The sensitivity level was 0.800, specificity was 0.625, and area under the curve for the combination diagnosis of Aβ42 and Hb was 0.7169, according to the ROC curve. The risk variables for PSCI, Aβ42 and Hb, are considerably lower in the blood of patients with PSCI compared to controls. The performance of differential diagnosis will be enhanced when the two are integrated.},
}

@article {pmid42289440,
year = {2026},
author = {Li, X and Rockall, AG and Edison, P and , and , and Aboagye, EO},
title = {A computational model to describe multi-regional brain architecture during neurodegeneration in Alzheimer's disease.},
journal = {Scientific reports},
volume = {},
number = {},
pages = {},
doi = {10.1038/s41598-026-54109-8},
pmid = {42289440},
issn = {2045-2322},
abstract = {We previously proposed an MRI-based machine learning model to describe the mesoscopic architecture of the human brain to aid in classifying subjects as having non-AD related pathology (nADrp) or AD related pathology (ADrp), including mild cognitive impairment (MCI) and Alzheimer's disease (AD). The method, developed on data from patients scanned at 1.5T showed high performance, but did not generalise well to scans obtained from 3T MRI. In the current work we overcome the problem and extend the approach to patients scanned longitudinally, and at different field strengths. Retrospective T1-MRI data from 1592 subjects scanned at 3T were included to develop the machine learning models. Three additional longitudinal datasets (n = 211) at different magnetic field strengths-1.5 and 3T-were adopted to evaluate the models. Radiomic features were extracted from each brain region. A logistic regression method with least absolute shrinkage and selection operator (LASSO) model selection was employed to classify nADrp from ADrp (classifier 1) or MCI from AD (classifier 2). Classifier 1 that discriminates nADrp from ADrp achieves high performance, with area under the curve (AUC) of the receiver operating characteristics (ROC) of 0.84 in the independent hold-out cross-sectional dataset. High performance was also seen in external testing datasets for classifier 1 (AUC of 0.70 to 0.96). Classifier 2 that discriminates MCI from AD achieves AUC of 0.79 in the independent hold-out dataset and moderate to good performance in the external testing datasets (AUC of 0.56 to 0.93). The new data analysis methods, trained on 3T data, demonstrate potential for aiding AD early detection and disease progression on both 3T and 1.5T scanners.},
}

@article {pmid42289507,
year = {2026},
author = {Yazi, S and Ozen, B and Buldu, B and Yalcin, E and Karakose, O and Cakmak, O and Somunkiran, S and Yananli, HR and Sehirli, US and Kirazli, O},
title = {The effect of canagliflozin on hippocampal dendrite morphology in a model of Alzheimer's disease induced by intracerebroventricular injection of streptozotocin.},
journal = {Brain structure & function},
volume = {231},
number = {6},
pages = {},
pmid = {42289507},
issn = {1863-2661},
mesh = {Animals ; *Canagliflozin/pharmacology/administration & dosage ; *Alzheimer Disease/pathology/chemically induced/drug therapy ; Male ; Streptozocin/administration & dosage ; *Dendrites/drug effects/pathology ; Rats ; *Hippocampus/drug effects/pathology ; Disease Models, Animal ; Donepezil/pharmacology ; Dendritic Spines/drug effects/pathology ; Pyramidal Cells/drug effects/pathology ; *Sodium-Glucose Transporter 2 Inhibitors/pharmacology ; Rats, Wistar ; Rats, Sprague-Dawley ; },
abstract = {Alzheimer's disease (AD) and diabetes mellitus (DM) share common pathophysiological features. However, the effects of antidiabetic drugs on neurodegeneration are not completely known. Canagliflozin, a novel option for DM treatment, is a dual inhibitor of sodium glucose co-transporter type 2 (SGLT2) and acetylcholinesterase. The aim of this study is to examine the morphological features of dendrites and dendritic spines of pyramidal neurons in hippocampus of AD model treated with canagliflozin. The model of AD was obtained by intracerebroventricular injection of streptozotocin. Then, the rats were divided into 3 groups: vehicle, donepezil, and canagliflozin. The injections were i.c.v. administered for 7 days. Behavioral tests were performed to evaluate memory, anxiety, and motor functions. Brain tissues were processed by Golgi impregnation method. Pyramidal neurons in the CA1 region were examined using Neurolucida software. Dendritic branching, total dendrite length, dendritic spine density, and dendritic spine types were analyzed. Compared to the vehicle group, the donepezil group and the canagliflozin group exhibited significantly higher dendritic branches (p = 0.0273, p = 0.0195) and total dendrite length (p = 0.0171, p = 0.0360), respectively. The total dendritic spine density (p < 0.0001) and the mushroom-type dendritic spine density (p = 0.0001) were significantly low in the donepezil group compared to the vehicle group. However, canagliflozin did not induce any significant alterations in the dendritic spine density. Canagliflozin treatment was as effective as donepezil treatment on hippocampal dendrite morphology. This morphological framework, indicating dendritic plasticity and remodeling, serve to better understand the cellular effects of canagliflozin. Therefore, our study may contribute to the development of novel strategies for therapy of AD.},
}

Animals
*Canagliflozin/pharmacology/administration & dosage
*Alzheimer Disease/pathology/chemically induced/drug therapy
Male
Streptozocin/administration & dosage
*Dendrites/drug effects/pathology
Rats
*Hippocampus/drug effects/pathology
Disease Models, Animal
Donepezil/pharmacology
Dendritic Spines/drug effects/pathology
Pyramidal Cells/drug effects/pathology
*Sodium-Glucose Transporter 2 Inhibitors/pharmacology
Rats, Wistar
Rats, Sprague-Dawley

@article {pmid42289538,
year = {2026},
author = {Piva, F and Boccalini, C and Ashton, NJ and Zetterberg, H and Blennow, K and Frisoni, GB and Veronese, M and Garibotto, V and Peretti, DE},
title = {Investigating AD and non-AD [[18]F]flortaucipir distribution patterns in a memory clinic cohort.},
journal = {European journal of nuclear medicine and molecular imaging},
volume = {},
number = {},
pages = {},
pmid = {42289538},
issn = {1619-7089},
abstract = {PURPOSE: Amyloid (A) deposition represents a specific pathological hallmark of Alzheimer's disease (AD). Clinical diagnostic protocols frequently rely on the combined use of amyloid (A)- and tau (T)- positron emission tomography (PET) imaging to distinguish AD from non-amyloid-associated neurodegenerative conditions. Many neurodegenerative disorders are characterized by distinct tauopathies, which result in different [[1][8]F]flortaucipir T-PET topographic patterns. The aim of this study was to investigate, in a memory clinic cohort, whether [[18]F]flortaucipir distribution patterns derived from scaled subprofile modelling using principal component analysis (SSM/PCA) could differentiate between A + and A - individuals, potentially eliminating the need for an A-PET.

METHODS: A total of 81 subjects were included in this study: 40 with AD characterized by both A and T accumulation (A + T +), 13 with suspected non-Alzheimer's pathology (A - T +), and 28 without A and T abnormality (A - T -). SSM/PCA was applied on [[18]F]flortaucipir images to identify two disease patterns (DPs), representing amyloid-positive (A + DP) and amyloid-negative (A- DP) accumulation. Each subject's imaging data was then compared to these DPs and the resulting similarity scores were used as inputs for three machine learning models - Support Vector Machine, Random Forest, and Multi-Layer Perceptron - to predict amyloid status. Finally, Spearman correlation analyses were conducted between SSM/PCA-derived scores and plasma biomarkers levels.

RESULTS: The two identified disease patterns exhibited distinct PET signatures consistent with current disease knowledge. Their representativeness was further supported by significant correlations with plasma biomarkers in nearly all cases. All machine learning models confirmed the capacity of the A + DP to predict AD pathology, correctly classifying at least 36 out of 40 cases. In contrast, the A - DP showed limited discriminative power for non-AD conditions, as indicated by its higher misclassification rate (best performance: 7 correct out of 13).

CONCLUSION: SSM/PCA applied on [[18]F]flortaucipir-PET imaging provide information on both A and T status, supporting its potential use as first and possibly sole examination in the investigation of suspected AD. While for non-AD cases, A-PET scans are still recommended.},
}

@article {pmid42289601,
year = {2026},
author = {Lin, CH and Lane, HY},
title = {Superoxide dismutase and glutathione interact to determine cognitive outcome among people with subjective cognitive decline (SCD): a prospective study.},
journal = {European archives of psychiatry and clinical neuroscience},
volume = {},
number = {},
pages = {},
pmid = {42289601},
issn = {1433-8491},
abstract = {BACKGROUND: Subjective cognitive decline (SCD) is an early sign of Alzheimer's disease, in which oxidative stress is implicated. Three primary endogenous antioxidants include superoxide dismutase (SOD), glutathione (GSH), and catalase (CAT). This current study aimed to explore the roles of these antioxidants in cognitive outcome of SCD.

METHODS: Sixty-seven adults with SCD were recruited. Cognitive function (assessed by the Alzheimer's disease assessment scale-cognitive subscale [ADAS-cog]), global function (by Alzheimer's Disease Cooperative Study scale for ADL [ADCS-ADL]), and plasma GSH, CAT, and SOD were measured at baseline and two years later.

RESULTS: Over the two-year course, the 67 participants' cognitive performance (mean ADAS-cog score: 5.2 ± 3.4 at baseline vs. 6.1 ± 5.2 at endpoint, P = .062) and global function (ADCS-ADL score: 68.5 ± 10.2 vs. 62.5 ± 13.3, P < .001) showed a deteriorating trend. Their GSH levels fell significantly (3.67 ± 2.70 vs. 2.81 ± 2.51 μm, P = .016), CAT rose (67.7 ± 23.4 vs. 91.9 ± 35.1 nmol/min/mL, P < .001), but SOD remained pretty constant (0.145 ± 0.053 vs. 0.158 ± 0.068 U/mL). Using generalized estimating equations to assess longitudinal changes in ADAS-Cog, we discovered that baseline ADAS-cog score (P < .001), BMI (P = .009), and baseline SOD×GSH interaction (P = .034) were associated with cognitive outcomes.

CONCLUSIONS: Cognitive decline in people with SCD was influenced by baseline cognitive level, BMI, and the interaction between SOD and GSH, suggesting that antioxidant interplay may play a crucial role in regulating oxidative stress and consequently cognitive aging.},
}

@article {pmid42289606,
year = {2026},
author = {Ren, D and Xu, J and Xiao, L and Zhang, T and Li, B and Li, R and Zhu, H},
title = {Oleanolic acid modulates neuronal regeneration through KLF5-mediated FGF13 mRNA degradation to alleviate Alzheimer's disease-like cognitive dysfunction.},
journal = {Journal of molecular medicine (Berlin, Germany)},
volume = {104},
number = {1},
pages = {},
pmid = {42289606},
issn = {1432-1440},
support = {No. 2023JJ30862//Natural Science Foundation of Hunan Province/ ; The 14th Five-year TCM Backbone Talent Training Plan of Hunan Province//The 14th Five-year TCM Backbone Talent Training Plan of Hunan Province/ ; },
mesh = {Animals ; *Alzheimer Disease/drug therapy/metabolism/genetics ; *Oleanolic Acid/pharmacology ; Rats ; *Kruppel-Like Transcription Factors/metabolism/genetics ; Male ; *RNA Stability/drug effects ; *Nerve Regeneration/drug effects ; *Cognitive Dysfunction/drug therapy/metabolism/etiology/genetics ; RNA, Messenger/genetics/metabolism ; Neurons/drug effects/metabolism ; Disease Models, Animal ; *Fibroblast Growth Factors/genetics/metabolism ; Rats, Sprague-Dawley ; Neural Stem Cells/drug effects/metabolism ; Neurogenesis/drug effects ; },
abstract = {Despite understanding the pathophysiology of Alzheimer's disease (AD), the mechanisms of neuronal regeneration mediated by oleanolic acid (OA) through m6A RNA methylation remain unexplored, forming the crux of this study. In a streptozotocin (STZ)-induced AD rat model, we administered OA and conducted behavioral tests to evaluate cognitive functions. We employed BrdU incorporation assays and immunofluorescence to investigate NSC proliferation, and Western blotting, chromatin immunoprecipitation (ChIP), RNA immunoprecipitation (RIP), and MeRIP-qPCR assays to analyze protein expression and RNA stability. Bioinformatic predictions focused on the interaction between KLF5, YTHDF2, and FGF13. OA significantly reversed cognitive impairment and enhanced NSC differentiation in the AD model. The modulation of OA on KLF5 expression led to the repression of YTHDF2, which was pivotal in the m6A-dependent RNA decay of FGF13, promoting axonal regeneration. Furthermore, FGF13 harbors multiple m6A modification sites, which contribute to its mRNA stability and translation, thereby influencing neuronal polarization and migration. In addition, the neuroprotective mechanism of OA also involved the upregulation of NSCs, while impaired neurogenesis and reduced NSC function are known to be associated with AD pathology. This research reveals that OA's therapeutic potential in AD is mediated through a previously unidentified mechanism involving modulation of m6A-dependent RNA regulation, highlighting the significance of m6A RNA methylation in neuronal regeneration. The findings pave the way for new therapeutic strategies targeting RNA modifications in neurodegenerative diseases.},
}

Animals
*Alzheimer Disease/drug therapy/metabolism/genetics
*Oleanolic Acid/pharmacology
Rats
*Kruppel-Like Transcription Factors/metabolism/genetics
Male
*RNA Stability/drug effects
*Nerve Regeneration/drug effects
*Cognitive Dysfunction/drug therapy/metabolism/etiology/genetics
RNA, Messenger/genetics/metabolism
Neurons/drug effects/metabolism
Disease Models, Animal
*Fibroblast Growth Factors/genetics/metabolism
Rats, Sprague-Dawley
Neural Stem Cells/drug effects/metabolism
Neurogenesis/drug effects

@article {pmid42289826,
year = {2026},
author = {Renssen, JWA and Sikkes, SAM and van der Landen, SM and Leeuwis, AE and Groot, C and van der Flier, WM and Ponds, RWHM and Pijnenburg, YAL},
title = {Concordance between domain-based neuropsychological profiles and clinical phenotypes in young-onset dementia.},
journal = {The Clinical neuropsychologist},
volume = {},
number = {},
pages = {1-15},
doi = {10.1080/13854046.2026.2684731},
pmid = {42289826},
issn = {1744-4144},
abstract = {Objective: Young-onset dementia (YOD; onset < 65 years) frequently presents with phenotypes that involve specific cognitive domains whilst relatively sparing episodic memory, such as behavioral variant frontotemporal dementia (bvFTD), posterior cortical atrophy (PCA), and primary progressive aphasias (PPA). We hypothesized that standard neuropsychological batteries may fail to identify these phenotypes and tested their ability to pick up cognitive deficits for YOD phenotypes based on their clinical criteria. Methods: In this observational study, we included 2,056 consecutive YOD patients from the Amsterdam Dementia Cohort, who were seen at Alzheimer Center Amsterdam, Amsterdam UMC between 2010 and 2023. Domain scores were created based on a neuropsychological battery comprising tests in memory, executive, visuospatial, and language. Using three qualitative strategies-normative domain-based classification, alignment with simulated clinical reasoning, and intra-individual profiling-we categorized patients in cognitive domain groups based on either count, kind, or severity of domain impairments. Results: Across approaches, typical (i.e., amnestic) Alzheimer's disease, PCA, and semantic variant PPA (svPPA) were relatively well recognized, yet bvFTD, logopenic variant PPA (lvPPA), and nonfluent variant PPA (nfvPPA) remained poorly detected. Intra-individual profiling added some nuance by confirming memory, visuospatial, and semantic deficits in typical AD, PCA, and svPPA, respectively, but unexpectedly highlighted executive impairments in nfvPPA and to a lesser extent in lvPPA. Conclusions: Our standard neuropsychological battery reliably identified key impairments in typical AD, PCA, and svPPA, but underperformed for bvFTD, lvPPA, and nfvPPA. Our findings underscore the need to augment test batteries with targeted social cognition and language measures to aid differential diagnosis in YOD.},
}

@article {pmid42290126,
year = {2026},
author = {Putri, CA and Faieta, J and Ebuenyi, ID},
title = {Role of Rehabilitation in the Management of Alzheimer's Disease and Related Dementias: Healthcare Provider Perspectives.},
journal = {Journal of primary care & community health},
volume = {17},
number = {},
pages = {21501319261461254},
doi = {10.1177/21501319261461254},
pmid = {42290126},
issn = {2150-1327},
mesh = {Humans ; *Alzheimer Disease/rehabilitation ; Female ; Quality of Life ; Male ; Qualitative Research ; *Attitude of Health Personnel ; *Health Personnel/psychology ; Interviews as Topic ; *Dementia/rehabilitation ; Middle Aged ; },
abstract = {IntroductionAlthough rehabilitation can improve the quality of life of individuals with Alzheimer's disease and Alzheimer's disease-related dementias (AD/ADRD), awareness and acceptance of its benefits vary across healthcare providers and care settings. The aim of this study was to explore the perspectives of healthcare providers on the adoption and utilization of rehabilitation among individuals with AD/ADRD.MethodsWe adopted an exploratory qualitative descriptive study design using semi-structured interviews. Using purposive sampling, ten healthcare providers that provide rehabilitation services for individuals with AD/ADRD were recruited from the Alzheimer's Disease Research Center (ADRC), University of Pittsburgh and the University of Pittsburgh Pepper Center.ResultsParticipants emphasized the substantial potential benefits of rehabilitation for this population. Interview data indicated that several participants viewed rehabilitation services as significantly enhancing the quality of life and wellbeing of individuals with AD/ADRD. Feedback underscored the important role of rehabilitation in optimizing care for individuals with AD/ADRD and highlighted key barriers to its broader implementation.ConclusionsOverall, the findings suggest that rehabilitation offers meaningful value in the management of AD/ADRD. Although participants identified several barriers, rehabilitation services were consistently viewed as beneficial for individuals with AD/ADRD. Addressing these gaps will be important for strengthening the effectiveness and reach of rehabilitation services.},
}

Humans
*Alzheimer Disease/rehabilitation
Female
Quality of Life
Male
Qualitative Research
*Attitude of Health Personnel
*Health Personnel/psychology
Interviews as Topic
*Dementia/rehabilitation
Middle Aged

@article {pmid42290548,
year = {2026},
author = {Bhat, R and Greeny, A and Viswanatha, GL and Mudgal, J and Hanumanthappa, S and Krishnadas, N},
title = {Anti-Neuroinflammatory and Neuroprotective Effects of Caffeic Acid in Experimental Models of Neurodegeneration: A Systematic Review and Meta-Analysis.},
journal = {Journal of biochemical and molecular toxicology},
volume = {40},
number = {6},
pages = {e70959},
doi = {10.1002/jbt.70959},
pmid = {42290548},
issn = {1099-0461},
mesh = {*Neuroprotective Agents/therapeutic use/pharmacology ; *Caffeic Acids/therapeutic use/pharmacology ; Animals ; Humans ; *Neurodegenerative Diseases/drug therapy/metabolism/pathology ; *Anti-Inflammatory Agents/therapeutic use/pharmacology ; Disease Models, Animal ; *Neuroinflammatory Diseases/drug therapy/metabolism ; },
abstract = {Caffeic acid, a naturally occurring polyphenol found in various dietary sources, has gained considerable interest for its antioxidant, anti-inflammatory, and neuroprotective properties. Preclinical studies suggest that caffeic acid may exert beneficial effects in models of Alzheimer's disease, Parkinson's disease, cerebral ischaemia, ageing, diabetes-associated cognitive decline, and neuroinflammation. To assess the neuroprotective activity of caffeic acid in neurodegenerative diseases. After performing a detailed literature search across various databases, such as Google Scholar, Embase, PubMed, Scopus, and Cochrane, a total of 44 unique studies were identified based on the framed eligibility criteria. This meta-analysis demonstrated that caffeic acid exerts significant effect on neurobiomarker panel: amyloid-β accumulation (IV: -1.84 [-3.08, -0.61], 95% CI, p = 0.004, I[2] = 8%), GFAP (IV: -2.03 [-2.91, -1.15], 95% CI, p < 0.00001,), AchE (IV: -1.98 [-3.44, -0.52], 95% CI, p = 0.008, I[2] = 85%), BDNF (IV: 1.14 [0.20, 2.09], 95% CI, p = 0.02, I[2] = 57%); Oxidative stress markers such as MDA (IV: -4.60 [-6.66, -2.55], 95%CI, p < 0.0001, I[2] = 99%) and LPO (IV: -2.12 [-3.49, -0.75], 95% CI, p = 0.002, I[2] = 98%), SOD (IV: 4.90 [3.72, 6.08], 95% CI, p < 0.00001, I[2] = 99%), CAT (IV: 21.35 [12.10, 30.61], 95% CI, p < 0.00001, I[2] = 94%), GSH (IV: 6.86 [5.28, 8.44], 95% CI, p < 0.00001, I[2] = 99%); Neuroinflammatory parameters including TNF-α (IV: -4.23 [-5.89, -2.57], 95% CI, p < 0.00001, I[2] = 83%), IL-6 (IV: -3.07 [-4.69, -1.45], 95% CI, p = 0.0002, I[2] = 78%) and IL-1β (IV: -5.09 [-8.12, -2.07], 95% CI, p = 0.0010, I[2] = 61%); Behavioural parameters like forced swim test (IV: -2.22 [-3.83, -0.61], 95% CI, p = 0.007, I[2] = 86%), open field test- number of rearing's (IV: 12.50 [0.55, 24.45], 95% CI, p = 0.04, I[2] = 89%), elevated plus maze test- time spent in open arms (IV: -30.45 [-53.67, -7.22], 95% CI, p = 0.01, I[2] = 81%); Apoptosis (Caspase-3) parameters (IV: -28.46 [-52.22, -4.70], 95% CI, p = 0.02, I[2] = 95%). Caffeic acid showed significant neuroprotective activity in neurodegenerative diseases based on pre-clinical evidence, making it a promising molecule for future RCTs.},
}

*Neuroprotective Agents/therapeutic use/pharmacology
*Caffeic Acids/therapeutic use/pharmacology
Animals
Humans
*Neurodegenerative Diseases/drug therapy/metabolism/pathology
*Anti-Inflammatory Agents/therapeutic use/pharmacology
Disease Models, Animal
*Neuroinflammatory Diseases/drug therapy/metabolism

@article {pmid42291413,
year = {2026},
author = {Sha, Y and Fu, H and Lu, K and Wang, G and Wang, Y},
title = {The role of YKL-40 in Alzheimer's disease pathology and drug targeting.},
journal = {PeerJ},
volume = {14},
number = {},
pages = {e21361},
pmid = {42291413},
issn = {2167-8359},
mesh = {Humans ; *Alzheimer Disease/drug therapy/metabolism/pathology ; *Chitinase-3-Like Protein 1/metabolism/antagonists & inhibitors ; Animals ; Biomarkers/metabolism ; Apoptosis ; Disease Progression ; },
abstract = {BACKGROUND: Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by the accumulation of amyloid-beta (Aβ) plaques, hyperphosphorylated tau tangles, and significant neuronal loss. Recent studies have implicated YKL-40, a glycoprotein commonly associated with inflammation and neural apoptosis, in the pathogenesis of AD.

METHODS: We conducted extensive searches across major scientific databases, including PubMed, Web of Science, and Embase. We selected peer-reviewed articles, review articles, and clinical studies focusing on YKL-40 in AD.

RESULTS: This review comprehensively analyses the multifaceted role of YKL-40 in AD, covering its cellular localization, biomarker associations, and pathological mechanisms. We also summarize the mechanistic pathways by which YKL-40 contributes to disease progression, highlighting its role in neuroinflammation, neural apoptosis, and disruption of the circadian regulation of immune responses. Moreover, the development of drugs that target YKL-40, such as humanized anti-YKL-40 antibodies and small molecules, offers promising strategies for blocking AD progression.

CONCLUSION: This review highlights the potential of YKL-40 as a novel drug target and its implications for enhancing diagnostic precision and treatment strategies in combating Alzheimer's disease.},
}

Humans
*Alzheimer Disease/drug therapy/metabolism/pathology
*Chitinase-3-Like Protein 1/metabolism/antagonists & inhibitors
Animals
Biomarkers/metabolism
Apoptosis
Disease Progression

@article {pmid42291615,
year = {2026},
author = {Booncharoen, K and Thanapornsangsuth, P and Pongpitakmetha, T and Sarutikriangkri, Y and Likitjaroen, Y and Thanprasertsuk, S},
title = {Enlarged perivascular spaces in subcortical white matter are linked to amyloid-tau depositions and cognitive decline: Data from a memory clinic in Thailand.},
journal = {Alzheimer's & dementia (Amsterdam, Netherlands)},
volume = {18},
number = {2},
pages = {e70399},
pmid = {42291615},
issn = {2352-8729},
abstract = {INTRODUCTION: Enlarged perivascular spaces (EPVSs) have been implicated in Alzheimer's disease (AD) pathogenesis, but their relationships with amyloid beta (Aβ) and tau pathology remain unclear.

METHODS: We conducted a cross-sectional study of 51 patients with amnestic mild cognitive impairment or mild dementia from a memory clinic in Thailand. EPVS severity in centrum semiovale (CSO) and basal ganglia (BG) was rated on T1-weighted magnetic resonance imaging. Aβ burden and tau deposition were assessed using positron emission tomography imaging. Cognitive change was measured using longitudinal Montreal Cognitive Assessment (MoCA) scores.

RESULTS: Higher CSO-EPVS severity was associated with greater Aβ and tau burden, particularly when CSO-EPVS exceeded BG-EPVS severity. No significant associations were observed for BG-EPVS. Greater CSO-EPVS severity was also linked to greater decline in follow-up MoCA scores.

DISCUSSION: CSO-EPVS may reflect region-specific processes linked to AD pathology, while their association with cognitive decline may be mediated by underlying amyloid and tau burden.},
}

@article {pmid42291616,
year = {2026},
author = {Lopez, S and Del Percio, C and Lizio, R and Noce, G and Carpi, M and Arnaldi, D and Famà, F and Pardini, M and Massa, F and Marinozzi, F and Bini, F and Treves, G and Soricelli, A and Salvatore, M and Giubilei, F and Ziccardi, L and Güntekin, B and Yener, G and Ferri, R and Lanuzza, B and Stocchi, F and Vacca, L and Coletti, C and Infarinato, F and Romano, P and Marizzoni, M and Frisoni, GB and Barone, P and Cappiello, A and Cuoco, S and Bonanni, L and D'Anselmo, A and Antonini, A and Fiorenzato, E and Cauzzo, S and Biundo, R and D'Antonio, F and De Pandis, MF and Marziali, S and Bruno, G and Carducci, F and Babiloni, C},
title = {Glymphatic clearance as revealed by diffusion tensor imaging along the perivascular space (DTI-ALPS) is associated with Alzheimer's disease neuropathology and periodic rsEEG alpha rhythms in mild cognitive impairment participants.},
journal = {Alzheimer's & dementia (Amsterdam, Netherlands)},
volume = {18},
number = {2},
pages = {e70384},
pmid = {42291616},
issn = {2352-8729},
abstract = {INTRODUCTION: We evaluated whether the brain glymphatic drainage function estimated by the diffusion tensor imaging along the perivascular space (DTI-ALPS) index relates to white matter (WM) integrity, Alzheimer's disease (AD) neuropathology, resting-state electroencephalogram (rsEEG) alpha rhythms underpinning quiet vigilance, and cognitive decline in mild cognitive impairment (MCI).

METHODS: Clinical, neuroimaging, and rsEEG data were analyzed in matched mild cognitive impairment due to AD (ADMCI) and MCI not due to AD (noADMCI) participants. DTI-ALPS index and aperiodic and periodic components of the rsEEG power spectra were calculated following standard pipelines.

RESULTS: Lower DTI-ALPS index was associated with higher AD neuropathology and WM lesions, lower periodic rsEEG alpha rhythms, and worse cognition in patients with ADMCI and noADMCI as a whole population, with the ADMCI (over noADMCI) group showing lower DTI-ALPS index, greater AD neuropathology, and lower periodic rsEEG alpha rhythms.

CONCLUSIONS: The DTI-ALPS index may capture glymphatic system impairment linked to AD neuropathology, vigilance dysfunction, and cognitive decline in MCI.},
}

@article {pmid42291728,
year = {2026},
author = {Zhang, Y and Yang, W and Tian, C},
title = {The lactate shuttle in ageing: a metabolic bridge between muscle fatigue and brain resilience.},
journal = {Frontiers in physiology},
volume = {17},
number = {},
pages = {1823430},
pmid = {42291728},
issn = {1664-042X},
abstract = {Traditionally, lactate was considered a glycolytic byproduct that causes muscle fatigue, but now its biological role is undergoing a significant paradigm shift. Emerging evidence suggests that lactate acts as an inter-organ metabolic and signaling mediator linking exercise-induced peripheral metabolic stress to central nervous system adaptation. This review explores how exercise drives lactate pulses and delivers them to the brain through the circulatory system and blood-brain barrier (BBB). Lactate has a dual function in the brain, serving not only as the preferred energy substrate for active neurons but also as a core signaling molecule. Through pathways involving G protein coupled receptor 81 (GPR81) and histone lactylation, lactate regulates neuroplasticity, cerebrovascular function, neuroinflammation, and antioxidant defense, thereby establishing cognitive resilience. During aging, multiple components of this proposed lactate signaling axis may become compromised, including skeletal muscle lactate production, circulatory and blood-brain barrier transport, and cellular responsiveness within the brain. Such multi-level impairment may contribute to neuromuscular co-aging and may increase vulnerability to neurodegenerative disorders, including Alzheimer's disease. Ultimately, we explored the translational potential of restoring the lactate signaling axis through multimodal strategies to promote healthy aging, including precise exercise prescriptions, GPR81 targeted therapy, metabolic interventions, and biomarker development. This review aims to combine metabolic science with evidence of neuroaging, providing a new theoretical framework for determining the primacy of exercise-driven brain health and advancing anti-aging interventions.},
}

@article {pmid42292037,
year = {2026},
author = {Sun, Y and Xu, Z and Cui, L and Guo, J and Zhang, X and Xiao, Y},
title = {Plant-Derived Exosome-Like Nanoparticles in Neurodegenerative Diseases: From Dual Bioactive-Delivery Roles to Translational Challenges.},
journal = {International journal of nanomedicine},
volume = {21},
number = {},
pages = {608292},
pmid = {42292037},
issn = {1178-2013},
mesh = {Humans ; *Exosomes/chemistry ; *Neurodegenerative Diseases/drug therapy ; Animals ; *Nanoparticles/chemistry ; Blood-Brain Barrier/metabolism ; Alzheimer Disease/drug therapy ; Neuroprotective Agents/pharmacokinetics/administration & dosage ; *Plants/chemistry ; Tissue Distribution ; },
abstract = {Neurodegenerative diseases, particularly Alzheimer's disease (AD) and related disorders, remain difficult to treat because of their multifactorial pathogenesis, limited disease-modifying therapies, and insufficient central nervous system exposure of many therapeutic agents. Plant-derived exosome-like nanoparticles (PELNs) are emerging as biogenic nanovesicles that combine intrinsic bioactivity with natural nanocarrier properties. Enriched with lipids, proteins, small RNAs, and phytochemicals, PELNs may exert neuroprotective effects while offering opportunities for gastrointestinal stability, systemic transport, and potential central nervous system delivery. This review critically summarizes the dual bioactive-delivery roles of PELNs in AD and related neurodegenerative disorders. We discuss their potential mechanisms in modulating neuroinflammation, glial cell-mediated immune responses, redox imbalance, mitochondrial dysfunction, pathological protein aggregation, neural repair, and gut-brain axis regulation. We further examine how administration routes, biodistribution patterns, cellular uptake, and blood-brain barrier (BBB) models influence the interpretation of evidence for central nervous system (CNS) targeting. In addition, recent advances in isolation, purification, characterization, cargo loading, and surface engineering strategies are reviewed in the context of improving stability, targeting capacity, and translational feasibility. Despite their promise, the clinical development of PELNs remains constrained by source-dependent heterogeneity, non-standardized isolation methods, insufficiently defined critical quality attributes, inconsistent dosing metrics, limited pharmacokinetic and biodistribution data, and unresolved long-term biosafety concerns. Establishing rigorous Chemistry, Manufacturing, and Controls (CMC) frameworks, reproducible quality-control assays, and evidence-based translational pathways will be essential for advancing PELNs from experimental bioactive vesicles to clinically relevant neurotherapeutic platforms.},
}

Humans
*Exosomes/chemistry
*Neurodegenerative Diseases/drug therapy
Animals
*Nanoparticles/chemistry
Blood-Brain Barrier/metabolism
Alzheimer Disease/drug therapy
Neuroprotective Agents/pharmacokinetics/administration & dosage
*Plants/chemistry
Tissue Distribution

@article {pmid42292330,
year = {2026},
author = {Mukhopadhyay, D and Das, P and Angom, RS and Dutta, S and Li, Z and Castanedes-Casey, M and Kulkarni, T and Chakravarty, T and Wang, E and Dickson, D and Rachamala, HK},
title = {Vascular endothelial growth factor receptor-1 (VEGFR-1) knock-down is protective against hypoxia, Aβ1-42 oligomer and Aβ1-42 fibril -induced neuronal cell death: implications in AD pathogenesis.},
journal = {Frontiers in neuroscience},
volume = {20},
number = {},
pages = {1799391},
pmid = {42292330},
issn = {1662-4548},
abstract = {INTRODUCTION: Recent transcriptome analysis has demonstrated increased expression of Vascular Endothelial Growth Factor receptor-1 (VEGFR-1/FLT1) and in AD brain. Increased expression of VEGFR1 and its ligand VEGFB were associated with a more rapid rate of cognitive decline, providing evidence of a potential link between increased VEGFR-1 expression in AD pathogenesis. In this study, we explored the potential role of VEGFR-1 expression in neurons on AD pathology.

METHODS: To confirm VEGFR1 expression in AD brains, we first performed immunostaining in AD brain sections (AD - Braak stage V-VI, and normal controls - Braak 0-II). And to determine a potential detrimental role of neuronal VEGFR1 expression on AD associated pathologies, we exposed SH-SY5Y human neuroblastoma cells and mouse primary neurons to either hypoxia conditions (1%O2) or 5 μ Aβ1-42 oligomers or fibrils for 24, 28 and 72hrs.

RESULTS: In this study, we found preferential staining of VEGFR-1 in the neuropil and neuronal cell bodies both in AD and Control hippocampus and increased VEGFR-1 immunoreactivity in dystrophic neuritic processes in the vicinity of Thio-S positive amyloid plaques in AD brains. And treatment of SH-SY5Y human neuroblastoma cell line and mouse primary neurons, with either hypoxia conditions or Aβ1-42 oligomers, resulted in increased VEGFR-1 expression and cleaved caspase 3 activation, leading to neuronal toxicities/cell death. Similarly, treatment with Aβ1-42 fibrils also increased VEGFR-1 and cleaved caspase 3 protein levels in the SH-SY5Y cells whereas treatment with Aβ1-42 monomers had no effect on VEGFR-1 expression. In addition, we show that over-expression of VEGFR-1 intracellular domains in SH-SY5Y cells directly induced neuronal toxicities and importantly, siRNA-mediated knockdown of VEGFR-1 in neurons prevented the hypoxia, Aβ1-42 oligomer and Aβ1-42 fibril-induced toxicities and cell death phenotypes. Treatment with either hypoxia or Aβ1-42 oligomers also reduced expression of cell survival genes including VEGFR-2 and Hippo pathway YAP1 and siRNA-mediated VEGFR-1 knockdown in the neurons normalized expression of both VEGFR-2 and YAP1. Using differential gene expression analysis, we demonstrated upregulation of several inflammatory/interferon-stimulated genes (ISGs) as well as increased expression of genes involved in activation of oxidative stress and cell death pathways in response to Aβ1-42 oligomers treatment in mouse primary neurons. And siRNA-mediated VEGFR-1 knockdown in the mouse primary neurons, reduced gene expression of both the ISGs and oxidative stress/cell death pathways in response to Aβ1-42 oligomer treatment.

DISCUSSION: In summary, these results show that siRNA-mediated knockdown of VEGFR-1 in neurons significantly prevented hypoxia, Aβ1-42 oligomer and Aβ1-42 fibril-induced cellular toxicities and cell death phenotypes, indicating a potential detrimental role of aberrant VEGFR-1 expression and signaling in response to AD associated pathologies.},
}

@article {pmid42292331,
year = {2026},
author = {Lago, M and Cerveira, M and Simonet, JX},
title = {Transient multidomain functional improvement in advanced Alzheimer's disease following high-dose psilocybin-containing mushroom administration: a case report.},
journal = {Frontiers in neuroscience},
volume = {20},
number = {},
pages = {1813281},
pmid = {42292331},
issn = {1662-4548},
abstract = {BACKGROUND: Advanced Alzheimer's disease (AD) is generally regarded as a stage of irreversible functional decline. Psilocybin is known to transiently alter large-scale brain network dynamics and to induce plasticity-related mechanisms in preclinical models, yet clinical data in advanced dementia remain lacking.

CASE PRESENTATION: We report the case of an octogenarian Japanese-American woman with a 10-year history of Alzheimer's disease, including 5 years of marked hypofunction and predominantly monosyllabic speech. Baseline features included chronic urinary incontinence, executive dysfunction, dysphagia, dependent mobility, flat affect, and severe reduction in spontaneous communication. The patient received 5 g of orally administered psilocybin-containing mushrooms (Enigma strain). The acute phase was marked by autonomic activation, clinically suspected hyperthermia, profuse sweating, and a prolonged deep sleep-like state. Approximately 19 h post-administration, spontaneous autobiographical speech emerged. Over subsequent days and weeks, functional improvements included restoration of urinary continence, improved ambulation, autonomous dressing, increased emotional responsiveness, sustained social interaction, contextual memory retrieval, preserved working memory for social context, and spontaneous conversational engagement.

CONCLUSION: This case documents transient multidomain functional improvement in advanced Alzheimer's disease following psilocybin administration. The findings do not imply disease reversal but suggest that residual functional capacity may persist in late-stage neurodegeneration and may become transiently accessible under specific neuromodulatory conditions.},
}

@article {pmid42292338,
year = {2026},
author = {Zeng, ZT and Tang, JX and Wang, SR and Lei, LZ and Xing, ZY and Wang, JM and Wu, J},
title = {Mechanisms of action and advances in application of music therapy in improving cognitive impairment based on the theory of neuroplasticity.},
journal = {Frontiers in neuroscience},
volume = {20},
number = {},
pages = {1828930},
pmid = {42292338},
issn = {1662-4548},
abstract = {As global population aging accelerates, preventing and treating cognitive impairment has become a major public health priority. Music therapy is a safe, well-tolerated non-pharmacological intervention with substantial potential to improve cognitive function. This review synthesizes the neurologic music therapy (NMT) framework, encompassing techniques targeting attention, memory, and executive function, delivered through both active and receptive approaches. Clinical investigations indicate that music therapy may improve cognition and neuropsychiatric symptoms in Alzheimer's disease (AD), vascular cognitive impairment (VCI), Parkinson's disease-related cognitive impairment, mild cognitive impairment (MCI), and traumatic brain injury (TBI); however, effects appear to vary by intervention duration and disease stage. This narrative review aims to provide a theoretical foundation and practical guidance for the non-pharmacological intervention of cognitive impairment by collating evidence on the neuroplasticity theoretical foundations, technical systems, and clinical applications of music therapy.},
}

@article {pmid42292389,
year = {2026},
author = {Li, E and Zhang, P and Feng, W},
title = {Neuroinflammation in Alzheimer's disease: glial crosstalk, pathological modulation, and therapeutic implications.},
journal = {Frontiers in immunology},
volume = {17},
number = {},
pages = {1783786},
pmid = {42292389},
issn = {1664-3224},
mesh = {Humans ; *Alzheimer Disease/pathology/metabolism/immunology/therapy ; Animals ; *Neuroinflammatory Diseases/metabolism/pathology ; Microglia/metabolism/pathology/immunology ; Astrocytes/metabolism/pathology/immunology ; Signal Transduction ; *Neuroglia/metabolism/pathology ; Amyloid beta-Peptides/metabolism ; },
abstract = {Alzheimer's disease (AD) remains a major therapeutic challenge despite the availability of amyloid-targeting disease-modifying therapies for selected patients with early symptomatic disease. These therapies have shown that disease modification is possible, but their benefits are modest and constrained by amyloid confirmation, safety monitoring, infusion delivery, access, and eligibility requirements. Neuroinflammation is increasingly viewed as a context-dependent modifying process that interacts with β-amyloid (Aβ), tau pathology, metabolic stress, and vascular dysfunction, rather than as an unequivocally established primary initiating driver. This review provides a selective, glia-centered synthesis of AD neuroinflammation focused on microglia, astrocytes, and their reciprocal crosstalk. We examine how microglial and astrocytic responses can support Aβ handling, plaque containment, tissue homeostasis, and synaptic protection, while chronic or poorly resolved glial signaling can amplify cytokine and complement responses, metabolic and oxidative stress, and neuronal vulnerability. Representative signaling nodes, including NF-κB, AMPK/mTOR, and PI3K/Akt, are discussed as organizing mechanisms linking inflammatory transcription, proteostatic stress, glial metabolism, and neuronal injury, rather than as equivalently validated therapeutic targets. Therapeutic implications are interpreted across three evidence tiers: approved anti-amyloid antibodies with indirect inflammatory relevance, clinically tested anti-inflammatory or immunomodulatory strategies that have not established disease-modifying efficacy, and experimental precision approaches aimed at glial-state modulation. Overall, the translational challenge is not broad suppression of neuroinflammation, but stage-specific identification and modulation of maladaptive glial states while preserving protective microglial and astrocytic functions.},
}

Humans
*Alzheimer Disease/pathology/metabolism/immunology/therapy
Animals
*Neuroinflammatory Diseases/metabolism/pathology
Microglia/metabolism/pathology/immunology
Astrocytes/metabolism/pathology/immunology
Signal Transduction
*Neuroglia/metabolism/pathology
Amyloid beta-Peptides/metabolism

@article {pmid42292675,
year = {2026},
author = {Singh, P and Karkhur, S and Verma, V and Gupta, S and Beri, A},
title = {Glaucoma and Systemic Neurodegenerative Diseases: The Brain-Eye Continuum.},
journal = {Journal of current glaucoma practice},
volume = {20},
number = {1},
pages = {26-30},
pmid = {42292675},
issn = {0974-0333},
abstract = {UNLABELLED: Glaucoma is a chronic, progressive optic neuropathy characterized by retinal ganglion cell (RGC) death and visual field loss. It is the leading cause of irreversible blindness globally, affecting more than 70 million people, and its prevalence is expected to rise with aging populations. Traditionally, glaucoma was defined primarily as a disease of intraocular pressure (IOP) dysregulation, but recent decades have reframed it as a complex neurodegenerative disorder involving multiple systemic and local risk factors. In parallel, systemic neurodegenerative diseases such as Alzheimer's disease (AD), Parkinson's disease (PD), and multiple sclerosis (MS) pose immense healthcare and socioeconomic burdens. The concept of the "eye as a window to the brain" arises from the fact that the retina and optic nerve are direct extensions of the central nervous system (CNS). This has positioned the eye as a valuable site for studying neurodegenerative processes noninvasively, using advanced imaging modalities such as optical coherence tomography (OCT) and optical coherence tomography angiography (OCTA). Glaucoma is a chronic neurodegenerative optic neuropathy, and the concept of the "eye as a window to the brain" highlights its overlap with systemic diseases such as AD, PD, and MS.

HOW TO CITE THIS ARTICLE: Singh P, Karkhur S, Verma V, et al. Glaucoma and Systemic Neurodegenerative Diseases: The Brain-Eye Continuum. J Curr Glaucoma Pract 2026;20(1):26-30.},
}

@article {pmid42292809,
year = {2026},
author = {Zou, Y and Lin, Y and Zhang, C and Li, Y and Chen, X and Ma, X and Chen, K and Liang, B and Liang, P},
title = {Microglial metabolic reprogramming drives the therapeutic effects of bavachinin on brain network function and memory in Alzheimer's disease.},
journal = {Frontiers in pharmacology},
volume = {17},
number = {},
pages = {1839602},
pmid = {42292809},
issn = {1663-9812},
abstract = {INTRODUCTION: Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by the accumulation of amyloid-β (Aβ) plaques and pervasive cognitive decline. Bavachinin, a natural flavonoid derived from the traditional medicinal herb Psoralea corylifolia, has previously been demonstrated to inhibit Aβ aggregation in vitro. However, its potential to alleviate cognitive impairment, restore large-scale brain network dysfunctions, and mitigate AD-related pathology in vivo remains elusive.

METHODS: In this study, we systematically evaluated the therapeutic efficacy of bavachinin on AD-associated pathology, cortical slow-wave activity (SWA), and behavioral phenotypes in 5xFAD transgenic mice. We utilized behavioral assessments to evaluate learning and memory, mesoscopic wide-field calcium imaging to assess cortical network dynamics, and histological analyses to measure cerebral Aβ deposition. Furthermore, pharmacological inhibition was employed to investigate the mechanistic role of mitochondrial oxidative phosphorylation (OXPHOS).

RESULTS: Behavioral assessments revealed that bavachinin administration significantly rescued deficits in learning and memory. Mesoscopic wide-field calcium imaging further demonstrated that bavachinin substantially enhanced the synchrony of cortical SWA while reducing its frequency in 5xFAD mice, indicating a restoration of network-level dynamics. Histological analyses confirmed a marked reduction in cerebral Aβ deposition, which occurred independent of Aβ production pathways. Mechanistically, bavachinin bolstered microglial Aβ phagocytosis and chemotactic migration by promoting mitochondrial OXPHOS, thereby revitalizing cellular energy metabolism. Notably, pharmacological inhibition of OXPHOS partially abrogated the therapeutic benefits of bavachinin, suggesting that the augmentation of mitochondrial function is a requisite for its anti-AD effects.

DISCUSSION: In summary, bavachinin alleviates cognitive impairment and neuropathology in AD model mice by driving microglial metabolic reprogramming and facilitating Aβ clearance. These findings highlight its robust potential as a therapeutic candidate for AD.},
}

@article {pmid42292813,
year = {2026},
author = {Kang, C and Zhou, X and Li, B and Li, J},
title = {Mitochondrial dysfunction in Alzheimer's disease: targeting the powerhouse with nanomedicine.},
journal = {Frontiers in pharmacology},
volume = {17},
number = {},
pages = {1755126},
pmid = {42292813},
issn = {1663-9812},
abstract = {Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by relentless cognitive decline. Despite decades of research dominated by the amyloid and tau hypotheses, clinical interventions targeting these classical hallmarks have yielded limited success in halting disease progression, underscoring a critical conceptual and therapeutic gap: the early, persistent, and under-addressed role of mitochondrial dysfunction as a primary driver of AD pathology. Beyond serving as passive victims of amyloid-beta toxicity, impaired mitochondria actively initiate and perpetuate a self-amplifying cycle through dysregulated bioenergetics, aberrant dynamics, compromised quality control, calcium dyshomeostasis, and exacerbated neuroinflammation-all of which collectively propel synaptic loss and neuronal death well before overt plaque deposition. This review provides a synthesized reappraisal of this mitochondrial-centric paradigm, systematically delineating the interconnected nature of mitochondrial failure as both an initiator and an amplifier of AD and arguing that it represents a central nexus linking sporadic and genetic forms of the disease. We further consolidate the emerging landscape of nanomedicine as a revolutionary strategy to bridge the current therapeutic gap, highlighting how diverse nanotherapeutic platforms-ranging from organic and inorganic nanocarriers and biomimetic vesicles to nanozymes and gene-modulating systems-are uniquely equipped to overcome the blood-brain barrier and achieve subcellular precision targeting of the mitochondrial compartment. By analyzing advances in nanotechnology designed explicitly to restore mitochondrial homeostasis through the normalization of redox balance, enhancement of mitophagy, and preservation of adenosine triphosphate synthesis, we demonstrate how this approach directly addresses the root of the neurodegenerative cascade that traditional drug development has failed to reach. Finally, we critically examine the translational hurdles and future trajectories of mitochondria-targeted nanotherapy, proposing a conceptual framework for multidisciplinary integration and arguing that mitochondrial nanomedicine represents not merely a symptomatic intervention but a requisite disease-modifying paradigm shift capable of intercepting the earliest triggers of AD.},
}

@article {pmid42292823,
year = {2026},
author = {Wu, C and Cong, X and Gao, Y and Liu, J and Duan, Y and Yu, H and Gao, S and Zhang, W},
title = {Pseudoginsenoside-F11: a comprehensive review of chemical structure, pharmacological activities, pharmacokinetics, and therapeutic potential.},
journal = {Frontiers in pharmacology},
volume = {17},
number = {},
pages = {1808278},
pmid = {42292823},
issn = {1663-9812},
abstract = {Pseudoginsenoside-F11 (PF11), an ocotillol-type saponin unique to American ginseng (Panax quinquefolius L.), is characterized by a distinctive 20,24-epoxy bridge. This review summarizes the current evidence regarding PF11's chemical structure, pharmacological effects, pharmacokinetics, and therapeutic potential. Preclinical studies have demonstrated that PF11 exerts multi-targeted neuroprotective effects in animal models of Alzheimer's disease, Parkinson's disease, and cerebral ischemia. These neuroprotective actions are mediated through the regulation of calcium homeostasis, restoration of the autophagy-lysosomal pathway, and modulation of microglial polarization. Beyond neuroprotection, PF11 offers additional beneficial effects: it protects the heart by antagonizing the β1-adrenoceptor, safeguards the kidneys via inhibition of the NF-κB/NLRP3 pathway, regulates metabolism as a partial PPARγ agonist, and mitigates tolerance to morphine and methamphetamine. Despite promising preclinical evidence, PF11 remains at an early translational stage due to poor oral bioavailability, incomplete pharmacokinetic characterization, and the absence of human studies. Addressing these limitations through formulation optimization, mechanistic validation, and rigorous clinical investigation will determine whether PF11 can progress from a natural product lead to a viable therapeutic candidate.},
}

@article {pmid42292841,
year = {2026},
author = {Shao, J and An, Y and Ding, R and Wang, S and Wang, X},
title = {Neuroprotective effects of traditional Chinese medicine using zebrafish models - a review.},
journal = {Frontiers in pharmacology},
volume = {17},
number = {},
pages = {1810881},
pmid = {42292841},
issn = {1663-9812},
abstract = {Neurological disorders, including Alzheimer's disease, Parkinson's disease, and stroke, remain major causes of global disability and mortality, with limited neuroprotective therapies available. Traditional Chinese medicine (TCM) offers multi-target therapeutic potential, but its mechanistic complexity requires systematic investigation using appropriate model systems. Zebrafish (Danio rerio) has emerged as a valuable vertebrate platform for TCM neuroprotection research due to its genetic homology with humans, optical transparency, and high-throughput screening compatibility. This review summarizes the application of zebrafish models in studying TCM for Alzheimer's disease, Parkinson's disease, cerebral ischemia, epilepsy, insomnia, depression, and spinal cord injury. Key findings indicate that TCM metabolites exert neuroprotective effects through multiple mechanisms, including anti-oxidative stress, anti-neuroinflammation, anti-apoptosis, neurotransmitter modulation, neurogenesis promotion, and vascular protection. Zebrafish models have proven particularly useful for high-throughput screening of active metabolites, real-time in vivo imaging of neurovascular processes, and rapid safety assessment. However, limitations such as the absence of a layered neocortex, differences in drug metabolism, and the predominantly acute nature of current models must be acknowledged. Addressing these challenges through model standardization, multi-omics integration, and cross-species validation will further enhance the translational relevance of zebrafish-based TCM research. This review provides a practical framework for leveraging zebrafish models to advance the mechanistic understanding and clinical development of neuroprotective TCM therapies.},
}

@article {pmid42292846,
year = {2026},
author = {Lindemann, L and Lambotte, J and Rothe, J and Messer, J and Diener, C and Pichereau, S and Cantrill, C and Mueggler, T and Honer, M and Beck, J and Steinbrecher, T and Tortelli, R and Gerlach, I and Ratni, H and Rodriguez Sarmiento, RM and Baumann, K},
title = {Pharmacology of nivegacetor (RG6289), a potent and selective gamma secretase modulator in clinical development for the treatment of Alzheimer's disease.},
journal = {Frontiers in pharmacology},
volume = {17},
number = {},
pages = {1783414},
pmid = {42292846},
issn = {1663-9812},
abstract = {BACKGROUND: Alzheimer's Disease (AD) is a prevalent neurodegenerative disorder which involves a complex pathobiology driven by amyloid-beta (Aβ) and tau pathologies, among other factors. Aβ peptides are generated via β-secretase (BACE1) and γ-secretase cleavage of amyloid precursor protein (APP). While long isoforms like Aβ42 are neurotoxic and aggregation-prone, shorter isoforms (Aβ38, Aβ37) are non-amyloidogenic. γ-secretase modulators (GSMs) shift production from longer to shorter peptides which is expected to slow down or halt (prevent) amyloid accumulation and its downstream effects.

METHODS: The novel GSM nivegacetor was evaluated in vitro using cell lines overexpressing human wild-type APP, or human APP with the Swedish mutation K670N/M671L (APPSwe). The in vitro selectivity of nivegacetor was tested on Notch-1, a representative gamma secretase substrate other than APP. Additionally, nivegacetor was profiled for its selectivity on a range of pharmacological targets. In vivo studies tested a dose-response and a time course of nivegacetor on soluble Aβ levels in brain tissue of APPSwe transgenic mice. Furthermore, the impact of two ADAD mutations, PSEN1 E280A (Columbian) and PSEN2 N141I (Volga German), on nivegacetor's potency was tested. Moreover, nivegacetor was tested for possible effects on [[3]H]florbetaben binding to Aβ plaque pathology in human AD brain tissue sections.

RESULTS: Nivegacetor lowered the production of Aβ42 and Aβ40 and concomitantly increased levels of Aβ37 and Aβ38 in vitro and in vivo in mice. Nivegacetor did not inhibit Notch-1 and showed a favorable selectivity profile on a broad range of targets. When tested on two ADAD mutations, nivegacetor was equipotent on the PSEN1 E280A mutation and significantly less potent on the PSEN2 N141I mutation compared to wild-type gamma secretase. Nivegacetor did not interfere with the detection of amyloid plaques by [[3]H]florbetaben in human AD brain tissue, which is an important prerequisite for the use of florbetaben as a PET tracer in clinical trials.

CONCLUSION: Nivegacetor is a potent, orally bioavailable GSM with favorable properties and is currently under investigation as a clinical candidate in a Phase 2A clinical trial in individuals with prodromal and early sporadic AD, and in a Phase 2 clinical trial in individuals carrying the PSEN1 E280A ADAD mutation.},
}

@article {pmid42292927,
year = {2026},
author = {Iqbal, A and Arif, S and Husnain, G and Ayouni, S},
title = {FUSION-AD: interpretable AI framework for risk assessment and subgroup discovery in Alzheimer's disease.},
journal = {Frontiers in neuroinformatics},
volume = {20},
number = {},
pages = {1799307},
pmid = {42292927},
issn = {1662-5196},
abstract = {INTRODUCTION: Alzheimer's disease (AD) is difficult to treat because of its multifactorial causes and heterogeneous progression across individuals. This study introduces FUSION-AD, a user-friendly and interpretable artificial intelligence framework for AD risk assessment and subgroup discovery.

METHODS: FUSION-AD integrates tree-based models, transformer-based neural networks, rule mining, and subgroup discovery to provide accurate and interpretable predictions. The framework was developed using the synthetic El Kharoua Alzheimer's Disease Dataset, which contains 2,149 structured clinical records from patients aged 60-90 years, with a mean age of 74.6 years and an average mini-mental state examination (MMSE) score of 21.7. The pipeline included data preprocessing, model benchmarking, feature-importance analysis, SHAP-based explanation, transformer attention analysis, association rule mining, and subgroup discovery.

RESULTS: Within the evaluated dataset, TabNet achieved the strongest point-estimate performance among the standalone benchmark models on the primary evaluation split, with an area under the receiver operating characteristic curve (AUROC) of 0.95, followed by XGBoost at 0.93, Random Forest at 0.92, and Logistic Regression at 0.89. Feature importance, SHAP values, and transformer attention consistently identified MMSE, Functional Assessment, and Memory Complaints as the most influential predictors. Association rule mining further highlighted diabetes and high body mass index as important risk factors. Subgroup discovery identified four clinical clusters, with prevalence ranging from 21.3 to 28.4%. Cluster 0 showed notable declines in daily functioning, with Functional Assessment decreasing by 2.1 and activities of daily living decreasing by 1.5, whereas Cluster 1 maintained daily functioning but showed increased behavioral symptoms.

DISCUSSION: FUSION-AD demonstrates that AD can be modeled in a way that balances predictive performance with interpretability within the studied dataset. The identified subgroup patterns suggest that lifestyle-driven profiles may benefit from preventive strategies, while cognitively impaired groups may require closer monitoring. These findings provide a foundation for future clinically oriented decision-support systems and require further validation using real-world clinical datasets.},
}

@article {pmid42293147,
year = {2026},
author = {Pinky, and Neha, and Kaushik, M and Tiwari, P and El-Tanani, M and Rabbani, SA and Parvez, S},
title = {Propranolol reinstates mitochondrial dynamics and synaptic memory pathways through CaMKII/CREB-BDNF/ PKMζ cascades in an AD-like rat model.},
journal = {Frontiers in aging neuroscience},
volume = {18},
number = {},
pages = {1729046},
pmid = {42293147},
issn = {1663-4365},
abstract = {BACKGROUND: Alzheimer's disease (AD) is a major neurodegenerative disorder characterized by amyloid-β (Aβ) accumulation, neurofibrillary tangles, and progressive cognitive decline. Despite significant advances in understanding its pathophysiology, current therapeutic options provide limited symptomatic relief. The present study investigated the nootropic and anti-amnesic effects of propranolol (PRO) in a scopolamine (SCP)-induced AD-like rat model.

METHODS: Wistar rats received PRO (10, 30, or 50 mg/kg, p.o.) or donepezil (DPZ; 1 mg/kg) for 17 days. Cognitive deficits were induced by SCP (1 mg/kg, i.p.) administration from day 9 onward. Behavioral performance was assessed using the Novel Object Recognition (NOR) and Elevated Plus Maze (EPM) tests. Molecular and cellular analyses were conducted to evaluate synaptic plasticity markers (CaMKII, CREB, BDNF, PKMζ), mitochondrial function, oxidative stress parameters, and inflammatory markers (GFAP, TNF-α).

RESULTS: Propranolol treatment significantly improved long-term memory performance, enhanced recognition index, and attenuated anxiety-like behavior in SCP-treated rats. These behavioral effects were associated with upregulation of CaMKII-CREB-BDNF-PKMζ signaling, improvement in mitochondrial membrane potential (Δψm), reduction in reactive oxygen species (ROS) generation and Aβ1-42 accumulation, and decreased expression of GFAP and TNF-α.

CONCLUSION: The findings suggest that propranolol mitigates SCP-induced cognitive impairments, potentially through modulation of synaptic plasticity- related signaling, mitochondrial function, and neuroinflammatory responses. These results indicate the therapeutic potential of propranolol in experimental models of AD-related neurodegeneration, warranting further investigation.},
}

@article {pmid42293149,
year = {2026},
author = {Lu, G and Shan, H and Yin, Y and Chen, L and Yu, K and Wei, Z and Chen, H and Hu, L and Qi, Y and Wu, T and Tao, S and Fan, X and Cheng, G},
title = {SVIP in plasma: a candidate blood-based biomarker for early detection of amnestic mild cognitive impairment.},
journal = {Frontiers in aging neuroscience},
volume = {18},
number = {},
pages = {1781331},
pmid = {42293149},
issn = {1663-4365},
abstract = {BACKGROUND: Amnestic mild cognitive impairment (aMCI) represents a critical clinical window for early intervention in Alzheimer's disease (AD). Identifying readily detectable, high-abundance plasma biomarkers for aMCI remains clinically important. Overexpression of Valosin-Containing Protein (VCP) has been shown to enhance autophagy and reduce tau levels in AD animal models. Notably, VCP, with a molecular weight of 90 kDa, typically assembles into hexamers, which is hypothesized to restrict its ability to cross the blood-brain barrier even under neurodegenerative conditions. In contrast, the small VCP-interacting protein (SVIP), with a molecular weight of only 9 kDa, interacts with VCP to maintain the dynamic stability of autophagosomes within cells. Therefore, we aim to explore plasma SVIP as a peripheral blood biomarker for aMCI and assess whether it can outperform VCP in detecting aMCI.

METHODS: This was a retrospective study based on the STAR (Shenzhen Multi-modal Aging Research) cohort. Participants were recruited as a convenience sample. Eighty-four participants (44 cognitively unimpaired [CU], 40 aMCI) were included, with diagnostic classification based on standardized clinical and neuropsychological criteria. Plasma levels of SVIP and VCP were measured using deep plasma proteomics enriched with biofunctional magnetic beads. Diagnostic performance was evaluated using Receiver Operating Characteristic (ROC) analysis and DeLong's test. This study was registered in the Chinese Clinical Trial Registry (ChiCTR2200066700).

RESULTS: Compared to the CU group, the aMCI group showed significantly decreased SVIP (p < 0.001), while no significant difference was observed in VCP levels (p = 0.823). The area under the curve (AUC) of SVIP in detecting aMCI was 0.836 (95% CI: 0.739 to 0.908), significantly higher than VCP [AUC = 0.513 (95% CI: 0.401 to 0.624)] (p < 0.0001, DeLong's test).

CONCLUSION: Plasma SVIP demonstrates significantly higher diagnostic accuracy than VCP for the detection of aMCI, suggesting its potential as a candidate blood-based biomarker pending large-scale pathophysiological validation.},
}

@article {pmid42293151,
year = {2026},
author = {Hu, J and Lai, J and Zhang, B and Jiang, X and Ma, H and Liu, Y},
title = {Mitochondrial dysfunction in Alzheimer's disease: connecting pathophysiology with neuroimaging.},
journal = {Frontiers in aging neuroscience},
volume = {18},
number = {},
pages = {1748227},
pmid = {42293151},
issn = {1663-4365},
abstract = {Alzheimer's disease (AD), primarily characterized by progressive cognitive decline, poses a significant global public health challenge. Emerging evidence indicates that mitochondrial dysfunction plays a central role in AD-related neurodegeneration. This dysfunction manifests as impaired energy metabolism and elevated oxidative stress, and it interacts with β-amyloid (Aβ) and phosphorylated tau (p-tau) pathologies, collectively forming a self-reinforcing vicious cycle. This review systematically explores the mechanisms underlying mitochondrial dysfunction in AD and highlights recent advancements in neuroimaging technologies, such as positron emission tomography (PET), magnetic resonance spectroscopy (MRS), and susceptibility-weighted imaging (SWI), for detecting mitochondrial abnormalities and metabolic disturbances. These multimodal imaging modalities enable the in vivo assessment of mitochondrial metabolism, oxidative stress levels, iron deposition, and the integrity of neural networks. Such capabilities not only enhance our understanding of the spatiotemporal progression of mitochondrial pathology in AD but also offer novel tools for early diagnosis, precise patient stratification, and objective evaluation of therapeutic efficacy. Accordingly, this review evaluates the substantial potential of integrating mitochondrial mechanism research with neuroimaging technologies in both foundational research and clinical practice related to AD.},
}

@article {pmid42293318,
year = {2026},
author = {van 't Hooft, JJ and van der Zwaag, W and Wink, AM and Barkhof, F and Schaefer, RS and Warren, JD and Pijnenburg, YAL and Tijms, BM},
title = {Music processing in behavioural variant frontotemporal dementia and Alzheimer's disease: a functional MRI study.},
journal = {Brain communications},
volume = {8},
number = {3},
pages = {fcag196},
pmid = {42293318},
issn = {2632-1297},
abstract = {Music engages brain regions involved in perceptual, socio-emotional and cognitive functions that may be relatively preserved in individuals with Alzheimer's disease but seem affected early in behavioural variant frontotemporal dementia. The effects of music in dementia are often assessed through observational studies, leaving the neurophysiological underpinnings of music processing in these dementia types unclear. Improved understanding of these mechanisms is relevant because the effectiveness of music therapy may depend on dementia types. In this study we investigated whether patients with behavioural variant frontotemporal dementia and Alzheimer's disease differ in music processing compared with healthy controls. We studied 60 participants (n = 35 female; aged 52-81), including 13 patients with behavioural variant frontotemporal dementia, 22 patients Alzheimer's disease, and 25 healthy controls. We designed a novel functional MRI paradigm based on passive listening to self-selected favourite music and experimenter-selected unfamiliar musical pieces using a sparse-sampling design. Activation patterns of favourite music listening (favourite > silence), unfamiliar music listening (unfamiliar > silence), and favourite music more than unfamiliar music (favourite > unfamiliar) were determined for each participant. Next, we compared activation patterns across groups for each contrast. Finally, associations between activation patterns and disease severity were investigated in behavioural variant frontotemporal dementia and Alzheimer's disease separately. The patient groups exhibited typical neuropsychological, socio-emotional and structural anatomical changes associated with Alzheimer's disease and behavioural variant frontotemporal dementia. Patients with behavioural variant frontotemporal dementia showed overall less activation during favourite music listening compared with Alzheimer's disease and healthy controls. When contrasting favourite and unfamiliar music, we found that patients with behavioural variant frontotemporal dementia showed reduced activation in the supplementary motor area, a region that has previously been implicated as an important region for semantic musical memory. Increased connectivity of the auditory cortices was observed in behavioural variant frontotemporal dementia compared with controls, potentially indicating network immaturity. Only patients with Alzheimer's disease exhibited activation in the caudate nucleus during unfamiliar music, a region associated with musical reward processing. Disease severity in Alzheimer's disease and behavioural variant frontotemporal dementia were associated with distinct patterns of functional activation. Our results confirm and expand the observation that music is processed differently in patients with behavioural variant frontotemporal dementia and Alzheimer's disease. The reduced activation in the supplementary motor area may explain altered music processing in behavioural variant frontotemporal dementia. These differences in music processing could have clinical implications in the selection of music therapy.},
}