@article {pmid41784914,
year = {2026},
author = {Neha, and Mandal, S and Sharma, V and Dhindsa, J and Aran, KR},
title = {PAR-1 in Alzheimer's Disease: Pathophysiological Insights and Mechanistic Perspectives.},
journal = {Current medical science},
volume = {},
number = {},
pages = {},
pmid = {41784914},
issn = {2523-899X},
abstract = {The G protein-coupled receptor (GPCR) known as protease-activated receptor-1 (PAR-1) is triggered by thrombin and plays a multifaceted role in the onset and progression of Alzheimer's disease (AD). AD is an irreversible neurodegenerative disease characterized by amyloid-β (Aβ) accumulation, neuroinflammation, tau hyperphosphorylation, and synaptic dysfunction. Thrombin activates PAR-1, which plays multiple roles in the brain. It exacerbates neuroinflammation and Aβ pathology but also protects synaptic plasticity. In a preclinical model, PAR-1 inhibition rescues cognitive deficits and decreases Aβ accumulation, suggesting therapeutic potential. However, PAR-1 activation promotes Tau hyperphosphorylation and neurofibrillary tangle formation, contributing to synaptic loss and cognitive decline. PAR-1 increases the permeability of the blood‒brain barrier (BBB), facilitating the entry of toxic substances into the brain and increasing neurodegeneration. Although strong preclinical evidence exists, no clinical trials have yet directly targeted PAR-1 in AD. This review summarizes current understanding of the PAR-1 mechanism in AD and highlights its roles in Aβ deposition, neuroinflammation, and tau pathology. It also discusses the challenges and opportunities for translating PAR-1 modulation into clinical therapies, including repurposing existing PAR-1 inhibitors. By addressing the dual role of PAR-1 function, researchers may develop novel multitarget strategies to combat the multifactorial pathophysiology of AD.},
}

@article {pmid41784832,
year = {2026},
author = {El-Baga, SE and Hassan, MH and Awadalla, EA and Abd El-Kader, AEM},
title = {Crocin Mitigates Glutamate Excitotoxicity and Tau Hyperphosphorylation by Modulating EAAT2 and Akt/Tau Pathway in a Scopolamine-induced Rat Model of Alzheimer's Disease.},
journal = {Neurochemical research},
volume = {51},
number = {2},
pages = {},
pmid = {41784832},
issn = {1573-6903},
abstract = {Alzheimer's disease (AD) is characterized by glutamatergic dysregulation and excitotoxicity, largely associated with impaired activity of the excitatory amino acid transporter 2 (EAAT2). Downregulation of EAAT2 results in glutamate accumulation, N-Methyl-D-Aspartate (NMDA) receptor overactivation, and neuronal injury. Crocin (Cr), a carotenoid compound extracted from saffron (Crocus sativus), exhibits potent antioxidant and neuroprotective properties, particularly in experimental models of neurodegeneration. Forty-eight adult male rats were divided into six groups: control (saline), crocin (50 mg/kg), scopolamine (3 mg/kg for 7 days), scopolamine followed by memantine (M) (20 mg/kg), scopolamine followed by crocin, and scopolamine followed by both memantine and crocin. This study aimed to evaluate the therapeutic potential of crocin, alone and in combination with memantine, in a scopolamine-induced rat model of Alzheimer's disease, with a focus on EAAT2 modulation. Scopolamine administration significantly elevated glutamate, NMDAR and p-tau levels while reducing p-Akt, GABA and EAAT2 levels, accompanied by marked hippocampal neurodegeneration. In contrast, crocin treatment, either alone or in combination with memantine, restored neurotransmitter balance, downregulated NMDAR, upregulated EAAT2, increased p-Akt expression level and reduced tau phosphorylation. Histological analysis further confirmed notable structural recovery of hippocampal neurons.},
}

@article {pmid41784652,
year = {2026},
author = {Chen, Y and Wang, Z and Chen, H and Cui, H and Li, S and , },
title = {Plasma p-tau217 assays effectively predict amyloid status but lack precision for tau staging in Alzheimer's disease.},
journal = {Journal of neurology},
volume = {273},
number = {3},
pages = {},
pmid = {41784652},
issn = {1432-1459},
support = {82471199//National Natural Science Foundation of China/ ; 82171582//National Natural Science Foundation of China/ ; },
abstract = {Blood-based biomarkers for Alzheimer's disease (AD) have demonstrated high performance in identifying amyloid-β (Aβ) pathology. However, the diagnostic accuracy of commercial plasma biomarker assays in predicting PET-defined AD stages-particularly late-stage tau accumulation-requires further evaluation. We included 229 participants from the Alzheimer's Disease Neuroimaging Initiative, all of whom underwent amyloid and tau PET imaging and testing with plasma assays. Among the plasma biomarkers, p-tau217 showed the strongest linear and non-linear associations with amyloid and tau PET. When distinguishing A + from A - T - participants, p-tau217 assays achieved the highest accuracy (AUC range: 0.85-0.91), outperforming other plasma biomarkers (AUC range: 0.66-0.81). However, the accuracy of plasma biomarkers, including p-tau217 assays, significantly decreased when differentiating A + T + from A + T - stages (AUC for p-tau217 assays: 0.69-0.77; AUC for other plasma biomarkers: 0.53-0.67; P < 0.05). These findings were replicated in an independent cohort (n = 334). Our study found that among currently available commercial plasma assays, including p-tau217 assays, they demonstrate high accuracy in classifying Aβ status but are less accurate in assessing tau pathology severity in Aβ positive individuals.},
}

@article {pmid41784383,
year = {2026},
author = {Suhandynata, RT and Bevins, EA and Metushi, IG},
title = {Endogenous Lithium Levels and Alzheimer Disease.},
journal = {Clinical chemistry},
volume = {72},
number = {3},
pages = {424-425},
doi = {10.1093/clinchem/hvaf174},
pmid = {41784383},
issn = {1530-8561},
}

@article {pmid41784299,
year = {2026},
author = {Luo, L and He, J and Liu, X and Zhuang, S and Xiao, Q},
title = {Association between anemia and cognitive dysfunction in the hypertensive older adults: a cross-sectional study.},
journal = {Aging & mental health},
volume = {},
number = {},
pages = {1-13},
doi = {10.1080/13607863.2026.2635536},
pmid = {41784299},
issn = {1364-6915},
abstract = {OBJECTIVES: Using 2011-2014 National Health and Nutrition Examination Survey (NHANES) data, the research aims to explore the association of anemia and cognitive dysfunction in older patients with hypertension.

METHOD: The study included 2005 older participants aged ≥60 years. Cognitive performance was evaluated by the Consortium to Establish a Registry for Alzheimer's Disease (CERAD) Word Learning subtest, the Animal Fluency Test (AFT) and the Digit Symbol Substitution Test (DSST). Multivariate logistic regression analysis and a weighted restricted cubic spline (RCS) curve were employed to examine the potential association between hemoglobin levels and cognitive dysfunction.

RESULTS: Anemia was associated with higher odds of cognitive dysfunction in hypertensive older adults (OR = 1.663, 95% CI: 1.082-2.557, p = 0.022). Higher level of hemoglobin was associated with reduced odds of cognitive dysfunction (OR = 0.880, 95% CI: 0.782-0.991, p = 0.036). Hemoglobin levels below 13.67 g/dL were significantly associated with increased odds of cognitive impairment.

CONCLUSION: This study indicates the existence of an association between anemia and cognitive dysfunction among hypertensive older adults. Hemoglobin levels may serve as a predictor of cognitive decline, with 13.67g/dL as a potential threshold for intensive cognitive monitoring in high-risk older populations with hypertension.},
}

@article {pmid41784271,
year = {2026},
author = {Wang, RM and Wang, ZQ},
title = {lncRNAs: key player in Aβ deposition.},
journal = {RNA biology},
volume = {23},
number = {1},
pages = {1-16},
doi = {10.1080/15476286.2026.2639017},
pmid = {41784271},
issn = {1555-8584},
abstract = {Alzheimer's disease (AD) is a typical neurodegenerative disorder, characterized by the deposition of β-amyloid (Aβ) plaques. β- and γ-secretases generate Aβ by cleaving amyloid precursor protein. The imbalance between its production and clearance leads to Aβ accumulation, causing neuronal damage through mechanisms such as inducing oxidative stress and inflammatory responses. Long non-coding RNAs (LncRNAs), composed of more than 200 nucleotides, usually do not encode proteins and are involved in processes such as gene expression regulation, chromatin remodelling, and cell cycle control. Studies have shown that LncRNAs play a key role in brain development and the maintenance of neuronal function, especially by influencing Aβ deposition to affect the progression of AD. This review summarizes the pathways by which LncRNAs affect Aβ deposition, classifies them according to their modes of action, discusses the existing problems in current research, and summarizes and prospects their role in the treatment of AD.},
}

@article {pmid41783892,
year = {2026},
author = {Zhang, J and Han, J and Liu, Q},
title = {Transfer RNA-derived small RNAs (tsRNAs) in Alzheimer's disease: emerging mechanisms and diagnostic potential.},
journal = {Medical review (2021)},
volume = {6},
number = {1},
pages = {87-90},
doi = {10.1515/mr-2025-0078},
pmid = {41783892},
issn = {2749-9642},
abstract = {Transfer RNA-derived small RNAs (tsRNAs), a class of non-coding RNAs derived from precursor or mature tRNAs, are now recognized as critical regulators in response to cellular stress. tsRNAs exhibit differential expression during brain aging and in age-related neurodegenerative disorders such as Alzheimer's disease (AD), suggesting their involvement in the molecular processes underlying neuronal aging and degeneration. This article summarizes recent advances in our understanding of tsRNA biogenesis, classification, and function, emphasizing their regulatory role in brain aging and AD pathology. We also highlight the diagnostic and therapeutic implications of tsRNAs and discuss future directions for exploring their mechanistic and clinical relevance.},
}

@article {pmid41783833,
year = {2026},
author = {Liu, L and Yu, L and Petyuk, VA and Kapasi, A and Yoo, HB and Saba, A and Yang, HS and Chhatwal, JP and Bennett, DA},
title = {Association of Aβ monomers with cerebral amyloid angiopathy in brains without parenchymal Aβ deposition.},
journal = {Brain communications},
volume = {8},
number = {2},
pages = {fcag051},
doi = {10.1093/braincomms/fcag051},
pmid = {41783833},
issn = {2632-1297},
abstract = {β-Amyloid (Aβ) deposition is a hallmark of both Alzheimer's disease and cerebral amyloid angiopathy. Whilst insoluble Aβ aggregates have been extensively studied, the role of soluble Aβ monomers in vascular amyloid pathology-and their association with cognitive decline-remains unclear in plaque-free brains. This study examined whether soluble cortical Aβ species are associated with cognitive outcomes and amyloid-related pathologies, including cerebral amyloid angiopathy, in the absence of parenchymal Aβ deposition. We examined post-mortem cortical tissue from nearly 200 individuals without parenchymal Aβ deposition, drawn from two longitudinal community-based cohorts. Soluble Aβ37, Aβ40 and Aβ42 were quantified by immunoassays, and total Aβ levels were measured using selected reaction monitoring proteomics. Associations with semiquantitative cerebral amyloid angiopathy burden and longitudinal cognitive trajectories were assessed using regression models adjusting for age, sex and education. Higher levels of soluble Aβ-particularly longer species such as Aβ42, reflected by elevated Aβ42/40 and reduced Aβ37/42 ratios-were significantly associated with greater cerebral amyloid angiopathy severity. Whilst immunoassay based total Aβ and Aβ ratio measures showed limited associations with cognitive outcomes, total Aβ levels quantified by selected reaction monitoring remained significantly associated with global cognitive decline. These findings support a pathogenic role for certain soluble Aβ monomers in vascular amyloid deposition. In contrast, cognitive impairment may be driven by other amyloid species such as oligomeric or extended Aβ forms. Aβ ratios may serve as specific markers for cerebral amyloid angiopathy and provide insights into early therapeutic strategies targeting vascular amyloid pathology.},
}

@article {pmid41783585,
year = {2026},
author = {Cheng, H and Kang, L and Xu, Y and Tanzi, RE and Zhang, C and Wang, C},
title = {Innovation breakthrough in the Alzheimer's disease pharmaceutical industry.},
journal = {NPJ drug discovery},
volume = {3},
number = {1},
pages = {9},
doi = {10.1038/s44386-026-00044-7},
pmid = {41783585},
issn = {3005-1452},
abstract = {Alzheimer's disease (AD) drug development has undergone cycles, driven initially by amyloid-β-based hypotheses and later setbacks by clinical failures. Recent advances in biotechnology, improved understanding of AD pathogenesis, and unmet medical needs have revitalized the field. This new wave is exemplified by lecanemab, the first fully FDA-approved disease-modifying therapy in two decades. We review approved and clinical-stage AD therapeutics using data from Cortellis and the FDA.},
}

@article {pmid41783572,
year = {2026},
author = {Liu, W and Xue, Y and Cao, C and Yang, L and Zhang, L},
title = {Copper Homeostasis and Cuproptosis in Neurological Disorders.},
journal = {Drug design, development and therapy},
volume = {20},
number = {},
pages = {580005},
doi = {10.2147/DDDT.S580005},
pmid = {41783572},
issn = {1177-8881},
abstract = {Neurological disorders such as Alzheimer's disease (AD) and Parkinson's disease (PD) pose a serious global public health threat, with complex etiologies involving genetic, environmental, and metabolic factors. Current data indicate that the prevalence of these disorders is rapidly increasing with the aging population, resulting in a growing economic and healthcare burden worldwide. In recent years, the imbalance of copper homeostasis has been increasingly implicated in the pathogenesis of neurological diseases. Copper overload can aggravate neuronal injury by inducing oxidative stress (OS), mitochondrial dysfunction, and protein misfolding, while copper deficiency disrupts the function of copper-dependent enzymes and leads to metabolic abnormalities. The mechanism of cuproptosis, proposed in 2022, describes a novel form of programmed cell death characterized by lipoylated protein aggregation and the loss of Fe-S cluster proteins, offering new insights into copper-related diseases. Multiple studies have demonstrated the crucial role of copper homeostasis and cuproptosis in the onset, progression, and treatment of neurological diseases. This narrative review summarizes the molecular mechanisms involved in copper homeostasis regulation and, on that basis, discusses the role of copper metabolism abnormalities in AD, PD, Huntington's disease (HD), amyotrophic lateral sclerosis (ALS), multiple sclerosis (MS), Wilson's disease (WD), Menkes disease (MD), and stroke. Additionally, we highlight the mechanisms of existing copper-regulating drugs and their therapeutic potential in neurological disorders, while pointing out the limitations of current drug development.},
}

@article {pmid41783522,
year = {2026},
author = {Ali, S and Kreshpa, W and Rosso, N and Piana, M and Roccatagliata, L and Cirone, A and Luigi, L and Campi, C and Pardini, M and Garbarino, S},
title = {A systematic study on the integration of MRI connectivity metrics for Alzheimer's diagnosis, staging, and cognitive decline prediction.},
journal = {Frontiers in neuroimaging},
volume = {5},
number = {},
pages = {1746464},
doi = {10.3389/fnimg.2026.1746464},
pmid = {41783522},
issn = {2813-1193},
abstract = {Alzheimer's disease (AD) is a degenerative neurological disorder marked by cognitive decline and functional disability. Despite the extensive use of magnetic resonance imaging (MRI) in machine learning (ML)-based AD studies, the relative and combined contributions of MRI-derived morphometric (MO), microstructural (MS), and graph-theoretical (GT) features are still not well explored in a unified, comparative framework. It remains unclear whether adding multimodal MRI-derived features consistently improves the predictive performance of ML-based approaches for AD diagnosis and cognitive decline. Addressing this gap, this study systematically analyzed the individual (MO, MS, GT) and combined (MO+MS, MO+GT, MS+GT, MO+MS+GT) utility of MRI-based feature sets. We developed an ensemble-based ML framework with a nested cross-validation module for two key tasks: (i) Alzheimer's disease cognitive stage classification (DSC) and (ii) longitudinal cognitive decline prediction (LCDP) in terms of mini-mental state examination (MMSE) score. In this study, we conducted feature ablation and statistical analysis to evaluate performance improvements resulting from the incremental addition of feature sets. The results of the study indicated that the proposed ensemble-based ML approach achieved the best predictive performance (balanced accuracy [BACC]: 0.898 ± 0.051) using a combination of MO and MS feature sets for cognitively normal (CN) vs. AD dementia (CN-ADD). In contrast, the best results for mild cognitive impairment (MCI) vs. ADD (MCI-ADD) and CN-MCI were achieved using the MO feature set alone, with BACC of 0.769 ± 0.116 and 0.652 ± 0.044, respectively. Likewise, for the LCDP task, the MO-based ensemble learner achieved an R[2] of 0.212 ± 0.177. These results demonstrate that MO features capture the most robust disease-related information, while multimodal integration offers task-specific and limited benefits. In addition, these findings demonstrate the potential of integrated MRI-derived features in ML frameworks for enhancing ADD diagnosis and cognitive decline prediction and underscore the importance of feature selection based on task complexity.},
}

@article {pmid41783485,
year = {2026},
author = {Piroli, GG and Myers, R and Holloway, L and Hayek, A and Linebaugh, E and Jones, JR and Skinner, C and Skinner, SA and Frizzell, N and Steet, R},
title = {Characterization of a UQCRC1 variant in a patient with progressive weakness, pain and sleep issues reveals a functional mitochondrial defect restored by mitochondrial transplantation.},
journal = {Molecular genetics and metabolism reports},
volume = {46},
number = {},
pages = {101302},
doi = {10.1016/j.ymgmr.2026.101302},
pmid = {41783485},
issn = {2214-4269},
abstract = {Primary mitochondrial defects underlie the heterogeneity of many rare inherited disorders. Pathogenic variants that disrupt the function of the multi-subunit protein complexes of the mitochondrial respiratory chain contribute to a range of neurological phenotypes and other clinical manifestations. These variants are also thought to contribute to the onset and progression of numerous more common neurodegenerative conditions such as Parkinson's and Alzheimer's disease. Here we describe an individual affected with progressive muscle weakness and pain harboring a paternally inherited missense variant in UQCRC1, encoding a subunit of Complex III. Biochemical characterization of cells from the proband and his father demonstrated normal steady-state levels of UQCRC1 and UQCRC2 protein. Functional assessment of mitochondrial respiration in lymphoblasts and fibroblasts, however, showed a clear deficit in respiratory parameters in the proband, with a more attenuated response in the father. Lastly, we demonstrate that healthy mitochondria isolated from HEK293 cells can be transferred to the patient lymphoblasts, restoring basal mitochondrial respiration and ATP production. Perspectives on the contribution of this variant to the patient phenotypes, and the potential of mitochondrial transplantation and different compounds as treatment modalities for patients with primary mitochondrial deficits, is discussed.},
}

@article {pmid41783359,
year = {2026},
author = {Silva-Pérez, M and Chin, J},
title = {A Balancing Act: Amyloid-β, Tau, and Excitation-Inhibition in Alzheimer's Disease.},
journal = {Epilepsy currents},
volume = {},
number = {},
pages = {15357597261428564},
doi = {10.1177/15357597261428564},
pmid = {41783359},
issn = {1535-7597},
}

@article {pmid41783273,
year = {2026},
author = {Tang, Z and Ding, AA and Zhang, Y and Wang, G and Shan, G},
title = {Testing disease progression under the proportional reduction in decline in Alzheimer's disease studies.},
journal = {Journal of applied statistics},
volume = {53},
number = {3},
pages = {431-446},
doi = {10.1080/02664763.2025.2514153},
pmid = {41783273},
issn = {0266-4763},
abstract = {To assess the treatment-placebo difference in Alzheimer's disease (AD) trials, saved time measure provides an easy interpretation of the treatment effect in months as an alternative measure to the treatment-placebo difference at the pre-specified visit that is often estimated from the fitted model. The current method to estimate saved time utilizes the disease progression curve of the placebo group, and this method is primarily descriptive. To fill the gap of the statistical inference for saved time, we propose to develop the likelihood ratio test and the score test under the proportional reduction in decline model. One AD trial data set was utilized to compare the proposed tests and the existing Wald-type test with regard to type I error rate and statistical power. We found that the likelihood ratio test and the score test have similar statistical power, but the score test has better control with regard to type I error rate. The two new tests are more powerful than the Wald test when a new treatment has proportional reduction in decline or constant delay, while the Wald test can have a higher statistical power when a constant treatment effect is expected from a new treatment.},
}

@article {pmid41783158,
year = {2025},
author = {Uemura, K and Hiro, S and Attachaipanich, S and Du, R and Yusof, NISM and Kinoshita, M and Hikosaka, M and Ohtsuki, G},
title = {Glioinflammation: disease-associated microglia and astrocytes in psychiatric disorders, neurodegeneration, and senescence.},
journal = {Frontiers in cellular neuroscience},
volume = {19},
number = {},
pages = {1669272},
doi = {10.3389/fncel.2025.1669272},
pmid = {41783158},
issn = {1662-5102},
abstract = {In this review, we synthesize recent conceptual and experimental advances in neuroscience, highlighting selected studies that delineate the roles of reactive microglia and astrocytes in the contexts of developmental inflammatory stress, neurodegenerative diseases, and cellular senescence. Since the characterization of disease-associated glial phenotypes in 2017, building on earlier pioneering discoveries, we focus here on disease-associated microglia (DAM) and disease-associated astrocyte (DAA) to reassess their contributions to glio-inflammation. It is now recognized that the stress-induced glial states are far from uniform; however, the ontogeny, molecular determinants, and functional consequences of this heterogeneity remain incompletely understood, particularly in psychiatric disorders, Alzheimer's disease, and amyotrophic lateral sclerosis. Accordingly, we compare the glial heterogeneity and its underlying mechanisms across translational mouse models and human neuropathology, considering their evolutionary and physiological contexts. While this review does not aim to be exhaustive, we propose an integrative framework that redefines glial stress responses through the combined lenses of inflammation, transcriptomics, mitochondrial dynamics, lipid metabolism, epigenomic regulation, and cellular senescence. Finally, we outline emerging frontiers for AI-enabled multi-omic physiological and pathological approaches, emphasizing their potential to illuminate glial state transitions and accelerate therapeutic discovery in the near future.},
}

@article {pmid41783143,
year = {2026},
author = {Kim, TH and Kwon, JG and Chao, JS and Kim, JW and Pak, CJ and Suh, HP and Lim, JS and Hong, JP},
title = {Structural and vascular alterations of deep cervical lymph nodes in amyloid PET-positive Alzheimer's disease patients.},
journal = {Cerebral circulation - cognition and behavior},
volume = {10},
number = {},
pages = {100533},
doi = {10.1016/j.cccb.2026.100533},
pmid = {41783143},
issn = {2666-2450},
abstract = {BACKGROUND: Impaired clearance of brain-derived waste via the glymphatic-lymphatic system has been implicated in Alzheimer's disease (AD) pathogenesis. Although animal studies highlight the role of deep cervical lymph nodes (dCLNs) in draining brain interstitial solutes, their characteristics in AD patients remain unknown. This study assessed structural and vascular alterations of dCLNs in AD using high-frequency color Doppler ultrasound (HFCDU).

METHODS: Twenty-five patients with amyloid PET-positive AD and 25 age-matched cognitively normal controls underwent HFCDU of dCLNs at neck zone 2-5. Lymph node number, shape, morphology, vascularity (via Superb Microvascular Imaging, SMI), and Solbiati index were quantified. Between-group differences were analyzed using logistic regression and receiver operating characteristic (ROC) analyses, and a simplified diagnostic score was developed from discriminative features.

RESULTS: A total of 482 lymph nodes were analyzed (210 from AD, 272 from controls). AD patients had fewer oval-shaped nodes (50% vs. 83%, p<0.001), more irregular morphology (23% vs. 1%, p<0.001), and less distinct internal structure (40% vs. 57%, p<0.001). In Zone 5, they also had fewer nodes (2.4 ± 1.8 vs. 3.8 ± 2.6, p=0.034) and reduced SMI positivity (75% vs. 91%, p=0.006). The count of oval, moderately vascularized (SMI ≤7) nodes in Zone 5 best discriminated AD (AUC=0.79). A composite score integrating these parameters yielded AUC=0.81 (sensitivity 64%, specificity 84%).

CONCLUSIONS: HFCDU demonstrated distinct morphological and vascular abnormalities of dCLNs in AD, particularly in Zone 5, suggesting impaired lymphatic drainage contributes to AD pathology and supporting lymphatic imaging as a potential biomarker for the failure of lymphatic drainage of the brain.},
}

@article {pmid41782936,
year = {2026},
author = {Gu, Y and Lin, Y and Li, L and Ma, J and Wei, S and Dai, Z and , },
title = {Spatiotemporal profiling of functional network overlapping modules in Alzheimer's disease.},
journal = {Network neuroscience (Cambridge, Mass.)},
volume = {10},
number = {1},
pages = {185-203},
doi = {10.1162/NETN.a.516},
pmid = {41782936},
issn = {2472-1751},
abstract = {Alzheimer's disease (AD) is characterized by progressive neural network degradation. In brain functional networks, overlapping module structures provide more accurate representations of brain function than nonoverlapping structures. Since the involvement of overlapping nodes in multiple modules can vary over time, investigating dynamic functional changes in the brain may provide deeper insights into the structural characteristics of these overlapping modules. However, the spatiotemporal dynamics of overlapping modular brain organization remain unclear. We employed resting-state fMRI to explore the overlapping modular organization and dynamic multilayer modules in 64 AD (Agemean = 74.04) and 61 healthy controls (HC, Agemean = 74.86) from the Alzheimer's Disease Neuroimaging Initiative. Compared with HC, AD exhibited increased overlapping modules and decreased modularity, with altered nodal overlapping probability, particularly in the superior frontal cortex and hippocampus. Higher nodal overlapping probability correlated with greater flexibility and was associated with larger amyloid deposits. Lasso regression analysis further revealed strong correlations between overlapping nodal characteristics and cognitive performance. Our findings suggest that overlapping nodes are critical components in AD, demonstrating high amyloid deposition, significant functional flexibility, and strong associations to cognitive behavior. These alterations may enhance the understanding of AD pathology and contribute to the development of biomarkers for improved diagnosis and therapeutic strategies.},
}

@article {pmid41782881,
year = {2026},
author = {Huang, R and Lin, BB and Lu, Z and Hao, Y and Li, C and Lin, Z and Zhang, Y and Wei, N and Chen, J},
title = {Identification of plasma inflammatory biomarkers for Alzheimer's disease reveals IFN-γ as a regulator of ACSL1-mediated microglia phenotype.},
journal = {Frontiers in immunology},
volume = {17},
number = {},
pages = {1770509},
doi = {10.3389/fimmu.2026.1770509},
pmid = {41782881},
issn = {1664-3224},
abstract = {BACKGROUND: The identification of plasma biomarkers for the diagnosis of Alzheimer's disease (AD) has been a longstanding research priority; however, few plasma biomarkers have yet been implemented in routine clinical practice.

METHODS: This study enrolled 141 participants, including 71 patients with AD, 44 individuals with mild cognitive impairment, and 28 cognitively healthy controls (HC). A total of 16 plasma inflammatory proteins were quantified using multiplex liquid-chip assays, and APOE genotyping was performed. The diagnostic utility of plasma proteins was assessed using the least absolute shrinkage and selection operator (LASSO) with nested cross-validation.

RESULTS: Patients with AD exhibited marked alterations in plasma inflammatory profiles, with elevated levels of IFN-γ, IL-33, and IL-18, and reduced levels of IL-7 and CCL11. Integrating inflammatory markers with clinical variables and APOE genotype substantially improved discrimination between AD and HC, increasing the area under the ROC curve from 0.863 to 0.953. Among all biomarkers, IFN-γ emerged as the most informative predictor and was significantly elevated in AD patients carrying the APOE ϵ4 allele. Analyses of single-nucleus RNA sequencing data further revealed pronounced enrichment of IFN-γ signaling in APOE4/4 AD-associated lipid droplet-accumulating microglia (LDAM), defined by high ACSL1 expression. Notably, IFN-γ stimulation enhanced ACSL1 expression in ApoE4-overexpressing HMC3 microglial cells.

CONCLUSION: These findings provide a new perspective on the involvement of plasma inflammatory markers for AD diagnosis, and suggest a novel link between IFN-γ and APOE ϵ4-associated AD risk through modulating the ACSL1-driven pathogenic LDAM phenotype.},
}

@article {pmid41782646,
year = {2026},
author = {Peeleman, N and Mc Laughlin, M and Theys, T and Vandenbulcke, M and Janssen, P},
title = {Epicranial electrical stimulation improves non-navigational spatial memory in macaque monkeys.},
journal = {Neuroimage. Reports},
volume = {6},
number = {1},
pages = {100331},
doi = {10.1016/j.ynirp.2026.100331},
pmid = {41782646},
issn = {2666-9560},
abstract = {BACKGROUND: The hippocampus and medial temporal lobe are crucial for spatial memory, and their dysfunction is linked to Alzheimer's disease (AD), with changes detectable even in preclinical stages. Recently, neuromodulation has gained interest as a potential treatment due to its beneficial effects on AD pathology and cognitive performance. However, outcomes vary significantly based on stimulation parameters and study conditions, and evidence from large animal models remains limited.

OBJECTIVE: To assess whether epicranial current stimulation (ECS) at 40 Hz can improve non-navigational spatial memory and hippocampal activations.

METHODS: Three rhesus macaques were implanted with spiral platinum electrodes bilaterally on the skull and were trained in a non-navigational spatial memory task. ECS was applied at 40 Hz or at 10 Hz and performance across multiple sessions was evaluated. We further performed ECS during fMRI to examine the spread of activations caused by ECS across the brain in a block-design experiment.

RESULTS: ECS at 40 Hz improved performance in a non-navigational spatial memory task, while 10 Hz ECS had minimal or negative effects. Concurrent ECS-fMRI showed extensive brain activations at 40 Hz, including significant hippocampal activations, which was not observed at 10 Hz.

CONCLUSIONS: Our results show that ECS could be a minimally-invasive and effective approach to improve memory performance and activate the hippocampus. ECS could represent a potential treatment for patients suffering from memory impairment.},
}

@article {pmid41782642,
year = {2026},
author = {Han, Z and Fu, W and Dai, M and Lu, R and Yu, J and Dong, W and Sang, Z},
title = {Emerging strategies for Alzheimer's disease: leveraging flavonoid derivatives for early diagnosis and neuroprotection.},
journal = {RSC medicinal chemistry},
volume = {},
number = {},
pages = {},
doi = {10.1039/d5md01026h},
pmid = {41782642},
issn = {2632-8682},
abstract = {Alzheimer's disease (AD) is a prevalent chronic and progressive neurodegenerative disorder predominantly affecting the elderly population. The etiology of AD is multifaceted, and despite extensive research, effective therapeutic options remain limited. Flavonoids, a diverse class of naturally occurring small molecules, exhibit a broad spectrum of pharmacological activities, including anti-inflammatory, antioxidant, and neuroprotective properties, which may have significant therapeutic implications for AD. However, the clinical application of flavonoids is hindered by their low bioavailability and poor blood permeability across the blood-brain barrier. In response to these challenges, researchers have synthesized various multifunctional compounds derived from naturally active flavonoids, thereby enhancing the therapeutic potential of these agents. Furthermore, the privileged structure of flavonoids has facilitated their advancement in the diagnostic realm of AD. This review aims to elucidate the beneficial roles and therapeutic potential of flavonoids and their derivatives in the treatment and diagnosis of AD. We further evaluated the absorption, distribution, metabolism, excretion, and toxicity (ADMET) properties of 36 flavonoid derivatives with anti-AD activity, thereby informing the rational design of novel flavonoid-based candidates for Alzheimer's disease.},
}

@article {pmid41782463,
year = {2026},
author = {Herriott, L and Coles, M and Fournier, N and Gaffney, E and Wagg, J},
title = {Quantitative Systems Pharmacology Models of Anti-Amyloid Treatments for Alzheimer's Disease: A Systematic Review.},
journal = {CPT: pharmacometrics & systems pharmacology},
volume = {15},
number = {3},
pages = {e70223},
doi = {10.1002/psp4.70223},
pmid = {41782463},
issn = {2163-8306},
abstract = {Quantitative systems pharmacology (QSP) models have emerged as useful tools for evaluating the efficacy of Alzheimer's disease (AD) therapies. Bringing together a clinical focus with the mechanistic detail of systems biology, QSP models are well suited to the complexity of AD and have been used to predict treatment outcomes and support regulatory submissions. Therapies targeting the amyloid pathway are prominent in the AD clinical trial landscape, with anti-amyloid monoclonal antibodies representing the first approved disease-modifying therapies. To inform and facilitate future QSP model development, a systematic review of published QSP models focused on amyloid-targeting therapies for AD was completed. The PubMed and Web of Science databases were searched on February 1, 2025, identifying 540 candidate publications. Predefined exclusion and inclusion criteria were applied to identify seven published AD QSP models used to simulate treatment effects for one or more anti-amyloid therapies. The structure, development, and predictions of the models were summarized. Shared and contrasting model features were identified across included models. A set of model quality features was scored against a checklist of 15 criteria adapted from "best practice" guidelines for QSP. Model quality scores were generally low, ranging from 40% to 53%. Key quality issues related to model validation and reproducibility were identified; in particular, none of the seven papers provided executable model code. This systematic review provides useful context to support ongoing efforts to develop and refine QSP models such that they may better inform therapeutic strategies for the treatment of AD.},
}

@article {pmid41782410,
year = {2026},
author = {Nguyen, ND and Vekilov, PG},
title = {Differential Responses of Amyloid-β 42 Aggregates to Resveratrol.},
journal = {Advanced biology},
volume = {10},
number = {3},
pages = {e00586},
doi = {10.1002/adbi.202500586},
pmid = {41782410},
issn = {2701-0198},
support = {E-2170//Welch Foundation/ ; V-E-0001//Welch Foundation/ ; 0001//Welch Center for Advanced Bioactive Materials Crystallization/ ; R01 AI150763/AI/NIAID NIH HHS/United States ; },
abstract = {Amyloid-β (Aβ) aggregation is targeted with small molecules as a pathway toward developing potential Alzheimer's disease (AD) therapies. Resveratrol, a natural polyphenol, has been proposed as an inhibitor of Aβ aggregation, but its mechanistic effects across distinct Aβ42 aggregates remain unresolved. To better evaluate resveratrol's potential to treat AD, here we focus on molecular-level insights into the mechanisms that underlie its interaction with several distinct classes of Aβ42 aggregates. In contrast to published approaches that are based on monitoring the evolution of the total fibrillar mass, we employ time-resolved in situ atomic force microscopy to explore the effects of resveratrol on Aβ42 amyloid and non-amyloid assemblies. While data suggest a weak interaction between resveratrol and low-molecular-weight Aβ42 species, we also observe a concentration-dependent reduction in fibrillization. In the presence of resveratrol, we observe a decrease in fibril thickness and end-dependent slowing of elongation; furthermore, the fibrils exhibit reduced mechanical integrity and fragment under minimal scanning stress. Importantly, resveratrol does not affect the formation or morphology of oligomers and amorphous aggregates. These findings suggest that resveratrol selectively targets the fibril pathway while leaving oligomeric assemblies unaltered. The results provide mechanistic insights into the differential effects of small molecules on Aβ42 assemblies and establish a framework for evaluating inhibitors of aggregation with single-aggregate resolution.},
}

@article {pmid41782334,
year = {2026},
author = {Zhou, H and Zhu, Y and Shi, X and Wang, L},
title = {MuloAD: A Multiomics Integration Model Utilizing Graph Convolutional Networks for Alzheimer's Disease Diagnosis and Biomarker Identification.},
journal = {The European journal of neuroscience},
volume = {63},
number = {5},
pages = {e70452},
doi = {10.1111/ejn.70452},
pmid = {41782334},
issn = {1460-9568},
abstract = {Early and accurate diagnosis of Alzheimer's disease (AD) remains challenging due to the limitations of single biomarker approaches and the complexity of disease pathogenesis. In this study, we present MuloAD, a graph convolutional neural network-based framework that integrates multiomics data for enhanced AD diagnosis and biomarker identification. The MuloAD leverages GraphSAGE to extract features from DNA methylation, mRNA expression and microRNA expression data independently, followed by a view correlation discovery network that captures cross-omics relationships in a higher dimensional label space. Using 350 samples from the ROSMAP cohort, MuloAD demonstrates superior classification performance compared to existing multiomics methods, delivering robust accuracy across different omics combinations. Feature-importance analysis identifies several key molecular biomarkers that exhibit significant differential expression between patients with AD and healthy controls. The results of ablation studies confirm the complementary value of multiomics integration compared to single-omics approaches. These findings highlight the potential of deep learning-driven multiomics integration in the diagnosis of neurodegenerative diseases and offer novel molecular targets for AD detection and therapeutic development.},
}

@article {pmid41782322,
year = {2026},
author = {Kaya, Y and Kırboğa, KK},
title = {Brain Organoids as Emerging Platforms for Modeling Neurodegenerative Diseases: Progress, Challenges, and Future Directions.},
journal = {Journal of neurochemistry},
volume = {170},
number = {3},
pages = {e70395},
doi = {10.1111/jnc.70395},
pmid = {41782322},
issn = {1471-4159},
abstract = {Neurodegenerative diseases are a group of disorders (such as Alzheimer's disease, Parkinson's disease, Huntington's disease, and amyotrophic lateral sclerosis) characterized by loss of function and death of neurons in different parts of the nervous system. These pathologies constitute a global burden, especially for aging populations. This circumstance leads to an increasing demand for understanding the fundamental mechanisms and development of therapeutic strategies. Conventional models, including two-dimensional cell culture and animal models, postmortem brain tissue provide an overview about neurodegenerative disorders but do not completely recapitulate cellular and molecular mechanisms of the human brain. Although three-dimensional (3D) brain organoids exhibit similar properties with physiological and pathological conditions of human brain, including interaction of neuronal, glial cells and self-organizing structure, protein aggregation, neuroinflammation, and neuronal degeneration. The integration of reprogrammed human induced pluripotent stem cells (iPSCs) with 3D brain organoid systems provides a clinical platform as a bridge between bench to bedside. Brain organoids have been used to elucidate novel insights into the molecular and genetic mechanisms underlying neurodegenerative diseases. Furthermore, brain organoids serve as a tool for in vitro disease modeling, drug screening and emergence of new treatments. Despite these clinical benefits, there are various limitations such as incomplete tissue maturation, lack of vascularization and incomplete cellular diversity in this 3D culture system. This review describes in detail the advantages and disadvantages of brain organoids usage in modeling neurodegenerative diseases from a contemporary perspective.},
}

@article {pmid41782208,
year = {2026},
author = {Wang, YC and Huang, AP and Huang, CW and Islam, MM and Kung, WM},
title = {Association Between Gout and the Risk of Dementia: A Meta-Analysis of Observational Studies and Biological Mechanisms.},
journal = {International journal of rheumatic diseases},
volume = {29},
number = {3},
pages = {e70582},
doi = {10.1111/1756-185x.70582},
pmid = {41782208},
issn = {1756-185X},
abstract = {BACKGROUND AND AIM: The relationship of gout with the risk of dementia has been a subject of importance in current studies. There is no comprehensive meta-analysis regarding their association. Hence, our team performed a systematic review and meta-analysis to examine the relationship of gout with the risk of dementia.

METHODS: We searched PubMed, EMBASE, Scopus, and Web of Science beginning at database commencement till 1 December 2022. For systematic review and meta-analysis, 2 independent reviewers comprised observational researches that assessed the relationship of gout with risk of dementia. This research pursued the Preferred Reporting Items for Systematic reviews and Meta-Analyses summarizing guidelines to extract and synthesize data. Our team applied the random-effects model to determine pooled risk ratios (RRs) with 95% confidence intervals (CIs).

RESULTS: Our study covered 5 observational studies. The pooled RR for the risk of overall dementia was 0.80 (95% CI: 0.58-1.10) with no evidence of publication bias. Moreover, the pooled RR demonstrated lesser risk of Alzheimer's disease (AD) at 0.70 (95% CI: 0.62-0.78) and vascular dementia at 0.68 (95% CI: 0.48-0.95) among patients with gout. An inverse association was observed in Asian people, but there was no relationship of gout with dementia among Western people.

CONCLUSION: In this meta-analysis of observational studies, gout was not significantly associated with overall dementia risk, although inverse associations were observed for AD and vascular dementia. These findings suggest potential heterogeneity by dementia subtype and population but should be interpreted cautiously given the observational design. Well-designed prospective studies and randomized trials are needed to clarify causality and underlying mechanisms.

PROTOCOL REGISTRATION: International Platform of Registered Systematic Review and Meta-analysis Protocols INPLASY2025110018; https://doi.org/10.37766/inplasy2025.11.0018.},
}

@article {pmid41782064,
year = {2026},
author = {Mak, E and Przybelski, SA and Reid, RI and Wiste, HJ and Fought, AJ and Schwarz, CG and Senjem, ML and Vemuri, P and Jack, CR and Lowe, VJ and Petersen, RC and Boeve, BF and Kantarci, K and , },
title = {α-synuclein positivity is associated with decline in brain microstructure in the Alzheimer's disease spectrum.},
journal = {Alzheimer's research & therapy},
volume = {},
number = {},
pages = {},
doi = {10.1186/s13195-026-01995-9},
pmid = {41782064},
issn = {1758-9193},
support = {P30 AG062677/AG/NIA NIH HHS/United States ; U01 NS100620/NH/NIH HHS/United States ; },
}

@article {pmid41782023,
year = {2026},
author = {Liu, J and Cao, J and Jia, L and Gan, Z and Zhao, X and Yang, A and Lai, S and Chen, F and Yang, YT and Zhao, XM},
title = {Impacts of host genetics on gut microbiome composition in Alzheimer's disease.},
journal = {Microbiome},
volume = {},
number = {},
pages = {},
doi = {10.1186/s40168-026-02342-8},
pmid = {41782023},
issn = {2049-2618},
support = {24JS2810100//Shanghai Science and Technology Commission Program/ ; 23JS1410100//Shanghai Science and Technology Commission Program/ ; 24KXZNA11//Shanghai Municipal Education Commission/ ; T2225015//National Natural Science Foundation of China/ ; ZDYF2024SHFZ058//Key Science and Technology Project of Hainan Province/ ; GZNL2024A01003//Major Project of Guangzhou National Laboratory/ ; 2023YFF1204800//National Key R&D Program of China/ ; },
abstract = {BACKGROUND: Host-microbiome interactions play essential roles in the development of Alzheimer's disease (AD), yet the host genetic impacts on gut microbial alterations in AD remain poorly understood.

RESULTS: Here, we simultaneously profiled host genotype and gut microbiome in 252 Chinese individuals with varying degrees of cognitive disability. Using the latent Dirichlet allocation topic model, we identified the Anaerostipes-enriched enterosignature (ES-Ana) at the microbial subgroup level as significantly negatively associated with cognitive disability, which could be recapitulated in external cohorts. With the whole-genome sequencing data, we performed microbiome genome-wide association studies for the ES-Ana relative abundance. We prioritized 41 lead genetic variants and confirmed that the high ES-Ana relative abundance showed a negative correlation with the polygenic risk score of AD, indicating its protective effect against AD. Furthermore, we identified 174 ES-Ana-associated genes, which are enriched in AD-related biological functions and phenotypes, and exhibite pervasive underexpression in glial cells during brain aging.

CONCLUSIONS: In summary, our study reveals the complex genetic effects on the gut microbiota in AD, and provides novel evidence for the roles of the gut-brain axis in AD. Video Abstract.},
}

@article {pmid41781798,
year = {2026},
author = {Sener, H and Ozer, F and Polat, OA and Ogurlu, B and Sonmez, HK and Gultekin, M and Horozoglu, F},
title = {Functional and structural retinal alterations in Alzheimer's disease: insights from photopic negative response (PhNR) and OCT-based analysis.},
journal = {Documenta ophthalmologica. Advances in ophthalmology},
volume = {},
number = {},
pages = {},
pmid = {41781798},
issn = {1573-2622},
abstract = {BACKGROUND: We evaluated retinal function and structure in Alzheimer's disease (AD) using photopic negative response (PhNR) from full-field electroretinography (ERG) and using optical coherence tomography (OCT)-based retinal layer measurements.

METHODS: Ninety eyes from 61 subjects (31 controls, 30 AD patients) were included. Full-field ERGs were recorded using chromatic red-on-blue stimulation (1.7 cd·s/m[2] flashes over an 8 cd/m[2] blue background) in accordance with the ISCEV extended PhNR protocol. The AD group included 16 females and 14 males with moderate cognitive impairment (mean MMSE 15.5 ± 3.9). ERG a-wave, b-wave, and PhNR amplitudes were recorded. Macular and peripapillary retinal nerve fiber layer (RNFL) thicknesses were measured by OCT.

RESULTS: A-wave (AD: - 13.4 ± 11.9 µV, control: - 32.5 ± 13.7 µV, p < 0.001), b-wave (AD: 59.1 ± 28 µV, control: 156 ± 48.8 µV, p < 0.001), PhNR (AD: - 21.4 ± 14.9 µV, control: - 51 ± 15.4 µV, p < 0.001) amplitudes were lower in AD. Thicknesses of the central INL (AD: 25 ± 6.6 µm, control: 25.2 ± 8.2 µm, p = 0.04), inferior OPL (AD: 32.7 ± 6.2 µm, control: 36.9 ± 8.9 µm, p = 0.01), and temporal OPL (AD: 29.3 ± 5.2 µm, control: 34.8 ± 7.0 µm, p = 0.001) were reduced in AD, while other retinal layers showed no significant differences between groups (p > 0.05). The b-wave amplitude showed the highest discriminative power with an AUC of 0.956, followed by the PhNR amplitude (AUC = 0.930) and the a-wave amplitude (AUC = 0.904).

CONCLUSION: AD was associated with a generalized reduction in full-field ERG amplitudes, accompanied by selective retinal layer changes on OCT. Among electrophysiological measures, b-wave amplitude demonstrated the highest ability to distinguish AD patients from controls.},
}

@article {pmid41781456,
year = {2026},
author = {Wen, J and Li, M and Xu, J and Sun, Y and Chen, X and Mao, Z},
title = {A meta-analysis of the effect of non-invasive neuromodulation techniques on improving cognitive function in patients with Alzheimer's disease.},
journal = {Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology},
volume = {47},
number = {4},
pages = {},
pmid = {41781456},
issn = {1590-3478},
support = {2021ZD0200407//Ministry of Science and Technology of the People's Republic of China/ ; },
abstract = {OBJECTIVE: This meta-analysis aimed to evaluate the efficacy of non-invasive neuromodulation techniques in improving global cognitive function in patients with Alzheimer's disease (AD) and Mild cognitive impairment (MCI). Non-invasive brain stimulation includes repetitive transcranial magnetic stimulation (rTMS), transcranial alternating current stimulation (tACS), and transcranial direct current stimulation (tDCS), and to compare the efficacy of the three.

METHODS: Searches were conducted in five databases: PubMed, Embase, Web of Science, Cochrane and Scopus. We searched these databases for randomized controlled trials on non-invasive neuromodulation techniques treatment for AD and MCI up to April 10, 2025, to conduct meta-analyses and network meta-analyses. The primary outcome measures were the scores on the Mini-Mental State Examination (MMSE), Montreal Cognitive Assessment (MoCA), and Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-cog). PROSPERO registration: CRD420251120672.

RESULTS: This study included 77 articles. Compared with the control group, rTMS, tACS, and tDCS can all improve the overall cognitive function of participants. The results of the meta-analysis showed that rTMS and tDCS can increase MMSE and MoCA scores and decrease ADAS-cog scores (p < 0.05). Network meta-analysis reveals tDCS is more effective than rTMS on MMSE and MoCA, but less effective on ADAS-cog.

CONCLUSIONS: rTMS, tACS, and tDCS can all improve the overall cognitive function of patients with AD and MCI, and are effective and safe treatment methods. When assessed using the MMSE and MoCA scales, the results show that the tDCS is superior to rTMS.},
}

@article {pmid41781367,
year = {2026},
author = {Atienza, M and Cantero, JL},
title = {In vivo mapping of cortical amyloid beta-myelin coupling in preclinical Alzheimer's disease.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {22},
number = {3},
pages = {e71268},
doi = {10.1002/alz.71268},
pmid = {41781367},
issn = {1552-5279},
support = {PID2023-149270OB-I00//Spanish Ministry of Science, Innovation and Universities/ ; PID2023-151095NB-I00//Spanish Ministry of Science, Innovation and Universities/ ; DGP_PIDI_2024_01337//Junta de Andalucía/ ; NEDG511//CIBERNED/ ; NED24PI01//CIBERNED/ ; },
abstract = {INTRODUCTION: Accumulating evidence suggests that amyloid-β (Aβ) preferentially deposits in poorly myelinated cortical regions and may interfere with remyelination. We hypothesized that this vulnerability would manifest as altered Aβ-myelin coupling in preclinical Alzheimer's disease (AD).

METHODS: We assessed spatial coupling between amyloid positron emission tomography (PET) and myelin content estimated from T1w/T2w ratio maps in 151 cognitively unimpaired older adults. Associations with preclinical AD, blood-based biomarkers, resting-state functional connectivity (rs-FC), and subjective memory complaints (SMC) were examined.

RESULTS: Compared with controls, Aβ[+] individuals exhibited increased positive and negative Aβ-myelin coupling in late- and early-myelinating regions, respectively, likely reflecting compensatory remyelination versus progressive myelin loss, along with disrupted rs-FC and greater SMC. Serum glial fibrillary acidic protein (GFAP) and plasma phosphorylated tau at threonine 181 (pTau-181) showed differential, region-specific associations with Aβ-myelin coupling, with GFAP partially mediating tau-related effects. Exploratory stratification suggested distinct biomarker profiles linked to the direction of coupling dominance, potentially reflecting different preclinical AD phases.

DISCUSSION: Aβ-myelin coupling may represent a sensitive, stage-dependent marker of early AD-related cortical pathology.},
}

@article {pmid41781326,
year = {2026},
author = {Hu, J and Gao, PY and Di, R and Chen, O and Tang, Y},
title = {Chronic Pain and Cognitive Dysfunction: Clinical Implement, Mechanism, and Therapeutic Strategy.},
journal = {The Journal of neuroscience : the official journal of the Society for Neuroscience},
volume = {46},
number = {9},
pages = {},
doi = {10.1523/JNEUROSCI.1251-25.2026},
pmid = {41781326},
issn = {1529-2401},
abstract = {Chronic pain (CP) is increasingly recognized not only as a sensory and emotional condition but also as a significant contributor to cognitive dysfunction. Growing evidence indicates that CP-induced cognitive dysfunction arises from a cascade of neurobiological processes, including persistent neuroinflammation, neurotransmitter dysregulation, and impaired synaptic plasticity. These mechanisms particularly affect the hippocampus and medial prefrontal cortex (mPFC)-regions essential for memory, attention, and executive function. Neuroimaging studies have documented structural atrophy and disrupted network connectivity in these brain areas in CP patients. At the molecular level, pro-inflammatory cytokines such as interleukin-1 beta (IL-1β) and tumor necrosis factor-alpha (TNF-α) impair glutamatergic and GABAergic signaling, disrupt long-term potentiation (LTP), and inhibit neurogenesis. Additionally, dysregulation of brain-derived neurotrophic factor (BDNF) signaling exacerbates synaptic vulnerability, contributing to cognitive decline. These mechanistic overlaps are particularly relevant in aging populations and in Alzheimer's disease (AD), where CP may act as a risk factor. This review integrates clinical and preclinical findings on CP-related cognitive dysfunction, outlines key molecular mechanisms, and explores emerging therapeutic strategies targeting inflammation, neurotransmitter systems, and synaptic repair. Understanding the interaction between chronic pain and cognition is critical for developing precision treatments that address both nociceptive and neurodegenerative pathways.},
}

@article {pmid41781178,
year = {2026},
author = {Vejdani-Jahromi, M and Calle, E and Ganem, O and Rohatgi, S and Farzaneh, H and Griffin, H and Zhu, S and Seah, J and Omid-Fard, N and Kozak, B and Ford, J and Romero, JM},
title = {Relationship between APOE Genotype Status and Imaging Features in Patients with Alzheimer Disease Being Considered for Antiamyloid β Therapy.},
journal = {AJNR. American journal of neuroradiology},
volume = {47},
number = {3},
pages = {708-713},
doi = {10.3174/ajnr.A9056},
pmid = {41781178},
issn = {1936-959X},
abstract = {BACKGROUND AND PURPOSE: Alzheimer disease (AD) is a progressive neurodegenerative disorder that predominantly affects the aging population. Anti-amyloid β (anti-Aβ) therapies, such as lecanemab, have been developed to slow disease progression. However, their use is occasionally associated with amyloid-related imaging abnormalities (ARIA), posing prominent clinical challenges. It has been shown that apolipoprotein E (APOE)-ε4 genotype is strongly associated with an increased risk of microhemorrhages in AD, but the influence of specific APOE genotypes on imaging features important for anti-Aβ therapy remains unclear. This study explores the association between APOE genotypes and key imaging biomarkers in patients being considered for lecanemab treatment.

MATERIALS AND METHODS: This retrospective study evaluated patients with AD who underwent APOE genotyping and were considered for lecanemab therapy. Key assessments included microhemorrhage counts, white matter hyperintensity (WMH) scores, perivascular space (PVS) evaluations, and cognitive function. Microhemorrhages were identified based on both SWI and GRE sequences in each patient. Six radiologists blinded to the patient's APOE genotype status independently conducted the imaging analyses.

RESULTS: A total of 85 patients were included in the study with rare genotypes excluded from analysis (3 patients). Among the common genotypes, e3/e4 was the most prevalent (55%). Statistical analysis revealed significant association between APOE genotype and microhemorrhage count based on the SWI and GRE sequences (P = .007 and P = .003, respectively). The mean identified microbleed count was 1 (based on SWI) and 0.5 (based on GRE) in the same cohort of patients, with the following genotype-specific means based on SWI sequence: e3/e3 = 0.7; e3/e4 = 0.6; and e4/e4 = 2.7. No significant associations were found between APOE genotype and Montreal Cognitive Assessment, WMH or PVS scores. Post hoc power analysis showed adequate power for SWI-based microbleed detection but low power for WMH and PVS.

CONCLUSIONS: In this cohort of patients with AD being evaluated for lecanemab therapy, a significant association was identified between APOE genotype and the number of microhemorrhages with higher mean counts of microbleeds detected on SWI sequence compared with microbleeds detected on the GRE sequence of the same patients. No significant associations were found between APOE genotype and WMH, PVS, or cognitive impairment.},
}

@article {pmid41780490,
year = {2026},
author = {Hasoon, J and Hamilton, CA and Firbank, M and Schumacher, J and Colloby, SJ and Donaghy, PC and Taylor, JP and Thomas, AJ},
title = {Multimodal biomarkers to predict dementia-free survival and cognitive decline in mild cognitive impairment with Lewy bodies.},
journal = {Parkinsonism & related disorders},
volume = {145},
number = {},
pages = {108265},
doi = {10.1016/j.parkreldis.2026.108265},
pmid = {41780490},
issn = {1873-5126},
abstract = {INTRODUCTION: Predicting conversion to dementia in mild cognitive impairment with Lewy bodies (MCI-LB) remains challenging. Furthermore, there is limited research combining predictive markers in MCI-LB. We explored the utility of Lewy body and Alzheimer's disease biomarkers for the prediction of future decline in MCI-LB.

METHODS: Eighty-seven participants were included (35 MCI-AD, 15 possible MCI-LB, 37 probable MCI-LB). Baseline assessment involved MRI, EEG, bloods and cognitive testing. Follow up was completed yearly with review of diagnosis and repeat cognitive testing. We evaluated the relationship between baseline biomarkers and dementia-free survival time. We also investigated biomarker effects on future cognitive decline using annualised change in ACE-R. The value of combining biomarkers with baseline cognitive test score was assessed using forward selection.

RESULTS: In probable MCI-LB, shorter dementia-free survival time was strongly associated with smaller hippocampal volume (hazard ratio = 2.36, 95% CI 1.41 - 3.94) and smaller posterior cortical volume (hazard ratio = 2.62, 95% CI 1.35 - 5.10). Reduced EEG dominant frequency, increased relative delta and theta power, reduced insula volume, increased plasma tau, and increased plasma GFAP were also associated with an increased hazard ratio. Posterior atrophy, hippocampal atrophy, and GFAP were significant predictors of ACE-R decline. Combining blood and MRI biomarkers improved model quality for dementia-free survival (GFAP and hippocampal atrophy) and cognitive test decline (AB ratio and posterior atrophy).

CONCLUSION: Blood, EEG and MRI biomarkers of dementia with Lewy bodies, neurodegeneration and Alzheimer's co-pathology demonstrate utility for prognosis in MCI-LB. Combining biomarkers across modalities improves prognostic accuracy.},
}

@article {pmid41780475,
year = {2026},
author = {Li, J and Yin, H and Qiu, Z and Fu, Y and Luo, Y and Wu, T and Zeng, Z and Qiu, Z and Deng, X and Wu, S and Zhang, Y and Cui, X and Jiang, M},
title = {Exploring the phthalates-induced neurotoxicity mechanisms of neurodegenerative diseases via network toxicology, single-cell transcriptomics and molecular dynamic simulation.},
journal = {Ecotoxicology and environmental safety},
volume = {312},
number = {},
pages = {119954},
doi = {10.1016/j.ecoenv.2026.119954},
pmid = {41780475},
issn = {1090-2414},
abstract = {Phthalates are considered to be a neurotoxicant, widely used in construction materials, packaging, and various medical products. Few studies have focused on the association between exposure to phthalates and risks on neurodegenerative diseases and thus this study delved into the potential mechanisms by which phthalates could cause neurodegenerative diseases. Firstly, using network toxicology, we discovered ten phthalates exert significant toxic effects on the blood-brain barrier (BBB), in which di(2-ethylhexyl) phthalate (DEHP) and diisobutyl phthalate (DiBP) also exhibit marked neurotoxicity, immunotoxicity, and ecotoxicity. Disease ontology (DO) analysis revealed that the impacts of these plasticizers on neurodegenerative diseases are primarily manifested in three major conditions, including Parkinson's disease (PD), Lewy body disease (LBD), and Alzheimer's disease (AD), and further demonstrated that phthalates may induce the pathogenesis of three neurodegenerative diseases via modulating cellular apoptosis and neuroinflammatory pathways, such as the PI3K-Akt and JAK-STAT pathways. Furthermore, we pinpointed the BCL2, BCL2L1, IL6, IL10 and CCND1 as hub genes through diagnostic models by utilizing sample data of PD patients' tissues. Interestingly, we found that BCL2 expressed in astrocytes plays a crucial role in the phthalates-induced neurotoxicity in single-cell analysis. Subsequently, molecular docking and dynamics simulations observed that ten phthalates form a stable interaction with BCL2, especially DEHP, and cellular experiments confirmed that both DEHP and its metabolite MEHP significantly decreased BCL2 level in MPP[+] -induced cell model and induced the transformation of astrocytes from the neuroprotective A2 to the pro-inflammatory A1 subtype. Therefore, our study offers novel insights into the neurotoxic effects of environmental pollutants, thereby establishing a theoretical foundation for the prevention and treatment of neurodegenerative diseases.},
}

@article {pmid41780439,
year = {2026},
author = {Lanza, G and Sorte, G and Bella, R and Garifoli, A and Lanuzza, B and Mogavero, MP and Morreale, M and Pastorello, G and Pennisi, M and Quercia, A and Palmigiano, A and Tripodi, M and Pani, T and Antelmi, E and Schenck, CH and Ferri, R},
title = {REM sleep behavior disorder as a shared motor phenotype: A multidimensional clinical study.},
journal = {Sleep medicine},
volume = {142},
number = {},
pages = {108880},
doi = {10.1016/j.sleep.2026.108880},
pmid = {41780439},
issn = {1878-5506},
abstract = {BACKGROUND: REM sleep behavior disorder (RBD) is increasingly recognized as a heterogeneous condition that may arise in different etiological contexts, including an isolated form that is often a prodromal synucleinopathy, antidepressant exposure, and RBD occurring in the context of clinically diagnosed tau-spectrum neurodegenerative syndromes. The aim of this study was to compare clinical, cognitive, neuroimaging, and polysomnographic features of isolated RBD (iRBD), antidepressant-associated RBD (iatroRBD), and tauopathy-associated RBD (tauRBD) associated with Alzheimer's disease, progressive supranuclear palsy, corticobasal degeneration, or frontotemporal dementia, within a single cohort.

METHODS: We conducted a retrospective analysis of patients with polysomnographically confirmed RBD evaluated at a tertiary sleep center, excluding individuals with established synucleinopathies. Patients were classified as iRBD (n = 26), iatroRBD (n = 16), or tauRBD (n = 6) based on the current criteria. Demographics, non-motor symptoms, Mini-Mental State Examination (MMSE) scores, neuroimaging reports, and detailed polysomnographic parameters were compared using non-parametric statistics and effect sizes.

RESULTS: Age, age at onset, and disease duration did not differ across groups. Sex distribution showed a significant male predominance in iRBD, with a more balanced distribution in iatroRBD and tauRBD. Cognitive performance differed markedly, with tauRBD patients showing significantly lower MMSE scores than both iRBD and iatroRBD, whereas cognition was largely preserved in the latter groups. Non-motor symptoms, including hyposmia and depressive symptoms, showed limited discriminatory value. Polysomnography revealed selective differences in REM sleep architecture, including reduced REM sleep percentage in tauRBD and prolonged REM sleep latency in iatroRBD, while REM atonia, limb movements, and respiratory parameters were broadly similar.

CONCLUSIONS: RBD appears to be a shared motor phenotype that can arise in different etiological contexts. In this cohort, cognitive status, sex distribution, and selected REM sleep features were the most informative contextual markers, whereas history-derived non-motor features available in this retrospective dataset (hyposmia and depressive symptoms) and routine PSG metrics showed limited discrimination.},
}

@article {pmid41780438,
year = {2026},
author = {Montenegro, MLV and Santos, AP and Pacheco, ABV and Kato, CFPA and Souza, LG and Ribeiro, MMC and Oliveira, PJ and Lucena Raulino, VA and Rabelo, WL and da Silva, TCN and Resende, LT and Barbosa, BJAP},
title = {Non-pharmacological interventions for sleep disorders in patients with Alzheimer's disease: An integrative review.},
journal = {Sleep medicine},
volume = {142},
number = {},
pages = {108874},
doi = {10.1016/j.sleep.2026.108874},
pmid = {41780438},
issn = {1878-5506},
abstract = {BACKGROUND: Alzheimer's disease (AD) is associated with behavioral and physical manifestations, such as sleep disturbances, which worsen the course of the disease and require effective management strategies. This review investigates non-pharmacological interventions available for the control of sleep disorders in patients with Alzheimer's disease.

METHODS: This is an integrative review, with searches carried out in the Public Medical Database, Science Direct, Scientific Electronic Library Online and Latin American and Caribbean Literature in Health Sciences, using the descriptors: "Alzheimer Disease", "Sleep Wake Disorders", "Sleep Disorders", and "Therapeutics". Original studies evaluating non-pharmacological treatments for sleep disorders in patients with AD and using specific instruments to assess improvement in sleep disorders were included.

RESULTS: The non-pharmacological interventions evaluated included bright light therapy, morning light exposure, personalized lighting intervention, blue-enriched white light exposure, transcranial magnetic stimulation, acupressure, multimodal exercise program, aromatic oil bath salts, light visor phototherapy, transcutaneous electrical nerve stimulation and deep brain stimulation. Additionally, one article investigated the combination of bright light exposure with walking, as well as the isolated effects of each intervention.

CONCLUSION: Non-pharmacological interventions for managing sleep disorders in patients with AD have shown promising strategies, including approaches such as light therapy, physical stimulation techniques, and acupressure, with results indicating potential benefits in improving sleep quality and mitigating behavioral and cognitive symptoms associated with the disease. However, current evidence highlights the need for future studies with more rigorous methodologies, larger population samples, and long-term follow-up to consolidate the efficacy and applicability of these interventions in clinical practice.},
}

@article {pmid41780284,
year = {2026},
author = {Wang, G and Li, T and Sun, Q and Peng, H and Ren, T and Fu, Y and Yao, Z and Hu, B},
title = {Multimodal graph fusion-based GCN for Alzheimer's disease diagnosis using fMRI and T1-weighted MRI.},
journal = {Neural networks : the official journal of the International Neural Network Society},
volume = {200},
number = {},
pages = {108748},
doi = {10.1016/j.neunet.2026.108748},
pmid = {41780284},
issn = {1879-2782},
abstract = {Alzheimer's disease (AD) is a progressive neurodegenerative disorder marked by both structural atrophy and functional dysregulation in the brain, yet its early detection remains elusive. Although recent efforts have leveraged artificial intelligence combined with multimodal neuroimaging to improve diagnostic accuracy, these methods often falter in harmonizing disparate data sources and lack the transparency needed for clinical adoption. In particular, the sheer dimensionality of functional Magnetic Resonance Imaging (fMRI) and T1-weighted Magnetic Resonance Imaging (T1w-MRI) features, together with complex inter-modality relationships, can lead to overfitting and hinder the reliable identification of robust biomarkers. To overcome the aforementioned challenges, we propose a novel Multimodal Graph Fusion Graph Convolutional Network (MGF-GCN) that integrates functional (fMRI) and structural (T1w-MRI) brain features for accurate and interpretable AD diagnosis. We construct brain graphs by incorporating nonlinear Granger causality (NGC) from resting-state fMRI (rs-fMRI) to capture inter-regional functional dependencies, alongside morphological features from T1-weighted MRI to enrich node attributes. To effectively align and enhance multimodal representations while preserving the underlying topological structure, we introduce a cross-attention-based graph fusion strategy. To further improve both performance and interpretability, we develop a Bayesian Self-Attention Graph Convolutional Network (BSAGCN), where attention weights are modeled as probability distributions, allowing for the identification of critical brain regions and minimizing noise sensitivity. All features are extracted based on the BN246 brain atlas, facilitating fine-grained localization of potential biomarkers. Experimental results show that our approach significantly outperforms existing methods in diagnostic accuracy and interpretability, providing new insights into the pathophysiological mechanisms of AD and offering valuable support for clinical decision-making.},
}

@article {pmid41781884,
year = {2026},
author = {Chiu, HC and Hsieh, YW and Cheng, CH},
title = {Baseline predictors of neurophysiological response to combined physical and cognitive training in older adults with subjective cognitive decline.},
journal = {BMC geriatrics},
volume = {},
number = {},
pages = {},
doi = {10.1186/s12877-026-07270-8},
pmid = {41781884},
issn = {1471-2318},
support = {NSTC-112-2410-H-182-030, NSTC-113-2314-B-182-064, NSTC-114-2314-B-182-016-MY3//National Science and Technology Council/ ; },
}

@article {pmid41781782,
year = {2026},
author = {Saha, P and Chouhan, A},
title = {Integrating ensemble machine-learning and fibril docking to discover potent, novel triazole-naphthalene tau-aggregation inhibitors.},
journal = {Molecular diversity},
volume = {},
number = {},
pages = {},
pmid = {41781782},
issn = {1573-501X},
abstract = {Tau-protein aggregation is a central pathological feature of Alzheimer's disease, so blocking fibril growth is an attractive therapeutic goal. We curated a high-quality set of 289 literature IC50 measurements for human-tau aggregation and trained a stacked-ensemble QSAR model (SVR + RF + XGB) that achieves fivefold CV Q[2] = 0.63, external R[2] = 0.57 and RMSE = 0.73 log-units. Applicability-domain analysis revealed no high-influence outliers in the calibration set, and a 5-nearest-neighbour density test confirmed that each of sixteen previously unreported 1,2,4-triazole-naphthalene derivatives (TND, TND-1…TND-15) lies in locally populated chemical space, albeit at the edge of the global domain. The model predicts pIC50 = 6.75-7.53 (IC50 ≈ 30-177 nM), nominating TND-9, TND-15 and TND-5 as top-ranked candidates based on predicted potency. Nearly all TNDs fall within the BBB window (MW ≈ 350-450 Da, TPSA < 90 Å[2]); most obey cLogP ≤ 5, and the few slightly above still map to the BOILED-Egg CNS-positive zone. Retrospective docking against phosphorylated-tau fibrils (PDB ID 6HRF) highlighted TND, TND-5 and TND-14 with sub-micromolar predicted affinity, forming key contacts in the microtubule-binding cleft. These docking results support binding plausibility rather than quantitative aggregation inhibition. TND-8, although highly ranked by docking, was deprioritised owing to low predicted GI absorption. Physicochemical and CNS-oriented ADMET filters further support developability of the top leads. The integrated workflow-combining rigorously validated QSAR, structure-based docking on the 6HRF polymorph and developability profiling-provides an open-source blueprint for tau-aggregation inhibitor discovery. Consensus ranking prioritises TND-5 for immediate in-silico follow-up, with TND, TND-14, TND-9 and TND-15 as secondary leads.},
}

@article {pmid41781781,
year = {2026},
author = {Sharmah, H and Ahmed, LA and Kemisetti, D and Kumar, S and Samanthula, KS and Panigrahy, UP and Ghosh, NS},
title = {Current advances in 7-hydroxycoumarin derivatives as potential therapeutic agents for Alzheimer's disease.},
journal = {Molecular diversity},
volume = {},
number = {},
pages = {},
pmid = {41781781},
issn = {1573-501X},
abstract = {Alzheimer's disease (AD), a multifactorial neurodegenerative disorder, remains a major cause of cognitive decline in the aging population. Current pharmacological interventions provide only symptomatic relief, highlighting the urgent need for novel therapeutic strategies capable of modifying disease progression. Coumarins, particularly 7-hydroxycoumarin and its synthetic derivatives, have attracted considerable interest due to their broad pharmacological potential, including cholinesterase inhibition, monoamine oxidase (MAO) inhibition, antioxidant, anti-amyloidogenic and metal-chelating activities. This review presents a comprehensive analysis of synthetic 7-hydroxycoumarin derivatives reported over the past 15 years as potential anti-Alzheimer agents, classifying them according to their actions on key pathological hallmarks of AD, such as acetylcholinesterase (AChE), butyrylcholinesterase (BuChE), MAO-B, β-amyloid (Aβ) aggregation, oxidative stress and neuroinflammation. Structure-activity relationship (SAR) analysis reveals that substitutions at the 7-, 3- and 4-positions of the coumarin scaffold critically influence pharmacological potency and selectivity, with aromatic and alkyl amine substitutions generally enhancing enzyme inhibition and neuroprotective effects. Several derivatives exhibited sub-micromolar to nanomolar inhibitory activity against AChE and MAO-B, along with antioxidant and anti-Aβ aggregation properties, supporting their multifunctional behaviour. Overall, this review highlights the therapeutic promise of 7-hydroxycoumarin derivatives as multitarget-directed ligands (MTDLs) and provides valuable insights for the rational design of new lead compounds for Alzheimer's disease.},
}

@article {pmid41781594,
year = {2026},
author = {Kariithi, BT and Kumar, P and Choonara, YE},
title = {Breaking the Barrier of Brain Disease Therapeutics: Advocating Targeted Drug Delivery for Improved Neuro-Resident Interventions.},
journal = {AAPS PharmSciTech},
volume = {27},
number = {3},
pages = {},
pmid = {41781594},
issn = {1530-9932},
abstract = {This paper provides an expert review of extant research into commercially utilized targeted drug delivery systems for brain therapeutics, with Glioblastoma Multiforme (GBM), Parkinson's Disease (PD), Alzheimer's Disease (AD) and Major Depressive Disorder (MDD), as case studies. While the paper highlights the progress made in developing effective drug delivery solutions, a common denominator across much of the research is the singular challenge posed by the Blood Brain Barrier (BBB) against the bulk of drug delivery options and treatments. The paper identifies critical pathways and transporting effective therapeutics through the barrier, and calls for further innovation into nano-systems, gels, and wafers with BBB-beating properties. The paper calls for the modernization of manufacturing regulatory systems, as well as increased preclinical studies and clinical trials to establish the utility of such nano-systems. Ultimately, the paper vouches for fast-tracking and even exemption of promising delivery solutions from phase IV studies but instead to accurately assess and evaluate the solutions' efficacy in a "real world" setting.},
}

@article {pmid41781371,
year = {2026},
author = {Zhang, L and Huang, Y and Huang, W and Huang, Q and Lin, Y and Gu, J},
title = {TDP-43 phosphorylation: Exploring kinases, phosphatases, and therapeutic potential in neurodegeneration.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261424284},
doi = {10.1177/13872877261424284},
pmid = {41781371},
issn = {1875-8908},
abstract = {TAR DNA-binding protein 43 (TDP-43) is a multifunctional DNA/RNA-binding protein whose abnormal phosphorylation and aggregation are central to the pathogenesis of several neurodegenerative diseases. TDP-43 proteinopathy, characterized by hyperphosphorylation and cytoplasmic accumulation, is a defining pathological feature of amyotrophic lateral sclerosis and frontotemporal lobar degeneration, and is frequently observed in Alzheimer's disease. The phosphorylation state of TDP-43 is dynamically regulated by a network of protein kinases-including CK1, GSK3β, CDC7, and PKA-and counterbalanced by phosphatases such as PP2A and PP1; however, the precise molecular mechanisms governing this equilibrium in disease remain incompletely understood. Notably, phosphorylated TDP-43 acquires prion-like properties, enabling self-templated aggregation and cell-to-cell propagation, which amplifies pathology and drives disease progression. These insights have catalyzed the development of therapeutic strategies aimed at modulating TDP-43 phosphorylation, with kinase inhibitors and phosphatase enhancers emerging as promising candidates for targeting TDP-43 proteinopathies. This review integrates current knowledge on the regulatory networks controlling TDP-43 phosphorylation, examines its role in prion-like spread, and evaluates emerging therapeutic approaches aimed at mitigating TDP-43-mediated neurodegeneration.},
}

@article {pmid41781369,
year = {2026},
author = {Patel, H and Choi, A and Weng, P and Karl, J and Joseph, S and Johnson, KG and Berger, M and Whitson, HE and Grewal, DS and Fekrat, S},
title = {Cerebrospinal fluid amyloid-β 42/40 ratio is associated with ganglion cell-inner plexiform layer thinning in individuals with and without amyloid pathology.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261423968},
doi = {10.1177/13872877261423968},
pmid = {41781369},
issn = {1875-8908},
abstract = {BackgroundRetinal imaging offers a noninvasive window into neurodegenerative changes, yet its relationship with established cerebrospinal fluid (CSF) biomarkers of Alzheimer's disease (AD) remains poorly understood. This study addresses a critical gap by examining whether retinal structural findings on optical coherence tomography (OCT) correlate with CSF biomarkers of AD pathology and neurodegeneration.ObjectiveTo determine if CSF biomarkers correlate with retinal OCT imaging findings in individuals with AD.MethodsIn this cross-sectional study, subjects underwent lumbar puncture for CSF collection and were imaged using the Zeiss Cirrus HD-5000 with AngioPlex.ResultsForty participants (73 eyes) were included in this study. Twenty-one had normal cognition and negative CSF AD biomarkers, 12 had normal cognition and positive CSF AD biomarkers, and seven had mild cognitive impairment. Central subfield thickness (CST), retinal nerve fiber layer (RNFL), and ganglion cell inner plexiform layer (GCIPL) thicknesses were associated with CSF amyloid-β 42/40 ratio (Aβ42/40), phosphorylated tau at threonine 181 (pTau181)/Aβ40 ratio, neurofilament light chain (NfL), and glial fibrillary acidic protein (GFAP) using multivariable generalized estimating equations. There were no statistically significant associations between CSF pTau181/Aβ40 ratio, NfL, or GFAP and CST, GCIPL thickness, or RNFL thickness (p > 0.05 for all). Aβ42/40 ratio was positively associated with GCIPL thickness (p = 0.02), but not with CST or RNFL thickness (p = 0.31 and p = 0.82, respectively).ConclusionsDecreased CSF Aβ42/40 ratio, a biomarker of amyloid plaque pathology, is associated with decreased GCIPL thickness. GCIPL thinning may correspond with CSF abnormalities consistent with amyloid pathology that is present even prior to cognitive decline.},
}

@article {pmid41780426,
year = {2026},
author = {Shor, Y and Said, R and Fainstein, N and Wolf, G and Stepanov, LS and Lachish, M and Ganz, T and Shwaiky, Y and Elad, A and Benyamini, H and Nevo, Y and Brock, Y and Gurevitz, J and Lifschytz, T and Lotan, A and Ben-Hur, T},
title = {Corrigendum to "The paradoxical protective effect of chronic stress on advanced Alzheimer's disease pathology". [Brain, Behav., Immun. 132 (2026) 106224].},
journal = {Brain, behavior, and immunity},
volume = {135},
number = {},
pages = {106519},
doi = {10.1016/j.bbi.2026.106519},
pmid = {41780426},
issn = {1090-2139},
}

@article {pmid41780257,
year = {2026},
author = {Cardenal, CV and Mahfooz, K and Garcia-Rates, S and Hasan, S and Greenfield, S},
title = {Therapeutic antagonism of a key toxin driving Alzheimer's disease: Comparison of a peptide variant and small molecule.},
journal = {Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie},
volume = {197},
number = {},
pages = {119125},
doi = {10.1016/j.biopha.2026.119125},
pmid = {41780257},
issn = {1950-6007},
abstract = {Among emerging therapeutic targets for Alzheimer's disease (AD), the α7 nicotinic acetylcholine receptor (α7-nAChR) has received much attention and now merits still more focus due to its role as the exclusive binding site for the toxic 14mer peptide T14. T14 is elevated in presymptomatic AD and initiates a pathological cascade involving calcium influx, mTORC1 activation, impaired autophagy, and β-amyloid accumulation. To interrupt this sequence, the cyclated variant of T14, NBP14, was developed, with consequent cognitive benefits in a preclinical mouse model. However, the high molecular weight of NBP14 posed potential limitations for therapeutic translation, prompting the design of NBP6B, a shorter, linear 6-mer variant with improved efficacy and bioavailability. This study aimed to evaluate the efficacy of NBP6B in antagonising T14-induced toxicity in comparison with two novel small molecules, which due to their lower molecular weight could have greater therapeutic potential. Using PC12 cells, T14 activity was assessed through calcium influx and cell viability assays, alongside therapeutic rescue by the drug candidates. To evaluate receptor specificity, α7-nAChR overexpression was employed to determine whether the small molecules acted via α7-dependent or independent pathways. While the small molecules offered favourable drug-like properties and potential for improved blood-brain barrier (BBB) permeability, NBP6B exhibited greater potency and selectivity, with effective antagonism in the nanomolar range, compared to the micromolar concentrations required for the small molecules. These findings thus support NBP6B as a promising and selective α7-targeted therapeutic for early-stage intervention in AD.},
}

@article {pmid41780099,
year = {2026},
author = {Zhao, R and Goldstein, SA},
title = {Amyloid precursor protein is a subunit of microglial Hv1 channels.},
journal = {Current opinion in immunology},
volume = {100},
number = {},
pages = {102751},
doi = {10.1016/j.coi.2026.102751},
pmid = {41780099},
issn = {1879-0372},
abstract = {Voltage-gated proton channels (Hv1) are key regulators of microglial activation, coupling proton extrusion to reactive oxygen species production, cellular pH homeostasis, and pro-inflammatory signaling. Dysregulated Hv1 activity exacerbates neuroinflammation and contributes to a range of central nervous system pathologies. Our recent work shows that proton channels in microglia are formed by the co-assembly of Hv1 pore-forming subunits and amyloid precursor protein (APP). APP, and its C99 transmembrane fragment, assemble with Hv1 to enhance channel activity, altering gating kinetics, modifying pharmacological properties, and amplifying inflammatory mediator release from microglia. Importantly, Alzheimer's disease-associated APP mutations further potentiate Hv1 activity, providing a mechanistic link between genetic risk factors and microglial dysfunction, offering APP-Hv1 as a new therapeutic target for neuroinflammatory disease. This review summarizes current views of microglial Hv1 function and highlights that Hv1, long thought to operate as homodimers despite exhibiting varied attributes in native cells, exhibits functional diversity through accessory subunit incorporation.},
}

@article {pmid41780055,
year = {2026},
author = {Valkenburg, C and van den Ent, M and Nederlof, M and Dirkzwager, R and Nokkert, L and Donker, M and Groot-Sluijsmans, B},
title = {Serenading the mind: positive and critical lived experiences of individuals with dementia with participatory community choirs.},
journal = {Arts & health},
volume = {},
number = {},
pages = {1-15},
doi = {10.1080/17533015.2026.2637142},
pmid = {41780055},
issn = {1753-3023},
abstract = {BACKGROUND: Participatory choirs gathering people with and without dementia, aiming at the well-being of participants and stigma-reduction, are promising; however, there is a lack of research on the challenging aspects of participatory choirs from the perspective of people with dementia.

METHODS: To understand these experiences, we conducted 14 semi-structured interviews with choir participants and mostly together with their loved ones from different participatory choirs, and seven researchers conducted participatory observations during choir rehearsals and performances.

RESULTS: Most participants valued singing in a participatory choir; however, the stories also showed that organizing the choir requires a balancing act for initiators, coordinators, and conductors on many levels. The four key themes identified in this study highlight participants' multiform experiences: (1) Balancing accessibility with aesthetics? (2) Choir as a warm bath, but too short? (3) High-quality music, but too challenging? (4) Self-reliant, but with limits?

CONCLUSIONS: The choir's approach requires attention to meet all members' varied needs and remains true to its core mission.},
}

@article {pmid41779765,
year = {2026},
author = {Kabakova, M and Patel, P and Bitterman, D and Wang, JY and Zafar, K and Fife, DA and Cohen, M and Kurtti, A and Jagdeo, J},
title = {Antiviral Treatment of Herpes Simplex Virus Decreases the Risk of Alzheimer's Disease and Dementia.},
journal = {Journal of drugs in dermatology : JDD},
volume = {25},
number = {3},
pages = {234-239},
doi = {10.36849/JDD.9474},
pmid = {41779765},
issn = {1545-9616},
abstract = {BACKGROUND: Alzheimer's disease (AD) and dementia create major global health and economic burdens. Herpes simplex virus (HSV) infects over 3 billion people, and chronic infection is increasingly linked to neurodegeneration.

OBJECTIVES: To evaluate whether antiviral therapy for oral, mucocutaneous, or anogenital HSV lowers the subsequent risk of AD and dementia.

METHODS: A retrospective cohort study with propensity-score matching was performed in the TriNetX Research Network. On 24 May 2024, 615,324 individuals with HSV were identified; those with prior AD, intracranial injury, or cerebral infarction were excluded. Matching balanced age, sex, race, body-mass index, smoking, diabetes, and hypertension between antiviral-treated and untreated groups. Therapies included acyclovir, valacyclovir, penciclovir, ganciclovir, valganciclovir, and famciclovir. Incidences of AD and dementia were identified by ICD-10 codes, and relative risks (RR) with 95% confidence intervals (CI) were calculated.

RESULTS: After matching, 231,277 patients per cohort (mean age 36.8 y; 67.7% female) were analyzed. Antiviral treatment for oral/mucocutaneous HSV significantly reduced the risk of AD (RR 0.87; 95% CI 0.73-0.92) and dementia (RR 0.83; 95% CI 0.77-0.90). No significant association was observed for anogenital HSV.

CONCLUSIONS: Antiviral therapy for oral or mucocutaneous HSV was associated with a 13% to 17% reduction in risk for AD and dementia. These findings suggest that early antiviral management of HSV infections may represent a feasible preventive strategy against neurodegenerative disease, meriting prospective confirmation. &nbsp.},
}

@article {pmid41779394,
year = {2026},
author = {Mak, E and Fought, AJ and Wiste, HJ and Przybelski, SA and Reid, RI and Schwarz, CG and Senjem, ML and Vemuri, P and Jack, CR and Lowe, VJ and Petersen, RC and Rocca, WA and Boeve, BF and Kantarci, K and , },
title = {Sex-Specific Associations of α-Synuclein Pathology With Tau Accumulation.},
journal = {JAMA network open},
volume = {9},
number = {3},
pages = {e260461},
doi = {10.1001/jamanetworkopen.2026.0461},
pmid = {41779394},
issn = {2574-3805},
abstract = {IMPORTANCE: Sex differences are increasingly recognized as modifiers of Alzheimer disease and related dementias, with women exhibiting greater tau burden and faster cognitive decline than men. Even though α-synuclein copathology frequently occurs in Alzheimer disease, its contribution to sex differences in disease progression is unclear.

OBJECTIVE: To test whether α-synuclein positivity, measured using cerebrospinal fluid seed amplification assay (SAA), is differentially associated with tau accumulation in women vs men across the Alzheimer disease continuum.

This cohort study used longitudinal tau positron emission tomography from the Alzheimer's Disease Neuroimaging Initiative collected between 2015 and 2023, with a median (IQR) follow-up of 1.23 (0.00-3.84) years. Participants were stratified by cerebrospinal fluid α-synuclein seed amplification assay status and sex. Participants were cognitively unimpaired or cognitively impaired (mild cognitive impairment or dementia) at baseline.

EXPOSURE: Cerebrospinal fluid α-synuclein status determined by SAA and dichotomized as SAA negative or SAA positive.

MAIN OUTCOMES AND MEASURES: Tau burden was quantified as standardized uptake value ratio (SUVr) in the medial temporal composite region of interest. Linear mixed-effects models tested SAA by sex by time interactions on longitudinal tau accumulation, adjusting for baseline age, baseline cognitive status, apolipoprotein E ε4 carrier status, and site. Sample size estimates were calculated to detect 25% and 50% treatment effects with 80% power in those with cognitive impairment.

RESULTS: Among 415 participants (mean [SD] age, 72.3 [7.6] years; 220 women [53%]; 69 SAA positive [17%] and 346 SAA negative [83%]), there was a significant interaction between SAA status, sex, and time on tau accumulation (β, 0.061; 95% CI, 0.030-0.093; P < .001). Women with positive SAA results exhibited the fastest tau accumulation compared with other groups (0.066 SUVr per year; 95% CI, 0.043 to 0.089 SUVr per year; P < .001). Clinical trials targeting tau pathology in cognitively impaired individuals with 18-month follow-up would require 129 SAA-positive women to detect a 25% treatment effect with 80% power, compared with 518 SAA-negative women.

CONCLUSIONS AND RELEVANCE: In this cohort study of participants across the Alzheimer disease continuum, α-synuclein copathology was associated with faster tau accumulation in women than men. These findings may inform sex-specific interpretation of α-synuclein biomarkers and trial design.},
}

@article {pmid41779265,
year = {2026},
author = {Ren, L and Zhang, W and Liu, Y and Wang, W},
title = {Value of lncRNA LINC00641 as a Potential Biomarker for Diagnosis of Alzheimer's Disease and Elucidation of its Underlying Molecular Mechanism.},
journal = {Journal of molecular neuroscience : MN},
volume = {76},
number = {1},
pages = {},
pmid = {41779265},
issn = {1559-1166},
support = {MSZ20203//Nantong Municipal Science and Technology Bureau Social Democracy Science and Technology Project/ ; },
abstract = {Alzheimer's disease (AD) is a neurodegenerative disease with progressive cognitive impairment as the main clinical manifestation. Long non-coding RNAs (lncRNAs) are crucial regulators of diverse cellular processes. This study examined the clinical significance and underlying mechanisms of LINC00641 in AD diagnosis. qRT-PCR was used to measure plasma LINC00641 levels in AD patients, and its diagnostic value was assessed using ROC curve. Cell proliferation was measured via the CCK-8 assay. Apoptosis and AD-related proteins were detected by ELISA. The interaction between LINC00641 and its downstream target miR-501-3p was validated through online network prediction and dual-luciferase reporter assay. Plasma LINC00641 expression was lower in AD patients than in controls. It correlated positively with Aβ42 and negatively with p-Tau181 and p-Tau217. Combining of LINC00641 with clinical markers obviously improved diagnostic accuracy for distinguishing AD patients. Overexpression of LINC00641 restored the viability of H19-7 cells after Aβ42 treatment, and reduced levels of cleaved Caspase-3, Aβ42, p-Tau181/Tau, and p-Tau217/Tau. Functionally, miR-501-3p acts downstream of LINC00641. The cellular effects of LINC00641 overexpression were reversed by co-transfection with miR-501-3p mimic. Overexpression of LINC00641 downregulated miR-501-3p expression, restoring neuronal cell viability and reducing cell damage. Targeting LINC00641 holds potential as a diagnostic biomarker and therapeutic candidate for AD, which requires further validation in animal models.},
}

@article {pmid41779114,
year = {2026},
author = {Medeiros, EB and Lidio, AV and Zabot, GC and Fenilli, GP and de Bem Silveira, G and Keller, GS and Carrion, FRA and De Felice, FG and Kluwe-Schiavon, B and Walls-Bass, C and Barichello, T and Budni, J},
title = {Exploring the Gut-Brain Connection: Are Probiotics the Next Frontier in Alzheimer's Disease Treatment?.},
journal = {Probiotics and antimicrobial proteins},
volume = {},
number = {},
pages = {},
doi = {10.1007/s12602-026-10927-w},
pmid = {41779114},
issn = {1867-1314},
}

@article {pmid41779032,
year = {2026},
author = {Yang, Q and Wang, Z and Deng, T and Xia, Y and Shi, F and Feng, J and Li, C},
title = {MRI In Vivo Detection of Amyloid-β Protein Deposition in Different Brain Regions of Patients with AD and MCI.},
journal = {Brain topography},
volume = {39},
number = {3},
pages = {},
pmid = {41779032},
issn = {1573-6792},
support = {KJQN202300137//Science and Technology Research Program of Chongqing Municipal Education Commission/ ; 2026WSJK088//Medical Research Project of Chongqing Munipal Health Commission/ ; 2022CDJYGRH-004//Fundamental Research Funds for the Central Universities of China/ ; },
abstract = {To investigate a non-invasive magnetic resonance imaging (MRI)-based method for detecting amyloid-β (Aβ) protein deposition in different brain regions of patients with mild cognitive impairment (MCI) and Alzheimer's disease (AD). This study included 80 patients with MCI and 62 patients with AD, who were randomly divided into training and testing sets at an 8:2 ratio. All participants underwent 18 F-florbetapir positron emission tomography (PET) imaging and three-dimensional T1-weighted MRI. The interval between MRI and PET examinations did not exceed 30 days. A deep learning-based three-dimensional VB-Net model was developed for brain region segmentation. All PET images were registered to the corresponding MRI images, and standardized uptake ratios for 109 brain regions were calculated and averaged. Following radiomics feature extraction and selection using multiple methods, six machine learning algorithms were applied to establish regression models. In addition, a lightweight transformer-based deep learning model was constructed by improving the original transformer architecture. A total of 1,409 features were extracted from each brain region in patients with MCI and AD. After feature selection, 46, 16, 47, 59, 17, and 72 features were retained for the construction of stochastic gradient regression (SGR), GBR, random forest regression (RFR), support vector regression (SVR), extreme gradient boosting (XGB), and k-nearest neighbor (KNN) models, respectively. Delong test analysis demonstrated that the RFR model achieved the best performance, with mean absolute error (MAE), mean squared error (MSE), R[2] score (RS), and Pearson correlation coefficient (PCC) values of 0.13 ± 0.05, 0.03 ± 0.02, 0.77 ± 0.22, and 0.89 ± 0.05 in the training set, and 0.23 ± 0.10, 0.09 ± 0.08, 0.36 ± 0.12, and 0.65 ± 0.09 in the testing set, respectively. For the deep learning model, the MAE, MSE, RS, and PCC in the testing set were 0.41 ± 0.17, 0.25 ± 0.18, - 0.83 ± 0.42, and - 0.01 ± 0.17, respectively. An artificial intelligence-based approach was successfully developed to quantitatively detect Aβ protein accumulation in different brain regions of patients with AD and MCI using MRI. This method is convenient and non-invasive and does not require cerebrospinal fluid puncture or exposure to ionizing radiation.},
}

@article {pmid41778964,
year = {2026},
author = {Stöckelmaier, J and Polato, G and Hritz, J and Oostenbrink, C},
title = {Evaluating the Impact of Phosphorylation on the Dynamics of the Tau Protein Proline-Rich Region.},
journal = {Journal of chemical theory and computation},
volume = {},
number = {},
pages = {},
doi = {10.1021/acs.jctc.5c02011},
pmid = {41778964},
issn = {1549-9626},
abstract = {The proline-rich region of the tubulin-associated unit (TAU) protein is of substantial interest in understanding neurodegenerative diseases due to its interaction with bridging integrator 1 (BIN1). The associated gene BIN1 is substantially associated with the development of Alzheimer's disease. Previous studies have underlined the importance of the conformation of the proline-rich region of TAU and the effect of its phosphorylation. In this study, we investigate the change in compactness between a four times phosphorylated TAU fragment (210-240) compared to the unphosphorylated (non-P) form using computational means. We apply our Ensemble Reconstruction from Fragments (ERF) approach to create two unbiased conformational ensembles from which a reweighted ensemble is derived that agrees with observables from nuclear magnetic resonance experiments. The resulting shift of the radius of gyration indicates a preference for relatively compact conformations for the non-P form, while the restraints derived from the experimental data do not substantially influence the compactness of the phosphorylated peptide.},
}

@article {pmid41778926,
year = {2026},
author = {Liu, Z and Zang, Z and Li, D and Wu, S},
title = {A self-priming dual-hairpin probe-mediated primer exchange reaction for label-free fluorescence detection of microRNA in Alzheimer's disease.},
journal = {Analytical methods : advancing methods and applications},
volume = {},
number = {},
pages = {},
doi = {10.1039/d5ay02058a},
pmid = {41778926},
issn = {1759-9679},
abstract = {The accurate detection of microRNA (miRNA) biomarkers associated with Alzheimer's disease (AD) is critical for early diagnosis and therapeutic monitoring. Herein, we report a label-free fluorescent bio-sensing platform that integrates a self-priming dual-hairpin probe with a primer exchange reaction (PER) for sensitive miRNA analysis in AD. Target binding triggers a conformational rearrangement of the probe, activating a self-priming hairpin that initiates enzyme-driven strand displacement amplification (SDA). Through cyclical extension and cleavage, the SDA process displaces a second hairpin structure, denoted as the PER template probe. Release of this probe enables primer binding and initiates the PER, yielding large amounts of G-rich single-stranded DNA products. These sequences fold into G-quadruplex structures that selectively bind thioflavin T, leading to a strong turn-on fluorescence response. The assay achieves a broad linear detection range from 0.5 fM to 100 pM, with an ultralow detection limit of 87 aM. Furthermore, this strategy offers a cost-effective, label-free fluorescence method for SDA-based detection and exhibits promising applicability in complex biological matrices.},
}

@article {pmid41778860,
year = {2026},
author = {Biber, S and Gothard, S and Murchison, CF and McLeod, L and Gauthreaux, K and HewaNadungodage, C and Cheng, E and Welsch, J and Culhane, JE and Yasuda, S and Stockwell, H and Allimatti, S and Bauer, M and Reader, JM and Kukull, W and Zozus, M and Das, S},
title = {A cross-consortium, stakeholder-driven model for implementing a modern electronic data capture and submission system across the Alzheimer's Disease Research Centers Program.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {22},
number = {3},
pages = {e71105},
doi = {10.1002/alz.71105},
pmid = {41778860},
issn = {1552-5279},
support = {U24 AG072122/AG/NIA NIH HHS/United States ; P30 AG086401/AG/NIA NIH HHS/United States ; P30 AG072931/AG/NIA NIH HHS/United States ; P30 AG062421/AG/NIA NIH HHS/United States ; P30 AG066518/AG/NIA NIH HHS/United States ; P30 AG066546/AG/NIA NIH HHS/United States ; },
abstract = {INTRODUCTION: The National Alzheimer's Coordinating Center (NACC) and Alzheimer's Disease Research Center (ADRC) Program advances dementia research by collecting and sharing standardized, longitudinal data, including the Uniform Data Set with the global research community. To modernize workflow and accelerate the availability of analyzable data, we co-developed a consortium-wide Electronic Data Capture and Submission system.

METHODS: A cross-disciplinary workgroup of ADRC and NACC members co-developed the system using a stakeholder-centered sociotechnical implementation model. Subgroups focused on requirements, development, and training. Surveys and pilot testing across centers guided design and priorities.

RESULTS: Research Electronic Data Capture was selected as the foundational platform. Deliverables included modular UDS version 4 instruments, embedded logic and automated quality checks, dynamic training resources, and an API-based submission pipeline to NACC. The platform was adopted across all 36 ADRCs and surveys indicated high user satisfaction.

DISCUSSION: Beyond infrastructure, this initiative provides a scalable, stakeholder-driven implementation model that supports higher-quality, more timely multicenter data submission, accelerating biomarker validation, early detection studies, and precision-medicine analyses.

HIGHLIGHTS: A cross-disciplinary workgroup of ADRC and NACC members designed a stakeholder-centric sociotechnical implementation model. The workgroup drove the adoption of a modernized data infrastructure across a national consortium. Deployed a modern electronic data capture and submission system for the ADRC program. Leveraged REDCap as a flexible, scalable tool for a large-scale EDCS system.},
}

@article {pmid41778859,
year = {2026},
author = {Yan, J and Zhang, J and Ye, X and Wang, H and Li, H and Li, W and Wu, H and Zhao, W},
title = {The spleen-brain axis in Alzheimer's disease and related dementias: Integrating immune and metabolic regulation.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {22},
number = {3},
pages = {e71243},
doi = {10.1002/alz.71243},
pmid = {41778859},
issn = {1552-5279},
support = {82575182//National Natural Science Foundation of China/ ; 82374547//National Natural Science Foundation of China/ ; 2022A1515220175//and Basic and Applied Basic Research Foundation of Guangdong Province/ ; },
abstract = {Emerging evidence highlights the central role of peripheral immune-metabolic regulation in the pathogenesis of Alzheimer's disease and related dementias (ADRD). Among peripheral organs, the spleen has gained increasing attention as a critical immune-metabolic hub linking systemic homeostasis to central neurodegeneration. This review systematically elucidates the regulatory functions of the spleen-brain axis from three complementary perspectives: (1) structural remodeling and immunopathological alterations of the spleen in ADRD; (2) spleen-driven immunometabolic crosstalk, which integrates immune function with iron homeostasis, glucolipid metabolism, and amino acid turnover, contributing to the progression of neurodegenerative pathology; and (3) key molecular pathways mediating immune-metabolic crosstalk, such as Toll-like receptor 4 (TLR4)-nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB), NLR family pyrin domain containing 3 (NLRP3) inflammasome, high-mobility group box 1 (HMGB1)-receptor for advanced glycation end-products (RAGE), and Janus kinase/signal transducer and activator of transcription protein (JAK/STAT) signaling. We systematically elucidate how splenic dysfunction drives a positive feedback loop involving systemic inflammation, metabolic disorder, and neuroinflammation. This novel perspective, which views the spleen as an integrated immune-metabolic regulator, highlights spleen-targeted interventions as a potential therapeutic strategy for ADRD.},
}

@article {pmid41778849,
year = {2026},
author = {Sai, I and Grill, JD and Younes, K and Winer, JR and Cody, KA and Sperling, R and Mormino, EC and Young, CB},
title = {Cognitive screening biases in a secondary prevention Alzheimer's disease clinical trial.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {22},
number = {3},
pages = {e71254},
doi = {10.1002/alz.71254},
pmid = {41778849},
issn = {1552-5279},
support = {AARFD-21-849349//Alzheimer's Association/ ; R00AG071837//National Institute of Health/ ; R01AG074339//National Institute of Health/ ; },
abstract = {INTRODUCTION: Alzheimer's disease (AD) prevention trials have multiple steps to identify cognitively unimpaired individuals with AD biomarker evidence. Cognitive/functional screening tests may be biased in ethnoracial minorities, impacting trial eligibility.

METHODS: A total of 6669 participants screened for the Anti-Amyloid Treatment in Asymptomatic Alzheimer's (A4) study were grouped by ethnoracial background and testing language. Ethnoracial/language differences in ineligibility reason, cognitive/functional test performance, and amyloid positivity rates were examined.

RESULTS: Ethnoracial minorities were least likely to meet eligibility criteria. Patterns of incorrect Mini-Mental State Examination items and impaired Clinical Dementia Rating functional domains differed between ethnoracial/language groups, suggesting potential test biases. The Free and Cued Selective Reminding Test yielded more similar exclusion rates across groups than Logical Memory. Cognitive/functional screening biases may impact subsequent biomarker screening as amyloid positivity rates were lowest in ethnoracial minorities.

DISCUSSION: Biases in cognitive/functional screening tests may be contributing to disproportionate exclusion of ethnoracial minorities in AD clinical trials.},
}

@article {pmid41778737,
year = {2026},
author = {Acosta, ML and Zhang, SX and Palacios, AG},
title = {Blood-retinal biomarker integration for precision prevention of Alzheimer's disease: Lessons from retinal aging and the unfolded protein response.},
journal = {Neural regeneration research},
volume = {},
number = {},
pages = {},
doi = {10.4103/NRR.NRR-D-25-01517},
pmid = {41778737},
issn = {1673-5374},
}

@article {pmid41778736,
year = {2026},
author = {Ma, X and Liu, J and Ma, Q and Hu, D and Wang, P and Yang, S and Wang, M and Li, Y and Wang, H and Liang, J and Shao, Y and Zhang, L},
title = {Ephrin and Eph family proteins: Molecular mechanisms of signaling pathways and their role in neural injury repair.},
journal = {Neural regeneration research},
volume = {},
number = {},
pages = {},
doi = {10.4103/NRR.NRR-D-25-01845},
pmid = {41778736},
issn = {1673-5374},
abstract = {Ephrins and Eph family proteins are key intercellular signaling molecules in the nervous system. They regulate processes such as neural development, synaptic plasticity, neural stem cell differentiation, as well as neurodegenerative diseases and neural injury repair through a unique bidirectional signaling mechanism. In recent years, with the deepening of research, the central role of Ephrin and Eph family proteins in the field of neuroscience has gradually emerged, making them a hot topic of study. The purpose of this review is to systematically explore the mechanisms of action of Ephrin and Eph family proteins and their pathways in the nervous system, revealing their critical roles in neural development, functional maintenance, and disease occurrence, while providing theoretical foundations and potential targets for the treatment of neurological disorders. The Ephrin-Eph signaling pathway plays an important role in processes such as neuronal migration, axon guidance, synapse formation and plasticity, and neural stem cell differentiation through a bidirectional signaling mechanism. Abnormalities in this pathway are closely related to the development of neurodegenerative diseases (such as Alzheimer's disease), impairments in neural injury repair, and the progression of neurological tumors. Increasing evidence highlights the core regulatory position and functional complexity of Ephrin and Eph family proteins in the processes of neural injury and repair. The review also discusses the key regulatory roles of Ephrin and Eph family proteins in neuronal migration and positioning, axon guidance, synapse formation and plasticity, as well as their important functions in neural stem cell differentiation, cell adhesion and repulsion balance, and myelin regeneration. Additionally, this review analyzes the emerging roles of Ephrin and Eph family proteins in regulating the inflammatory microenvironment after neural injury, maintaining blood-brain barrier integrity, and facilitating neural function recovery. This review also summarizes the cellular and molecular mechanisms that support these functions, particularly the dynamic regulatory network of Ephrin-Eph bidirectional signaling and its interactions with other signaling pathways, such as Wnt and MAPK. Future research needs to further elucidate the molecular mechanisms of the Ephrin-Eph signaling pathway, develop highly specific small molecule inhibitors, gene therapy, and immunotherapy strategies, and integrate interdisciplinary technologies (such as single-cell multi-omics, optogenetics, and nanotechnology) to promote clinical translation, paving new avenues for precise treatment of neurological diseases.},
}

@article {pmid41778732,
year = {2026},
author = {Xiang, X and Tang, Y and Song, L and Li, Z and Law, BYK},
title = {Ocular-brain co-immunotherapy targeting amyloid-beta in Alzheimer's disease: Challenges and promising therapeutic avenues.},
journal = {Neural regeneration research},
volume = {},
number = {},
pages = {},
doi = {10.4103/NRR.NRR-D-25-01399},
pmid = {41778732},
issn = {1673-5374},
}

@article {pmid41778730,
year = {2026},
author = {Zhang, Y and Jiang, H and Zhang, F and Liao, J},
title = {Targeted nanovesicular delivery of dexmedetomidine modulates microglial lysosomal function via Sirt3 signaling to ameliorate neurodegenerative pathology.},
journal = {Neural regeneration research},
volume = {},
number = {},
pages = {},
doi = {10.4103/NRR.NRR-D-25-00234},
pmid = {41778730},
issn = {1673-5374},
abstract = {Neuroinflammation and lysosomal dysfunction in microglia are increasingly recognized as critical pathological drivers of Alzheimer's disease, yet current anti-inflammatory or neuroprotective agents have limited brain delivery efficiency and cellular specificity. To address these challenges, this study proposes a novel nanotherapeutic paradigm based on extracellular nanovesicles (ENVs) for targeted modulation of microglial function. This research explored the potential of a novel nanotherapeutic platform involving ENVs functionalized with aptamers and encapsulating dexmedetomidine (Dex) to alleviate microglia-associated neuroinflammation in Alzheimer's disease. The effects on microglial lysosomal function, neuroinflammation, and cognitive performance were evaluated in an Alzheimer's disease mouse model. Cholesterol-conjugated PEG 2000 aptamers were used to modify extracellular nanovesicles derived from microglial cells. The nanovesicles (ZH-1c-ENVs) were loaded with Dex using ultrasound-assisted methods. Particle size, morphology, and drug release kinetics were characterized using dynamic light scattering and transmission electron microscopy. In vitro assays assessed microglial cell uptake and cytotoxicity, while in vivo biodistribution was evaluated in a mouse model. Proteomics, western blotting, quantitative reverse transcription-polymerase chain reaction, and immunofluorescence were employed to analyze the effects of ZH-1c-ENVs@Dex on microglial inflammation, lysosomal activity, and amyloid-beta clearance. Cognitive function improvements were assessed using the Morris water maze. ZH-1c-ENVs@Dex achieved efficient drug encapsulation and crossed the blood-brain barrier, delivering Dex selectively to microglial cells. Proteomic analysis revealed activation of the Sirtuin 3 signaling pathway, which reduced microglial inflammation and enhanced lysosomal function. These changes promoted amyloid-beta clearance in vitro and alleviated neuroinflammation in vivo. Treatment significantly improved cognitive performance in Alzheimer's disease mice. The ZH-1c-ENVs@Dex system represents a promising nanomedicine strategy for Alzheimer's disease therapy by modulating Sirtuin 3 activity, restoring microglial function, and improving cognitive outcomes. This study lays the groundwork for clinical translation of aptamer-modified ENVs as precision nanomedicines for neurodegenerative diseases. The ZH-1c-ENVs@Dex system integrates clinically safe components, efficiently traverses the blood-brain barrier, and selectively targets microglia, exhibiting remarkable potential for the treatment of Alzheimer's disease and related neurodegenerative disorders. This scalable and highly biocompatible nanovesicular platform offers a clinically translatable strategy with substantial therapeutic promise for neuroinflammatory and neurodegenerative diseases.},
}

@article {pmid41778726,
year = {2026},
author = {Zhang, C and Bhattacharyya, R},
title = {Targeting sigma receptors for Alzheimer's disease treatment.},
journal = {Neural regeneration research},
volume = {},
number = {},
pages = {},
doi = {10.4103/NRR.NRR-D-25-01574},
pmid = {41778726},
issn = {1673-5374},
}

@article {pmid41778725,
year = {2026},
author = {Rizvi, FAS and Jimoh, Y and Allouh, MZ and Rahmon, D and Chaudhry, GR},
title = {Mesenchymal stem cell therapies for neurodegenerative diseases: Advancements, challenges, and opportunities.},
journal = {Neural regeneration research},
volume = {},
number = {},
pages = {},
doi = {10.4103/NRR.NRR-D-25-01147},
pmid = {41778725},
issn = {1673-5374},
abstract = {Neurodegenerative diseases, including multiple sclerosis, amyotrophic lateral sclerosis, Huntington's disease, retinal degenerative diseases, Alzheimer's disease, and Parkinson's disease, continue to pose a significant clinical challenge due to the progressive loss of neural tissue structure and function. Stem cell-based therapies are gaining attention for the treatment of neurodegenerative diseases. Mesenchymal stem cells, particularly those derived from perinatal tissues, exhibit remarkable plasticity, along with immunomodulatory, neurotrophic, and regenerative capabilities. Mesenchymal stem cells primarily influence their environment through paracrine signaling and can also differentiate into neural lineages, aiding in neuronal repair. Tissue-specific progenitor cells, such as neural stem cells and retinal progenitor cells, offer greater therapeutic precision. This review examines advancements in mesenchymal stem cell-based therapies for neurodegenerative diseases, discusses relevant clinical trials, and highlights the challenges, while proposing that personalized regenerative treatments utilizing lineage-restricted progenitors may improve patient outcomes in these complex disorders.},
}

@article {pmid41778724,
year = {2026},
author = {Lin, B and Chai, L and Zuo, S and Dai, Y and Chen, L and Huang, J},
title = {Electroacupuncture improves spatial learning and memory functions in triple-transgenic Alzheimer's disease model mice by enhancing glutamatergic synapse plasticity in the entorhinal cortex-hippocampal CA1 circuit.},
journal = {Neural regeneration research},
volume = {},
number = {},
pages = {},
doi = {10.4103/NRR.NRR-D-25-00606},
pmid = {41778724},
issn = {1673-5374},
abstract = {Alzheimer's disease is characterized by impairment in episodic memory and visuospatial skills, which is related to the deterioration of glutamatergic synapses within the entorhinal cortex-hippocampal circuit. While electroacupuncture shows therapeutic promise for Alzheimer's disease, its underlying mechanisms remain poorly understood. This study investigated whether the effects of electroacupuncture on spatial memory involves improving synaptic plasticity in this circuit using triple-transgenic Alzheimer's disease mice. The intervention consisted of a 4-week daily electroacupuncture treatment at DU20/DU24 acupoints or sham treatment. Our findings revealed that electroacupuncture triggered a cascade of neuroplastic events, leading to significant cognitive improvements. Crucially, these therapeutic effects were completely abrogated by chemogenetic inhibition of the entorhinal cortex-hippocampal CA1 circuit, establishing its causal necessity. Our multi-level analyses revealed that electroacupuncture attenuated tau hyperphosphorylation, restored dendritic spine density, and boosted long-term potentiation. This was accompanied by an increase in crucial synaptic proteins and activation of the NMDAR-CaMKII-CREB signaling cascade. The key findings of this study reveal a multi-level neurorestorative cascade induced by electroacupuncture, by simultaneously reducing tau pathology, rebuilding synaptic architecture, and enhancing synaptic function in the entorhinal-hippocampal circuit, driven by the NMDAR-CaMKII-CREB pathway. Collectively, these results provide evidence that electroacupuncture ameliorates spatial memory deficits in Alzheimer's disease model mice by specifically enhancing synaptic plasticity in the entorhinal cortex-hippocampal circuit.},
}

@article {pmid41778687,
year = {2026},
author = {Lou, Y and Ma, Y and Xiang, L and Sun, J},
title = {Regression analysis of interval-censored competing risks data with missing causes of failure: A direct likelihood approach.},
journal = {Statistical methods in medical research},
volume = {},
number = {},
pages = {9622802261420820},
doi = {10.1177/09622802261420820},
pmid = {41778687},
issn = {1477-0334},
abstract = {Regression analysis of interval-censored competing risks data is often required and plays an important role in many areas. For the situation, in addition to competing risk and interval censoring, another feature that makes the analysis difficult is that the failure cause may be unknown or missing. Most existing methods for addressing these challenges rely on two-stage estimation procedures, which could suffer efficiency loss and high computational cost. To overcome these, we propose a direct likelihood approach based on a mixture model framework. The proposed method accounts for both competing risks and missingness of event types directly in a likelihood function and facilitates estimation through a sieve maximum likelihood estimation, simplifying the estimation procedure and thus enhancing the estimation efficiency. The consistency and asymptotic normality of the resulting estimators are established, and the idea behind the proposed approach can be extended to other competing risks model frameworks. We demonstrate the promising performance of the proposed method in a comprehensive simulation study and illustrate its practical utility with an application to an Alzheimer's disease study.},
}

@article {pmid41778553,
year = {2026},
author = {Tegethoff, P and Taute, M and Rutt, S and Neziraj, F and Hufnagel, A and Perneczky, R and Kurz, C},
title = {Subjective Cognitive Complaints and Objective Cognitive Performance Across Diagnostic Groups in Memory Clinic Patients: A Cross-Sectional Comparison of the SCD-Q and CFQ Questionnaires.},
journal = {Journal of geriatric psychiatry and neurology},
volume = {},
number = {},
pages = {8919887261429550},
doi = {10.1177/08919887261429550},
pmid = {41778553},
issn = {1552-5708},
abstract = {BackgroundThis study evaluated the diagnostic value and factorial structure of the Subjective Cognitive Decline Questionnaire (SCD-Q) and the Cognitive Failures Questionnaire (CFQ) in the context of early detection of cognitive decline in a memory clinic setting.MethodsA total of 128 patients were included (AD/MCI: n = 50; non-AD dementia: n = 10; mixed dementia: n = 16; subjective cognitive decline [SCD]: n = 21). Participants completed the modified SCD-Q17 and CFQ and underwent standardized cognitive assessment. Principal component and cluster analyses, regression models, and ROC analyses were used to examine psychometric properties and diagnostic performance.ResultsThe SCD-Q17 correlated with objective cognition (CERAD: r = -0.29 to -0.35, P = 0.023-0.005) and differentiated SCD from mixed dementia (AUC = 0.71). The CFQ primarily reflected executive and attentional failures and showed moderate discrimination for non-AD dementia (SCD vs NADD: AUC = 0.67). Cluster analyses identified 2 profiles (impaired vs unimpaired) for both instruments (κ = 0.47). PCA indicated a more redundant structure for the SCD-Q17, whereas the CFQ showed a broader multidimensional structure.ConclusionsRelative to CERAD performance, both questionnaires distinguished cognitively impaired from unimpaired individuals, but neither provided sufficient precision to classify specific clinical entities.},
}

@article {pmid41777739,
year = {2026},
author = {Qian, Y and Kong, W and Wang, S and Wen, G and Yu, Y},
title = {MOMHCA-SG: a multi-head cross-attention and similar graph convolutional network framework for Alzheimer's disease cell type classification.},
journal = {Frontiers in neuroscience},
volume = {20},
number = {},
pages = {1728558},
pmid = {41777739},
issn = {1662-4548},
abstract = {INTRODUCTION: Alzheimer's disease (AD) is a complex neurodegenerative disorder with di-verse cellular and molecular characteristics. Due to its heterogeneous nature, early detection and understanding of AD are challenging, and conventional unimodal approaches often fail to capture the intricate interactions across different biological layers.

METHODS: We propose MOMHCA-SG, a novel multi-omics integration framework that combines a multi-head cross-attention mechanism (MHCA) with a graph convolutional network (GCN) guided by similarity network fusion (SNF). The framework first employs an autoencoder (AE) for dimensionality reduction and feature extraction, followed by MHCA to model inter-omic dependencies. A contrastive learning strategy is then utilized to refine latent representations, while the GCN performs final cell-type classification using fused similarity networks derived from both scRNA-seq and scATAC-seq datasets related to AD.

RESULTS: Extensive experiments on publicly available AD datasets demonstrate that MOMHCA-SG attains superior performance in both integration and classification tasks, achieving an ARI of 0.99, NMI of 0.98, and AMI of 0.98, with classification accuracy exceeding 0.98. Downstream bioinformatics analyses further identify key genes and signaling pathways potentially involved in AD pathogenesis, supporting the framework's biological interpretability.

DISCUSSION: MOMHCA-SG effectively preserves feature integrity during high-dimensional processing, dynamically integrates heterogeneous omics data, and captures cross-modality relationships. These capabilities highlight its potential as a powerful tool for elucidating disease mechanisms and advancing precision medicine in neurodegenerative disorders.},
}

@article {pmid41777674,
year = {2026},
author = {Izydorczak, M and Oumov, M and Udhwani, MV and Fostok, F and Coronas-Samano, G and Sanganahalli, BG and Herman, P and Hyder, F and Verhagen, JV},
title = {Behavioral deficits and exacerbated neural and hemodynamic odor responses during lifespan of a mouse model of late onset Alzheimer's disease expressing humanized APOEε4 and Trem2*R47H.},
journal = {Frontiers in aging neuroscience},
volume = {18},
number = {},
pages = {1622135},
pmid = {41777674},
issn = {1663-4365},
abstract = {Alzheimer's disease (AD) poses a significant global health challenge, being the most prominent cause of dementia with prevalence increasing as the population ages. While the majority of AD cases are late-onset (LOAD), current animal models predominantly represent the more aggressive, faster progressing early-onset AD (EOAD), limiting their ability in assessing early biomarkers and gaining deeper understanding of LOAD progression. This study explores a promising translatable model, the APOE4.TREM2 mouse, which combines the APOE4 allele and the Trem2 p.R47H mutation, both linked to increased AD risk in the human population. We performed behavioral phenotyping and measured hemodynamics and neurovascular coupling in dorsal olfactory bulbs (dOB) during odor stimulation of the APOE4.TREM2 mouse line. Experimental evidence of olfactory dysfunction prior to clinical symptoms suggests the opportunity of utilizing smell testing and fMRI as tools for screening of AD, both for preclinical and clinical studies. Here we assess and confirm the translatability of the APOE4.TREM2 mouse LOAD model, reporting exacerbated anxiety, deficits in odor-based foraging and spatial memory, and exacerbated odor-evoked dOB neural and intrinsic responses, but stable neurovascular coupling, in an age-dependent manner.},
}

@article {pmid41777595,
year = {2025},
author = {Xu, J and Gao, C and Zhang, J and Lu, J and Xuan, Y and Wang, S and Bu, C},
title = {Advancements in Imaging Technologies and AI Integration for Neurodegenerative Disease Management: A Narrative Review.},
journal = {Molecular imaging},
volume = {24},
number = {},
pages = {15353508251393056},
pmid = {41777595},
issn = {1536-0121},
abstract = {BACKGROUND: Neurodegenerative diseases, characterized by progressive neuronal degeneration, are increasingly prevalent due to global aging trends and impose a significant burden on patients. No cure currently exists, with oxidative stress and inflammation serving as key drivers of disease progression. Advances in imaging technologies and artificial intelligence (AI) offer new opportunities for early diagnosis, monitoring, and treatment evaluation. This review aims to summarize the role of advanced neuroimaging modalities and AI integration in improving the diagnosis, monitoring, and management of neurodegenerative diseases, while highlighting current challenges and future directions.

MATERIAL AND METHODS: A narrative review was conducted based on published literature on neuroimaging techniques in neurodegenerative diseases. Key modalities included structural and functional magnetic resonance imaging (MRI, fMRI), diffusion tensor imaging (DTI), positron emission tomography (PET), and single-photon emission computed tomography (SPECT). The integration of AI in image analysis was evaluated for its impact on diagnostic accuracy and workflow efficiency. Sources were selected from peer-reviewed journals focusing on clinical applications, technical advancements, and multimodal imaging strategies. Results Structural MRI, fMRI, and DTI provide detailed insights into brain atrophy and microstructural integrity, while PET and SPECT enable molecular-level assessment of metabolism and pathology. AI-enhanced analysis reduces interpretation variability and improves diagnostic precision. Despite these advances, high costs, limited accessibility, and inter-expert subjectivity remain major barriers. Emerging multimodal approaches and AI-driven tools show promise in enabling earlier detection and personalized treatment monitoring.

CONCLUSION: The integration of advanced imaging and AI holds transformative potential for neurodegenerative disease management. Future efforts should prioritize cost reduction, improved accessibility, and seamless multimodal data fusion to translate these technologies into routine clinical practice.},
}

@article {pmid41777513,
year = {2026},
author = {Özmen, SG and Harı, E and Kurt, E and Gürvit, H and Demiralp, T},
title = {The Relationship of Modulation Generated in Brain Intrinsic Connectivity Networks by Simple Sensory Stimuli and Cognitive Performance.},
journal = {Noro psikiyatri arsivi},
volume = {63},
number = {},
pages = {192-200},
pmid = {41777513},
issn = {1300-0667},
abstract = {INTRODUCTION: This study aimed to investigate the modulation of simple sensory stimuli on brain intrinsic connectivity networks in the Alzheimer's disease continuum (ADC) using functional magnetic resonance imaging (fMRI).

METHODS: fMRI and neuropsychological assessment data of 88 cases in ADC were analysed. fMRI data were recorded in a session including blocks of light stimuli flickering at 20 Hz frequency and in the resting state from 21 Alzheimer's disease dementia (ADD), 34 mild cognitive impairment (MCI) and 33 subjective cognitive impairment (SCI). CONN (functional connectivity toolbox) software was used for functional connectivity analyses of fMRI data. Bonferroni correction was applied according to the number of ROIs in functional connectivity analyses and the significance threshold was determined as pFWE <0.0033.

RESULTS: As a result of the analysis of the resting state data, decreased connectivity was detected between the posterior cingulate cortex seed of the default mode network and the temporal and parietal areas in ADD compared to the SCI and MCI groups. Decreased functional connectivity was detected between the anterior insula and anterior cingulate cortex seeds of the salience network and the temporal, frontal and cingulate cortices in ADD compared to the SCI and MCI groups. However, in the data of flickering light stimulation at a frequency of 20 Hz, increased functional connectivity was detected between the right lateral prefrontal cortex seed of the frontoparietal network, which could not be captured with the resting state data, and the precuneus in the MCI group compared to the SCI group.

CONCLUSIONS: The increase in connectivity between the frontoparietal network and precuneus may be a compensatory response in the early stages of the disease. In addition, it was thought that fMRI images performed using simple sensory stimuli were more sensitive to cognitive decline in the early stages of the disease compared to resting state data and could have biomarker potential.},
}

@article {pmid41777449,
year = {2026},
author = {Yue, J and Zhang, J and Wang, X and Shi, Y},
title = {Robust Topographical Representation for Longitudinal Propagation of Tau Pathology.},
journal = {Medical image computing and computer-assisted intervention : MICCAI ... International Conference on Medical Image Computing and Computer-Assisted Intervention},
volume = {15971},
number = {},
pages = {584-593},
pmid = {41777449},
abstract = {Tau pathology is a hallmark of Alzheimer's disease (AD), and longitudinal tau positron emission tomography (PET) provides valuable insights into disease progression. However, the integration of tau PET data into computational models remains limited by challenges in encoding topographical information and ensuring longitudinal consistency. Existing biomarker-based representations often lack spatial flexibility and fail to account for covariance between brain regions. Additionally, traditional approaches often treat longitudinal scans as independent observations, neglecting temporal coherence. To address these limitations, we propose a novel Multiresolutional Reeb Graph representation that encodes the spatiotemporal propagation of tau topographical information. Our method constructs Reeb graphs to capture tau topography at a static time point and extends them into a multiresolutional framework to model disease evolution. We introduce a topology-based measurement for quantifying pathology spatial distribution similarity, and a severity interleaving distance for robust longitudinal staging. The efficiency of the proposed representation is validated in two downstream tasks: an integrated subtyping and staging system, and the longitudinal pathology prediction. The promising results compared with the current methods demonstrate the great potential of the proposed representation to enhancing the application of longitudinal tau PET data, and offering a reliable approach for studying AD progression.},
}

@article {pmid41777448,
year = {2026},
author = {Zhang, H and Nie, X and Yue, J and Li, Y and Ringman, J and Shi, Y},
title = {GPU Accelerated Modeling of Cortical Radial and Tangential Connectivity Changes in Neurodegeneration.},
journal = {Medical image computing and computer-assisted intervention : MICCAI ... International Conference on Medical Image Computing and Computer-Assisted Intervention},
volume = {15971},
number = {},
pages = {342-351},
pmid = {41777448},
abstract = {The diffusion MRI signals in the human cerebral cortex are strongly associated with neurodegenerative diseases. Although models like NODDI have been extensively used to characterize cortical microstructure degeneration, they fall short in capturing detailed, orientation-specific connectivity changes within the cortex. In this study, we introduce a method to decompose cortical tissue diffusion signal to radial and tangential components. Our approach uses data from multi-shell diffusion imaging and combines it with anatomical information from brain surfaces. By applying a GPU accelerated probabilistic optimization framework, we can accurately and efficiently estimate these diffusion components while keeping the results smooth and consistent with the cortical anatomy. We test our method on data from HCP subjects and a clinical dataset of patients with autosomal dominant Alzheimer's Disease (ADAD) subjects. Our results demonstrate that the proposed method can more effectively reveal cortical gray matter connectivity changes related to tau pathology than metrics from the NODDI model. Our codebase is publicly available at https://github.com/Haibaobob/FOD-ctx-decomp.},
}

@article {pmid41777445,
year = {2025},
author = {Sreenivasmurthy, SG and Budhwani, SM and Mohanty, S and Villarreal, ME and Shah, P and John, SK and Natarajan, C and Ramaswamy, K and Sheth, K and Wong, E and Phan, PC and Lopez, JL and Gill, SK and Currie, J and Garza, K and Limon, A and Green, TA and Krishnan, B},
title = {PLD1-Dependent Regulation of Synaptic Integrity: Implications for Cognitive Resilience and Alzheimer's Disease Pathogenesis.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.64898/2025.12.08.692971},
pmid = {41777445},
issn = {2692-8205},
abstract = {Dysregulation of Phospholipase D1 (PLD1) has been implicated in the progression of neurodegenerative diseases, including Alzheimer's Disease (AD). This study investigated PLD1 signaling in synaptic integrity and cognition during aging and in a late-onset AD mouse model, hypothesizing differential effects of PLD1 modulation on synaptic vulnerability. AAV2-mediated gene transfer was employed to overexpress (PLD1 OXP) or attenuate (PLD1 ATT) PLD1 in aged wild-type (WT) and 3xTg-AD mice. To validate these constructs, differentiated PC12 cells were utilized. Within these cells, a model of post-mitotic neurons, PLD1 OXP exhibited a notable reduction in both the average neurite length and the percentage of neurite-bearing cells. This suggests that elevated PLD1 activity exerts a significant influence on neurite outgrowth. Conversely, PLD1 ATT did not inhibit neurite formation, indicating it is not detrimental at the cellular level. These cellular findings paralleled in vivo observations - electrophysiological studies revealed PLD1 OXP impaired long-term potentiation (LTP) and synaptic transmission, particularly in aged WT mice, whereas PLD1 ATT improved synaptic function in 3xTg-AD mice. Behaviorally, PLD1 ATT enhanced spatial working memory and reduced anxiety-like behavior, notably in 3xTg-AD mice. These results highlight that tight PLD1 regulation is vital for maintaining synaptic integrity and cognitive resilience. Thus, PLD1 attenuation may serve as an important complement to immunotherapeutic approaches by strengthening synaptic resilience in neurodysfunctional states, including AD and related dementia (ADRD).},
}

@article {pmid41777158,
year = {2025},
author = {Pinna, G and Bortolato, M},
title = {The role of neuroactive steroids in psychiatric and neurological disorders: Neurobiology and therapeutic perspectives.},
journal = {Neuroscience and biobehavioral reviews},
volume = {179},
number = {},
pages = {106438},
doi = {10.1016/j.neubiorev.2025.106438},
pmid = {41777158},
issn = {1873-7528},
abstract = {Neuroactive steroids, encompassing both peripherally derived hormones and neurosteroids synthesized de novo within the central nervous system, have emerged as pivotal modulators of brain physiology and pathology. This rapidly evolving field is transforming our understanding of how steroid signaling influences neural function, paving the way for novel biomarkers and targeted therapeutic strategies. Acting on specific neuronal receptors, these compounds finely regulate excitability, synaptic integration, and network dynamics, thereby linking endocrine and neural mechanisms in the maintenance of brain homeostasis. Over the past three decades, these mediators have been shown to exert broad influences on neurotransmitter systems, the hypothalamic-pituitary-adrenal (HPA) axis, and neuroinflammatory pathways. Mounting evidence implicates both neurosteroids and peripheral neuroactive steroids in the pathophysiology of numerous psychiatric and neurological disorders, including depression, bipolar disorder, anxiety disorders, PTSD, schizophrenia, autism spectrum disorder, substance use disorders, epilepsy, Alzheimer's disease, Parkinson's disease, tic disorders, and multiple sclerosis. This review synthesizes current evidence on how neurosteroids (and, more broadly, neuroactive steroids) contribute to the endogenous regulation of neural excitability, affective reactivity, and immune signaling, and explores how their dysregulation may represent a shared mechanism of vulnerability across diverse brain disorders. Finally, we highlight emerging therapeutic opportunities, underscored by recent advances such as zuranolone and ganaxolone, and discuss future challenges in optimizing delivery, enhancing receptor specificity, and refining clinical trial design to establish neurosteroid-based interventions as a versatile platform for treating and preventing complex neuropsychiatric disease.},
}

@article {pmid41777041,
year = {2026},
author = {Kumari, K and Bai, A and Geeta, F and Wadhwani, N and Kumar, R and Kumar, A and Kumari, R and Bai, L and Muskan, F and Kashish, F and Yousafzai, M},
title = {Risk of Dementia in Patients With Type 2 Diabetes Using SGLT2 Inhibitors Versus DPP-4 Inhibitors: A Systematic Review and Meta-Analysis.},
journal = {Endocrinology, diabetes & metabolism},
volume = {9},
number = {2},
pages = {e70174},
doi = {10.1002/edm2.70174},
pmid = {41777041},
issn = {2398-9238},
abstract = {BACKGROUND: Type 2 diabetes mellitus (T2DM) is a known risk factor for dementia, yet the cognitive impact of different glucose-lowering therapies remains unclear. Emerging evidence suggests sodium-glucose cotransporter-2 (SGLT2) inhibitors may confer neuroprotective benefits compared to dipeptidyl peptidase-4 (DPP-4) inhibitors.

OBJECTIVE: To compare the risk of incident dementia among patients with T2DM initiating SGLT2 inhibitors versus DPP-4 inhibitors.

METHODS: A systematic search of PubMed, Scopus, and the Cochrane Central Register of Controlled Trials was conducted through June 1, 2025. The primary outcome was all-cause dementia. Secondary outcomes included Alzheimer's disease and vascular dementia. Random-effects models were used to pool adjusted hazard ratios (HRs), and subgroup analyses explored heterogeneity by age, sex, and specific SGLT2 agents.

RESULTS: Nine retrospective cohort studies encompassing 2,433,086 individuals (601,692 SGLT2i users; 1,831,394 DPP-4i users) met inclusion criteria. SGLT2 inhibitors were associated with a significantly lower risk of all-cause dementia (HR = 0.74; 95% CI: 0.62-0.87), Alzheimer's disease (HR = 0.62; 95% CI: 0.52-0.74), and vascular dementia (HR = 0.54; 95% CI: 0.49-0.60) compared to DPP-4 inhibitors. Subgroup findings were largely consistent across age and sex. Dapagliflozin and empagliflozin showed significant benefit, while canagliflozin did not.

CONCLUSION: Use of SGLT2 inhibitors is significantly associated with lower dementia risk compared to DPP-4 inhibitors in patients with T2DM. Prospective trials are warranted to confirm these findings and explore underlying mechanisms.},
}

@article {pmid41776966,
year = {2026},
author = {Jeran, LC and Blawert, A and Grünewald, A and Staack, S and Jannes, A and Thyrian, JR},
title = {Views on dementia among informal caregivers of people with dementia: A scoping review and thematic analysis of qualitative studies.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261420210},
doi = {10.1177/13872877261420210},
pmid = {41776966},
issn = {1875-8908},
abstract = {BackgroundAlzheimer's disease is common in later life and affects the person with dementia as well as their family. As the disease progresses, declining functions of activities of daily living increase dependence on relatives for support, who can become caregivers.ObjectiveTo summarize the current state of knowledge regarding caregivers' views on Alzheimer's disease and other types of dementia, and to identify overarching themes.MethodsWe conducted a scoping review using PRISMA guidelines. Inclusion criteria were: a) qualitative studies or qualitative sections of mixed-methods studies about views on dementia among informal caregivers, b) publication between 2013 and 2023, c) publication in a peer-reviewed journal, d) English or German language. The search was carried out in five scientific databases (MEDLINE, PsycInfo, PSYNDEX, CINHAL, Web of Science). Information on authors, years, settings, participants, aims, methods, type of analysis, and results were extracted. Using reflexive thematic analysis, themes of views on dementia reported in the given articles were summarized.ResultsWe identified 42 relevant studies reporting views on dementia in informal caregivers and constructed seven themes: "Dementia as natural cognitive decline", "Dementia as caregiver burden", "Dementia as stigmatized experience", "Dementia as transition in relationship dynamics", "Dementia as uncertainty", "Dementia as enriching experience" and "Dementia as self-inflicted vs. externally determined".ConclusionsViews on dementia among informal caregivers encompass complex, multi-dimensional attitudes and perceptions warranting a nuanced dementia discourse and offering various starting points for interventions. "Dementia as transition in relationships dynamics" emerged as an especially important topic requiring more attention in dementia research.},
}

@article {pmid41776730,
year = {2026},
author = {Lim, S and Lee, Y},
title = {Longitudinal analysis of hippocampal subfield atrophy and network centrality associated with cognitive decline in Alzheimer's disease progression.},
journal = {Medical physics},
volume = {53},
number = {3},
pages = {e70379},
doi = {10.1002/mp.70379},
pmid = {41776730},
issn = {2473-4209},
support = {RS-2024-00354252//National Foundation of Korea/ ; },
abstract = {BACKGROUND: Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by structural degeneration of the hippocampus. Previous studies have demonstrated that specific hippocampal subfields, such as the cornu ammonis (CA)1 and the subiculum, are susceptible to AD-related atrophy. However, most previous studies have focused on cross-sectional volumetric changes without investigating the interrelationships between subfields or their network-level functions throughout the disease progression.

PURPOSE: To examine the longitudinal volumetric changes in the hippocampal subfields over 2 years in individuals who progressed from mild cognitive impairment (MCI) to AD. In addition, we aimed to investigate the associations between cognitive decline, inter-region structural correlation, and network-based centrality profiles of subfields based on atrophy covariance and changes in subfield volume.

METHODS: T1-weighted magnetic resonance images of 258 participants who progressed from MCI to AD were obtained from the Alzheimer's Disease Neuroimaging Initiative. Hippocampal subfield volumes were extracted at baseline and during follow-up using FreeSurfer's longitudinal pipeline (v7.4.1). The subfield volume changes were examined using the paired-t tests. Cognitive decline was measured as the percentage change in the Mini-Mental State Examination (MMSE) scores. The partial Pearson's correlations between subfield volume changes and MMSE change were calculated after adjusting for baseline age, sex, education level, and apolipoprotein ε4 status. A structural covariance network was constructed using inter-subfield partial correlations. Four graph-theoretical centrality measurements (degree, betweenness, closeness, and eigenvector) were computed from the network to identify structurally central subfields.

RESULTS: Most hippocampal subfields demonstrated important volume decreases over 2 years, with the left fimbria, subiculum head, and dentate gyrus head showing the most atrophy. The left hippocampus showed significantly greater volume decreases than the right hippocampus. Volume changes in the left presubiculum body, the CA3 head, and the dentate gyrus head were strongly correlated with MMSE decline. Notably, structured covariance patterns between anatomically and functionally relevant subfields within the CA1-CA3-CA4-dentate gyrus axis and subiculum complex were found by inter-regional analysis. Network-based analysis identified the left CA1 head and left dentate gyrus head as central hubs across all four-centrality metrics. Other subfields, including the left subiculum head and left molecular layer head, also showed high centrality in several respects, indicating their possible coordinating functions in hippocampal degeneration.

CONCLUSIONS: This study provides a comprehensive longitudinal analysis of hippocampal subfield atrophy, inter-regional co-atrophy patterns, and network centrality during MCI-to-AD progression. Our findings demonstrate that several subfields, including the left CA1 and dentate gyrus, are structurally and functionally central in the hippocampal atrophy network. The integration of volumetric, correlation-based, and graph theory-based approaches offers new insights into the coordinated degeneration of the hippocampus in AD, emphasizing the importance of subfield-level network dynamics in understanding the disease progression.},
}

@article {pmid41746390,
year = {2026},
author = {Kural, I and M Mombeek, LM and Wilson, DM},
title = {Role of mitochondria in neuronal function and survival in the enteric and central nervous systems.},
journal = {Cellular and molecular life sciences : CMLS},
volume = {83},
number = {1},
pages = {},
pmid = {41746390},
issn = {1420-9071},
support = {11P4G24N//Fonds Wetenschappelijk Onderzoek/ ; G0A9625FWO//Fonds Wetenschappelijk Onderzoek/ ; },
abstract = {UNLABELLED: Mitochondria are indispensable organelles that not only generate cellular energy through oxidative phosphorylation but also regulate calcium homeostasis, redox balance, and apoptotic signaling. Given the high metabolic demands of neurons, mitochondrial function and resilience mechanisms are essential for neuronal development, maturation, and survival; when these systems fail, pathological outcomes can arise. This review highlights the critical role of mitochondria in maintaining neuronal function, with discussion related to both the central (CNS) and enteric (ENS) nervous systems. We present how mitochondrial dysfunction, through impaired bioenergetics, oxidative stress, defective quality control, and altered dynamics, can drive neuronal cell loss. Furthermore, we highlight the link between mitochondrial defects and nervous system pathological outcomes in both primary mitochondrial disorders, such as mitochondrial neurogastrointestinal encephalomyopathy, and secondary mitochondrial disorders, such as Alzheimer, Parkinson, and Huntington disease, as well as amyotrophic lateral sclerosis. By integrating evidence from the CNS and ENS, this review highlights the central role of mitochondria in supporting and preserving neuronal health, as well as the potential of mitochondria as therapeutic targets in neurodegenerative disease.

GRAPHICAL ABSTRACT: [Image: see text]},
}

@article {pmid41776683,
year = {2026},
author = {Shin, H and Lee, S and Seo, W and Yoon, SH and Cho, I and Ye, S and Park, I and Yoon, S and Park, M and Kim, S and Lee, S and Kim, HY and Kim, I and Kim, Y},
title = {YIAD-0501 directly dissociates aggregates of full-length and N-terminal pyroglutamate-modified forms of Aβ.},
journal = {Alzheimer's research & therapy},
volume = {},
number = {},
pages = {},
doi = {10.1186/s13195-026-01999-5},
pmid = {41776683},
issn = {1758-9193},
support = {RS-2018-NR031048//Basic Science Research Program, National Research Foundation of Korea (NRF), Ministry of Health & Welfare and Ministry of Science and ICT, Republic of Korea/ ; RS-2018-NR031048//Basic Science Research Program, National Research Foundation of Korea (NRF), Ministry of Health & Welfare and Ministry of Science and ICT, Republic of Korea/ ; RS-2018-NR031048//Basic Science Research Program, National Research Foundation of Korea (NRF), Ministry of Health & Welfare and Ministry of Science and ICT, Republic of Korea/ ; RS-2025-00523607//Mid-Career Researcher Program, Ministry of Health & Welfare and Ministry of Science and ICT, Republic of Korea/ ; RS-2021-NR059653//Mid-Career Researcher Program, Ministry of Health & Welfare and Ministry of Science and ICT, Republic of Korea/ ; RS-2024-00349158//Ministry of Health & Welfare and Ministry of Science and ICT, Republic of Korea/ ; RS-2024-00418203//Korea Institute for Advancement of Technology/ ; },
}

@article {pmid41776672,
year = {2026},
author = {Ishiguro, T and Kurihara, M and Nishida, Y and Kikkawa-Saito, E and Kasuga, K and Takenoshita, N and Kubota, S and Kuroha, Y and Ishii, K and Hamada, M and Sanjo, N and Ishikawa, K and Nojima, H and Kamada, J and Aoyagi, K and Shimizu, S and Murakami, H and Takahashi, T and Onodera, O and Iwatsubo, T and Yamada, M and Yokota, T and Iwata, A and Ikeuchi, T},
title = {Prospective study on clinical utility of plasma p-Tau217 and other biomarkers in Japanese memory clinics using the LUMIPULSE platform.},
journal = {Alzheimer's research & therapy},
volume = {},
number = {},
pages = {},
doi = {10.1186/s13195-026-01997-7},
pmid = {41776672},
issn = {1758-9193},
support = {JP25dk0207070//Japan Agency for Medical Research and Development/ ; JP25dk0207070//Japan Agency for Medical Research and Development/ ; },
}

@article {pmid41776603,
year = {2026},
author = {Lin, Y and Shi, Y and Chen, L and Chen, Z and Zhong, H and Zhong, Y and Zeng, R and Chen, X and Lin, F and Cai, G},
title = {Consumption of coffee and tea and the risk of developing neurodegenerative diseases: a cohort study in the UK biobank.},
journal = {Nutrition journal},
volume = {},
number = {},
pages = {},
doi = {10.1186/s12937-026-01291-0},
pmid = {41776603},
issn = {1475-2891},
support = {2022Y2005//Clinical Research Center for Precision Diagnosis and Treatment of Neurological Diseases of Fujian Province/ ; },
abstract = {BACKGROUND: Coffee and tea are among the most consumed drinks worldwide. Increasing evidence indicates an association between coffee or tea intake and neurodegenerative diseases. However, most studies have focused on the association of coffee or tea alone; studies on the interactive associations between coffee and tea and neurodegenerative diseases are few. Therefore, this study aimed to explore the individual or interactive associations between coffee and tea intake and neurodegenerative diseases and their various subtypes.

METHODS: This study included 134,425 participants without neurodegenerative diseases at baseline in UK Biobank. A total of 6483 participants developed neurodegenerative diseases during a median follow-up time of 13.5 years. The median daily coffee intake was two cups, and the median daily tea intake was three cups. A restricted cubic spline was used to explore the nonlinear associations between coffee or tea intake and neurodegenerative diseases. The individual or interactive associations between coffee and tea intake and neurodegenerative diseases were assessed using the Cox proportional-hazards model.

RESULTS: An individual association was noted between coffee or tea intake and neurodegenerative diseases. A significant J-shaped association was found between coffee intake and all-cause neurodegenerative diseases (Pnonlinear = 0.004) and vascular neurodegenerative diseases (Pnonlinear = 0.023), with increased risk at higher consumption. Moreover, a nonlinear association was observed between tea intake and all-cause neurodegenerative diseases (Pnonlinear = 0.004), vascular neurodegenerative diseases (Pnonlinear = 0.031), other neurodegenerative diseases (Pnonlinear = 0.002), and vascular dementia (VD) (Pnonlinear = 0.026). Furthermore, a significant interactive association was noted between coffee and tea intake among all-cause neurodegenerative diseases (Pinteraction = 0.004); Further, this interaction was also observed in Alzheimer's disease (AD) (Pinteraction = 0.006).

CONCLUSIONS: Excessive coffee consumption was significantly associated with an increased risk of all-cause neurodegenerative diseases and vascular neurodegenerative diseases. The results also showed that tea intake was associated with a reduced risk of all-cause neurodegenerative disease, vascular neurodegenerative disease, other neurodegenerative diseases, and VD. Moreover, coffee and tea had an interactive relationship with all-cause neurodegenerative diseases and AD, with specific combinations significantly associated with reduced risk of disease onset.},
}

@article {pmid41776543,
year = {2026},
author = {Uzoechi, SC and Campbell, CJ and Badeaux, CJ and Kwak, SS and Kim, DY and Yun, Y},
title = {Recapitulating Alzheimer's disease pathophysiology with a microfluidic neurospheroid-grafted endothelial barrier model.},
journal = {Molecular brain},
volume = {},
number = {},
pages = {},
doi = {10.1186/s13041-026-01285-3},
pmid = {41776543},
issn = {1756-6606},
support = {A069137//Cure Alzheimer's Fund/ ; 1R01AG082093-01/NH/NIH HHS/United States ; 1UG3EB036466-01/NH/NIH HHS/United States ; 2429044//National Science Foundation/ ; },
abstract = {BACKGROUND: Traditional two-dimensional (2D) models do not adequately capture the complex cellular interactions, brain-specific architecture, and progressive pathology of Alzheimer's disease (AD). Three-dimensional (3D) organoid and microfluidic technologies provide more physiologically relevant platforms for studying AD-associated neurovascular dysfunction.

METHODS: We developed a membrane-free microfluidic endothelial barrier model integrated with neurospheroids derived from familial AD (FAD) neural progenitor cells. Human endothelial cells were cultured within perfusable microfluidic channels to establish a vascular-like interface rather than a fully specialized BBB endothelium. Pre-differentiated neurospheroids were grafted into the brain chamber. Endothelial barrier integrity, tight-junction expression, phosphorylated tau (pTau), and Aβ42/Aβ40 production and distribution between compartments were assessed using immunofluorescence imaging and ELISA.

RESULTS: The neurospheroid-grafted endothelial barrier construct captured key AD-associated phenotypes. ReN-AD-D4 models exhibited increased endothelial barrier permeability, reduced ZO-1 expression, and elevated pTau relative to controls. The platform supported endogenous Aβ generation, accumulation, and endothelial-associated deposition at the endothelial barrier. ELISA demonstrated differential Aβ42 and Aβ40 distribution, consistent with isoform-selective behavior reported in AD pathology. Collectively, these results indicate co-occurring neuronal and endothelial barrier alterations within the integrated 3D system.

CONCLUSION: This microfluidic endothelial barrier-neurospheroid platform enables quantitative assessment of amyloid-β accumulation, spatial distribution, and compartmentalized secretion alongside tau pathology and endothelial barrier integrity changes. Integrating human endothelial monolayers with FAD-derived neurospheroids, the system is scalable and compatible with high-content imaging. Although it does not model BBB-specific transport mechanisms, it provides a robust framework for hypothesis-driven studies of neurovascular interactions and therapeutic screening applications.},
}

@article {pmid41776457,
year = {2026},
author = {Tang, Y and Yang, R and Zhang, M and Zhou, C and Chen, M and Pan, H and Qin, Y and Gui, Y and Fan, G},
title = {Classifying drug-related problems of neurodegenerative diseases in the physician-pharmacist joint clinic of neurology: an application of the PCNE method.},
journal = {BMC geriatrics},
volume = {},
number = {},
pages = {},
doi = {10.1186/s12877-026-07234-y},
pmid = {41776457},
issn = {1471-2318},
support = {22QA1411400//Shanghai Science and Technology Development Funds/ ; 81973289//National Natural Science Foundation of China/ ; },
}

@article {pmid41775989,
year = {2026},
author = {He, Y and Mockett, BG and Schoderboeck, L and McDonald, KO and Logan, BJ and Sateesh, S and Jones, OD and Hughes, SM and Abraham, WC},
title = {Virus-mediated gene transfer of soluble amyloid precursor protein-alpha via systemic injection in a mouse model of Alzheimer's disease.},
journal = {Gene therapy},
volume = {},
number = {},
pages = {},
pmid = {41775989},
issn = {1476-5462},
support = {16-597//Manatu Hauora | Health Research Council of New Zealand (HRC)/ ; 16-597//Manatu Hauora | Health Research Council of New Zealand (HRC)/ ; 16-597//Manatu Hauora | Health Research Council of New Zealand (HRC)/ ; 16-597//Manatu Hauora | Health Research Council of New Zealand (HRC)/ ; 16-597//Manatu Hauora | Health Research Council of New Zealand (HRC)/ ; },
abstract = {Alzheimer's disease (AD) is the most common neurodegenerative disorder, yet effective preventive or therapeutic strategies remain limited. A hallmark of AD pathology is the accumulation of insoluble amyloid-β (Aβ) aggregates, which are targeted by recent antibody-based therapies. Conversely, soluble amyloid precursor protein-alpha (sAPPα), a non-amyloidogenic cleavage product of APP, possesses neuroprotective, neurotrophic, and synaptogenic properties, and the ability to enhance memory. This study evaluated the therapeutic efficacy of adeno-associated virus variant PHP.eB (AAV-PHP.eB) encoding human sAPPα in the APPswe/PS1dE9 transgenic mouse model of AD. Six-month-old female wild-type and transgenic mice received a single intravenous injection via the tail vein. Three months post-injection, brain tissue was harvested for electrophysiological and histological analyses. The treatment significantly increased cortical sAPPα levels and fully restored hippocampal long-term potentiation (LTP) in transgenic mice. Post-mortem analyses revealed a substantial reduction in amyloid plaque burden in both the hippocampus and cortex, with minimal plaque progression from the time of injection. However, no significant changes were observed in astrocytic (GFAP) or microglial (Iba-1) coverage, nor in soluble and insoluble Aβ1-40 or Aβ1-42 levels. These findings suggest that systemic AAV-PHP.eB-mediated sAPPα delivery can ameliorate synaptic dysfunction and aggregated amyloid pathology in AD, highlighting its potential as a therapeutic strategy.},
}

@article {pmid41775954,
year = {2026},
author = {Hwang, G and Lee, SH and Han, SW and Yang, Y and Lee, S and Kim, Y and Kim, Y and Park, RW},
title = {Longitudinal association of chronic periodontitis with all-cause dementia, Alzheimer disease, vascular dementia, and mild cognitive impairment: a distributed network analysis.},
journal = {GeroScience},
volume = {},
number = {},
pages = {},
pmid = {41775954},
issn = {2509-2723},
support = {2120240615426//National Research Foundation of Korea/ ; RS-2024-00335936//Korea National Institute of Health/ ; },
abstract = {Chronic periodontitis (CPO) is prevalent among older adults and may elevate dementia risk. Evidence regarding its association with dementia subtypes and the effect of disease progression remains unclear. This study aimed to assess the relationship between CPO and dementia development, including subtypes, and evaluated whether the clinical course modifies this risk. Electronic health records of patients aged ≥ 60 years from six institutions were analyzed. A 10-year longitudinal analysis assessed the incidence of all-cause dementia, Alzheimer disease (AD), vascular dementia (VaD), and a composite outcome of all dementia or mild cognitive impairment (MCI). After propensity score stratification, hazard ratios (HRs) with 95% confidence intervals (CIs) were estimated using Cox proportional hazards models. Institutional results were pooled by meta-analysis. Sensitivity analyses using 5-year lag periods and subgroup analyses by surgical treatment or tooth extraction after CPO diagnosis were performed. Among 19,421 patients with CPO and 860,383 without, 24,173 cases of all-cause dementia were identified. CPO was associated with increased risk of all-cause dementia (HR: 1.51; 95% CI: 1.42-1.60), AD (HR: 1.57; 95% CI: 1.45-1.70), VaD (HR: 1.60; 95% CI: 1.39-1.85), and dementia or MCI (HR: 1.55; 95% CI: 1.47-1.64). These associations persisted across lag periods. Among patients with CPO, those who underwent surgical treatment had higher dementia risk than those without (HR: 1.71 vs. 1.45; p = 0.045). Tooth extraction was also linked to increased risk (HR: 1.75 vs. 1.44; p = 0.008). CPO was associated with elevated dementia risk across subtypes. The higher risk observed among patients undergoing surgical treatment or tooth extraction suggests that the severity of chronic periodontitis is related to cognitive decline. These findings underscore the importance of oral health management in dementia prevention among older adults.},
}

@article {pmid41775741,
year = {2026},
author = {Gervasoni, J and Di Maio, A and Serra, M and Cicchinelli, M and Santucci, L and Ciasca, G and Nuzzo, T and Li, Q and Thiolat, ML and Morelli, M and Urbani, A and Errico, F and Bezard, E and Usiello, A},
title = {Ultra-performance liquid chromatography-mass spectrometry analysis of post-mortem brain tissue reveals specific amino acid profile dysregulation in Parkinson's disease and Alzheimer's disease patients.},
journal = {NPJ Parkinson's disease},
volume = {},
number = {},
pages = {},
doi = {10.1038/s41531-026-01306-x},
pmid = {41775741},
issn = {2373-8057},
support = {PRIN 2022 - COD. 2022XF7YYL_02//Ministry of University and Research/ ; project MNESYS (PE0000006) - A Multiscale integrated approach to the study of the nervous system in health and disease//NEXTGENERATIONEU (NGEU) and funded by the Ministry of University and Research (MUR), National Recovery and Resilience Plan (NRRP)/ ; },
abstract = {Previous metabolomic studies have reported significant alterations in circulating amino acids in Parkinson's disease (PD). However, it remains unclear whether these changes reflect central nervous system pathology or are restricted to peripheral metabolism. To address this issue, here we measured the levels of a panel of amino acids in post-mortem brain samples from MPTP-intoxicated monkeys, with and without L-DOPA treatment, and from PD patients at different Braak Lewy body (LB) stages through targeted UPLC-MS. In untreated MPTP monkeys, the putamen showed significant increases in glutamate, aspartate, GABA, phenylalanine, branched-chain amino acids, and serine. L-DOPA treatment further altered this profile, increasing glycine, threonine, and citrulline levels. In contrast, no amino acid changes were detected in the superior frontal gyrus (SFG) of MPTP monkeys, regardless of treatment. In PD patients, caudate-putamen analysis revealed consistent serine upregulation at Braak LB stages 3-4 and 6, with stage 6 additionally showing increased proline and reduced phosphoethanolamine. No amino acid changes were observed in the PD SFG, whereas Alzheimer's disease SFG samples showed marked amino acid increases. Together, these findings demonstrate region-specific amino acid dysregulation in PD, preferentially affecting nigrostriatal targets and supporting disease-specific metabolic signatures across neurodegenerative disorders.},
}

@article {pmid41775699,
year = {2026},
author = {Chen, HJ and Guo, Y and Huang, W and Zhang, K and Liu, T and Chen, F},
title = {Stage-Dependent mediation of white matter hyperintensities between plasma biomarkers and cognitive function in Alzheimer's disease.},
journal = {Translational psychiatry},
volume = {},
number = {},
pages = {},
doi = {10.1038/s41398-026-03927-5},
pmid = {41775699},
issn = {2158-3188},
abstract = {White matter hyperintensities (WMHs) are common in Alzheimer's disease (AD) and may contribute to cognitive impairment. However, the associations between regional WMH volumes, cognitive domains, and plasma biomarkers remain unclear. This study aimed to explore these relationships across the AD spectrum. A total of 311 participants were enrolled, including healthy controls (HC), individuals with subjective cognitive decline (SCD), mild cognitive impairment (MCI), and AD. All participants underwent comprehensive neuropsychological assessment, brain magnetic resonance imaging, and plasma biomarker analysis. WMH volumes were segmented using United Imaging software and classified based on anatomical location: juxtaventricular WMH (juxWMH), periventricular WMH (pWMH), juxtacortical WMH (jcWMH), and deep WMH (dWMH). Correlations among regional WMH volumes, plasma biomarkers, and cognitive domains were analyzed with multiple comparisons. Path analysis was used to assess potential mediation effects. Mediation analyses using bootstrapping were conducted separately in cognitively unimpaired and cognitively impaired groups to assess WMH-mediated pathways between biomarkers and cognition. Compared with HC, SCD, and MCI groups, the AD group showed significantly increased log-transformed (lg) juxWMH volumes (all P < 0.05, Bonferroni corrected). The AD group showed significantly larger lgpWMH and lgjcWMH volumes than HC, SCD and AD groups (all P < 0.05). Lower plasma Aβ42/Aβ40 ratio was associated with higher lgjuxWMH, lgpWMH, and lgjcWMH volumes. Higher lgjuxWMH volume was associated with worse memory (r = -0.16, P = 0.006), language (r = -0.34, P < 0.001), and executive function (r = 0.18, P = 0.003). Similar trends were found for lgpWMH and lgjcWMH volumes. Mediation analysis revealed that in cognitively unimpaired individuals, juxWMH and pWMH primarily mediated amyloid-cognitive associations, while in cognitively impaired patients, mediation expanded to include neuroinflammatory and neurodegeneration pathways across multiple location-specific WMH. Location-specific WMH demonstrate stage-dependent mediation patterns in AD pathophysiology, evolving from amyloid-driven changes to multi-factorial processes. These findings provide insights for developing targeted therapeutic strategies at different disease stages.},
}

@article {pmid41775686,
year = {2026},
author = {Oatman, SR and Reddy, JS and Atashgaran, A and Wang, X and Min, Y and Quicksall, Z and Vanelderen, F and Carrasquillo, MM and Liu, CC and Yamazaki, Y and Nguyen, TT and Heckman, M and Zhao, N and DeTure, M and Murray, ME and Bu, G and Kanekiyo, T and Dickson, DW and Allen, M and Ertekin-Taner, N},
title = {Integrative epigenomic landscape of Alzheimer's Disease brains reveals oligodendrocyte molecular perturbations associated with tau.},
journal = {Nature communications},
volume = {17},
number = {1},
pages = {},
pmid = {41775686},
issn = {2041-1723},
support = {RF1 AG051504/AG/NIA NIH HHS/United States ; U01 AG046139/AG/NIA NIH HHS/United States ; R01 AG061796/AG/NIA NIH HHS/United States ; U19 AG074879/AG/NIA NIH HHS/United States ; P50AG016574//U.S. Department of Health & Human Services | NIH | National Institute on Aging (U.S. National Institute on Aging)/ ; R37AG027924//U.S. Department of Health & Human Services | NIH | National Institute on Aging (U.S. National Institute on Aging)/ ; },
abstract = {Alzheimer's disease (AD) brains have variable neuropathologic and biochemical changes. Capturing epigenetic factors associated with this variability can reveal novel biological insights into AD pathophysiology. Here, we conduct an epigenome-wide association study of DNA methylation in 472 AD brains with neuropathologic and biochemical brain protein levels core to AD pathogenesis. Using a novel regional methylation (rCpGm) approach, we identify 5478 significant associations, 99.7% of which associate with tau biochemical measures, and 93 concordant associations in external datasets. Transcriptome-methylome integration reveals enrichment in oligodendrocyte genes, including known AD risk gene BIN1, myelination genes MYRF, MBP and MAG previously implicated in AD, and novel genes like LDB3. Further characterization of these perturbations in independent AD and primary tauopathy datasets highlights consistent tau-related associations. In summary, we uncover the integrative epigenomic landscape of AD, demonstrate tau-related oligodendrocyte gene perturbations as a common potential pathomechanism across tauopathies and share findings via our Multiomic Atlas.},
}

@article {pmid41775656,
year = {2026},
author = {Yari Eili, M and Hajialiasgari, F and Roozbahani, MH and Rezaeenour, J and Shafiee Sabet, M and Mohammadi, S and Atashi, A},
title = {Analysis of Patients' Mobility Patterns: Insights From a Process Mining-Based Longitudinal Study.},
journal = {Inquiry : a journal of medical care organization, provision and financing},
volume = {63},
number = {},
pages = {469580261422675},
doi = {10.1177/00469580261422675},
pmid = {41775656},
issn = {1945-7243},
abstract = {Patient mobility is a crucial indicator in healthcare resource allocation and improvement. This mobility is due to the uneven distribution of healthcare facilities in its provincial sense. The objective here is to designate the Alzheimer's disease patients' mobility patterns in Iran. Through this longitudinal study, by applying process mining techniques on the 28 425 physician office visits recorded in the Salamat Health Insurance (SHI) database between 2019 and 2023, the inter-provincial patient mobility patterns across Iran are revealed. Based on the extracted knowledge about the most essential care flows, patient mobility patterns in provinces with the highest rates of trajectories are constructed, a task that traditional statistical methods cannot assess in healthcare. The inter-provincial process model of patients with the highest count of out-of-province patient mobility (more than 50%) is attributed to Ilam, Alborz, Sistan, and North and South Khorasan provinces; though, Tehran, Alborz, and Isfahan provinces are the preferred medical destinations for 70% of AD treatment. The provinces with the lowest count of patient mobility are Qom, Yazd, Fars, Gilan, Isfahan, Eastern Azerbaijan, and Khorasan Razavi, with rates <1%. The potential of process mining techniques in addressing new problems in healthcare services and the integration between the 2 disciplines is introduced here to better understand their contribution to the health industry. The top provinces with the highest counts of referrals from other provinces (eg, Tehran, Alborz, and Isfahan) have also a high count of the specialist share. Consequently, efforts should be made to promote a rational balance in medical resource allocation throughout provinces nationwide, thereby eliminating the monopolistic status of a particular province.},
}

@article {pmid41775642,
year = {2026},
author = {Pin, G and Horowitz, T and Guedj, E and Felician, O and Ceccaldi, M and Koric, L},
title = {Isolated medial temporal lobe amnesia (MTLA): Predictor of cerebral amyloidosis or marker of phenotype-specific vulnerability?.},
journal = {Revue neurologique},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.neurol.2026.02.149},
pmid = {41775642},
issn = {0035-3787},
abstract = {BACKGROUND: Medial temporal lobe amnestic syndrome (MTLA) is classically considered a hallmark of Alzheimer's disease (AD). However, emerging evidence suggests etiological heterogeneity, challenging the assumption that MTLA universally reflects AD pathology.

OBJECTIVE: To determine the prevalence of amyloid pathology in isolated MTLA, identify phenotypic and genetic risk factors, and characterize associated network vulnerabilities in amnestic mild cognitive impairment (aMCI).

METHOD: This retrospective observational study analyzed 55 patients with isolated MTLA at the aMCI stage. Participants underwent neuropsychological testing, cerebrospinal fluid (CSF) biomarker analysis, amyloid PET, and 18FDG-PET. Patients were stratified by amyloid status (positive/negative) and compared for APOE genotype, clinical features, and metabolic patterns. Statistical analyses included the Kruskal-Wallis test for non-parametric group comparisons and chi-square tests for categorical genetic associations.

RESULTS: Amyloid pathology was observed in only 67% (37/55) of MTLA patients, dissociating the syndrome from AD in one-third of cases. Amyloid-positive patients demonstrated a significantly higher APOE ɛ4 carrier rate compared to amyloid-negative peers (χ[2]=7.02, df=2, P=0.030), while 18FDG-PET revealed inferotemporal hypometabolism in amyloid-positive cases, marking early decontextualized memory impairment.

CONCLUSION: MTLA syndrome is not homogeneous on the biological level and amyloid pathology and APOE ɛ4 genotype stratify patients into distinct subgroups. Amyloid-positive cases demonstrate inferotemporal hypometabolism, suggesting AD-related network vulnerability. By contrast, amyloid-negative MTLA group shows no systemic brain network vulnerabilities, likely due to its heterogeneous etiological origins. These findings advocate for a precision medicine framework integrating biomarkers to guide therapeutic strategies, moving beyond syndromic diagnoses to target underlying mechanisms.},
}

@article {pmid41775631,
year = {2026},
author = {Valdivia, G and Moreno, C and He, K and Contreras, D and Tran, T and Ramnaugh, AD and Xu, W and Contreras, A and Fernandez, DC and Severin, D and Hattar, S and Gallagher, M and Kirkwood, A},
title = {Circadian changes in CA1 LTP are driven by shifts in excitation-inhibition balance and reverse direction after puberty in mice.},
journal = {The Journal of neuroscience : the official journal of the Society for Neuroscience},
volume = {},
number = {},
pages = {},
doi = {10.1523/JNEUROSCI.2244-25.2026},
pmid = {41775631},
issn = {1529-2401},
abstract = {Long-term potentiation (LTP), the best-characterized form of Hebbian synaptic plasticity, is well known to be under strong circadian regulation. In mice and rats, both nocturnal species, most studies indicate that LTP in the hippocampal CA1 region is more robust when induced during the dark phase. Our examination of the underlying mechanisms at the CA3-CA1 synapse in mice of all sexes indicates that the capacity to support LTP does not differ between the light and dark phases of the 24-hour day. Instead, the magnitude of theta-burst stimulation-induced LTP (TBS-LTP) correlates with daily fluctuations in the ratio of synaptic excitation to inhibition (E/I ratio): both the E/I ratio and TBS-LTP are higher during the dark phase. On the other hand, LTD induced with low-frequency stimulation did not change across the circadian cycle. Consistent with a causal relationship between the E/I ratio and TBS-LTP, blockade of inhibition abolishes the light-dark difference in TBS-LTP induction. Likewise, pairing-induced LTP, which is not constrained by inhibitory recruitment, does not differ between cycles. Supporting this model, in the APP/PS1 model of AD we found that neither the E/I ratio nor TBS-LTP varies across the light-dark cycle, despite preserved circadian regulation of locomotor activity. Finally, we made the intriguing observation that these daily oscillations reverse direction after puberty in WT mice, shifting from being larger in the dark cycle of 2-month-old mice to being larger in the light cycle in 8-month-old mice. This developmental switch may reflect an age-dependent reorganization of circadian control over hippocampal plasticity.Significance statement Long-term potentiation (LTP) is strongly shaped by circadian rhythms and is typically greater during the dark phase in nocturnal rodents. At the CA3-CA1 synapse, we find that the intrinsic capacity to support LTP is similar across light and dark periods; instead, multiple independent lines of evidence indicate that a daily oscillation in excitation-inhibition (E/I) balance is the primary drivers of the circadian changes in LTP induction. Notably, in the APP/PS1 model of Alzheimer's disease, neither the E/I ratio nor TBS-LTP varies across the day. Finally, we identify a developmental switch in which the direction of these oscillations reverses between two and eight months of age, highlighting an age-dependent reorganization of circadian regulation of hippocampal plasticity in both health and disease.},
}

@article {pmid41775373,
year = {2026},
author = {Katakami, S and Kanemoto, H and Taomoto, D and Satake, Y and Suehiro, T and Sato, S and Yoshiyama, K and Kashibayashi, T and Takahashi, R and Tagai, K and Shinagawa, S and Ishii, K and Kazui, H and Ikeda, M},
title = {White Matter Hyperintensities and Neuropsychiatric Symptoms in Neurodegenerative Diseases.},
journal = {Journal of clinical neurology (Seoul, Korea)},
volume = {22},
number = {2},
pages = {183-192},
doi = {10.3988/jcn.2025.0408},
pmid = {41775373},
issn = {1738-6586},
support = {JP21dk0207056/AMED/Japan Agency for Medical Research and Development/Japan ; },
abstract = {BACKGROUND AND PURPOSE: Neuropsychiatric symptoms (NPS) are frequent in dementia and mild cognitive impairment (MCI), yet their reported associations with white matter hyperintensities (WMHs) remain inconsistent. We examined item-level associations between WMHs and NPS across Alzheimer's disease dementia (ADD), dementia with Lewy bodies (DLB), and amnestic MCI (aMCI).

METHODS: This multicenter retrospective study involved 523 patients: 276 with ADD, 67 with DLB, and 180 with aMCI. Three-dimensional T1-weighted and T2-fluid-attenuated inversion recovery magnetic resonance images were processed with BAAD (Brain Anatomical Analysis using Diffeomorphic Deformation) software to quantify WMH volume (WMHV) and gray matter volume (GMV), normalized to total intracranial volume (TIV). NPS were assessed using the Neuropsychiatric Inventory. Multiple regression analyses were performed within each group, adjusting for GMV/TIV, age, sex, years of education, Clinical Dementia Rating-Sum of Boxes score, and institution.

RESULTS: In the aMCI group, higher WMHV/TIV was positively associated with depression, apathy, and disinhibition, and negatively with delusions. Subregional analyses revealed NPS-specific topographic patterns. No significant associations were detected in the ADD or DLB group. GMV/TIV was positively associated with delusions in the ADD group, but negatively associated with hallucinations in the DLB group.

CONCLUSIONS: Associations between WMHs and NPS were evident in the aMCI group but absent in the ADD and DLB groups, suggesting a stage-dependent effect. WMHs may contribute to NPS primarily in prodromal stages, whereas their influence may be overshadowed by neurodegenerative pathology in dementia. Clarifying the mechanisms underlying WMHs is critical for evaluating their potential as intervention targets.},
}

@article {pmid41775372,
year = {2026},
author = {Lee, JY and Lee, M and Lim, JS and Oh, MS and Yu, KH and Kim, YE and Ma, HI and Kim, YJ and Park, JH and Jung, YH},
title = {Early Onset, High Comorbidity Burden, and Regional Disparities of CADASIL: A Nationwide Cohort Study in South Korea.},
journal = {Journal of clinical neurology (Seoul, Korea)},
volume = {22},
number = {2},
pages = {173-182},
doi = {10.3988/jcn.2025.0373},
pmid = {41775372},
issn = {1738-6586},
support = {2205-09-01//Myongji Hospital/Korea ; RS-2023-00262527/NRF/National Research Foundation of Korea/Korea ; },
abstract = {BACKGROUND AND PURPOSE: To compare the epidemiological and clinical features of the rare patients with cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) with age- and sex-matched controls in a nationwide cohort from South Korea.

METHODS: This observational cohort study analyzed newly diagnosed CADASIL patients aged at least 20 years and matched controls using data from the National Health Information Database for 2004-2022. The cumulative incidence of CADASIL was assessed by age and sex, and compared between regions. Neurologic and systemic diseases were compared between the CADASIL and control groups.

RESULTS: The study analyzed 816 CADASIL patients and 816 age- and sex-matched controls aged 56.8±15.2 years (mean±standard deviation), among whom 48.3% were male. The cumulative incidence of CADASIL was 1.86 per 100,000 people (95% confidence interval [CI]=1.85-1.87 per 100,000), and peaked at 60-69 years of age. In terms of regional distribution, the incidence was highest for Jeju, at 39.67 per 100,000 (95% CI 37.84-41.49 per 100,000). Neurologic diseases were more frequent in CADASIL patients, including Alzheimer's disease (33.1% vs. 20.0%), vascular dementia (84.9% vs. 5.0%), epilepsy (34.6% vs. 15.9%), stroke (70.7% vs. 27.6%), parkinsonism (18.9% vs. 11.0%), and depression (60.8% vs. 44.9%). Systemic diseases such as diabetes mellitus (78.9% vs. 68.9%) were also more common in CADASIL patients, while cancer (27.9% vs. 38.7%) and myocardial infarction (10.0% vs. 13.6%) were less common than in controls. The onset ages of all diseases were lower in CADASIL patients.

CONCLUSIONS: This study has provided a precise nationwide estimate of the CADASIL incidence and its regional distribution in South Korea. CADASIL patients showed higher incidence rates and earlier onsets of diverse clinical manifestations.},
}

@article {pmid41775321,
year = {2026},
author = {Lu, YH and Zhu, XP and Li, S and Zhang, FN and Cai, CB and Tian, M and Zhu, YH and Zeng, LH and Tan, J and Yu, CY and Chen, J},
title = {From scaffold to effector: reframing GFAP in neurodegeneration.},
journal = {Journal of advanced research},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.jare.2026.02.051},
pmid = {41775321},
issn = {2090-1224},
abstract = {BACKGROUND: Neurodegenerative disorders impose a growing global burden, yet disease-modifying therapies remain limited. Glial fibrillary acidic protein (GFAP) has shifted from a passive astrocytic marker to an active effector shaping neurodegenerative pathology.

AIM: of Review: This review synthesizes mechanistic and translational evidence that defines GFAP as a proteoform-governed hub and highlights its value for biomarker-guided precision intervention. Key Scientific Concepts of Review: An extensive literature search across major databases was conducted using predefined keywords and strict inclusion criteria, covering mechanistic, pathological, and clinical studies. Evidence supports a GFAP proteoform code in which alternative splicing generates functionally distinct isoforms and PTMs encode context-dependent assembly dynamics and signaling outputs. We summarize how GFAP proteoforms integrate cytoskeletal remodeling with inflammatory transcriptional programs (notably STAT3 and NF-κB), proteostasis stress, and mitochondrial dysfunction, thereby coupling astrocyte state transitions to neuronal vulnerability and synaptic impairment. Disease trajectories are context specific: GFAP dysfunction drives primary toxicity in Alexander disease (AxD); in Alzheimer's disease (AD), isoform-specific mechanisms intersect with amyloidogenic machinery and track early preclinical astrocyte activation; and in frontotemporal dementia (FTD), Parkinson's disease (PD) and amyotrophic lateral sclerosis (ALS), GFAP reflects inflammatory-metabolic coupling during progression. Translationally, ultrasensitive plasma assays reveal GFAP elevation years to decades before symptom onset, complementing NfL and amyloid/tau within AT(N)-oriented diagnostic frameworks. Therapeutically, we evaluate precision strategies beyond global suppression, including ASO-based modulation, targeting STAT3/NF-κB-driven reactive programs, and restoring proteostasis via chaperone/autophagy pathways. Future progress hinges on isoform-/PTM-specific probes, conformational sensors, and spatial proteomic atlases validated in prospective longitudinal cohorts. In conclusion, GFAP represents both a mechanistic driver and a scalable biomarker, offering a translationally actionable axis to advance precision medicine in neurodegeneration.},
}

@article {pmid41775152,
year = {2026},
author = {Yang, M and Xia, Q},
title = {Clarifying the clinical and methodological boundaries of plasma and salivary p-Tau181 in Alzheimer's disease.},
journal = {Journal of the neurological sciences},
volume = {483},
number = {},
pages = {125834},
doi = {10.1016/j.jns.2026.125834},
pmid = {41775152},
issn = {1878-5883},
}

@article {pmid41775065,
year = {2026},
author = {Esmaeili, A and Dashtian, K and Zare-Dorabei, R and Kerman, K and Mahdavi, M},
title = {A tri-responsive sensor based on co-encapsulated organic probes and multifunctional bimetallic V/Ce-MOF nanozyme in a hydrogel for the detection of l-Serine in saliva.},
journal = {Talanta},
volume = {305},
number = {},
pages = {129594},
doi = {10.1016/j.talanta.2026.129594},
pmid = {41775065},
issn = {1873-3573},
abstract = {Rapid and accurate detection of l-Serine, a key potential biomarker of neurological diseases such as Alzheimer, Parkinson and Amyotrophic lateral sclerosis (ALS) disease, is crucial for public health. Herein, we prepared a tri-responsive sensor capable of colorimetric, fluorimetric, and electrochemical detection. This portable sensor integrates co-encapsulated organic probes with a multifunctional bimetallic cerium/vanadium metal-organic framework (UiO-66-NH2(Ce/V)) nanozyme activity, all embedded within a biocompatible agarose-based hydrogel for detection of l-serine in a saliva sample. Physicochemical and electrochemical analyzes confirmed that the UiO-66-NH2(Ce/V) nanozyme, with peroxidase-like activity, facilitated the oxidation of tetramethylbenzidine (TMB) in the colorimetric assay, ortho-phenylenediamine (OPD) in the fluorometric assay and TMB in the electrochemical assay. The oxidation of these probes resulted in the formation of colored compounds in the colorimetric and fluorometric sensors, as well as created sharp anodic peaks in the electrochemical sensors via Vmax of 3.99 M[-1], 5.85 M[-1] and 0.002 M[-1], respectively. The results prove that increasing the concentration of l-serine inhibited the oxidation-reduction reactions, causing a reduction in the intensity of both the colors and the sensor peaks. It demonstrated a wide linear detection range of 5 to 250 μM for the colorimetric sensor, 1-250 μM for the fluorometric sensor, and 0.3-250 μM for the electrochemical sensor with a detection limit of 0.27 μM, 0.26 μM, and 0.076 μM, respectively. These sensors were applied to the detection of l-serine in human saliva samples, achieving recovery rates between 92.20% and 107.50% with RSD of <5%, and excellent reproducibility. The findings suggest that these sensors have significant potential for use in hospitalized healthcare systems to monitor disease biomarkers and represent a promising approach for early diagnosis of disease.},
}

@article {pmid41775023,
year = {2026},
author = {Kinchin, I and Conlon, J and Boland, E and Fitzpatrick, R and Leroi, I and Coast, J},
title = {Self-reporting quality of life in mild-to-moderate Alzheimer's disease and Lewy body dementia: Comparing capability and health-focused measures using response process validation.},
journal = {Social science & medicine (1982)},
volume = {396},
number = {},
pages = {119102},
doi = {10.1016/j.socscimed.2026.119102},
pmid = {41775023},
issn = {1873-5347},
abstract = {BACKGROUND: Capability measures offer theoretical advantages for assessing wellbeing in health economics and outcomes research, yet their feasibility for self-reporting by people living with dementia remains to be established. This exploratory study compares the feasibility of self-reporting on capability versus health-focused quality of life measures among people living with mild-tomoderate dementia, using response process validation.

METHODS: Twenty-three community-dwelling participants living with Alzheimer's disease (n = 11) or Lewy body dementia (n = 12) completed four measures using concurrent think-aloud cognitive interviewing: two capability measures (ICECAP-O, ICECAP-SCM) and two health-focused measures (QoL-AD, and AQoL-4D). Errors were coded using Tourangeau's four-stage response model (comprehension, retrieval, judgement, response). Completion times, support requirements, and error patterns were compared across measures and diagnostic groups.

RESULTS: Capability measures showed higher error rates (13.7-18.3%) than health-related measures (5.1-8.4%) despite shorter completion times. Comprehension errors (51.2% of all errors) were most common across all measures, particularly for abstract concepts like dignity and doing things that make you feel valued. Retrieval errors were rare (4.9%), suggesting memory is not the primary barrier. Diagnostic groups showed distinct error profiles. Participants living with Lewy body dementia showed higher rates of comprehension errors (57.4% vs 42.9%), whilst participants living with Alzheimer's disease showed more response-selection difficulties (25.7% vs 14.9%).

CONCLUSIONS: While self-reporting remains feasible in mild-to-moderate Alzheimer's disease and Lewy body dementia, capability measures pose greater cognitive demands than health-focused measures, primarily due to comprehension of abstract concepts and distinguishing capability from functioning rather than memory retrieval. Measures should be validated for specific dementia subtypes, and hybrid approaches anchoring capability judgements in concrete experiences warrant exploration. This exploratory study provides preliminary response process validity evidence to inform measure selection in dementia research and clinical practice, ensuring people living with dementia can meaningfully participate in health economics and policy decisions that affect their care.},
}

@article {pmid41774666,
year = {2026},
author = {Fu, Y and Zhu, W and Wang, Z},
title = {MLC-GCN: Multi-Level Generated Connectome Based GCN for AD Detection.},
journal = {IEEE transactions on bio-medical engineering},
volume = {PP},
number = {},
pages = {},
doi = {10.1109/TBME.2026.3670101},
pmid = {41774666},
issn = {1558-2531},
abstract = {Resting state fMRI (rsfMRI) is widely used to differentiate Alzheimer's Disease (AD) and identify biomarkers but its obscure features and noises challenge the present models. Brain graph convolution network (GCN) provides a good interpretation but suffers from the inferior performance due to the insufficient feature representation. Population GCN improves the precision of detection by involving the phenotypic information but fails in the bio logical interpretation. The GCN taking a single generated connectome as input focuses only on the low-level inter regional temporal correlation and is incapable to exploit hierarchical spatial functional features. In this paper, we propose a multi-level connectome-generated GCN (MLC GCN) to enhance the feature extraction for the individual connectome. First, we construct multiple connectomes in parallel through stacked spatiotemporal feature extractors (STFEs), effectively enhancing the hierarchical features and reducing the noise. Each generated connectome is then input into the GCN for further feature extraction, and the output of all GCNs is concatenated for a multilayer percep tron to predict AD. We use independent cohort validations ontwomedicaldatasetsADNIandOASIS-3,andexperiment results demonstrate MLC-GCN obtains better performance for differentiating normal control, mild cognitive impairment and AD than current GCN architectures and other AD classifiers. The proposed MLC-GCNrevealshighinterpreta tion in terms of learning clinically reasonable connectome nodes and connectivity features.},
}

@article {pmid41774485,
year = {2026},
author = {Ptomey, LT and Helsel, BC and Montgomery, RN and Washburn, RA and Sherman, JR and Szabo-Reed, AN and Vidoni, ED and Gorczyca, AM and Bodde, A and Clina, JG and Williams, KN and Donnelly, JE},
title = {Effectiveness of a Remote Physical Activity Intervention in Individuals with Alzheimer's Disease and their Caregivers: Results from a Randomized Trial.},
journal = {Medicine and science in sports and exercise},
volume = {},
number = {},
pages = {},
doi = {10.1249/MSS.0000000000003974},
pmid = {41774485},
issn = {1530-0315},
abstract = {PURPOSE: Individuals with Alzheimer's disease and related dementias (ADRD) and their caregivers often experience reduced physical activity (PA), diminished functional fitness, and heightened health risks. Remotely delivered PA interventions may offer scalable and accessible solutions. This study compared a 6-month, group-based dyadic PA program delivered via real-time videoconferencing (RGV) with an enhanced usual care (EUC) condition on changes in moderate-to-vigorous physical activity (MVPA) and functional fitness among dyads consisting of individuals with ADRD and their caregiver.

METHODS: Dyads were randomized to either the RGV or EUC arm. Both arms received wearable activity trackers and twice-monthly individualized support. The RGV group additionally participated in live, thrice-weekly group exercise sessions via videoconference. Outcomes included accelerometer-assessed MVPA and standardized measures of functional fitness.

RESULTS: Ninety-nine dyads enrolled, with 90% retention at 6 months. Mean session attendance in the RGV arm was 74% for individuals with ADRD and 69.5% for caregivers. Neither group significantly increased daily MVPA, and there were no significant between-group differences in changes in daily MVPA or sedentary time (all p > 0.05). However, significant within-group improvements occurred in upper-body strength (arm curls) and aerobic capacity (2-minute step test) for both individuals with ADRD and caregivers (all p < 0.05). Compared with EUC, the RGV group showed greater improvements in aerobic capacity among individuals with ADRD (β = 8.97, p = 0.04) and in both arm curls (β = 1.67, p = 0.02) and aerobic capacity (β = 11.3, p < 0.001) among caregivers.

CONCLUSIONS: Although MVPA did not increase in the RGV arm, both individuals with ADRD and caregivers demonstrated clinically meaningful gains in functional fitness, supporting the feasibility and benefit of remote dyadic PA programs.},
}

@article {pmid41774419,
year = {2026},
author = {Bahmani, M and Marvi, H and Khosravi, H and Abolghasemi, V},
title = {A CNN-transformer fusion for EEG-based discrimination of Alzheimer's and frontotemporal dementia.},
journal = {Physical and engineering sciences in medicine},
volume = {},
number = {},
pages = {},
pmid = {41774419},
issn = {2662-4737},
abstract = {Dementia is a progressive neurodegenerative disorder that severely impacts cognitive functions and daily living, especially in aging populations. Among its subtypes, Alzheimer's disease (AD) and frontotemporal dementia (FTD) exhibit overlapping clinical symptoms, making early and accurate differentiation a critical challenge. Electroencephalography (EEG), as a non-invasive and cost-effective modality, provides valuable insights into the neurophysiological disruptions associated with these conditions. This study aims to develop a robust EEG-based diagnostic framework capable of accurately classifying AD, FTD, and healthy controls (HC) by integrating domain-specific signal processing with advanced deep learning techniques. This study employed a publicly accessible dataset consisting of resting-state EEG recordings from a total of 88 participants, comprising 29 individuals with AD, 23 diagnosed with FTD, and 36 age-matched HC. The proposed model integrates Common Spatial Pattern (CSP) filtering with a sequential modified hybrid architecture that combines Convolutional Neural Networks (CNNs) and a Vision Transformer (ViT). By fusing domain-informed spatial filtering with deep hierarchical feature learning, the model captures both local signal characteristics and global contextual dependencies. A 10-fold cross-validation approach was employed to assess model performance and generalizability. The proposed model achieved notable classification accuracies of 95.86%, 94.76%, 94%, and 92.14% for the AD/HC, FTD/HC, AD/FTD, and AD/FTD/HC classification tasks, respectively. These results underscore the diagnostic potential of EEG-based deep learning frameworks in distinguishing among neurodegenerative conditions and highlight their promise in supporting more precise and individualized clinical interventions. This study presents a novel end-to-end EEG classification pipeline that fuses domain-guided spatial filtering with deep neural feature learning. The promising results suggest that the proposed method could serve as a valuable component in future clinical decision support systems for dementia, contingent upon further validation in real-world clinical settings.},
}