@article {pmid41957682,
year = {2026},
author = {Huang, Y and Guo, J and Yao, F and Feng, B and Gong, D and Dang, K and Hu, T and Deng, S and Liu, Y and Tan, C and Wang, J},
title = {Integrating single-cell and spatial transcriptomics to reveal the spatiotemporal dynamics of retinal cells during ischemia-reperfusion injury progression in rats.},
journal = {Cell & bioscience},
volume = {16},
number = {1},
pages = {},
pmid = {41957682},
issn = {2045-3701},
abstract = {UNLABELLED: Retinal ischemia–reperfusion (I/R) injury is a key pathological process in retinal-associated diseases such as glaucoma. However, the spatiotemporal dynamics and cell interactions during this injury are not fully understood. This study integrated single-cell RNA sequencing and spatial transcriptomics to map retinal cell responses in a rat I/R injury model at acute, subacute, and chronic stages. We identified 14 cell populations and tracked gene expression changes over time. Retinal ganglion cells (RGCs) showed activation of apoptotic, autophagic, and oxidative stress pathways within 24 h. Spatial analysis revealed RGCs co-localized with Müller glial and microglial cells in the optic nerve and inner retina, with RGC death driven by ligand-receptor interactions (e.g., Ncam1-Ncam1, App-Sorl1). Transcription factors (Sox9/Sox8) in Müller cells regulated TNF/JAK-STAT signaling, while Alzheimer’s-related Mapt exhibited spatiotemporal specificity in RGCs, suggesting shared neurodegenerative pathways. This study constructed a panoramic spatiotemporal dynamic map of retinal I/R injury progression, providing important clues for the development of potential therapeutic targets for glaucoma and related retinal diseases.

SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s13578-026-01571-6.},
}

@article {pmid41963962,
year = {2026},
author = {Li, Y and Wu, H and Yang, J and Weedor, JG and Ding, H and Cui, W and Cui, B and He, Z and Zhang, W and Xing, Y and Zeng, F and Huang, X and Zheng, K and Shen, Y and Yu, Y and Pan, W and Yang, X},
title = {Clostridium butyricum ameliorates Toxoplasma gondii-induced neuropsychiatric disorders by attenuating glial-mediated synaptic pruning via the gut-brain axis.},
journal = {Journal of neuroinflammation},
volume = {23},
number = {1},
pages = {},
pmid = {41963962},
issn = {1742-2094},
support = {Nos. 202310313083Y//the Training Programs of innovation and Entrepreneurship for College Students in Jiangsu Province/ ; Nos. X202510313020//the Training Programs of innovation and Entrepreneurship for College Students in Jiangsu Province/ ; Nos. X202510313017//the Training Programs of innovation and Entrepreneurship for College Students in Jiangsu Province/ ; No. JC20250007//the Faculty Development Grant of Basic Medical Sciences in Xuzhou Medical University/ ; Nos. 82372283//the National Natural Science Foundation of China/ ; No. QL-YB022//the XZHMU-QL Joint Research Fund/ ; No. 2022M710120//China Postdoctoral Science Foundation/ ; },
abstract = {UNLABELLED: Gut microbiota dysbiosis contributes to Toxoplasma gondii (T. gondii)-induced neuropsychiatric disorders (TNDs); however, the underlying mechanisms remain largely elusive. Here, we identified the critical role of butyrate-producing bacteria in TNDs in mice. Decreased abundance of butyrate-producing bacteria was consistently observed in patients with Alzheimer’s disease and T. gondii-infected mice. Dietary supplementation with Clostridium butyricum (C. butyricum), a gut commensal butyrate-producing bacterium, reversed gut microbiota dysbiosis, ameliorated intestinal barrier disruption and inflammation, and reduced endotoxemia. Coincidentally, C. butyricum administration suppressed microglial and astrocytic activation, rescued synaptic ultrastructure damage and synaptic loss, thus alleviating cognitive impairment and anxiety/depression-like behaviors. Mechanistically, C. butyricum treatment mitigated the abnormal synaptic pruning mediated by glial cells and C1q to prevent the neuropathology induced by T. gondii infection. Importantly, fecal microbiota transplantation from C. butyricum-supplemented mice into antibiotic-treated recipients recapitulated the therapeutic effects on gut and brain pathology observed in infected mice. Together, our findings suggest that C. butyricum ameliorates TNDs by modulating glial cell-mediated abnormal synaptic pruning via the gut-brain axis, highlighting the therapeutic potential efficacy of butyrate-producing bacteria against TNDs.

SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s12974-026-03761-y.},
}

@article {pmid41964003,
year = {2026},
author = {Bohannon, DG and Geller, A and Simmons, SK and Cintron, JA and Martenis, WE and Stalnacker, K and Masse, A and Kwon, MJ and Zhang, YL and Levin, JZ and Kunwar, PS and Sheng, M},
title = {Impaired removal of dying brain cells by microglia in Gpr34 deficient mice.},
journal = {Journal of neuroinflammation},
volume = {23},
number = {1},
pages = {},
pmid = {41964003},
issn = {1742-2094},
abstract = {UNLABELLED: GPR34, a G protein-coupled receptor present selectively in microglia and other myeloid cells, is highly expressed in homeostatic microglia but is downregulated in disease associated microglia (DAM) such as those found in Alzheimer’s disease brain. However, little is known about GPR34’s role in microglia function or brain development. Here, we studied Gpr34 knockout (KO) mice at postnatal 18-day (P18) and 3 months (3 mo) age. In the brains of P18 Gpr34 KO mice, there were elevated numbers of neurons, oligodendrocytes and microglia, many of which were IHC-positive for the cell death markers cleaved-caspase 3, phospho-RIP3, or annexin V. P18 KO animals showed a reduced localization of microglia in areas of high cell death, while the increased evidence of cell death way largely resolved in 3 mo animals. While the uptake of bacterial particles was not impacted ex-vivo, KO microglia showed increased intracellular accumulation of endogenous cargo, myelin basic protein (MBP) and synaptosomal-associated protein 25 (SNAP25), suggesting altered handling of apoptotic debris without a global phagocytic defect. Notably, transcriptomic analysis revealed persistent impact of immune pathways even at 3 months, at the stage where KO mice also displayed sustained hypolocomotion. Collectively, these results indicate that murine Gpr34 contributes to early clearance of dying cells and may influence a long-lasting impact on microglia state and behavior.

SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s12974-026-03777-4.},
}

@article {pmid41987206,
year = {2026},
author = {Zheng, M and Li, M and Liu, S and Guan, R and Liu, X},
title = {RNA-binding proteins: a comprehensive review of multifaceted regulatory mechanisms in neuroinflammation and implications in the pathogenesis of neurological disorders.},
journal = {Journal of neuroinflammation},
volume = {23},
number = {1},
pages = {},
pmid = {41987206},
issn = {1742-2094},
support = {82230063//National Natural Science Foundation of China/ ; },
abstract = {Neuroinflammation stands as a cornerstone pathological hallmark across a spectrum of neurological disorders, drawing intensified scientific scrutiny owing to its profoundly intricate and multi-layered regulatory networks. At the heart of this complexity, RNA-binding proteins (RBPs) emerge as masterful post-transcriptional orchestrators, exerting precise control over a vast array of neuroinflammatory cascades. Mounting evidence underscores that RBPs transcend their classical roles in RNA sensing and innate immune recognition, actively shaping pivotal biological pathways—ranging from inflammatory signal transduction and programmed cell death to metabolic reprogramming, epigenetic remodeling and dynamic crosstalk with non-coding RNAs. Furthermore, the functional versatility of RBPs is amplified by nuanced alterations in their nucleocytoplasmic trafficking, stress granule formation, post-translational modifications, and RNA-binding specificities, all of which intricately fine-tune their regulatory impact within the neuroinflammatory milieu. Strikingly, the cell type-specific actions of RBPs in neurons, microglia, and astrocytes unveil a sophisticated tapestry of molecular specialization, offering transformative insights into their context-dependent functions. Abnormal function of RNA-binding proteins is closely related to neurodegenerative diseases such as Alzheimer’s disease, Parkinson’s disease, amyotrophic lateral sclerosis, and multiple sclerosis. In addition, RNA-binding proteins are involved in various pathological processes, including central nervous system infections, stroke, high-altitude cerebral hypoxia, and traumatic brain injury. This review systematically organizes the multifaceted regulatory mechanisms of RNA-binding proteins in neuroinflammation. It deeply explores their key roles in the occurrence and development of nervous system diseases. The review aims to construct a comprehensive theoretical framework and provide a scientific basis for developing new diagnostic methods and targeted therapeutic strategies.},
}

@article {pmid41992251,
year = {2026},
author = {Duggan, MR and Jacobsen, E and Yang, S and Zeng, X and Kandala, S and Joynes, CM and Karikari, TK and Nimgaonkar, VL and Kamboh, MI and Snitz, BE and Ferrucci, L and Yolken, R and Ganguli, M and Walker, KA},
title = {CMV titer associations with cognition and the plasma proteome implicate FLT1 and neurovascular mechanisms as potential moderators.},
journal = {Journal of neuroinflammation},
volume = {23},
number = {1},
pages = {},
pmid = {41992251},
issn = {1742-2094},
support = {R01 AG083874/AG/NIA NIH HHS/United States ; U24 AG082930/AG/NIA NIH HHS/United States ; },
abstract = {UNLABELLED: Immune processes play complex roles in Alzheimer’s disease and related dementias (ADRD), but it remains unclear whether host defenses against common microbes also contribute to ADRD, and what underlying mechanisms may account for these relationships. Using antibody and plasma proteomic data from the Monongahela-Youghiogheny Healthy Aging Team study (n = 1,003; mean age = 78.0 yrs; follow up 7.6 yrs), the present study detected accelerated decline across a variety of cognitive domains and altered plasma abundance of FLT1 (also known as Vascular Endothelial Growth Factor Receptor 1) among participants with elevated cytomegalovirus (CMV) titers. After analyses in the Baltimore Longitudinal Study of Aging (n = 323) and the UK Biobank (n = 956) revealed CMV titer associations with higher cross-sectional cognition and greater cognitive decline were moderated by plasma FLT1 abundance, we leveraged two-sample Mendelian Randomization to uncover causal roles for host immune responses to CMV, including limiting brain amyloidosis. Using multi-cohort proteomic signatures of CMV antibody levels and plasma FLT1, bioinformatic analyses suggested that host immune responses to CMV may impact neurologic health through alterations in lymphocytic immunoregulatory cascades, with circulating FLT1 abundance capturing the extent to which these effects may be transmitted across the blood–brain-barrier. In addition to detecting pleiotropic associations of CMV titers with neurocognitive outcomes, our findings highlight FLT1 as an important molecular moderator of these effects, and extend our understanding of the biological basis by which host immune responses to common microbes may contribute to ADRD.

SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s12974-026-03800-8.},
}

@article {pmid42202206,
year = {2026},
author = {Dai, D and Zhang, N and Zhang, H and Tang, Y},
title = {Longitudinal Feature Disentanglement With Cross-Time Contrastive Learning for Alzheimer's Disease Diagnosis.},
journal = {IEEE journal of biomedical and health informatics},
volume = {PP},
number = {},
pages = {},
doi = {10.1109/JBHI.2026.3697253},
pmid = {42202206},
issn = {2168-2208},
abstract = {Longitudinal structural Magnetic Resonance Imaging (sMRI) is pivotal for capturing dynamic brain atrophy patterns associated with the progression of Alzheimer's Disease (AD). However, effectively leveraging longitudinal data remains challenging due to the difficulty in modeling complex inter-temporal correlations and the presence of inherent noise and redundancy. To address these issues, this paper proposes a novel Longitudinal Feature Disentanglement Network for AD diagnosis and progression prediction. Specifically, we design a lightweight 3D convolutional encoder with a weight-sharing strategy to extract spatial representations from dual-time-point images. A Variational Autoencoder (VAE)-based mechanism is then introduced to disentangle these representations into stable features that encapsulate disease-specific identity and marginal features that account for noise and irrelevant variations. To further enhance the disentanglement capability, we incorporate a cross-time-point contrastive learning mechanism to enforce the temporal consistency of stable features, alongside a longitudinal feature reconstruction module that ensures the preservation of comprehensive information by recombining decoupled features. Extensive experiments conducted on the Alzheimer's Disease Neuroimaging Initiative (ADNI) dataset demonstrate that our proposed method outperforms state-of-the-art approaches in both AD diagnosis and MCI-to-AD conversion prediction tasks. Furthermore, visualization analysis validates the model's effectiveness in isolating discriminative brain regions and interpreting the decision-making process.},
}

@article {pmid42202283,
year = {2026},
author = {Zhang, Z and Yang, H and Zhu, M and Guo, R and Chen, F and Dong, H and Cui, Y and Yang, H},
title = {Nonlinear kernel-based high-dimensional inference for set-based genetic association studies.},
journal = {Briefings in bioinformatics},
volume = {27},
number = {3},
pages = {},
doi = {10.1093/bib/bbag275},
pmid = {42202283},
issn = {1477-4054},
support = {81872717//National Natural Science Foundation of China/ ; 252W7713D//the Science and Technology Program of Hebei Province/ ; 246W7703D//the Science and Technology Program of Hebei Province/ ; ZD2018022//Education Department of Hebei Province/ ; H2019206558//Natural Science Foundation of Hebei Province/ ; JYFY 23ZR013//Hebei Key Laboratory of Forensic Medicine/ ; 20260608//Medical Science Research Projects of Hebei/ ; 20200856//Medical Science Research Projects of Hebei/ ; },
mesh = {Humans ; Polymorphism, Single Nucleotide ; *Alzheimer Disease/genetics/diagnostic imaging ; *Genetic Association Studies/methods ; Algorithms ; Computer Simulation ; *Genome-Wide Association Study ; *Models, Genetic ; Nonlinear Dynamics ; Principal Component Analysis ; },
abstract = {Nonlinear genetic architectures, including epistasis and threshold effects, are increasingly recognized as contributors to complex disease risk, yet most existing SNP-set association tests rely on linear modeling assumptions, resulting in reduced power and unstable inference when genetic effects are nonlinear or heterogeneously distributed across variants. To address this limitation, we propose a nonlinear high-dimensional inference framework for set-based genetic association analysis that integrates scalable kernel representations with valid statistical inference. The framework combines distance correlation-based sure independence screening to reduce ultra-high dimensional predictors, kernel principal component analysis with Nyström approximation for nonlinear feature extraction, and de-sparsified LASSO to enable asymptotically valid hypothesis testing in high dimensions, together with a two-stage omnibus testing strategy that adaptively aggregates evidence across complementary signal models. Extensive simulation studies demonstrate that the proposed method maintains well-calibrated Type I error and consistently achieves higher power than established set-based approaches, including Sequence Kernel Association Test and adaptive Sum of Powered Score test, particularly under nonlinear and heterogeneous genetic effect scenarios, while remaining competitive in linear settings. Application to Alzheimer's Disease Neuroimaging Initiative data identifies gene-level associations with brain regional volumes that converge on neuronal excitability, calcium signaling, and cytoskeletal regulation, biological processes centrally implicated in neurodegeneration. Together, this work provides a robust and scalable framework for nonlinear set-based inference in genome-wide studies, expanding the analytical toolbox for dissecting complex genetic contributions to disease.},
}

Humans
Polymorphism, Single Nucleotide
*Alzheimer Disease/genetics/diagnostic imaging
*Genetic Association Studies/methods
Algorithms
Computer Simulation
*Genome-Wide Association Study
*Models, Genetic
Nonlinear Dynamics
Principal Component Analysis

@article {pmid42202469,
year = {2026},
author = {Jessen, F and Dell'Agnello, G and Zimmer, JA and Sapin, C and Dichter, S and Doty, E and Epelbaum, S and Evans, CD and Hauck, PM and Khanna, R and Brooks, DA and Sims, JR and Agosta, F and , },
title = {Efficacy and safety of donanemab in the European eligible population: TRAILBLAZER-ALZ 2 post-hoc analyses.},
journal = {The journal of prevention of Alzheimer's disease},
volume = {13},
number = {8},
pages = {100605},
doi = {10.1016/j.tjpad.2026.100605},
pmid = {42202469},
issn = {2426-0266},
abstract = {BACKGROUND: In the European Union (EU), donanemab is indicated in adults with early symptomatic Alzheimer's disease who are apolipoprotein E ε4 non-carriers or heterozygotes. Among these, patients without superficial siderosis at baseline, uncontrolled hypertension, or anticoagulant use are eligible.

OBJECTIVE: To assess efficacy and safety of donanemab in the EU-eligible population.

METHODS: A post-hoc conservative hybrid imputation method was implemented for clinical efficacy analyses during the TRAILBLAZER-ALZ 2 placebo-controlled period. In the 78-week long-term extension (LTE) participants in the early-start (randomised to donanemab) and delayed-start (randomised to placebo with donanemab initiation during the LTE) groups were compared to a propensity-weighted external control. Participants were switched to placebo after meeting amyloid-based treatment course completion criteria.

RESULTS: By 76 weeks, donanemab-treated participants in the EU-eligible population had a mean Clinical Dementia Rating Scale (CDR)-Sum of Boxes change from baseline difference from placebo of -0.7 points (95% confidence interval, -1.0, -0.4) and a 40.3% lower risk of disease progression to the next stage (per CDR-Global score). Treatment benefit increased over 154 weeks for non-carriers and heterozygotes, including those meeting treatment course completion criteria by 52 or 76 weeks. In the placebo-controlled period, 119 (19.5%) and 49 (8.0%) donanemab-treated eligible participants experienced amyloid-related imaging abnormalities-edema/effusion and infusion-related reactions, respectively. Safety findings were similar among donanemab-treated participants in the placebo-controlled period and LTE delayed-start group.

CONCLUSIONS: Consistent with previous TRAILBLAZER-ALZ 2 and LTE findings, donanemab significantly slowed disease progression compared to controls with a manageable safety profile in non-carriers and heterozygotes.},
}

@article {pmid42202585,
year = {2026},
author = {Parmar, R and Sehra, N and Maurya, IK and Kumar, V and Tikoo, K and Jain, R},
title = {Glycine-zipper-derived synthetic amino acid-containing peptides as amyloid-β aggregation inhibitors: structural and mechanistic investigations.},
journal = {Bioorganic chemistry},
volume = {179},
number = {},
pages = {110033},
doi = {10.1016/j.bioorg.2026.110033},
pmid = {42202585},
issn = {1090-2120},
abstract = {The hydrophobic C-terminus domain of amyloid-beta (Aβ) plays a vital role in the formation of neurotoxic assemblies that form senile plaques. Modified segment-based peptides are considered a promising strategy, as they can alter and inhibit the oligomerization and disorient the neurotoxic oligomers of Aβ. A glycine-zipped segment-based hexapeptide, Ile-Gly-Leu-Met-Val-Gly-OH (Aβ32-37), was selected for structural modifications, including replacement of key residues with unnatural amino acids. The synthesized hexapeptides inhibited Aβ42-induced cytotoxicity at 2-10 μM doses and rescued PC-12 cells. The most active peptide, Ile-Gly-Leu-Met-Val-Phg-OH (35), showed 96.4%, 90.1%, and 80.4% cell viability against Aβ42-induced toxicity at 10 μM, 4 μM, and 2 μM, respectively. Th-T and ANS fluorescence assays provide insight into the kinetics of inhibition. CD spectroscopy investigations revealed that peptide 35 restricted the formation of β-sheet conformation and the disintegration of pre-existing β-sheets. The disappearance of Aβ42 fibrillary networks in electron microscopy (HRTEM and STEM) confirmed the absence of Aβ42 aggregation. DLS study endorsed these findings by adding an in-depth mechanistic understanding of the inhibition process. In silico studies reveal binding interactions between Aβ42 and the peptide 35, corroborating the experimental observations (Kd = 8.75 nM). We conclude that peptide 35 reduces Aβ aggregation, exhibits β-sheet-breaking propensity, and lacks cytotoxicity, highlighting its promise as a potential therapeutic for AD.},
}

@article {pmid42202980,
year = {2026},
author = {Sánchez-Valle, R and Alcolea, D and Ferrer, GA and Balasa, M and Naranjo, IC and Fortea, J and Lladó, A and Lleó, A and Montes, AM and Lozano, LM and Martínez-Lage, P and Matias-Guiu, JA and Mendioroz, M and Martinez, DAP and Ripoll, GP and Riverol, M and Sanchez-Juan, P and Bondía, HV and , },
title = {Appropriate use recommendations of the Spanish Society of Neurology's Behavioural Neurology and Dementia Study Group on anti-amyloid antibodies in the treatment of Alzheimer disease.},
journal = {Neurologia},
volume = {},
number = {},
pages = {502075},
doi = {10.1016/j.nrleng.2026.502075},
pmid = {42202980},
issn = {2173-5808},
abstract = {INTRODUCTION: Two anti-amyloid monoclonal antibodies (mAb) have recently been approved by the European Commission for the treatment of Alzheimer disease (AD). In this context, the Spanish Society of Neurology's Behavioural Neurology and Dementia Study Group decided to issue a consensus statement gathering the recommendations of national experts on the appropriate use of anti-amyloid mAb. The document provides recommendations on practical aspects of the use of these drugs in Spain, which are intended to complement the indications described by regulators.

DEVELOPMENT: Fifty-seven members of the study group participated in the consensus process (January-September 2025), which includes recommendations on criteria for selecting candidates, adverse reactions, monitoring, criteria for suspension of treatment, shared physician-patient decision-making, and requirements of prescribing centres. All participants were invited to revise the complete document, specifically asked whether they agreed with the content of each section, and invited to share their comments.

CONCLUSIONS: The introduction of the first anti-amyloid mAb represents a paradigm shift in the management of AD, but is not free of challenges. The participating experts showed a high level of consensus on basic clinical and practical considerations, with the requirements of prescribing centres and criteria for treatment suspension being the areas that generated the most debate. Participants noted concerns about equity of access and implementation into current care, particularly if insufficient resources are allocated to this implementation. This document will require updates in line with new knowledge and/or approval of new drugs in this class.},
}

@article {pmid42203047,
year = {2026},
author = {Alruwaili, NS and Al-Kuraishy, HM and Fawzy, MN and Al-Gareeb, AI and Fahad, EH and Batiha, GE},
title = {Thyronines and Thyronamines Dual Modulators of Synaptic Plasticity, Cognitive Decline, and Geriatric Depression in the Aging Brain.},
journal = {Behavioural brain research},
volume = {},
number = {},
pages = {116296},
doi = {10.1016/j.bbr.2026.116296},
pmid = {42203047},
issn = {1872-7549},
abstract = {The aging brain induces cognitive deterioration and geriatric depression via synaptic dysfunction, neuroinflammation, and bioenergetic failure. Recent evidence identifies thyroid hormones (thyronines: T3, T4) and their decarboxylated derivatives (thyronamines, especially 3-iodothyronamine, T1AM) as essential endogenous regulators of these processes. Thyronines influence both genomic and non-genomic pathways in glutamatergic, GABAergic, cholinergic, and monoaminergic signaling, thereby modulating learning and memory. With aging, diminished expression of thyroid hormone transporters (MCT8, OATP1C1) and compromised astrocytic conversion of T4 to T3 result in brain-specific hypothyroidism, facilitating amyloid-β accumulation, tau hyperphosphorylation, and hippocampal dysfunction. In contrast, T1AM stimulates trace amine-associated receptor 1 (TAAR1), promoting ERK1/2 phosphorylation, triggering autophagy through mTOR inhibition, and diminishing Aβ neurotoxicity in preclinical models. In geriatric depression, thyronines regulate monoaminergic transmission, whereas T1AM metabolites affect histaminergic pathways. Both hypothyroidism and hyperthyroidism significantly elevate the risk of Alzheimer's disease via distinct mechanisms: deficiency hinders glucose transport and amyloid-beta clearance, whereas excess disrupts mitochondrial respiration and activates stress kinases. The U-shaped dose-response relationship highlights the necessity for precise therapeutics. Selective modulators of thyronine and thyronamine receptors with improved brain penetration are promising approaches for addressing age-related cognitive decline and late-life depression.},
}

@article {pmid42203089,
year = {2026},
author = {Nasim, N and Cheng, MY and Park, HH and Valenzuela, A and Andrew, P and Wexler, AS and Chandrasekaran, V and Van Winkle, LS and Bein, K and Lein, PJ},
title = {Comparing effects of gaseous vs. particulate components of traffic-related air pollution on Alzheimer's disease biomarkers in a genetically susceptible rat model.},
journal = {Neurotoxicology},
volume = {},
number = {},
pages = {103472},
doi = {10.1016/j.neuro.2026.103472},
pmid = {42203089},
issn = {1872-9711},
abstract = {Epidemiological data link traffic-related air pollution (TRAP) to increased risk of Alzheimer's disease (AD) and AD-related dementia (ADRD), and while experimental animal studies corroborate this association, most utilized exposure paradigms that failed to recapitulate the complexity of current, real-world TRAP exposure. Furthermore, the specific components of TRAP that promote AD pathogenesis remain unknown. This study assesses AD-relevant pathology in a transgenic rat model of AD (TgF344-AD) following chronic exposure to the gas phase vs. particulate matter (PM) components of TRAP in emissions from light-duty only (LDV) vs. combined light- and heavy-duty (LDV+HDV) vehicles. Male and female TgF344-AD rats were transported to the Caldecott Tunnel Exposure Facility (CTEF) at 1 month of age after being randomly assigned to one of six exposure groups: (1) filtered air (FA), (2) LDV+HDV gases only; (3) LDV PM only; (4) LDV+HDV PM only; (5) LDV PM and gases; and (6) LDV+HDV PM and gases. AD-relevant endpoints were quantified in 4-, 9-, 12-, and 15- month-old animals. Cortical Aβ levels at the 4, 9, and 15-month timepoints were significantly influenced by sex-by-exposure interactions. Amyloid plaque accumulation in the entorhinal cortex and hippocampus exhibited significant sex-dependent effects at 9 and 12 months so males and females were analyzed separately across all timepoints. At 9 months, females exposed to LDV+HDV PM had increased amyloid plaques in the hippocampus, and at 15 months, both females and males exposed to LDV PM and females exposed to LDV PM and gases exhibited significantly increased plaque levels in the entorhinal cortex. The rate of plaque accumulation over all four time points was accelerated in the entorhinal cortices of both sexes exposed to LDV and LDV+HDV PM alone or in combination with gases. There were no exposure effects on phosphorylated tau or Thioflavin S staining; however, the rate of neuronal cell loss with increasing age was significantly increased by exposure to LDV emissions in both females and males. Collectively, these findings demonstrate that chronic exposure to ambient TRAP in real-time promoted AD-relevant outcomes in the TgF344-AD rat with effects that varied according to age, sex, and brain region. TRAP effects occurred more prominently in groups exposed to LDV PM. Further research is needed to determine the mechanism(s) by which sex-dependent TRAP effects exacerbate AD pathogenesis so that effective interventions can be developed to improve the health of the aging brain.},
}

@article {pmid42203095,
year = {2026},
author = {Kobayashi, H and Moizumi, A and Maeda, T and Kurita, H and Tokuraku, K and Kuragano, M},
title = {Amyloid-β aggregation disrupts actomyosin architecture and impairs contractility in human brain vascular smooth muscle cells.},
journal = {Experimental cell research},
volume = {},
number = {},
pages = {115082},
doi = {10.1016/j.yexcr.2026.115082},
pmid = {42203095},
issn = {1090-2422},
abstract = {Amyloid-β (Aβ) accumulation within cerebral vessels underlies cerebral amyloid angiopathy (CAA) and Alzheimer's disease (AD). In CAA, Aβ deposits along leptomeningeal and cortical vessel walls are strongly associated with intracerebral hemorrhage and vascular dysfunction. However, the cellular mechanisms remain incompletely understood. Based on our prior work showing that aggregated Aβ disrupts human brain microvascular endothelial cells, we now address the mural layer by testing how Aβ affects human brain vascular smooth muscle cells (hBSMCs), focusing on actomyosin architecture and contractile function to comprehensively reveal the effects of Aβ on the cerebral vasculature. We combined single-cell imaging of quantum dot-labeled Aβ (QDAβ) with F-actin labeling (Alexa Fluor 488-phalloidin/SiR-actin), confocal 3D reconstructions, and a collagen gel contraction assay to associate Aβ deposition dynamics with cytoskeletal organization and force output. Aβ formed deposits at the cell edge of hBSMCs, accompanied by disorganization of the F-actin network and the emergence of abnormal F-actin aggregates. In addition, time-lapse imaging revealed the progressive accumulation of QDAβ-positive deposits with concomitant disorganization of stress fibers and the condensation of activated myosin II. Functionally, gels containing Aβ-exposed hBSMCs failed to shrink compared with non-treated/DMSO controls, consistent with reduced hBSMC-mediated matrix contraction. Together, these data suggest that Aβ deposition is associated with disorganization of cortical and contractile actin networks in hBSMCs and reduced hBSMC-mediated matrix contraction, providing a potential cellular framework linking local cytoskeletal pathology to impaired vasomotion and perivascular clearance in CAA.},
}

@article {pmid42203570,
year = {2026},
author = {Ho, NCW and Zhukovsky, P and Rajji, TK and Bowie, CR and Brooks, H and Butters, MA and Chen, Y and Fischer, CE and Flint, AJ and Herrmann, N and Lanctôt, KL and Lee, A and Mah, L and Marawi, T and Pollock, BG and Ryan, JD and Schoer, N and Ma, C and Voineskos, AN and Mulsant, BH and , },
title = {Brain Structures and Cognitive Decline: Moderation Analysis of the PACt-MD Randomized Clinical Trial of Brain Stimulation Plus Cognitive Remediation in Older Adults With Remitted Depression or Mild Cognitive Impairment.},
journal = {The American journal of geriatric psychiatry : official journal of the American Association for Geriatric Psychiatry},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.jagp.2026.04.008},
pmid = {42203570},
issn = {1545-7214},
abstract = {OBJECTIVE: To identify which patients with remitted major depressive disorder (rMDD) or mild cognitive impairment (MCI) benefit from cognitive remediation (CR) plus transcranial direct current stimulation (tDCS).

DESIGN: We conducted a moderator analysis to examine the effects of baseline brain magnetic resonance imaging (MRI) measures on the impact of CR + tDCS on cognitive decline in Prevention of Alzheimer's dementia with CR plus tDCS in MCI and Depression (PACt-MD), a double-masked randomized two-arm controlled trial with assessments at baseline, two months, and yearly for three to seven years.

SETTING: Five academic hospitals in Toronto, Canada.

PARTICIPANTS: A total of 246 participants with rMDD, MCI, or both, with an analyzable baseline MRI.

INTERVENTION: CR + tDCS or sham CR + sham tDCS.

MEASUREMENTS: Overall cortical thickness, overall fractional anisotropy, and cortical thickness in an a-priori composite region of interest (ROI); changes in global cognition, executive function, or verbal memory.

RESULTS: Overall cortical thickness moderated decline in global cognition (Χ² = 10.43, df = 3, p = 0.015); ROI cortical thickness moderated treatment-related changes in global cognition (Χ² = 29.05, df = 3, p <0.001), executive function (Χ² = 11.57, df = 3, p = 0.009), and verbal memory (Χ² = 16.08, df = 3, p = 0.001).

CONCLUSION: Future work needs to confirm that cortical thickness can be used to select adults at risk for dementia who are the most likely to benefit from CR + tDCS. CLINCIALTRIALS.

GOV IDENTIFIER: NCT02386670.},
}

@article {pmid42204017,
year = {2026},
author = {Musaeus, CS and Frederiksen, KS and Waldemar, G and Kjær, TW and Vestergaard, MB and Andersen, BB and Høgh, P and Hasselbalch, SG and Kidmose, P and Hemmsen, MC and Rank, ML and Larsson, HBW and Lindberg, U},
title = {Epileptiform discharges in neurodegenerative diseases linked to atrophy but not associated with iron depositions.},
journal = {GeroScience},
volume = {},
number = {},
pages = {},
pmid = {42204017},
issn = {2509-2723},
abstract = {Epileptiform discharges in Alzheimer's disease (AD) and Lewy body dementia (DLB) may be associated with cognitive decline. Iron accumulation has been implicated in neurodegenerative processes; however, its relationship to epileptiform discharges remains unknown. In addition, the relationship between iron deposition, structural brain changes, and epileptiform discharges remains unclear. The objective is to investigate whether iron deposition and structural brain atrophy are associated with epileptiform discharges in patients with AD, DLB, and healthy controls (HCs). A total of 25 patients with AD, 10 patients with DLB, and 15 HCs were included in the analysis. The participants underwent MRI including quantitative susceptibility mapping (QSM) and structural T1-weighted imaging. We examined the four regions of interest, which are tied to iron deposition and AD pathology. Ear-EEG recordings were used to quantify spike frequency (epileptiform discharges/24 h). No significant group differences were found for susceptibility across regions. Susceptibility was not associated with spike frequency. Patients with AD exhibited significant hippocampal atrophy. Higher hippocampal volume was associated with lower spike rates in adjusted models. Susceptibility and hippocampal volume were associated, and in a multilinear model with age, hippocampal volume accounted for a larger proportion of the explained variance. This study found no evidence linking iron deposition to epileptiform discharges in AD or DLB. Instead, hippocampal atrophy appears more strongly associated with epileptiform discharges, which could indicate that the underlying pathological processes rather than iron are the primary driving factor for epileptiform discharges.},
}

@article {pmid42204067,
year = {2026},
author = {Tong, Y and He, JN and Zhou, L and Zhang, J and Ho, BM and Du, L and Yip, YWY and Bisnauthsing, H and Chan, PP and Tham, CC and Pang, CP and Chu, WK},
title = {Mitochondrial dysfunction in neurodegenerative disorders: mechanisms and therapeutic advances.},
journal = {Molecular biomedicine},
volume = {7},
number = {1},
pages = {},
pmid = {42204067},
issn = {2662-8651},
mesh = {Humans ; *Neurodegenerative Diseases/metabolism/therapy/pathology/genetics ; *Mitochondria/metabolism/pathology/genetics ; Animals ; Oxidative Phosphorylation ; Oxidative Stress ; Mitochondrial Dynamics ; },
abstract = {Mitochondrial dysfunction is a core pathogenic mechanism underlying a broad spectrum of neurodegenerative disorders, from Alzheimer's and Parkinson's diseases to inherited optic neuropathies and mitochondrial ataxias. This review provides a comprehensive analysis of how defects in mitochondrial and nuclear DNA converge to disrupt oxidative phosphorylation, mitochondrial dynamics, calcium homeostasis, and quality control pathways, leading to energy depletion, oxidative stress, and neuronal degeneration across multiple disease contexts. Building on this mechanistic foundation, we examine how these shared pathogenic principles manifest distinctly in major neurodegenerative diseases, while also discussing representative mitochondrial optic neuropathies as tractable disease models that have yielded critical mechanistic and therapeutic insights. We further review recent advances in diagnostic technologies that enhance our ability to detect and stratify mitochondrial pathologies for therapeutic intervention. On the therapeutic front, we provide a comprehensive evaluation of the rapidly evolving landscape, analyzing strategies ranging from metabolic modulators and antioxidants to pioneering gene-targeted therapies, organelle replacement approaches, and emerging epitranscriptomic interventions. Finally, we identify persistent challenges in clinical translation and outline pivotal future directions essential for developing effective, mechanism-informed combination therapies against mitochondrial dysfunction in neurodegeneration.},
}

Humans
*Neurodegenerative Diseases/metabolism/therapy/pathology/genetics
*Mitochondria/metabolism/pathology/genetics
Animals
Oxidative Phosphorylation
Oxidative Stress
Mitochondrial Dynamics

@article {pmid42204143,
year = {2026},
author = {Villalón-Reina, JE and Zhu, AH and Nabulsi, L and Thomopoulos, SI and Moreau, CA and Feng, Y and Chattopadhyay, T and Benavidez, SM and Kushan, L and John, JP and Joshi, H and Ba Gari, I and Lawrence, KE and Nir, TM and Jahanshad, N and Bearden, CE and Kia, SM and Marquand, AF and , and Thompson, PM},
title = {Lifespan normative modeling of brain microstructure.},
journal = {Nature communications},
volume = {17},
number = {1},
pages = {},
pmid = {42204143},
issn = {2041-1723},
support = {R01 AG060610/AG/NIA NIH HHS/United States ; RF1AG057892//U.S. Department of Health & Human Services | NIH | Fogarty International Center (FIC)/ ; R01 MH085953/MH/NIMH NIH HHS/United States ; K01MH135160//U.S. Department of Health & Human Services | NIH | National Institute of Mental Health (NIMH)/ ; },
mesh = {Humans ; Female ; *White Matter/diagnostic imaging/pathology ; Child, Preschool ; Child ; *Brain/diagnostic imaging ; Male ; Diffusion Tensor Imaging ; Adolescent ; Bayes Theorem ; Aged, 80 and over ; Middle Aged ; Aged ; Adult ; Young Adult ; Schizophrenia/diagnostic imaging/pathology ; *Longevity ; Alzheimer Disease/diagnostic imaging/pathology ; Cognitive Dysfunction/diagnostic imaging/pathology ; },
abstract = {Normative models of brain metrics based on large populations could be extremely valuable for detecting brain abnormalities in patients with a variety of disorders, including degenerative, psychiatric and neurodevelopmental conditions, but no such models exist for the brain's white matter (WM) microstructure. Here we present a large-scale normative model of brain WM microstructure - based on 19 international diffusion MRI datasets covering almost the entire lifespan (totaling N = 54,583 individuals; age: 4-91 years). We extracted regional diffusion tensor imaging (DTI) metrics using a standardized analysis and quality control protocol and used hierarchical Bayesian regression (HBR) to model the statistical distribution of derived WM metrics as a function of age and sex. We extracted the average lifespan trajectories and corresponding centile curves for each WM region. We illustrate the utility of the method by applying it to detect and visualize profiles of WM microstructural deviations in a variety of contexts: in mild cognitive impairment, Alzheimer's disease, and 22q11.2 deletion syndrome - a neurogenetic condition that markedly increases risk for schizophrenia. The resulting large-scale model provides a common reference to identify disease effects on the brain's microstructure in individuals or groups, and to compare disorders, and discover factors affecting WM abnormalities. The derived normative models are a valuable resource publicly available to the community, adaptable and extendable to future datasets as the available data expands.},
}

Humans
Female
*White Matter/diagnostic imaging/pathology
Child, Preschool
Child
*Brain/diagnostic imaging
Male
Diffusion Tensor Imaging
Adolescent
Bayes Theorem
Aged, 80 and over
Middle Aged
Aged
Adult
Young Adult
Schizophrenia/diagnostic imaging/pathology
*Longevity
Alzheimer Disease/diagnostic imaging/pathology
Cognitive Dysfunction/diagnostic imaging/pathology

@article {pmid42204442,
year = {2026},
author = {Jadhav, VS and Kow, RL and Beale, AD and Baum, M and McMillan, PJ and Latimer, CS and Liachko, NF and Kraemer, BC},
title = {Loss of SMARCAD1 Mitigates Tauopathy.},
journal = {Aging cell},
volume = {25},
number = {6},
pages = {e70543},
doi = {10.1111/acel.70543},
pmid = {42204442},
issn = {1474-9726},
support = {I01BX005762//U.S. Department of Veterans Affairs/ ; IK6BX006467//U.S. Department of Veterans Affairs/ ; R01AG066729/NH/NIH HHS/United States ; R01NS0064131/NH/NIH HHS/United States ; P30AG066509/NH/NIH HHS/United States ; U19AG066567/NH/NIH HHS/United States ; },
mesh = {Animals ; *Tauopathies/metabolism/genetics/pathology ; Humans ; Caenorhabditis elegans/metabolism/genetics ; *DNA Helicases/metabolism/genetics/deficiency ; tau Proteins/metabolism/genetics ; *Caenorhabditis elegans Proteins/metabolism/genetics ; HEK293 Cells ; Disease Models, Animal ; },
abstract = {Tauopathies are neurodegenerative diseases characterized by the accumulation of misfolded tau protein and include Alzheimer's disease (AD) and related dementia disorders. Identifying new strategies to treat tauopathy remains an important gap in the field. Using forward and reverse genetic approaches in C. elegans, we identified smrd-1, the C. elegans homolog of SMARCAD1, as a potent modifier of tauopathy phenotypes in a transgenic model of tauopathy. Loss of smrd-1 function rescues tauopathy-associated neuronal dysfunction and neurodegeneration in C. elegans models of tauopathy. Loss or reduction of smrd-1/SMARCAD1 decreases phosphorylated and total tau protein levels by reducing tau mRNA transcripts in C. elegans and mammalian HEK-tau cells. Loss of smrd-1 rescues tau-driven abnormal H3K9me3 chromatin methylation. Immunohistochemistry in human postmortem AD brain tissue showed SMARCAD1 depletion in a subset of cases that also exhibit depletion of MSUT2. Loss of smrd-1/SMARCAD1 rescues tau-mediated neurodegeneration via a tau mRNA lowering mechanism accompanied by changes in chromatin conformation.},
}

Animals
*Tauopathies/metabolism/genetics/pathology
Humans
Caenorhabditis elegans/metabolism/genetics
*DNA Helicases/metabolism/genetics/deficiency
tau Proteins/metabolism/genetics
*Caenorhabditis elegans Proteins/metabolism/genetics
HEK293 Cells
Disease Models, Animal

@article {pmid42204484,
year = {2026},
author = {Dwarkanth, PS and Anitha, R and Babu, GH and Ahammad, SKH and Karamti, H and Kumar, A and Oza, AD and Moges, DM},
title = {Correction: An efficient Alzheimer's disease detection by NV classifier with BWTDL approach using MRI image.},
journal = {BMC medical imaging},
volume = {26},
number = {1},
pages = {},
doi = {10.1186/s12880-026-02457-2},
pmid = {42204484},
issn = {1471-2342},
}

@article {pmid42204549,
year = {2026},
author = {Trujillo-Estrada, L and Bettinetti-Luque, M and Andreo-Lopez, J and da Cunha, C and Morales-Cabello, M and Campos-Moreno, C and Sanchez-Mejias, E and Forner, S and Martini, AC and Sanchez-Varo, R and Gutierrez, A and LaFerla, FM and Baglietto-Vargas, D},
title = {Visceral adipose tissue differentially affects tau and Aβ pathology in 3xTg-AD mice.},
journal = {Cell communication and signaling : CCS},
volume = {},
number = {},
pages = {},
doi = {10.1186/s12964-026-02964-3},
pmid = {42204549},
issn = {1478-811X},
support = {B1-2021_32//University of Malaga, Spain/ ; 961.662//Universidad de Málaga/ ; PI21/00915//Instituto de Salud Carlos III/ ; U54-AG054349/NH/NIH HHS/United States ; A2015535S//BrightFocus Foundation/ ; PID2019-108911RA-100//Ministerio de Ciencia e Innovación/ ; AARG-22-928219/ALZ/Alzheimer's Association/United States ; BEAGAL18/00052//Ministerio de Ciencia e Innovación, programa Beatriz Galindo/ ; INTAR25-11//IBIMA Plataforma Bionand/ ; },
abstract = {BACKGROUND: Alzheimer's disease (AD) is a complex disorder involving multiple cellular and molecular mechanisms. Recent evidence suggests that metabolic alterations play a crucial role in AD progression. Likewise, diabetes and obesity-two major metabolic diseases-are well-established risk factors for AD. These conditions are associated with a significant expansion of white adipose tissue (WAT). Here, we hypothesize that visceral WAT may act as a key mediator between peripheral metabolic dysfunction and brain illnesses.

METHODS: Immunohistochemistry and biochemical approaches were used to evaluate the WAT from WT and db/db mice. Similar techniques were applied to examine the brain tissue of 3xTg-AD mice that received white epididymal fat pads from WT or db/db donors and determine the impact of adipose tissue transplantation on tau and Aβ pathology.

RESULTS: Our study revealed that recipient 3xTg-AD mice that received db/db fat pads developed profound changes in tau pathology due to increased expression of the cyclin-dependent kinase 5 activator p25 compared with 3xTg-AD mice that received fad pads from WT or sham mice. This increment in p25/cdk5 was associated with a prominent inflammatory response induced by the WAT transplant. Moreover, the opposite effect on Aβ pathology was found. The reduction in Aβ levels was correlated with an increase in microglial phagocytic capacity.

CONCLUSIONS: Overall, our study demonstrated a novel crosstalk between AD and metabolic disorders through white adipose signaling resulting in differential effects on tau and Aβ pathology mediated by an activated immune response.},
}

@article {pmid42204559,
year = {2026},
author = {Reijner, N and Ramos, MR and Jacobs, E and Toen, DV and Tijms, B and Rozemuller, AJM and van der Weerd, L and Barkhof, F and van de Berg, WDJ and Jonkman, LE},
title = {T1-weighted/T2-weighted ratio reflects microstructural changes in Alzheimer's disease.},
journal = {Alzheimer's research & therapy},
volume = {},
number = {},
pages = {},
doi = {10.1186/s13195-026-02093-6},
pmid = {42204559},
issn = {1758-9193},
abstract = {BACKGROUND: The T1-weighted/T2-weighted ratio (T1w/T2w-ratio) has been considered as a relatively simple neuroimaging approach to map myelin content in the aging and diseased brain. However, we hypothesize that any process affecting the tissue microstructural integrity also contributes to observed changes in the T1w/T2w-ratio. Here, we aim to evaluate the ability of T1w/T2w-ratio to detect microstructural changes, specifically within the paradigm of Alzheimer's disease (AD).

METHODS: Postmortem in-situ T1-weighted and T2-weighted MRI scans of 27 control and 51 AD brain donors were processed into standardized T1w/T2w-ratio images and parcellated into cortical regions according to the brainnetome atlas. Using an identical pipeline, antemortem MRI scans of 9 AD cases were processed. Immunohistochemical staining and digital quantification were performed for amyloid-beta (4G8), phosphorylated tau (AT8), neuro-axonal damage (NfL), myelin (PLP), microglia (IBA1), and iron (Meguro) in 9 cortical regions. Data was analysed using linear mixed models.

RESULTS: Whole cortex T1w/T2w-ratio was 15% lower in AD compared to controls and was 13% lower in the hippocampus of typical AD compared to atypical AD clinical phenotypes. Additionally, a strong correlation was found between antemortem and postmortem T1w/T2w-ratios (r = 0.85). Whole-brain associations between T1w/T2w-ratio and histological changes were found in both control and AD patients: T1w/T2w-ratio associated with myelin density (Controls: β = 0.229; AD: β = 0.312) and microglia density (Controls: β=-0.090; AD: β=-0.496). In AD but not in controls, T1w/T2w-ratio associated with amyloid-beta (β = 0.233), phosphorylated tau (β=-0.220), and neuro-axonal damage (β = 0.170). Iron load showed contrasting associations in controls and AD (Controls: β=-0.359; AD: β = 0.154).

CONCLUSION: The findings in this study suggest that the T1w/T2w-ratio is mainly associated with myelin density in healthy controls, but is a broader indicator of microstructural integrity in Alzheimer's disease, where it additionally largely associates with accumulation of amyloid-beta, phosphorylated tau and neuro-axonal damage. Therefore, the T1w/T2w-ratio is not a myelin-specific marker in AD, but could be a valuable neuroimaging tool for tracking longitudinal microstructural changes when interpreted alongside established AD pathology biomarkers.},
}

@article {pmid42204590,
year = {2026},
author = {Tu, D and Zheng, Y and Ding, P and Shen, M and Tang, W and Wei, B and Wang, H},
title = {Cholesterol metabolism in neurodegenerative diseases: mechanisms and therapeutic advances.},
journal = {Molecular neurodegeneration},
volume = {},
number = {},
pages = {},
doi = {10.1186/s13024-026-00951-3},
pmid = {42204590},
issn = {1750-1326},
abstract = {Cholesterol metabolites are abundant in the central nervous system (CNS) that regulate cell membrane fluidity, signal transduction, and inter- and intracellular vesicular transport, as well as cell proliferation/cell death or migration. Brain cholesterol synthesis and metabolism are tightly coupled to the functional homeostasis of neurons, glial cells or microglia, and dysregulation of these processes has been strongly implicated in neurodegenerative diseases such as Alzheimer's disease (AD), Parkinson's disease (PD), and Huntington's disease (HD). This review provides a comprehensive overview of how cholesterol synthesis, esterification, efflux, uptake, and oxidation affect the CNS function, highlighting the function of key enzymes or metabolites in distinct brain cell types during neurodegeneration. Based on single-cell/nucleus RNA sequencing data from the brains of AD, PD, and HD patients, we summarize cell-type-specific genes in cholesterol metabolism pathways, shedding new light to understand cellular heterogeneity. The role of cholesterol-derived neurosteroids in neurodegenerative diseases is also discussed. Furthermore, how cholesterol metabolites modulate the formation, aggregation, and degradation of amyloid-β (Aβ), α-synuclein and huntingtin, as well as Tau protein phosphorylation are outlined. Finally, future research directions are proposed that aim to understand neurodegenerative diseases with new angle.},
}

@article {pmid42204616,
year = {2026},
author = {McKiernan, E and Swann, P and Mak, E and Prats-Sedano, M and Savulich, G and Bentley, A and Williams, G and Su, L and O'Brien, JT},
title = {Seven tesla MRI reveals amygdala and hippocampal subfield atrophy in dementia with Lewy bodies.},
journal = {Alzheimer's research & therapy},
volume = {},
number = {},
pages = {},
doi = {10.1186/s13195-026-02091-8},
pmid = {42204616},
issn = {1758-9193},
support = {AS-CTF-17b-003/ALZS_/Alzheimer's Society/United Kingdom ; RG 9611/ALZS_/Alzheimer's Society/United Kingdom ; BRC-1215-20014//NIHR Cambridge Biomedical Research Centre/ ; BRC-1215-20014//NIHR Cambridge Biomedical Research Centre/ ; BRC-1215-20014//NIHR Cambridge Biomedical Research Centre/ ; BRC-1215-20014//NIHR Cambridge Biomedical Research Centre/ ; BRC-1215-20014//NIHR Cambridge Biomedical Research Centre/ ; BRC-1215-20014//NIHR Cambridge Biomedical Research Centre/ ; BRC-1215-20014//NIHR Cambridge Biomedical Research Centre/ ; BRC-1215-20014//NIHR Cambridge Biomedical Research Centre/ ; MR/T033371/1//Dementias Platform UK/ ; ARUK-SRF2017B-1//Alzheimer's Research UK/ ; LB002/209//Lewy Body Society/ ; },
abstract = {The 7T-DLB study investigated whether atrophy of individual hippocampal and amygdala subfields is present in dementia with Lewy bodies (DLB) as well as in Alzheimer's disease (AD) in which it has previously been established. MRI at standard clinical and research field strengths may have insufficient resolution to reveal the presence of atrophy in these regions in DLB; seven tesla MRI is ideally placed to examine subtle volumetric differences in these brain areas due to increased signal to noise ratio and tissue contrast.In this prospective, cross-sectional, seven tesla imaging study, 20 participants with probable DLB underwent MRI, clinical assessment, and cognitive testing, alongside a patient comparison group of 25 participants with probable AD, and 19 healthy controls. Scans were segmented using FreeSurfer automated pipelines. Hippocampal and amygdala subfield volumes were compared between diagnostic groups using a generalised linear model with age, sex, education, and total intracranial volume as covariates. Associations between volumes and cognition were examined using Kendall's tau. Exploratory analyses investigated associations between subfield volumes and visual hallucinations scores, and in a sub-set of 41 participants (DLB = 13, AD = 17, controls = 11), with plasma ptau-217 concentrations.Four (of 13) hippocampal subfields (molecular layer, subiculum, presubiculum, and entorhinal cortex) and five (of nine) amygdala subfields (accessory basal, central, medial and cortical nuclei, and anterior amygdaloid area) were significantly smaller in DLB compared to controls (pFDR<0.05). In DLB, significant correlations between subfield volumes and Addenbrookes Cognitive Examination Scores were found for seven hippocampal subfields (Cornu Ammonis (CA)1, CA2/3, CA4, molecular layer, dentate gyrus, hippocampal amygdala transition area, and presubiculum), and five amygdala subfields (basal, accessory basal, central, cortical, and cortico-amygdala transition area) (all pFDR<0.05). Exploratory analyses suggest that amygdala subfield volumes may be associated with visual hallucinations, though these provisional findings require replication.We conclude that structural seven tesla MRI reveals volumetric differences in individual hippocampal and amygdala subfields between DLB and controls, as well as between AD and controls where they have previously been described. Atrophy of individual subfields may potentially help explain the presence of cognitive and non-cognitive symptoms in DLB.},
}

@article {pmid42204625,
year = {2026},
author = {Deng, J and Li, D and Li, Z and Pan, Y and Xiong, J},
title = {MicroRNA-7: a versatile player and core target in brain disorders.},
journal = {Journal of translational medicine},
volume = {},
number = {},
pages = {},
doi = {10.1186/s12967-026-08313-9},
pmid = {42204625},
issn = {1479-5876},
abstract = {OBJECTIVE: This article provides a systematic review of the biological characteristics, regulatory mechanisms, and roles of MicroRNA-7 (miR-7) in the nervous system, as well as explores its clinical translation potential and challenges.

METHODS: A review analysis integrating the progress of basic and clinical research related to miR-7.

RESULTS: Characteristics and Regulation: miR-7 is highly expressed in mammalian brain tissues, with its function finely regulated by ceRNA networks (such as ciRS-7 and lncRNA SNHG1) and epigenetic modifications, forming a multi-layer dynamic regulatory system.

MECHANISMS OF ACTION: It plays multi-faceted intervention roles in protein aggregation, neuroinflammation, mitochondrial dysfunction, and tumor progression by targeting key factors such as α-synuclein, NLRP3 inflammasome, EGFR/PI3K/AKT/mTOR pathway, and mitochondrial-related proteins (e.g. VDAC1). Role in Disease: It has significant pathophysiological implications in diseases such as Parkinson's disease, Alzheimer's disease, ischemic stroke, cerebral hemorrhage, and glioblastoma. Translational Potential: Changes in miR-7 expression in bodily fluids (blood, cerebrospinal fluid) and extracellular vesicles demonstrate diagnostic and prognostic potential; delivery systems based on nanomedicine (e.g. liposomes, graphene oxide, AAV vectors) and their combination therapy strategies (e.g. in conjunction with chemotherapy and immunotherapy) enhance its brain targeting and therapeutic efficiency.

CONCLUSION: miR-7 is a key regulatory molecule in brain diseases, with significant value for basic research and clinical translation. Future advancements should leverage cutting-edge technologies such as single-cell sequencing, spatial transcriptomics, and intelligent responsive nanocarriers to deepen the understanding of its regulatory networks and address challenges such as mechanism complexity, delivery system targeting, and the lack of clinical translation standards, to accelerate its transition from basic research to clinical application.},
}

@article {pmid42204658,
year = {2026},
author = {Merlino, L and Rainone, F and Tollitt, J and Chinnadurai, R and Rusconi, F and Hernandez, G and Battini, GG and Colombo, PM and Stewart, S and Dunne, RA and Kalra, PA},
title = {Impact of CKD and COPD co-existence on mortality, vascular dementia, and Alzheimer's dementia; a comparative cohort study.},
journal = {BMC nephrology},
volume = {},
number = {},
pages = {},
doi = {10.1186/s12882-026-05076-9},
pmid = {42204658},
issn = {1471-2369},
abstract = {BACKGROUND: Chronic kidney disease (CKD) and chronic obstructive pulmonary disease (COPD) are common conditions associated with increased risks of mortality and cognitive impairment. However, the association between COPD and dementia outcomes in patients with CKD remains incompletely understood.

METHODS: We conducted a retrospective observational cohort study using the TriNetX Global Collaborative Network, including patients aged 18-80 years with CKD stages 3-5, excluding those with prior dialysis, transplantation, dementia, or mild cognitive impairment before cohort entry. Two cohorts were identified: CKD with COPD, defined using classical ICD-10 COPD codes (J41-J44), and CKD without COPD. A secondary sensitivity analysis used a broader respiratory disease definition including asthma, bronchiectasis, and other chronic respiratory conditions. Cohorts were propensity score matched (1:1) for demographic characteristics, comorbidities, smoking exposure, and laboratory parameters. Outcomes included all-cause mortality, non-Alzheimer's dementia, and Alzheimer's disease, assessed over a maximum follow-up of 5 years using Kaplan-Meier and Cox proportional hazards analyses.

RESULTS: Two cohorts were identified: CKD with COPD (n = 270 566) and CKD without COPD (n = 821 399). After propensity score matching, 234 317 patients remained in each cohort. CKD with COPD was associated with a higher observed risk of mortality compared with CKD alone (18.5% vs. 14.5%; HR 1.17; 95% CI 1.16-1.19; p < 0.001). The composite outcome of non-Alzheimer's dementia was also more frequent in the CKD with COPD cohort (4.6% vs. 3.9%; HR 1.07; 95% CI 1.04-1.10; p < 0.001). No significant association was observed for vascular dementia alone or mild cognitive impairment alone. Alzheimer's disease incidence was low in both cohorts, and lower observed hazards were identified in the COPD cohort (HR 0.85; 95% CI 0.80-0.91; p = 0.002), although these findings should be interpreted cautiously given the relatively short follow-up and higher competing mortality in the COPD cohort.

CONCLUSIONS: Among patients with CKD, coexisting COPD was associated with higher observed risks of mortality and non-Alzheimer's dementia during follow-up. Further longitudinal studies with longer follow-up and competing-risk methodology are warranted.},
}

@article {pmid42204862,
year = {2026},
author = {Jiménez, DA and Bagnati, PM and Flores-Montes, RE and Fernández, ML and Zuno-Reyes, A and Aguillon, D and Alaez-Verson, C and Becerra-Solano, LE and Behrens, MI and Branda, K and Chrem, P and Custodio, N and Ducaine, W and Dumois-Petersen, S and Figuera, L and Castaño, ML and Longoria, EM and Matute, E and Sánchez, V and Slachevsky, A and Sosa, AL and Surace, E and Takada, L and Yaeger, L and Ziegemeier, E and Guerra, JJL and , },
title = {Recommendations for genetic counseling for individuals at risk of autosomal dominant Alzheimer's disease in Latin America.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {22},
number = {5},
pages = {e71502},
doi = {10.1002/alz.71502},
pmid = {42204862},
issn = {1552-5279},
support = {K01AG073526/AG/NIA NIH HHS/United States ; SG-20-690363/ALZ/Alzheimer's Association/United States ; //Foundation for Barnes-Jewish Hospital/ ; //McDonnell International Scholars Academy, Washington University in St. Louis/ ; 11231023//ANID/FONDECYT/ ; },
mesh = {Humans ; *Genetic Counseling/methods ; *Alzheimer Disease/genetics/psychology ; Latin America ; Genetic Testing ; Genetic Predisposition to Disease ; },
abstract = {Autosomal dominant Alzheimer's disease (ADAD) represents a small but impactful subset of Alzheimer's cases. Asymptomatic individuals at genetic risk face substantial personal and family implications when considering predictive testing for known familial variants. Genetic counseling and testing (GCT) frameworks remain limited in Latin America (LatAm). Recommendations for GCT in LatAm were developed through an iterative, multidisciplinary consensus process. Evidence inputs included a structured literature review, site-level recommendations from participating LatAm centers, and a qualitative synthesis of focus groups with experienced investigators. The resulting model includes pre-test evaluation, sample collection, result disclosure, and structured follow-up. Core elements comprise mental health assessment, psychoeducation, exploration of expectations and decision-making needs, guided disclosure with emotional support, and a suggested 3-month post-disclosure reassessment using validated psychological measures. Our framework provides structured guidance for the safe and ethical delivery of GCT for ADAD through a multidisciplinary, culturally informed, and patient-centered approach in LatAm.},
}

Humans
*Genetic Counseling/methods
*Alzheimer Disease/genetics/psychology
Latin America
Genetic Testing
Genetic Predisposition to Disease

@article {pmid42191647,
year = {2026},
author = {Wang, J and Sun, F},
title = {The role of neddylation in mediating radiation-induced neuronal DNA damage and neuroinflammation: Implications for neurodegenerative diseases.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261447533},
doi = {10.1177/13872877261447533},
pmid = {42191647},
issn = {1875-8908},
abstract = {Neddylation is a post-translational modification that regulates multiple cellular processes, including DNA damage responses and inflammatory signaling. Dysregulation of these pathways has been implicated in neuronal dysfunction and neurodegeneration. This review summarizes current evidence from the literature regarding the role of neddylation in modulating neuronal responses to ionizing radiation-induced DNA damage, with a focus on mechanisms relevant to genomic instability and neuroinflammation. We reviewed experimental and mechanistic studies investigating neddylation-regulated DNA damage repair, telomere integrity, mitochondrial function, and inflammatory signaling in neuronal and neural-related models, particularly in the context of ionizing radiation exposure. Evidence from the literature indicates that neddylation influences key components of the DNA damage response, including repair pathway choice, telomere stability, and mitochondrial homeostasis, as well as inflammatory signaling cascades. Ionizing radiation serves as an experimental paradigm to investigate these processes under conditions of acute genomic stress. While ionizing radiation does not recapitulate the full complexity of neurodegenerative diseases, radiation-based models provide mechanistic insight into neddylation-regulated pathways that may contribute to neuronal dysfunction. The potential relevance of these mechanisms to Alzheimer's disease and other neurodegenerative disorders warrants cautious interpretation and further investigation.},
}

@article {pmid42191654,
year = {2026},
author = {Isei, MO and Okeowo, OM and Okoye, CN and Sobodu, TO},
title = {Enhancing global Alzheimer's disease drug outcomes by comprehensive African data integration.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261452117},
doi = {10.1177/13872877261452117},
pmid = {42191654},
issn = {1875-8908},
abstract = {Alzheimer's disease (AD) remains the leading cause of dementia worldwide and continues to pose a substantial therapeutic challenge. Although recent advances in disease-modifying treatments targeting amyloid-β pathology have generated cautious optimism, their translational impact is limited by persistent gaps in population and geographic representation within clinical trials. African populations, the most genetically diverse worldwide, remain markedly underrepresented in AD genomic and therapeutic studies. This gap limits the identification of ancestry-specific genetic risk factors and differential treatment responses and may contribute to the high attrition rates observed across AD drug development pipelines. We examine how the limited inclusion of African cohorts restricts insights into AD pathobiology and reduces the external validity of emerging therapeutic strategies. We highlight opportunities arising from the systematic integration of African population and clinical data, which have the potential to reveal novel biological mechanisms and expand the global relevance of candidate interventions. Persistent barriers, including insufficient research infrastructure and frequent substitution of African American cohorts for indigenous African populations, continue to obscure population-specific variation and hinder the development of a representative evidence base. Advancing the field will require coordinated and context-appropriate recruitment strategies, predictive modeling approaches grounded in region-specific data, and long-term investment in research capacity across the continent. A globally representative scientific framework that captures the full spectrum of human genetic heterogeneity is essential for accelerating progress in AD drug development. Integrating African population and data into clinical research will strengthen scientific rigor, enhance generalizability, and facilitate the development of globally equitable therapeutic strategies.},
}

@article {pmid42191751,
year = {2026},
author = {Okda, M and El-Masry, SM and Helmy, MW and Abbas, H},
title = {Herbosomal nanocarriers using natural-origin surfactants: a quercetin-based strategy for Alzheimer's disease and oxidative-stress-driven neurodegeneration.},
journal = {Scientific reports},
volume = {16},
number = {1},
pages = {},
pmid = {42191751},
issn = {2045-2322},
mesh = {*Quercetin/chemistry/pharmacology/administration & dosage ; *Oxidative Stress/drug effects ; *Alzheimer Disease/drug therapy/pathology/metabolism ; *Surface-Active Agents/chemistry ; Animals ; Antioxidants/chemistry/pharmacology/administration & dosage ; *Drug Carriers/chemistry ; Neuroprotective Agents ; Polysorbates/chemistry ; *Nanoparticles/chemistry ; },
abstract = {Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by oxidative stress, neuroinflammation, and cholinergic dysfunction. Quercetin (QUE) is a multifunctional flavonoid with potent antioxidant and anti-inflammatory effects and proven neuroprotective, anticancer, antimicrobial, and hepatoprotective potential. However, its therapeutic translation, particularly in the management of Alzheimer's disease, is severely limited by low aqueous solubility, low bioavailability, and rapid metabolism. The current study aims to develop QUE-loaded herbosomes as an advanced phytophospholipid delivery system for AD treatment, with a focus on replacing the synthetic surfactant Tween 80 with natural-origin betaine surfactants to overcome the drawbacks of poor biocompatibility and chronic toxicity associated with conventional surfactants. QUE herbosomes were developed using the thin-film hydration method and evaluated for physicochemical characteristics, stability, and in vitro release behavior. Formulation variables were optimized to obtain herbosomal systems with favorable nanoscale properties and sustained drug release. DSC and FTIR analyses confirmed successful incorporation of quercetin within the vesicular structure. Compared with QUE suspension, the optimized QUE herbosomal formulations (F5 &F6) showed significantly higher effect in aluminum chloride-induced AD as evidenced by Behavioral testing, biochemical, and Histopathological analyses. These findings suggest that the developed QUE herbosomes with natural-origin surfactants offer a safe and biocompatible alternative to synthetic surfactant herbosomes, improving therapeutic outcomes in AD and holding promise for other oxidative stress-related neurodegenerative conditions.},
}

*Quercetin/chemistry/pharmacology/administration & dosage
*Oxidative Stress/drug effects
*Alzheimer Disease/drug therapy/pathology/metabolism
*Surface-Active Agents/chemistry
Animals
Antioxidants/chemistry/pharmacology/administration & dosage
*Drug Carriers/chemistry
Neuroprotective Agents
Polysorbates/chemistry
*Nanoparticles/chemistry

@article {pmid42191803,
year = {2026},
author = {Jalili, M and Babaei, P and Golshekan, M and Abedinzade, M and Andalib, S},
title = {Quercetin-loaded cellulose nanofibers improve memory, learning, and attenuate endoplasmic reticulum stress in a rat model of Alzheimer's disease.},
journal = {Scientific reports},
volume = {},
number = {},
pages = {},
doi = {10.1038/s41598-026-54595-w},
pmid = {42191803},
issn = {2045-2322},
abstract = {Alzheimer's disease (AD) lacks effective disease-modifying therapy. This study evaluated the neuroprotective efficacy of quercetin-loaded cellulose nanofibers (QNP) in a streptozotocin (STZ)-induced AD rat model, focusing on memory impairment and endoplasmic reticulum (ER) stress. Forty-eight male Wistar rats were randomly allocated to six groups (n = 8): Control, AD model (ICV STZ 3 mg/kg on days 1 and 3), STZ + empty cellulose nanoparticles, STZ + free quercetin (10 mg/kg IP), STZ + QNP (10 mg/kg IP, equivalent quercetin dose), and STZ + donepezil (1 mg/kg IP) for 14 days. Morris water maze testing revealed that QNP significantly reduced escape latency during acquisition (31%, P < 0.001 vs. AD model) and increased time spent in the target quadrant during the probe trial (P < 0.01). QNP treatment resulted in significantly greater improvement compared to an equivalent dose of free quercetin (P < 0.05). RT-PCR demonstrated XBP-1 mRNA splicing exclusively in the AD model group, indicating activation of the unfolded protein response (UPR). Both free quercetin and QNP completely prevented this splicing, demonstrating potent suppression of ER stress. Cellulose nanofiber-mediated delivery significantly enhances quercetin's bioavailability and therapeutic efficacy, ameliorating cognitive deficits in AD likely via mitigation of ER stress. QNP represents a promising, biocompatible nano-therapeutic strategy for Alzheimer's disease.},
}

@article {pmid42191897,
year = {2026},
author = {Zhang, XY and Ho, HL and Feng, ZP and Sun, HS},
title = {TRPM7 kinase: a target for multimodal drug development in neurological disorders.},
journal = {Acta pharmacologica Sinica},
volume = {},
number = {},
pages = {},
pmid = {42191897},
issn = {1745-7254},
abstract = {Neurological disorders impose a rising global burden and often remain challenging to treat with conventional interventions, as their pathologies arise from interconnected cascades involving ionic imbalance, oxidative stress, mitochondrial dysfunction, and neuroinflammation. Transient receptor potential melastatin 7 (TRPM7) is a bifunctional "chanzyme" combining a divalent-permeable cation channel with a C-terminal α-kinase domain. This review synthesizes current knowledge of TRPM7 kinase, including its structural organization and regulation, and surveys its physiological roles in the nervous system. Converging genetic and pharmacological evidence links TRPM7 kinase activity to diverse brain pathologies, including ischemic and hypoxic-ischemic injury, epilepsy, Alzheimer's disease, and glioblastoma. Notably, TRPM7 kinase inactivation or inhibition exerts multimodal neuroprotection by attenuating apoptosis, oxidative stress, inflammation, and cytoskeletal remodeling. We also summarize emerging small-molecule modulators that probe kinase function, while acknowledging key limitations in selectivity, potential off-target effects, and uncertain brain penetration. Beyond these pharmacological challenges, critical gaps remain in defining kinase-channel coupling, cell type-specific substrate networks, and therapeutic windows in translational models. Overall, by integrating oxidative, inflammatory, and metabolic signaling with cytoskeletal control, TRPM7 kinase represents an underexplored but promising therapeutic node for modulating the complex injury pathways that underlie many neurological disorders. TRPM7 structure and its kinase-regulated signaling pathways in neurological disease. Schematic overview of TRPM7 structure and its involvement in cytoskeletal remodeling and glioblastoma progression, glial stem cells maintenance, nuclear translocation under OGD/R, Aβ degradation in Alzheimer's disease, seizure susceptibility and ischemic-related apoptosis and neuroinflammation. Abbreviations: Aβ amyloid-beta, OGD/R oxygen-glucose deprivation/reoxygenation. Created in https://BioRender.com .},
}

@article {pmid42191917,
year = {2026},
author = {Jiménez-Huete, A and Ulloa Bravo, JS and Martín-Bastida, A and Rognoni, T and Montoya-Murillo, G and Rodríguez-Oroz, MC and Riverol, M and , },
title = {CogStrat: web-based tools for predicting incident cognitive impairment in cognitively normal older adults.},
journal = {Journal of neural transmission (Vienna, Austria : 1996)},
volume = {},
number = {},
pages = {},
pmid = {42191917},
issn = {1435-1463},
abstract = {Early identification of individuals at increased risk of cognitive impairment is crucial for timely intervention. We developed and evaluated Cox proportional hazards models and translated them into web-based applications to predict incident cognitive impairment in cognitively normal older adults using clinical data, with optional biomarker inputs. Data were drawn from cognitively unimpaired participants in the Alzheimer's Disease Neuroimaging Initiative (ADNI). Models included demographic and neuropsychological variables, with optional genetic, neuroimaging, and fluid (plasma and CSF) biomarkers. Performance was assessed using the C-index, calibration slope, and decision curve analysis, with internal validation via bootstrap resampling. Key models were externally validated in the Harvard Aging Brain Study. The ADNI sample comprised 729 participants (median age 73 years; 45% male). A clinical model including age, education, Montreal Cognitive Assessment, and delayed word recall showed acceptable discrimination (C-index 0.721; CI 0.672-0.772) and strong calibration (slope 0.940). Adding biomarkers improved performance, with the highest discrimination observed for a model including FDG and florbetapir PET uptake (C-index 0.805; CI 0.759-0.886). Discrimination remained stable after internal and external validation, while calibration was weaker for most plasma biomarkers. Five web applications (CogStrat) were developed using clinical data alone or combined with hippocampal volume, CSF tau/Aβ42, plasma neurofilament light chain, or FDG and florbetapir PET. These tools provide individualized risk group classifications, 5-year risk estimates, and 10-year cumulative incidence curves. CogStrat translates prognostic models into freely accessible, interactive tools that support risk stratification of cognitive impairment in cognitively normal older adults.},
}

@article {pmid42191948,
year = {2026},
author = {Chiaravalloti, A and Motta, C and Bonomi, CG and Poli, M and Di Russo, C and Schillaci, O and Martorana, A},
title = {Plasma phosphorylated tau biomarkers map onto [^18F]FDG PET hypometabolism: a voxel-wise study in a clinical cohort with CSF-confirmed AD subgroup analysis.},
journal = {European journal of nuclear medicine and molecular imaging},
volume = {},
number = {},
pages = {},
pmid = {42191948},
issn = {1619-7089},
abstract = {PURPOSE: To examine voxel-wise associations between plasma phosphorylated tau biomarkers and cerebellum-normalised [^18F]fluorodeoxyglucose ([^18F]FDG) positron emission tomography (PET) uptake in cognitively impaired patients, and whether these associations persist in a cerebrospinal fluid (CSF)-confirmed Alzheimer's disease (AD) subgroup.

METHODS: One hundred consecutive patients who underwent brain [^18F]FDG PET and plasma biomarker assessment within ≤ 6 months were included. Images were spatially normalised, smoothed, and divided voxel-wise by a subject-specific bilateral cerebellar reference value derived from Automated Anatomical Labelling 3 (AAL3) cerebellar regions. Voxel-wise multiple regressions tested associations with plasma Aβ42/Aβ40, p-tau181, p-tau181/Aβ42, p-tau217, and p-tau217/Aβ42, adjusting for age and sex, in the full cohort and the CSF-confirmed AD subgroup (n = 58).

RESULTS: In the full cohort, plasma p-tau181 and p-tau181/Aβ42 showed negative associations with cerebellum-normalised [^18F]FDG uptake, predominantly in bilateral ventral temporal/fusiform regions. The strongest and most spatially consistent finding involved p-tau181/Aβ42. Plasma Aβ42/Aβ40 and p-tau217 showed no suprathreshold associations, whereas p-tau217/Aβ42 showed only a small focal cluster. In the CSF-confirmed AD subgroup, p-tau181/Aβ42 remained the most consistent tau-related marker, showing negative associations with cerebellum-normalised [^18F]FDG uptake in temporal/temporo-limbic and posterior cortical regions, whereas p-tau217 and p-tau217/Aβ42 showed no suprathreshold clusters.

CONCLUSIONS: After voxel-wise cerebellar normalisation, plasma p-tau181/Aβ42 showed the most robust association with [^18F]FDG PET hypometabolism, predominantly involving bilateral ventral temporal/fusiform regions in the full cohort and temporal/temporo-limbic and posterior cortical regions in the CSF-confirmed AD subgroup. The heterogeneous full-cohort findings may partly reflect AD-versus-non-AD biological separation. Overall, plasma tau biomarkers and [^18F]FDG PET provide complementary molecular and metabolic information.},
}

@article {pmid42191949,
year = {2026},
author = {Robinson, CG and Binette, AP and Horie, K and Sato, C and Schindler, SE and Bateman, RJ and Benzinger, TLS and Janelidze, S and Singleton, E and Stomrud, E and An, GZ and Pedersen, TJ and Palmqvist, S and Mattsson-Carlgren, N and Morris, JC and Hansson, O and Gordon, BA and Ossenkoppele, R},
title = {Tau-PET and CSF MTBR-tau243 comparisons validate increased tau aggregation in females.},
journal = {European journal of nuclear medicine and molecular imaging},
volume = {},
number = {},
pages = {},
pmid = {42191949},
issn = {1619-7089},
support = {P01AG026276/AG/NIA NIH HHS/United States ; P01AG003991/AG/NIA NIH HHS/United States ; R01AG070941/AG/NIA NIH HHS/United States ; 5T32AG058518/AG/NIA NIH HHS/United States ; R01AG083740/AG/NIA NIH HHS/United States ; SG-23-1061717/ALZ/Alzheimer's Association/United States ; },
abstract = {BACKGROUND: Females consistently demonstrate greater tau Positron Emission Tomography (PET) tracer signal. Although interpreted as reflecting greater Alzheimer disease (AD) pathology, it's unclear whether differences arise from biological mechanisms or methodological factors. Microtubule binding region tau species containing residue 243 (MTBR-tau243) in cerebrospinal fluid (CSF) is a biomarker of aggregated tau but avoids PET limitations such as off-target binding. Comparing tau-PET and CSF MTBR-tau243, including sex interactions, can help elucidate the origin of sex differences in tau.

PURPOSE: Conduct a cross-sectional analysis of CSF MTBR-tau243 and tau-PET by sex in the Swedish BioFINDER-2 (BioFINDER-2) Study and Charles F. and Joanne Knight Alzheimer Disease Research Center (Knight-ADRC).

METHODS: Participants had CSF MTBR-tau243, tau-PET, and Aβ status defined by the CSF Aβ42/40 ratio. Tau-PET was measured using [[18]F]Flortaucipir (Knight-ADRC, N = 219) and [[18]F]RO948 (BioFINDER-2, N = 446). We tested the interaction between sex and CSF MTBR-tau243 on tau-PET burden in a temporal meta region-of-interest (ROI) across all participants and in Aβ-positive participants.

RESULTS: In both cohorts, CSF MTBR-tau243 was associated with tau-PET temporal meta-ROI burden (BioFINDER-2: β = 1.1, p = < 0.0001 and Knight-ADRC: β = 0.7, p = < 0.0001), and this association did not differ by sex (BioFINDER-2 β = 0.04, p = 0.6 and Knight-ADRC: β = 0.009, p = 0.9). Among Aβ-positive subgroups, results remained consistent for the main effect (BioFINDER-2: β = 1.1, p = < 0.0001 and Knight-ADRC: β = 0.7, p = < 0.0001) and interaction (BioFINDER-2: β = 0.04, p = 0.7 and Knight-ADRC: β = 0.06, p = 0.6).

CONCLUSION: The lack of sex moderating the association between tau-PET and CSF MTBR-tau243 indicates that higher tau-PET signal in females reflects greater susceptibility to tau pathology rather than a methodological artifact.},
}

@article {pmid42192129,
year = {2026},
author = {Zhang, Y and Sun, J and Cai, Y and Xu, Z and Li, X and Wei, W and Liu, P and Sun, Q and Wang, ZH and Cui, Y},
title = {FAM134B-mediated ER-phagy degrades APP and suppresses Alzheimer's disease pathology.},
journal = {The EMBO journal},
volume = {},
number = {},
pages = {},
pmid = {42192129},
issn = {1460-2075},
support = {2024ZD0530100//MOST | National Key Research and Development Program of China (NKPs)/ ; 92578120,32370806//MOST | National Natural Science Foundation of China (NSFC)/ ; 2042025kf0001,2042022dx0003//MOE | Fundamental Research Funds for the Central Universities (Fundamental Research Fund for the Central Universities)/ ; },
abstract = {Endoplasmic reticulum autophagy (ER-phagy) is a selective autophagy pathway in which receptor proteins target ER membranes and proteins for degradation, yet its role in Alzheimer's disease (AD) remains unclear. Here, we identify FAM134B/RETREG1 as a specific ER-phagy receptor mediating amyloid precursor protein (APP) degradation. FAM134B directly interacts with ER-localized wild-type and familial mutant APP via their C-terminal domains and recruits LC3 through its LC3-interacting region (LIR) to promote APP delivery to phagophores for lysosomal degradation. In AD, epigenetic silencing at the FAM134B promoter suppresses its transcription by limiting TFEB/TFE3 binding despite their nuclear enrichment. This transcriptional suppression impairs ER-phagy, leading to APP accumulation and exacerbated AD pathology. AAV-mediated hippocampal expression of wild-type, but not LIR-mutant, FAM134B in 5XFAD mice restores ER-phagy, enhances APP clearance, reduces Aβ deposition, preserves synaptic and myelin integrity, and improves cognitive performance. These findings establish FAM134B downregulation as an upstream pathogenic event in AD, suggesting ER-phagy enhancement as a promising strategy to suppress Aβ generation at its source.},
}

@article {pmid42192197,
year = {2026},
author = {Liang, C and Zhou, Y and Zhuang, K and Wang, S and Zhong, L and Can, D and Lei, A and Li, H and Zhang, J and Leng, L},
title = {Microglial mitochondria transfer to astrocytes via GPNMB-enriched extracellular vesicles alleviates cognitive deficits in tauopathy mice.},
journal = {Nature neuroscience},
volume = {},
number = {},
pages = {},
pmid = {42192197},
issn = {1546-1726},
support = {2024J010001 to LL.//Natural Science Foundation of Fujian Province (Fujian Provincial Natural Science Foundation)/ ; },
abstract = {Alzheimer's disease (AD) is an irreversible neurodegenerative disease characterized by cognitive decline. The precise molecular mechanisms that underlie the pathogenesis of AD remain elusive. Here we show that glycoprotein nonmetastatic melanoma protein B (GPNMB) is produced by microglia and transferred to astrocytes through extracellular vesicles (EVs) in PS19 tau pathology mice. Tau is cleaved in microglia to generate N-terminal fragments that form a complex on mitochondria with Parkin/Nix and GPNMB, promoting the secretion of EVs containing mitochondria. Functional mitochondria transferred to astrocytes via EVs markedly improve astrocytic functions and attenuate the cognitive impairments and pathogenic features in PS19 mice. By contrast, microglial GPNMB deficiency eliminates mitochondrial EV secretion and mitochondrial transfer to astrocytes, thereby impairing astrocytic functions and exacerbating cognitive impairment in PS19-CcKO (CX3CR1 cre Gpnmb floxp) mice. GPNMB-enriched EVs from PS19 mice alleviate the pathological phenotypes of PS19 mice, offering potential insights for AD treatment.},
}

@article {pmid42192211,
year = {2026},
author = {Gaur, A and Wong, M and Chen, JJ and Kang, Y and Tahoulas, D and Jeor, K and Raguram, KH and Gallagher, D and Rapoport, M and Herrmann, N and Lanctôt, KL},
title = {Synaptic biomarkers in Alzheimer's disease dementia and mild cognitive impairment: A systematic review and meta-analysis.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {22},
number = {5},
pages = {e71501},
doi = {10.1002/alz.71501},
pmid = {42192211},
issn = {1552-5279},
support = {PTCG-20-700751/ALZ/Alzheimer's Association/United States ; /CAPMC/CIHR/Canada ; //Toronto Rehabilitation Institute/ ; ASRP #21-11//Alzheimer Society Research Program/ ; },
mesh = {Humans ; *Alzheimer Disease/cerebrospinal fluid/blood ; *Biomarkers/cerebrospinal fluid/blood ; *Cognitive Dysfunction/cerebrospinal fluid/blood ; *Synapses/metabolism ; Synaptosomal-Associated Protein 25/cerebrospinal fluid ; },
abstract = {INTRODUCTION: Alzheimer's disease (AD) is characterized by synaptopathy, a neuropathological feature that can contribute to underlying cognitive decline. Here, we evaluate potential cerebrospinal fluid (CSF) and blood-based synaptic biomarkers in AD dementia and its earliest clinical stage, mild cognitive impairment (MCI).

METHODS: Articles that measured a subset of CSF and/or blood-based synaptic biomarkers in AD dementia, MCI, and/or healthy controls were included. A random-effects model was used to determine standardized mean differences and 95% confidence intervals.

RESULTS: In total, 65 study cohorts were included for meta-analysis and 12 for qualitative review. Several CSF (synaptosomal-associated protein 25 [SNAP-25], growth-associated protein 43 [GAP-43], neuronal pentraxin receptor, neuronal pentraxin-1, neuronal pentraxin-2, synaptotagmin-1, syntaxin-1B, and vesicle-associated membrane protein 2) and blood-based (SNAP-25, GAP-43, and synaptotagmin-1) synaptic biomarkers were altered in AD dementia and/or MCI.

DISCUSSION: Further evaluation of these identified biomarkers may enrich our understanding of AD pathophysiology and disease trajectory, as well as inform future treatment interventions.},
}

Humans
*Alzheimer Disease/cerebrospinal fluid/blood
*Biomarkers/cerebrospinal fluid/blood
*Cognitive Dysfunction/cerebrospinal fluid/blood
*Synapses/metabolism
Synaptosomal-Associated Protein 25/cerebrospinal fluid

@article {pmid42192214,
year = {2026},
author = {Altschuler, F and Castro-Laguardia, AM and Canziani, V and O'Byrne, DF and Hazelton, J and Migeot, J and Maito, M and García, AM and Bruno, MA and Magrath, N and Slachevsky, A and Behrens, MI and Custodio, N and Ávila-Funes, JA and Matallana, D and Aguillón, D and Santamaria-García, H and Resende, E and Takada, L and Brusco, LI and Yokoyama, JS and Miller, B and Ibáñez, A and Medel, V and Campo, CG},
title = {Mapping the neurovascular landscape in aging and dementia: cerebral small vessel disease markers in a multicenter Latin American cohort.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {22},
number = {5},
pages = {e71468},
doi = {10.1002/alz.71468},
pmid = {42192214},
issn = {1552-5279},
support = {/TW/FIC NIH HHS/United States ; /NH/NIH HHS/United States ; SG-20-725707/ALZ/Alzheimer's Association/United States ; AARG-25-1490306/ALZ/Alzheimer's Association/United States ; //Global Brain Health Institute/ ; //Rainwater Charitable Foundation/ ; //Consejo Nacional de Investigaciones Científicas y Técnicas/ ; //National Institutes of Health (US)/ ; 13240170//Agencia Nacional de Investigación y Desarrollo/ ; 11251578//Agencia Nacional de Investigación y Desarrollo/ ; //FONDECYT de exploración 13240170/ ; /AG/NIA NIH HHS/United States ; },
mesh = {Humans ; *Cerebral Small Vessel Diseases/diagnostic imaging/epidemiology/pathology ; Latin America/epidemiology ; Cross-Sectional Studies ; Magnetic Resonance Imaging ; Female ; Male ; Aged ; *Aging/pathology ; White Matter/diagnostic imaging/pathology ; *Dementia/diagnostic imaging ; *Alzheimer Disease/diagnostic imaging ; Risk Factors ; Middle Aged ; Cohort Studies ; Brain ; Biomarkers ; },
abstract = {INTRODUCTION: Cerebral small vessel disease (CSVD) is a key contributor to cognitive impairment and dementia, yet few studies have compared CSVD across dementia variants, particularly in underrepresented populations.

METHODS: In a multicenter cross-sectional study, we analyzed magnetic resonance imaging (MRI) markers of CSVD, including white matter hyperintensities (WMHs), lacunes, and cerebral microbleeds, along with cardiometabolic risk factors and cognitive performance using regression models in 1675 participants (790 healthy controls, 642 with Alzheimer's disease [AD], and 243 with frontotemporal dementia [FTD]) from six Latin American countries.

RESULTS: AD showed the greatest CSVD burden, whereas FTD exhibited an intermediate profile driven by elevated WMHs. Blood pressure and smoking were the strongest correlates of WMHs, while diabetes was associated with microbleeds. WMH burden was linked to global and domain-specific cognitive impairment.

DISCUSSION: This first large-cohort Latin American study identifies WMHs as a key vascular substrate of cognitive impairment, with AD showing the greatest CSVD burden.},
}

Humans
*Cerebral Small Vessel Diseases/diagnostic imaging/epidemiology/pathology
Latin America/epidemiology
Cross-Sectional Studies
Magnetic Resonance Imaging
Female
Male
Aged
*Aging/pathology
White Matter/diagnostic imaging/pathology
*Dementia/diagnostic imaging
*Alzheimer Disease/diagnostic imaging
Risk Factors
Middle Aged
Cohort Studies
Brain
Biomarkers

@article {pmid42192504,
year = {2026},
author = {Li, P and Liu, L and Wu, Y and Liu, M and Trojanowska, M and Fan, H},
title = {STUB1-mediated ubiquitination regulates Fli-1 stability and CD4[+]T cell activation during inflammation.},
journal = {Molecular medicine (Cambridge, Mass.)},
volume = {},
number = {},
pages = {},
doi = {10.1186/s10020-026-01494-5},
pmid = {42192504},
issn = {1528-3658},
support = {R35GM149203/GM/NIGMS NIH HHS/United States ; R01AG081807/AG/NIA NIH HHS/United States ; },
abstract = {BACKGROUND: Fli-1, a member of the ETS transcription factor family, has been implicated in multiple inflammatory and immune-related disorders, including sepsis, lupus, Alzheimer's disease, and post-traumatic stress disorder (PTSD). Recent studies further suggest a critical role for Fli-1 in CD4[+] T cells in graft-versus-host disease, systemic sclerosis, and PTSD; however, its precise function and regulation during inflammatory CD4[+] T cell responses remain incompletely understood.

METHODS: Wild-type and CD4⁺ T cell-specific Fli-1 knockout mice were administered LPS via intraperitoneal injection. Survival rates and splenic T cell activation were subsequently assessed. In vitro, cultured Jurkat and HEK cells were utilized to investigate the STUB1/Fli-1-related signaling pathway.

RESULTS: Here, we demonstrate that Fli-1 expression is markedly upregulated in splenic CD4⁺ T cells in a murine model of endotoxemia. CD4⁺ T cell-specific deletion of Fli-1 significantly improves survival and attenuates splenic CD4⁺ T cell activation. Mechanistically, we identify STUB1 as a novel E3 ubiquitin ligase for Fli-1 that promotes K27-linked ubiquitination and proteasomal degradation under basal conditions. Inflammatory stimulation disrupts the STUB1/HSP70 interaction, reducing STUB1-mediated ubiquitination and enhancing Fli-1 protein stability. Consistent with these findings, Fli-1 knockout reduces TNFα, IFNγ, and IL-10 expression, whereas STUB1 knockout enhances their expression in Jurkat cells. Gain- and loss-of-function studies further reveal that Fli-1 modulates NFκB signaling, a key pathway in T cell activation.

CONCLUSIONS: Collectively, our results identify the STUB1/Fli-1 axis as a previously unrecognized regulator of CD4⁺ T cell function and a potential therapeutic target for inflammatory diseases.},
}

@article {pmid42192558,
year = {2026},
author = {Aggad, WS and Ghosh, R and Almohaimeed, HM and Mohammedsaleh, ZM and Saleh, FM and Almars, AI and Jyothi, SR and Panigrahi, R and Kumer, A and Dhara, B},
title = {Exosome-mediated gut-brain axis signaling in neurodegenerative diseases: Mechanisms, experimental evidence, and therapeutic perspectives-A narrative review.},
journal = {Animal models and experimental medicine},
volume = {},
number = {},
pages = {},
doi = {10.1002/ame2.70226},
pmid = {42192558},
issn = {2576-2095},
support = {PNURSP2026R213//Princess Nourah Bint Abdulrahman University/ ; },
abstract = {The stomach and the brain are connected by a sophisticated two-way communication mechanism called the gut-brain axis. Extracellular vesicles, particularly exosomes, that move bioactive substances between the stomach and the brain, such as proteins, lipids, metabolites, and microRNAs, may improve the gut-brain axis. In the past years, the role of exosome-mediated communication has been recognized as significant in relation to the etiology, continued progression, and potential treatment of neurodegenerative disorders. The authors of this review article present a summary of the current understanding of the relationship of gut microbiome, exosome biogenesis, and the pathophysiological development of neurodegenerative diseases. Evidence from laboratory studies, animal studies, and newly emerging human studies suggests that microbiome-based metabolites and inflammatory mediators may modulate how exosomes are produced, what they carry, and how they interact with the blood-brain barrier. These exosomal signals may impact neuroinflammation, neuronal signaling, and the spread of pathological proteins of neurodegenerative diseases, such as Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, and Huntington's disease. In addition, they examine some possible ways to target the gut-brain axis from a therapeutic perspective, including manipulating the gut microbiome, providing probiotics and/or prebiotics, performing fecal microbiota transplantation, and/or using engineered extracellular vesicles as vehicles for drug delivery. The authors also outline some of the methodological differences that make it difficult to assess the effects of exosomes.},
}

@article {pmid42192571,
year = {2026},
author = {Skrehot, JT and Kurouski, D},
title = {Biophysical assessment of the molecular mechanisms of Tau aggregation and its role in Alzheimer's disease.},
journal = {Protein science : a publication of the Protein Society},
volume = {35},
number = {6},
pages = {e70635},
doi = {10.1002/pro.70635},
pmid = {42192571},
issn = {1469-896X},
mesh = {*tau Proteins/metabolism/chemistry ; *Alzheimer Disease/metabolism/pathology ; Humans ; Animals ; Protein Processing, Post-Translational ; *Protein Aggregation, Pathological/metabolism ; Neurofibrillary Tangles/metabolism/pathology ; Protein Aggregates ; },
abstract = {Alzheimer's disease (AD) is characterized by the intracellular aggregation of the microtubule-associated protein Tau. While the presence of large, insoluble neurofibrillary tangles has long been the primary focus of this research, a paradigm shift in the field now highlights smaller, soluble oligomers as the more neurotoxic Tau species leading to neuronal death and cognitive decline. This leaves the important and ill-understood question of what molecular events lead to the conversion of healthy, functional Tau into these toxic oligomers. This review addresses the knowledge gap by investigating existing literature on the upstream mechanisms responsible for the onset of neurodegeneration and connecting it to disease pathogenesis. By synthesizing evidence from molecular biophysics, cellular biology, and neuropathology, this review summarizes the most recent understanding of factors contributing to pathological Tau aggregation, including post-translational modifications, lipids, and metal ions, among others. This review also discusses how neurotoxic Tau aggregates contribute to the onset of AD. By connecting these factors with findings from mammalian brain studies, this review establishes a comprehensive timeline of pathology that demystifies the transition from physiological Tau to toxic oligomers and links specific molecular triggers to the onset of neurodegeneration.},
}

*tau Proteins/metabolism/chemistry
*Alzheimer Disease/metabolism/pathology
Humans
Animals
Protein Processing, Post-Translational
*Protein Aggregation, Pathological/metabolism
Neurofibrillary Tangles/metabolism/pathology
Protein Aggregates

@article {pmid42192747,
year = {2026},
author = {Ved, A and Gajjar, TB and Kakkad, A and Ganesan, S and Shankhyan, A and Jayabalan, K and Mishra, S and Jain, B and Arora, V and Gulati, M and Behl, T and Akhtar, A},
title = {Neurovascular Uncoupling in Alzheimer's and Parkinson's Diseases: Mechanisms and Therapeutic Strategies.},
journal = {Brain sciences},
volume = {16},
number = {5},
pages = {},
doi = {10.3390/brainsci16050434},
pmid = {42192747},
issn = {2076-3425},
abstract = {Neurovascular coupling (NVC) maintains appropriate cerebral blood flow (CBF) in response to neuronal activity, and its disturbance, known as neurovascular uncoupling (NVU), is increasingly recognised as a major contributor to neurodegenerative disease. Alzheimer's disease (AD) NVU is caused by Aβ buildup, tau pathology, endothelial dysfunction, and persistent neuroinflammation, leading to poor CBF control and blood-brain barrier (BBB) disintegration. Parkinson's disease (PD) is characterised by α-synuclein aggregation, oxidative stress, mitochondrial dysfunction, and dopaminergic neuronal loss, all of which impede cerebrovascular regulation. These disease-specific mechanisms interact via similar vascular pathways, establishing NVU as a critical connection between neuronal degeneration and cerebrovascular dysfunction. This study highlights the critical role of NVU in neurodegeneration by investigating shared and disease-specific processes in AD and PD. Tau pathology disturbs vascular regulation in AD, whereas dopaminergic neuron loss impairs cerebrovascular control in PD. Both Aβ and α-synuclein are linked to endothelial dysfunction and oxidative stress, albeit originating in different pathologies. Comparative analysis reveals distinct vascular abnormalities in each condition, as well as shared processes such as inflammation and BBB disruption. The study also covers developments in biomarker discovery and neuroimaging techniques that allow for exact characterisation of NVU, facilitating early diagnosis and treatments. In addition, lifestyle changes and pharmacological treatments for oxidative stress and endothelial injury are being examined. This study highlights the significance of NVU as a fundamental pathogenic mechanism, underscoring its importance for comprehending disease development and formulating novel therapeutic strategies.},
}

@article {pmid42192756,
year = {2026},
author = {Tang, S and Fu, G and Yu, W and Zhou, M and Chen, T and Song, Z and Cheng, S and Li, P},
title = {Modulating Th17/Treg Balance in Alzheimer's Disease: Therapeutic Insights from Natural Compounds and Immunometabolism.},
journal = {Brain sciences},
volume = {16},
number = {5},
pages = {},
doi = {10.3390/brainsci16050443},
pmid = {42192756},
issn = {2076-3425},
support = {82575038//National Natural Science Foundation of China/ ; 2023RC3166//Science and Technology Innovation Program of Hunan Province/ ; 2023JJ20033//Natural Science Foundation of Hunan Province for Excellent Youth Project/ ; 23B0373//Outstanding Youth Project for Scientific Research of the Hunan Provincial Department of Education/ ; 2025JJ60910//Youth Student Basic Research Project of the Natural Science Foundation of Hunan Province/ ; S202410541053//Hunan Provincial College Students' Innovation and Entrepreneurship Training Program Project/ ; },
abstract = {Background/Objectives: Alzheimer's disease (AD) is a neurodegenerative disorder characterized by progressive cognitive decline and chronic neuroinflammation. Increasing evidence suggests that the imbalance between pro-inflammatory Th17 cells and anti-inflammatory regulatory T (Treg) cells plays a critical role in AD pathogenesis. However, a comprehensive synthesis of how natural compounds modulate Th17/Treg balance in AD remains lacking. This review aims to summarize current preclinical evidence on Th17/Treg dysregulation and evaluate the immunomodulatory potential of natural compounds in AD. Methods: This review focuses on preclinical evidence derived from experimental AD models and related inflammatory models to evaluate how natural compounds modulate Th17/Treg balance, neuroinflammation, and cognitive function, with an emphasis on underlying molecular and immunometabolic mechanisms. Results: Th17/Treg imbalance contributes significantly to AD-associated neuroinflammation and disease progression. Representative natural compounds, including paeoniflorin, quercetin, and ganoderic acid A, have demonstrated the ability to rebalance Th17/Treg responses, suppress neuroinflammation, and improve neuronal survival in experimental models. These compounds are highlighted due to their relatively stronger evidence in AD-related models and more clearly defined immunomodulatory mechanisms. These effects are partially mediated through modulation of key signaling pathways and immunometabolic reprogramming. Conclusions: Targeting Th17/Treg balance with natural compounds represents a promising multi-target immunomodulatory strategy for AD. However, most current evidence is derived from preclinical or non-AD models, and clinical validation remains limited. Future studies should prioritize AD-specific models and translational research to evaluate therapeutic potential in humans.},
}

@article {pmid42192778,
year = {2026},
author = {Ramírez Hernández, E and Netzahualcoyotzi, C and Hurtado-Alvarado, G and Sánchez, JL and Pereyra Morales, A and Arredondo-Zamarripa, D and Hernández-Zimbrón, LF and Papy-Garcia, D and Guevara, J and Gutiérrez Ponce, N and Gomez-Henao, W and Garfias, Y and Ortiz Chavez, G and Zenteno, E},
title = {The Effect of Metabolic Syndrome on Alzheimer's Disease: Physical Activity as a Preventive and Therapeutic Measure.},
journal = {Brain sciences},
volume = {16},
number = {5},
pages = {},
doi = {10.3390/brainsci16050465},
pmid = {42192778},
issn = {2076-3425},
support = {PAPIIT IA208726//Universidad Nacional Autónoma de México/ ; PAPIIT IN222724//Universidad Nacional Autónoma de México/ ; PAPIIT IN204624//Universidad Nacional Autónoma de México/ ; },
abstract = {Epidemiological and clinical research on neurodegenerative diseases has shown that metabolic dysregulations increase the risk of developing Alzheimer's Disease (AD). Many metabolic changes can be grouped into metabolic syndrome (MetS), which is defined as the presence of three or more risk factors, including insulin resistance, hyperglycemia, hypertension, central obesity, and dyslipidemia. These changes cause systemic effects that are crucial in triggering neuroinflammation and neurodegeneration, key factors in AD development. All these factors impair energy metabolism in peripheral tissues and the brain by decreasing glucose utilization, leading to alterations in O-GlcNAcylation, glycosylation, mitochondrial function, oxidative stress, chronic inflammation, synaptic dysfunction, autophagy impairment, and blood-brain barrier (BBB) dysfunction. However, these factors are modified and largely influenced by lifestyle choices. A newer perspective emphasizes that regular exercise is vital for maintaining brain metabolism as we age. Current evidence suggests that engaging in physical activity for individuals with metabolic syndrome reduces their risk of Alzheimer's disease, enhances prognosis, and improves cognitive abilities. This review explores how metabolic syndrome relates to Alzheimer's and highlights possible strategies for prevention and treatment.},
}

@article {pmid42192824,
year = {2026},
author = {Delucchi Danhier, R and Mertins, B},
title = {Combining Linguistic, Behavioral and Visuospatial Measures to Characterize Multidomain Impairment in Dementia.},
journal = {Brain sciences},
volume = {16},
number = {5},
pages = {},
doi = {10.3390/brainsci16050511},
pmid = {42192824},
issn = {2076-3425},
abstract = {Background/Objectives: Visuospatial impairments are among the earliest cognitive symptoms in Alzheimer's disease (AD) and related dementias (ADRD), yet standard assessments often lack ecological validity and focus on isolated domains. This study examines whether integrating linguistic, behavioral, and eye-tracking measures provides a more comprehensive characterization of cognitive deficits within a multimodal, exploratory framework. Methods: Twenty older adults (10 with mild to moderate dementia, including AD/ADRD, and 10 age-matched controls) completed three tasks: (1) oral narrative production, (2) visuospatial behavioral tasks (manipulation, recognition, reproduction), and (3) free-viewing eye-tracking. Linguistic, behavioral (time, errors), and fixation-based measures were analyzed using non-parametric statistics, with emphasis on effect sizes and cross-domain patterns. Results: The clinical group differed consistently from controls across domains. Linguistic measures showed increased output but reduced quality, including lower syntactic complexity, more grammatical errors, greater pragmatic deviations, and reduced gist comprehension. Behavioral tasks revealed slower performance and more frequent failures. Eye-tracking differences were less pronounced, showing a tendency toward longer fixations and less efficient visual exploration. A composite multimodal index showed clear separation between groups, indicating a consistent pattern of impairment across measures. Conclusions: Cognitive differences in dementia are expressed across multiple domains, with the strongest effects in linguistic and behavioral measures. These findings highlight the value of multimodal profiles for capturing multidimensional impairment. Results should be interpreted as exploratory and require confirmation in larger, confirmatory studies.},
}

@article {pmid42192839,
year = {2026},
author = {Valverde, HP and Clark, BJ and Hogeveen, J and Clark, VP},
title = {Noninvasive Brain Stimulation Techniques and Their Efficacy in Treating Cognition and Memory in Mild Cognitive Impairment and Alzheimer's Disease-A Systematic Review.},
journal = {Brain sciences},
volume = {16},
number = {5},
pages = {},
doi = {10.3390/brainsci16050527},
pmid = {42192839},
issn = {2076-3425},
abstract = {BACKGROUND/OBJECTIVES: The growing aging population is susceptible to cognitive and memory impairment, most commonly due to Alzheimer's disease, with no cures currently available. Noninvasive brain stimulation (NIBS) techniques may serve to improve cognition and delay catastrophic memory loss.

METHODS: A systematic review of NIBS research on cognitive impairment was carried out using PubMed, with additional backward citation searching. A total of 81 studies using NIBS were included.

CONCLUSIONS: The reviewed studies show that NIBS holds promise in improving memory deficits in patients with cognitive impairment. While the longevity of benefits from transcranial electrical stimulation appears limited, its short-term effects may provide benefits when used consistently. Transcranial magnetic stimulation appears to provide longer-lasting benefits. Transcranial focused ultrasound stimulation may also provide further benefits through more precise targeting of deeper brain structures compared to other NIBS techniques. Together, these results suggest that NIBS shows promise for the treatment of symptoms related to cognitive and memory impairment, and may help to alleviate some of the growing issues associated with the increasing level of Alzheimer's disease in an aging population.},
}

@article {pmid42193043,
year = {2026},
author = {Zamzuri, ZE and Kamaruzzaman, MA and Teoh, SL and Yahaya, MF},
title = {A Review of the Effect of Peripheral Amyloid β on the Central Nervous System.},
journal = {Current issues in molecular biology},
volume = {48},
number = {5},
pages = {},
doi = {10.3390/cimb48050438},
pmid = {42193043},
issn = {1467-3045},
support = {FF-2025-443//Universiti Kebangsaan Malaysia Faculty of Medicine Fundamental Grants (GFFP)/ ; },
abstract = {Alzheimer's disease (AD) is a progressive neurodegenerative disorder classically defined by cerebral amyloid β (Aβ) plaque deposition and tau pathology. In recent years, AD has increasingly been recognized as a multisystem disorder rather than a purely brain-restricted condition, as mounting evidence indicates that Aβ metabolism is a dynamic, bidirectional process involving both central and peripheral compartments. Peripheral tissues, particularly platelets, liver, kidneys, and the gastrointestinal tract, contribute substantially to circulating Aβ levels and influence cerebral amyloid burden. Platelets are now considered the predominant source of peripheral Aβ, accounting for the majority of plasma Aβ under physiological and pathological conditions, while the liver and kidneys play critical roles in Aβ clearance through receptor-mediated uptake, enzymatic degradation and excretion. Disruption of these peripheral clearance pathways elevates circulating Aβ, increasing its transport into the brain via blood-brain barrier (BBB) mechanisms by enhanced RAGE-mediated influx and impaired LRP1-dependent efflux in AD. Peripheral Aβ entry into the central nervous system exacerbates neuroinflammation, mitochondrial dysfunction, and oxidative stress, thereby accelerating neuronal damage and disease progression. This review synthesizes updated evidence on peripheral sources of Aβ, differences between central and peripheral Aβ pools, mechanisms of Aβ transport across the BBB, pathological consequences of peripheral Aβ on the brain and emerging therapeutic strategies targeting peripheral Aβ metabolism, highlighting the importance of a systemic perspective in AD pathogenesis and treatment.},
}

@article {pmid42193047,
year = {2026},
author = {Wang, K and Yang, X and Magwood, G and Xu, C and Navia, RO and Neils-Strunjas, J and Li, X},
title = {Family-Based GWAS of Cognitive Endophenotypes Reveals Genetic Architecture of Memory and Executive Function in Alzheimer's Disease.},
journal = {Current issues in molecular biology},
volume = {48},
number = {5},
pages = {},
doi = {10.3390/cimb48050442},
pmid = {42193047},
issn = {1467-3045},
abstract = {Alzheimer's disease (AD), the most common cause of dementia, is characterized by progressive memory and cognitive decline. Conventional genome-wide association studies (GWAS) comparing AD cases and controls may miss genetic influences that act along a continuum of cognitive function. Using data from 3007 participants in the National Institute on Aging Late-Onset Alzheimer's Disease Family Study (NIA-LOAD GWAS), we conducted a family-based GWAS of eight quantitative cognitive phenotypes encompassing episodic memory (Logical Memory IA and IIA), working memory (Digit Span Forward, Backward, and Ordering), and semantic fluency (Animal, Fruit and Vegetable, and Vegetable Fluency). Family-based association testing in PLINK v1.9 identified numerous single nucleotide polymorphisms (SNPs) associated with cognitive phenotypes at genome-wide significant (p < 5 × 10[-8]) levels. Notably, genome-wide significant variants with cognatic functions were localized to genes implicated in synaptic function, neurodevelopment, and neurodegeneration, including TOMM40 (rs2075650), ERBB4 (rs1521543), APLP2 (rs12281267, rs959354), PTPRD (rs1353983, rs970347, rs1392511), NCAM2 (rs2826728), GRM7 (rs6788201), PAX5 (rs2988003, rs2381595), NRG1 (rs16875655), and NRG3 (rs1937957). Furthermore, the TOMM40 (rs2075650) was significantly associated with AD as a binary outcome (p = 4.60 × 10[-24]) and APLP2 (rs12281267, rs959354), APOE (rs405509), PTPRD (rs1353983, rs970347, rs1392511) were associated with AD (p < 0.001). Additionally, several pathways including the ERBB4 signaling pathway (adjusted p = 2.82 × 10[-3]), driven by ERBB4, NRG1, and NRG3 may contribute to cognitive impairments. This study provides a comprehensive resource of cognitive endophenotype associations in AD families, advancing understanding of the genetic architecture underlying memory, executive function, and cognitive aging, and highlights new therapeutic targets for replication and functional follow-up.},
}

@article {pmid42193226,
year = {2026},
author = {Kim, G and Lee, J and Kwon, S and Yeom, E and Lee, DS},
title = {Peroxiredoxin-Mediated Redox Regulation in Neurons: From Neurite Development to Degeneration.},
journal = {Antioxidants (Basel, Switzerland)},
volume = {15},
number = {5},
pages = {},
doi = {10.3390/antiox15050604},
pmid = {42193226},
issn = {2076-3921},
support = {RS-2026-25479839//National Research Foundation of Korea/ ; RS-2023-00301914//National Research Foundation of Korea/ ; P0025489//Ministry of Trade, Industry and Energy/ ; },
abstract = {In the nervous system, reactive oxygen species (ROS) serve essential roles in intracellular signaling, but their dysregulation can impair neuronal function and survival. Peroxiredoxins (Prdxs) have classically been regarded as antioxidant enzymes that scavenge peroxides, yet a growing body of evidence indicates that their roles in the brain extend beyond ROS removal. They are increasingly recognized as regulators of redox-dependent processes with isoform-specific roles. In this review, we discuss the functions of Prdxs in the brain from a broad cellular perspective, focusing on their roles in neuronal differentiation, mitochondrial and endoplasmic reticulum (ER) homeostasis, and major neurological disorders including Alzheimer's disease, Parkinson's disease, and ischemic stroke. Prdx isoforms show distinct condition-dependent functions regulated by localization, regulatory state, and cellular environment. Collectively, a broader view of Prdxs as dynamic modulators of neural cell biology may help us understand their coordinated integrate their roles in the coordinated regulation of redox-sensitive cellular processes. Clarifying the isoform-specific and cell-type-specific dependent mechanisms underlying their function will be essential in defining the roles of Prdxs in brain physiology and diseases and to evaluating their therapeutic potential.},
}

@article {pmid42193260,
year = {2026},
author = {Virk, JP and Fernando, MG and Asih, PR and Martins, RN},
title = {Translational Feasibility of Curcumin for Treatment of Alzheimer's Disease: A Critical Appraisal of Clinical Challenges.},
journal = {Antioxidants (Basel, Switzerland)},
volume = {15},
number = {5},
pages = {},
doi = {10.3390/antiox15050638},
pmid = {42193260},
issn = {2076-3921},
abstract = {The absence of robust and effective treatments for Alzheimer's disease remains a major challenge in modern medicine. As one of the leading causes of death, its increasing prevalence and complex chronic pathogenesis impose a substantial societal and healthcare burden, intensifying the need for effective therapeutic strategies. Current treatments remain limited, with minimal impact on cognitive decline in symptomatic patients. Curcumin, the bioactive ingredient in turmeric, has taken precedence over other natural products due to its potent antioxidative and anti-inflammatory properties. Numerous publications have extensively reported on the therapeutic effect of curcumin in animal models of Alzheimer's disease. However, no curcumin formulation has demonstrated consistent clinical efficacy against Alzheimer's or other neurodegenerative diseases to date. Over the years, many critics have argued that curcumin's undesirable chemical properties, mainly low bioavailability and rapid metabolism, pose significant barriers to its therapeutic use to target the brain. Considerable funding and research effort on emerging technologies such as nanoparticles and intranasal delivery continue to drive curcumin preclinical and clinical trials, prompting reflection on the rationale for continued investment. This narrative review critically dissects this disconnect, arguing that many purported benefits remain insufficiently substantiated, and identifying important opportunities where future research may hold promise for an effective treatment.},
}

@article {pmid42193280,
year = {2026},
author = {Kwak, S and Kim, JK and Lee, YU and Baek, HS and Kwon, YJ and Park, MN and Hong, JH and Lee, SB and Kim, HW and Kim, S},
title = {The Central Role of Neuronal Cell Death in Alzheimer's Disease Pathobiology.},
journal = {Biomedicines},
volume = {14},
number = {5},
pages = {},
doi = {10.3390/biomedicines14050953},
pmid = {42193280},
issn = {2227-9059},
support = {RS-2023-00249115//National Research Foundation of Korea/ ; RS-2023-00246208//National Research Foundation of Korea/ ; RS-2023-00243836//National Research Foundation of Korea/ ; RS-2024-00405401//Ministry of Education/ ; RS-2024-00439078//National Research Foundation of Korea/ ; RS-2025-16068346//National Research Foundation of Korea/ ; },
abstract = {Alzheimer's disease (AD) is a progressive neurodegenerative disorder in which amyloid β accumulation, tau pathology, chronic neuroinflammation, and metabolic stress converge to drive synaptic dysfunction and neuronal loss. Rather than resulting from a single mechanism, increasing evidence indicates that neurodegeneration in AD is mediated by the coordinated activation of multiple regulated cell death pathways. These pathways include apoptosis, necroptosis, pyroptosis, ferroptosis, and autophagy-dependent cell death, each characterized by distinct molecular mediators and execution programs. Evidence from human brain tissues, animal models, and in vitro systems demonstrates that core pathological drivers such as amyloid β and tau pathology, oxidative stress, and sustained neuroinflammation engage these death pathways in a spatially, temporally, and cell-type-dependent manner across neurons and glial populations. In this review, we synthesize the current knowledge on regulated cell death mechanisms in AD, emphasizing their molecular signatures, cellular specificity, and stage-dependent involvement, together with recent advances in immunohistochemical, imaging, and biofluid-based approaches for detecting neuronal death. By integrating evidence across molecular, cellular, and system levels, this review positions regulated cell death as a unifying framework for understanding neurodegeneration and developing pathway-specific biomarkers and combinatorial neuroprotective strategies.},
}

@article {pmid42193325,
year = {2026},
author = {Xiao, B and Chen, YQ and Wang, S},
title = {Integrative Multi-Omics and Machine Learning Analysis Identifies Therapeutic Targets and Drug Repurposing Candidates for Alzheimer's Disease.},
journal = {Biomedicines},
volume = {14},
number = {5},
pages = {},
doi = {10.3390/biomedicines14050998},
pmid = {42193325},
issn = {2227-9059},
abstract = {Background/Objectives: Alzheimer's disease (AD) remains a progressive neurodegenerative disorder with limited therapeutic options. This study aimed to develop an integrative multi-omics computational pipeline to identify diagnostic biomarkers and prioritize druggable therapeutic targets for AD. Methods: We integrated transcriptomic data from 1047 samples (547 AD, 500 controls) using weighted gene co-expression network analysis (WGCNA) and three machine learning algorithms (LASSO, Random Forest, SVM) with strict separation of training, feature selection, and evaluation. Single-cell RNA sequencing of 48,481 nuclei from entorhinal cortex, two-sample Mendelian randomization (MR) with Bayesian colocalization, and structure-based molecular docking with triplicate 500 ns molecular dynamics (MD) simulations were also employed. Results: Machine learning identified 10 consensus biomarker genes involved in synaptic vesicle cycling, ion transport, and calcium homeostasis (internal test AUC = 0.891, 95% CI: 0.836-0.946; external validation on GSE48350: AUC = 0.847, 95% CI: 0.798-0.896). Covariate-adjusted differential expression and MR with Bayesian colocalization converged on eight immune-related therapeutic targets including APOE, TREM2, and TYROBP (p<0.05; Bonferroni-corrected threshold p<0.00625). Single-cell analysis revealed oligodendrocyte expansion in AD (28.5% versus 24.8%), with target genes predominantly expressed in microglia and astrocytes. Virtual screening of 2634 FDA-approved drugs prioritized 10 exploratory repurposing candidates; indomethacin-TREM2 and celecoxib-CSF1R are primary exploratory candidates given structurally validated binding pockets. Triplicate MD simulations (15 μs aggregate) showed force-field-consistent structural stability (RMSD ≤ 3.2 Å). A quantitative multi-omics convergence framework identified four Tier 1 targets (APOE, TREM2, TYROBP, CX3CR1) supported by ≥5 analytical layers (Pperm=0.0003; note: three of five layers share the same transcriptomic input). Conclusions: These findings provide a multi-evidence computational framework linking diagnostic biomarkers and druggable neuroinflammatory targets for AD. All predictions require experimental validation in biochemical and cellular models before clinical conclusions can be drawn.},
}

@article {pmid42193339,
year = {2026},
author = {Kopp, K and Silva, P and Damm, F and Cosma, NC},
title = {Clonal Hematopoiesis of Indeterminate Potential as an Emerging Interdisciplinary Risk Factor in Alzheimer's Disease: Current Evidence and Future Directions.},
journal = {Biomedicines},
volume = {14},
number = {5},
pages = {},
doi = {10.3390/biomedicines14051012},
pmid = {42193339},
issn = {2227-9059},
abstract = {Clonal hematopoiesis of indeterminate potential (CHIP) is an age-related condition affecting over 10-20% of individuals older than 70 years, characterized by the expansion of hematopoietic stem cell clones carrying somatic mutations in leukemia-associated driver genes in the absence of overt hematologic disease. Initially recognized as a precursor to hematologic malignancies, CHIP has since been implicated in diverse non-malignant disorders, notably increasing the risk of cardiovascular events by 40%. Recent epidemiological and experimental evidence suggests a potential disease-modifying influence of CHIP in neurodegenerative diseases, particularly Alzheimer's disease (AD), although findings remain heterogeneous and sometimes contradictory. This review synthesizes recent evidence linking CHIP to AD risk, neuropathology, and disease progression. In this study, we summarize population-based cohort studies reporting a 36 to 54% reduction in the odds of clinical AD among CHIP carriers, alongside emerging data indicating that DNMT3A and TET2 mutations may exert divergent effects on neurodegeneration. Mechanistic insights from experimental models are examined, highlighting the ability of mutated myeloid cells to infiltrate the central nervous system and modulate neuroinflammation and amyloid clearance. We discuss conflicting findings and analyze how CHIP-driven vascular disease and stroke confound neuroprotective signals. We propose that CHIP may differentially influence AD and vascular contributions to cognitive impairment and dementia, shaping mixed dementia phenotypes. Methodological challenges, including survivor bias, competing risks, variable mutation detection thresholds, and incomplete Apolipoprotein E stratification, are discussed. Ultimately, our review clarifies that CHIP is not a simple protective factor, but a complex systemic modulator that reshapes the neurodegenerative and vascular drivers of cognitive decline, necessitating cross-disciplinary neuro-hematology collaboration to establish its role as a novel risk stratificator for improving diagnostic precision and personalizing clinical outcomes in Alzheimer's disease.},
}

@article {pmid42193414,
year = {2026},
author = {Targett, IL and Hancock, JT and Craig, TJ},
title = {Diet, Metabolism and Synaptic Function: Integrating Evidence Across Models in Neurodegeneration Research.},
journal = {Biomedicines},
volume = {14},
number = {5},
pages = {},
doi = {10.3390/biomedicines14051089},
pmid = {42193414},
issn = {2227-9059},
abstract = {The brain has a higher energy demand per unit weight than any other organ in the body; however, links between metabolism, diet and neurological function have historically been underexplored. This partly stems from early assumptions that brain metabolism is primarily dependent on glucose and ketone bodies, whereas more recent evidence indicates broader metabolic flexibility and complex cell-type specialisation. In the past few decades, brain metabolism has become increasingly recognised as relevant to neurological and mental health, and many neurodegenerative disorders are accompanied by changes in brain energy utilisation. In parallel, epidemiological studies associate hypercaloric dietary patterns and metabolic disorders-particularly type-2 diabetes mellitus-with increased risk of later cognitive decline and sporadic Alzheimer's disease, although causal pathways remain difficult to establish in humans. In this narrative review, we summarise selected findings linking "unhealthy" diets to synaptic function, focusing on synaptic plasticity, neuroinflammation and adult hippocampal neurogenesis, and we distinguish between evidence from human observational studies and mechanistic insights from animal and cellular models. We also discuss candidate mechanisms-including insulin resistance-linked signalling changes, lipid-driven inflammatory amplification, oxidative stress, and altered lipid handling-that may contribute to synaptic vulnerability. Finally, we outline translational considerations and key knowledge gaps (including physiological exposure levels and heterogeneity of experimental paradigms) that currently limit inference from preclinical models to clinical intervention.},
}

@article {pmid42193441,
year = {2026},
author = {Yunusova, N and Svarovsky, D and Panfilova, P and Ryabova, A and Kaigorodova, E and Sidenko, E and Gervas, P and Molokov, A and Kondakova, I},
title = {Evolution of Concepts Regarding the Diagnostic and Prognostic Significance of Glial Fibrillary Acidic Protein (GFAP)-Positive Extracellular Vesicles.},
journal = {Biomedicines},
volume = {14},
number = {5},
pages = {},
doi = {10.3390/biomedicines14051116},
pmid = {42193441},
issn = {2227-9059},
abstract = {This review demonstrates that the diagnostic and prognostic significance of glial fibrillary acidic protein (GFAP) is not limited to its use as a marker of astrocytic damage but should also be considered in the context of the diversity of GFAP isoforms, their heterogeneous tissue-specific expression and their pronounced association with extracellular vesicles (EVs). The data presented in this review indicate that GFAP-positive (GFAP+) EVs possess broad clinical relevance in both acute and chronic pathologies of the nervous system, including ischemic stroke, traumatic brain injury, glioblastoma, and potentially diabetic and drug-induced polyneuropathy. Particular attention is given to the critical analysis of methodological approaches for studying GFAP+ EVs, including discussion of their proposed biogenesis, mechanisms of intravesicular incorporation of cytoskeletal fragments, and the hypothetical sorption of GFAP within the vesicular protein corona. A principal conclusion of this work is that, despite the high translational potential of GFAP+ vesicles as a novel liquid biopsy platform, further implementation of this approach in clinical practice will require standardization of EV isolation protocols, harmonization of phenotyping methodologies in accordance with MISEV 2023 recommendations, and large-scale prospective studies aimed at validating the biological nature, origin, and clinical reproducibility of identified GFAP-associated vesicular subpopulations.},
}

@article {pmid42193479,
year = {2026},
author = {Toklucu, ES and Shen, S and Wang, C and Zhang, C},
title = {RIPK 1 in Alzheimer's Disease: Research Progress Integrating Pathogenesis on Necroptosis-Related Neuroinflammation, and Potential Therapeutic Strategies.},
journal = {Biomedicines},
volume = {14},
number = {5},
pages = {},
doi = {10.3390/biomedicines14051155},
pmid = {42193479},
issn = {2227-9059},
support = {WZ2026//Cure Alzheimer's Fund/ ; },
abstract = {Background/Objectives: Alzheimer's disease (AD) is the most common cause of dementia worldwide; however, there is incomplete understanding of AD pathogenesis, and there are few disease-modifying treatments for AD. Research has begun to demonstrate that necroptosis, which is a regulated type of cell death mediated by receptor-interacting protein kinase 1 (RIPK1), plays a significant role in neurodegeneration and neuropathology associated with AD. The purpose of this review is to summarize current research regarding the role of RIPK1 in AD and possible therapeutic uses of RIPK1 inhibitors. Methods: This study is a narrative review of the literature summarizing experimental and clinical studies on RIPK1 signaling, necroptosis, neuroinflammation, and blood-brain barrier (BBB) dysfunction in AD. Results: The cumulative evidence demonstrates that RIPK1 activation associates with common AD pathways and particularly increases the severity of amyloid-β (Aβ) and tau pathology; promotes microglial activation; decreases the integrity of the BBB; and increases neuroinflammatory signaling in AD. Preclinical studies have shown that inhibiting RIPK1 genetically or pharmacologically in preclinical models decreased the extent of neurodegeneration and the rate of cognitive decline. Conclusions: RIPK1 is a key molecular link between necroptosis and neuroinflammation in AD. While the preclinical data are encouraging, further clinical research will be necessary to investigate RIPK1 changes in the brain, which may help better understand AD and establish the safety and effectiveness of potential therapeutic RIPK1 inhibitors in AD.},
}

@article {pmid42193907,
year = {2026},
author = {Albensi, BC and Adlimoghaddam, A},
title = {Targeting Mitochondrial Dysfunction in Alzheimer's Disease Neurons: Lithium Boosts Oxidative Phosphorylation.},
journal = {Cells},
volume = {15},
number = {10},
pages = {},
doi = {10.3390/cells15100896},
pmid = {42193907},
issn = {2073-4409},
support = {AARF-22-967198/ALZ/Alzheimer's Association/United States ; },
mesh = {Animals ; *Alzheimer Disease/metabolism/pathology/drug therapy ; *Oxidative Phosphorylation/drug effects ; *Mitochondria/metabolism/drug effects/pathology ; *Neurons/metabolism/drug effects/pathology ; Mice ; *Lithium/pharmacology/therapeutic use ; Mice, Inbred C57BL ; Electron Transport Complex IV/metabolism ; Mice, Transgenic ; Energy Metabolism/drug effects ; Oxygen Consumption/drug effects ; Hippocampus/pathology/metabolism ; },
abstract = {Alzheimer's disease (AD) is characterized by the accumulation of amyloid beta (Aβ) and neurofibrillary tangles in brain tissue; however, AD is multifactorial, and different etiopathogenic mechanisms involve factors that can affect mitochondrial function, which are associated with AD. While high-dose lithium is a well-established mood stabilizer, accumulating evidence suggests that low-dose lithium provides significant neuroprotection by reversing AD pathology, cognitive impairment, and inflammation. Despite these findings, there is limited information on how lithium affects brain energy metabolism. In the current study, we investigated the effect of lithium (0, 0.1, 1, and 10 mM) on mitochondrial function in AD neurons. Neuronal cells were isolated from the hippocampi of embryonic day 14-17 (E15-E17) control (C57BL/6) mice and 3xTg-AD mice. Mitochondrial oxygen consumption rate (OCR), mitochondrial Cytochrome C Oxidase (COX) activity, total ATP activity, and the expression of mitochondrial complex protein involved in oxidative phosphorylation (OXPHOS) were measured in control vs. 3xTg-AD in the presence and absence of lithium treatment. In the present study, lithium treatment significantly increased (p < 0.05) mitochondrial OCR, COX, total ATP, and levels of mitochondrial complex protein subunits (Complex I-V) in 3xTg-AD neurons. However, lithium had no effect on energy metabolism in control neurons. Together, these data indicate that lithium improves mitochondrial function under pathological states. Overall, these results have important implications for the treatment of disorders in which brain energy regulation is compromised, including AD. Particularly, our results highlight a role for lithium in regulating bioenergetics in early-stage AD and suggest that neuronal cells may be a crucial therapeutic target for preventing AD.},
}

Animals
*Alzheimer Disease/metabolism/pathology/drug therapy
*Oxidative Phosphorylation/drug effects
*Mitochondria/metabolism/drug effects/pathology
*Neurons/metabolism/drug effects/pathology
Mice
*Lithium/pharmacology/therapeutic use
Mice, Inbred C57BL
Electron Transport Complex IV/metabolism
Mice, Transgenic
Energy Metabolism/drug effects
Oxygen Consumption/drug effects
Hippocampus/pathology/metabolism

@article {pmid42193936,
year = {2026},
author = {Sepehrimanesh, M and Melen, SV and Yeasmin, F and Ojo, VA and Walden, F and Urmee, H and Etheridge, J and Nasu, AK},
title = {Emerging Therapeutic Strategies for Neurodegenerative Diseases: A Comprehensive Review of Recent Advances and Future Directions.},
journal = {Cells},
volume = {15},
number = {10},
pages = {},
doi = {10.3390/cells15100928},
pmid = {42193936},
issn = {2073-4409},
mesh = {Humans ; *Neurodegenerative Diseases/therapy ; Animals ; Neuroprotective Agents/therapeutic use ; Genetic Therapy ; },
abstract = {Neurodegenerative diseases, including Alzheimer's disease (AD), Parkinson's disease (PD), and amyotrophic lateral sclerosis (ALS; Lou Gehrig's disease), represent a growing global health burden characterized by progressive neuronal loss and functional decline. Despite decades of intensive research, effective disease-modifying therapies remain limited, underscoring the urgent need for innovative therapeutic strategies. This review highlights recent advances in the understanding of disease etiology and emerging treatment approaches, with a particular focus on modalities with translational potential. We discussed novel disease-modifying interventions, including gene and cell therapies, RNA-targeting strategies, and immunotherapies aimed at clearing misfolded proteins such as amyloid-β, tau, and α-synuclein. In parallel, we examined the evolving recognition of neuroinflammation and mitochondrial dysfunction as actionable therapeutic targets, alongside progress in precision medicine and biomarker-guided approaches that enable early diagnosis and individualized treatment. Additionally, we summarized developments in repurposed pharmacological agents, neuroprotective compounds, and lifestyle interventions, emphasizing the importance of integrative, multimodal strategies. Across AD, PD, and ALS, convergent molecular mechanisms, including protein misfolding, oxidative stress, and disrupted proteostasis, present opportunities for cross-disease therapeutic targeting. Finally, we addressed key challenges and future directions, including translating preclinical efficacy into clinical success, optimizing CNS-targeted delivery systems, and navigating ethical considerations surrounding gene editing and stem cell therapies.},
}

Humans
*Neurodegenerative Diseases/therapy
Animals
Neuroprotective Agents/therapeutic use
Genetic Therapy

@article {pmid42193973,
year = {2026},
author = {Bushra, N and Hull, T and Fakhre, D and Muschol, M},
title = {Self-Assembly of Amyloid Fibrils into Fibrillar Superstructure Monitored with Thioflavin T.},
journal = {Biomolecules},
volume = {16},
number = {5},
pages = {},
doi = {10.3390/biom16050622},
pmid = {42193973},
issn = {2218-273X},
mesh = {*Benzothiazoles/chemistry ; *Amyloid/chemistry/ultrastructure/metabolism ; Muramidase/chemistry/metabolism ; Humans ; Fluorescent Dyes/chemistry ; },
abstract = {Deposits of insoluble protein plaques, which are mostly composed of fibrils from disease-specific amyloid proteins, are histological markers of various human disorders. These range from non-neuropathic amyloidosis such as light chain amyloidosis or type II diabetes to well-known neuro-degenerative diseases such as Alzheimer's Disease and Parkinson's Disease. There are indications that these types of fibrillar suprastructures display biological activity distinct from the individual fibrils they are composed of. Yet, little is known about the mechanisms underlying the assembly of fibrillar suprastructures. An understanding of secondary fibril self-assembly into mesoscopic and macroscopic suprastructures is also critical for their application as novel biomaterial. The paucity of experimental data and theoretical models on fibrillar supra-assembly likely relates to the experimental and conceptual challenges in following this type of assembly on multiple length- and timescales, and in characterizing the distinct morphologies formed. Here, we report that the amyloid dye thioflavin T (ThT) is augmented during self-assembly of isolated lysozyme fibrils. We provide evidence that this augmentation of ThT fluorescence results from the unquenching of fibril-bound ThT during fibril binding. Combining ThT fluorescence, optical density, and fluorescence quenching kinetics with optical and electron microscopy, we propose that fibril self-assembly is driven by a transition from reaction-limited ordered assembly to diffusion-limited random cross-linking of fibrils.},
}

*Benzothiazoles/chemistry
*Amyloid/chemistry/ultrastructure/metabolism
Muramidase/chemistry/metabolism
Humans
Fluorescent Dyes/chemistry

@article {pmid42194007,
year = {2026},
author = {Di Crescenzo, T and Papiri, G and Membrino, V and Alia, S and Cecati, M and Campagna, R and Silvestrini, M and Luzzi, S and Vignini, A},
title = {The Interplay Between Immunometabolism and Neuroinflammation in Alzheimer's Disease.},
journal = {Biomolecules},
volume = {16},
number = {5},
pages = {},
doi = {10.3390/biom16050656},
pmid = {42194007},
issn = {2218-273X},
mesh = {Humans ; *Alzheimer Disease/metabolism/immunology/pathology ; Animals ; *Neuroinflammatory Diseases/metabolism/immunology ; Microglia/metabolism/immunology ; Inflammation/metabolism ; },
abstract = {Alzheimer's disease (AD) is a multifactorial neurodegenerative disorder characterized by progressive cognitive decline and neuropathological hallmarks such as amyloid-β plaques and neurofibrillary tangles. In recent years, chronic neuroinflammation has emerged as a central mechanism linking genetic, metabolic, and immune dysfunctions in AD. Activated microglia and astrocytes release pro-inflammatory cytokines and reactive oxygen species that exacerbate synaptic and neuronal injury, while impaired clearance mechanisms and blood-brain barrier disruption further sustain inflammation. A growing body of research highlights the role of immunometabolism-the bidirectional interaction between immune activation and cellular metabolism-in shaping glial phenotypes and disease progression. Dysregulation of glucose, lipid, and amino acid metabolism, together with alterations in key metabolites such as lactate, NAD[+], and reactive oxygen species, promotes a maladaptive inflammatory state. Genetic factors including APOE4 and TREM2 variants affect microglial lipid handling pathways, while systemic metabolic disorders and gut microbiota alterations amplify neuroinflammatory cascades. Natural bioactive compounds, particularly polyphenols, have gained attention for their ability to modulate immunometabolic pathways. By activating AMPK and SIRT1 and inhibiting mTOR and NLRP3 inflammasome signaling, polyphenols may tune mitochondrial function, redox homeostasis, and autophagy, promoting adaptation to chronic metabolic stress. Therefore, metabolic-immune interactions represent pleiotropic therapeutic avenues for AD. Understanding how immunometabolites and nutrient-sensing pathways regulate compartmentalized inflammation in the CNS may pave the way for novel interventions that combine metabolic precision with neuroprotective efficacy.},
}

Humans
*Alzheimer Disease/metabolism/immunology/pathology
Animals
*Neuroinflammatory Diseases/metabolism/immunology
Microglia/metabolism/immunology
Inflammation/metabolism

@article {pmid42194017,
year = {2026},
author = {Serfilippi, T and Piccirillo, S and Preziuso, A and Terenzi, V and Ciancio, R and Magi, S and Lariccia, V and Secondo, A},
title = {Allosteric Activation of GDH/TCA Pathway Reduces Pathological Build-Up and Promotes Neuronal Survival in an In Vitro Model of Alzheimer's Disease.},
journal = {Biomolecules},
volume = {16},
number = {5},
pages = {},
doi = {10.3390/biom16050667},
pmid = {42194017},
issn = {2218-273X},
support = {2022ZTKFXS//Ministero dell'università e della ricerca/ ; "Ricerca Scientifica di Ateneo" (RSA) Grant (2023-2025)//Marche Polytechnic University/ ; },
mesh = {*Alzheimer Disease/metabolism/pathology ; *Neurons/metabolism/pathology/drug effects ; Animals ; Humans ; Rats ; *Glutamate Dehydrogenase/metabolism ; Amyloid beta-Peptides/metabolism ; Oxidative Stress/drug effects ; Cell Survival/drug effects ; *Citric Acid Cycle/drug effects ; Mitochondria/metabolism/drug effects ; Allosteric Regulation/drug effects ; Calcium/metabolism ; Membrane Potential, Mitochondrial/drug effects ; Reactive Oxygen Species/metabolism ; Peptide Fragments ; Cell Line, Tumor ; },
abstract = {Mitochondrial dysfunction is a relevant hallmark of Alzheimer's disease (AD), contributing to the impaired metabolic homeostasis involved in neuronal loss and cognitive decline. In this study, we target the metabolic dysfunction occurring in AD through a novel pharmacological approach involving the modulation of glutamate dehydrogenase (GDH), which converts glutamate to α-ketoglutarate and supports the tricarboxylic acid (TCA) cycle. In our experimental models (i.e., differentiated SH-SY5Y cells and primary rat cortical neurons exposed to glyceraldehyde and amyloid-beta peptide 1-42, respectively), the allosteric GDH activator 2-Aminobicyclo-(2,2,1)-heptane-2-carboxylic acid (BCH) increased mitochondrial ATP production, improved cellular bioenergetics, and reduced oxidative stress, ultimately promoting neuronal survival. Ionic dysfunctions in AD are linked to disrupted calcium homeostasis and organelle storing properties. In this context, GDH activation potentiated mitochondrial and endoplasmic reticulum calcium buffering capacity by enhancing store-operated calcium entry. Oxidative stress, largely driven by mitochondrial ROS overproduction, represents another major contributor to AD pathology. In our AD models BCH-mediated GDH activation reduced ROS formation and restored mitochondrial membrane potential (ΔΨm). Importantly, these metabolic and ionic improvements were associated with decreased accumulation of amyloid-β (Aβ1-42) and phosphorylated tau (pTau), two key AD biomarkers. Overall, modulation of the GDH/TCA pathway represents a promising approach for restoring metabolic dysfunctions and counteracting oxidative stress and ionic dysregulation and therefore AD neurodegeneration.},
}

*Alzheimer Disease/metabolism/pathology
*Neurons/metabolism/pathology/drug effects
Animals
Humans
Rats
*Glutamate Dehydrogenase/metabolism
Amyloid beta-Peptides/metabolism
Oxidative Stress/drug effects
Cell Survival/drug effects
*Citric Acid Cycle/drug effects
Mitochondria/metabolism/drug effects
Allosteric Regulation/drug effects
Calcium/metabolism
Membrane Potential, Mitochondrial/drug effects
Reactive Oxygen Species/metabolism
Peptide Fragments
Cell Line, Tumor

@article {pmid42194036,
year = {2026},
author = {White, ZJ and Hall, SE},
title = {Irisin as an Exerkine of Neuroprotection in Aging and Alzheimer's Disease.},
journal = {Biomolecules},
volume = {16},
number = {5},
pages = {},
doi = {10.3390/biom16050687},
pmid = {42194036},
issn = {2218-273X},
mesh = {Humans ; *Alzheimer Disease/metabolism/pathology ; Animals ; *Fibronectins/metabolism/pharmacology ; *Aging/metabolism ; *Neuroprotection ; *Exercise ; Myokines ; Brain/metabolism ; *Neuroprotective Agents/pharmacology ; Amyloid beta-Peptides/metabolism ; },
abstract = {Alzheimer's disease (AD) is a neurodegenerative disease impacting over 6 million Americans, with cases projected to increase to over 14 million by 2060. The AD pathology leads to difficulty completing everyday tasks or conversations, and ultimately, progresses to disrupt the most basic bodily functions and require full-time caretaking. While disease-modifying therapy remains elusive, reducing the incidence of AD is crucial to mitigate the projected increase in cases. Exercise has emerged as an effective strategy to promote brain health in late adulthood and to protect against the onset of AD. Exercise opposes several disease processes, including cognitive dysfunction, amyloid beta aggregation, tau phosphorylation, and deficits in hippocampal volume, mitochondrial function, cerebral blood flow, and neurogenesis, through various pathways, including the systemic release of exerkines. The exerkine irisin is an important mediator of the beneficial relationship between exercise and the brain. Previous work administering irisin therapeutically to healthy and preclinical AD mice has demonstrated irisin use to replicate multiple exercise-induced effects in the brain and protect against AD-induced deficits. Although irisin is suggested as a promising strategy for promoting brain health in late adulthood, our understanding of irisin signaling and its protective effects against AD remains incomplete. This review will investigate irisin as an important, physiologically relevant promoter of brain health in aging and AD.},
}

Humans
*Alzheimer Disease/metabolism/pathology
Animals
*Fibronectins/metabolism/pharmacology
*Aging/metabolism
*Neuroprotection
*Exercise
Myokines
Brain/metabolism
*Neuroprotective Agents/pharmacology
Amyloid beta-Peptides/metabolism

@article {pmid42194061,
year = {2026},
author = {Richardsen, BYP and Humpel, C},
title = {Live-Cell Imaging of Microglia in Organotypic Brain Slices Using Microcontact Printing.},
journal = {Biomolecules},
volume = {16},
number = {5},
pages = {},
doi = {10.3390/biom16050713},
pmid = {42194061},
issn = {2218-273X},
mesh = {Animals ; *Microglia/cytology/metabolism/drug effects ; *Brain/cytology/metabolism/diagnostic imaging ; Mice ; Microscopy, Fluorescence ; Lipopolysaccharides/pharmacology ; Granulocyte-Macrophage Colony-Stimulating Factor/pharmacology ; Mice, Inbred C57BL ; },
abstract = {Microglia are brain immune cells that phagocytose cell debris and beta-amyloid plaques in patients with Alzheimer's disease. They develop from round amoeboid cells into ramified microglia or large macrophages, which can be studied in three-dimensional organotypic mouse brain slices. In a recent publication, we showed for the first time that we can track GFAP+ astrocytes and laminin+ vessels in organotypic brain slices using live-cell imaging . The aim of the present study was to use microcontact printing on organotypic brain slices to label microglia with Iba1 and CD11b antibodies and visualise them through live-cell imaging. We show that microglia can be easily labelled with antibodies and tracked via live-cell fluorescence microscopy for up to 20 days. Incubation in lipopolysaccharide (LPS) or granulocyte-macrophage colony-stimulating factor (GM-CSF) stimulates the migration of round amoeboid microglia, whereas interleukin-10 induces their differentiation into ramified forms. Taken together, we show the first-time live cell imaging of microglia in organotypic mouse brain slices using microcontact printing.},
}

Animals
*Microglia/cytology/metabolism/drug effects
*Brain/cytology/metabolism/diagnostic imaging
Mice
Microscopy, Fluorescence
Lipopolysaccharides/pharmacology
Granulocyte-Macrophage Colony-Stimulating Factor/pharmacology
Mice, Inbred C57BL

@article {pmid42194074,
year = {2026},
author = {Li, J and Long, Q and Zhu, B},
title = {Akkermansia muciniphila and Alzheimer's Disease: Mechanisms, Evidence and Translational Potential.},
journal = {Biomolecules},
volume = {16},
number = {5},
pages = {},
doi = {10.3390/biom16050726},
pmid = {42194074},
issn = {2218-273X},
support = {CSTB2025NSCQ-GPX0455//Chongqing Municipal Government/ ; 2026MSXM099//Chongqing Medical Scientific Research Project/ ; },
mesh = {*Alzheimer Disease/microbiology/metabolism ; Humans ; Animals ; *Akkermansia ; Gastrointestinal Microbiome ; Brain/metabolism ; },
abstract = {Akkermansia muciniphila (A. muciniphila) is a bacterium that breaks down mucus and is studied for its effects on metabolism and the immune system. Studies show that it affects Alzheimer's disease (AD) by protecting the gut barrier, reducing inflammation, and influencing communication between the immune system, the brain, and mitochondria. This review summarizes mechanistic, preclinical, and translational evidence connecting A. muciniphila to AD, including products such as short-chain fatty acids (SCFAs), and structural or secreted proteins including Amuc_1100 and extracellular vesicles (AmEVs). We also discuss differences between bacterial strains, differences in research methods, and findings that change under different conditions, which make the results harder to interpret. Animal studies suggest neuroprotective effects, but clinical evidence is still limited. Clinical use will need human studies at the strain level, confirmation in humanized models, and early trials using biomarkers to test safety and causal effects.},
}

*Alzheimer Disease/microbiology/metabolism
Humans
Animals
*Akkermansia
Gastrointestinal Microbiome
Brain/metabolism

@article {pmid42194082,
year = {2026},
author = {Ilić, BS},
title = {Epigallocatechin Gallate as a State-Dependent Modulator of Amyloid-β: Molecular Simulation-Guided Mechanistic Synthesis for Structure-Based Inhibitor Design.},
journal = {Biomolecules},
volume = {16},
number = {5},
pages = {},
doi = {10.3390/biom16050734},
pmid = {42194082},
issn = {2218-273X},
support = {451-03-137/2025-03/200113//Ministry of Science, Technological Development and Innovation of the Republic of Serbia/ ; },
mesh = {*Catechin/analogs & derivatives/chemistry/pharmacology ; *Amyloid beta-Peptides/chemistry/metabolism/antagonists & inhibitors ; Molecular Dynamics Simulation ; Humans ; Drug Design ; Alzheimer Disease/drug therapy/metabolism ; },
abstract = {Amyloid-β (Aβ) aggregation is a central mechanistic feature of Alzheimer's disease, involving heterogeneous conformational ensembles that evolve through monomeric, oligomeric, and fibrillar states. Understanding how small molecules modulate these state-dependent processes remains a major challenge in medicinal chemistry. This review examines the molecular mechanisms by which (-)-epigallocatechin-3-gallate (EGCG) perturbs Aβ aggregation, with a focus on insights derived from molecular dynamics (MD) simulations integrated with experimental data. MD studies employing structural, dynamical, and interaction-based descriptors (e.g., β-sheet content, contact maps, and salt bridge persistence) reveal that EGCG acts as a state-dependent modulator: it redistributes monomeric ensembles by masking aggregation-prone regions, induces topology switching in oligomers that suppresses seeding competence, and destabilizes protofibrillar β-sheet networks through interfacial and node-targeting interactions. Methodological analysis highlights the importance of force field selection, sampling depth, and aggregate model dependence, leading to a hierarchy of mechanistic confidence that distinguishes well-supported trends from model-specific observations. From a medicinal chemistry perspective, EGCG is best interpreted as a mechanistic probe rather than as a lead compound, informing the design of biostable modulators through principles such as bioisosteric replacement, topology control, and interfacial targeting. Collectively, this work provides a framework for translating the state-dependent aggregation mechanisms into rational therapeutic strategies.},
}

*Catechin/analogs & derivatives/chemistry/pharmacology
*Amyloid beta-Peptides/chemistry/metabolism/antagonists & inhibitors
Molecular Dynamics Simulation
Humans
Drug Design
Alzheimer Disease/drug therapy/metabolism

@article {pmid42194093,
year = {2026},
author = {Cid, REC and Ortega, A and Crenshaw, K and Vaccari, JPR and Carrasquillo, MM and Vaillancourt, D and Zheng, DD and Hinton, D and Sfakianaki, E and Crocco, EA and Casellas, H and Kuchenbecker, LA and Ramirez, S and Abascal, T and Abel, T and Wang, WE and Duara, R and Ertekin-Taner, N and Loewenstein, DA},
title = {Common Medical Comorbidities, Demographic Factors and Levels of Plasma Biomarkers of Alzheimer's Disease and Neurodegeneration in Black/African American Older Adults.},
journal = {Biomolecules},
volume = {16},
number = {5},
pages = {},
doi = {10.3390/biom16050747},
pmid = {42194093},
issn = {2218-273X},
support = {23A10//Florida Department of Health/ ; AG077677/AG/NIA NIH HHS/United States ; },
mesh = {Humans ; *Alzheimer Disease/blood/epidemiology/ethnology ; *Biomarkers/blood ; Female ; Male ; Black or African American ; Aged ; tau Proteins/blood ; Comorbidity ; Glial Fibrillary Acidic Protein/blood ; Aged, 80 and over ; Neurofilament Proteins/blood ; Demography ; },
abstract = {Emerging evidence suggests that systemic physiological factors may influence plasma biomarker concentrations of Alzheimer's disease (AD) and related neurodegenerative processes, potentially affecting their specificity for central nervous system pathology. This study examined the relationship of demographic factors and medical comorbidities with plasma biomarkers of AD and neurodegeneration in a community-dwelling cohort of Black/African American (B/AA) older adults (N = 141). Participants underwent plasma assessment of phosphorylated tau at threonine 217 (p-Tau217), glial fibrillary acidic protein (GFAP), and neurofilament light chain (NfL). Results showed associations between plasma p-Tau217 and amyloid PET positivity, and significant intercorrelations among p-Tau217, GFAP, and NfL. Stepwise regression models incorporated demographics, amyloid PET status, and laboratory measures of renal, metabolic, and lipid function as predictors for each biomarker. p-Tau217 was primarily predicted by amyloid PET and renal function; GFAP by age and sex; and NfL by renal function, age, and sex. Findings indicate plasma biomarker concentrations in B/AA older adults reflect both central AD-related pathology and systemic physiological factors, particularly renal function, and demographic influences. Results underscore the importance of accounting for comorbid medical conditions and demographic characteristics when interpreting blood-based biomarkers and highlight the need for comprehensive medical phenotyping to improve diagnostic specificity and clinical utility.},
}

Humans
*Alzheimer Disease/blood/epidemiology/ethnology
*Biomarkers/blood
Female
Male
Black or African American
Aged
tau Proteins/blood
Comorbidity
Glial Fibrillary Acidic Protein/blood
Aged, 80 and over
Neurofilament Proteins/blood
Demography

@article {pmid42194406,
year = {2026},
author = {Barczak, A},
title = {The Utility of Addenbrooke's Cognitive Examination III (ACE-III) in Differentiating Neurodegenerative Disorders with Psychotic Symptoms: A Narrative Review.},
journal = {Healthcare (Basel, Switzerland)},
volume = {14},
number = {10},
pages = {},
doi = {10.3390/healthcare14101313},
pmid = {42194406},
issn = {2227-9032},
abstract = {Psychotic symptoms, including delusions and hallucinations, frequently complicate the course of Alzheimer's disease (AD), dementia with Lewy bodies (DLB), Parkinson's disease dementia (PDD), and frontotemporal dementia (FTD). Their presence accelerates decline, worsens outcomes, and complicates management. Cognitive screening in such patients is essential yet challenging due to attentional fluctuation, impaired insight, and diagnostic overlap. Addenbrooke's Cognitive Examination III (ACE-III) is a multidomain tool with higher sensitivity than the MMSE. Evidence indicates that ACE-III captures disorder-specific cognitive-psychotic profiles: memory impairment in AD with delusions of theft, visuospatial and attentional deficits in DLB with hallucinations, or executive dysfunction in FTD with paranoid ideation. Mini-ACE (M-ACE), a shorter derivative, is useful in acute psychiatric or advanced dementia settings. This review synthesizes evidence on ACE-III and M-ACE in psychosis-related neurodegeneration, highlights their role in differentiating from primary psychiatric psychoses, and identifies knowledge gaps, particularly in atypical AD variants, mixed dementia, and autosomal dominant AD. ACE-III emerges as a practical and informative tool, but psychosis-specific normative data and longitudinal studies are needed.},
}

@article {pmid42194776,
year = {2026},
author = {Pappolla, MA and Pappolla, SL and Nader, R and Hamza, MK and Fang, F and Fang, X},
title = {Evaluating Cognition Across Aging and Traumatic Brain Injury: Integrating Neurological and Neuropsychological Approaches.},
journal = {Journal of clinical medicine},
volume = {15},
number = {10},
pages = {},
doi = {10.3390/jcm15103822},
pmid = {42194776},
issn = {2077-0383},
abstract = {Background/Objectives: The evaluation of cognition is central to many neurological conditions, including traumatic brain injury, Alzheimer's disease, Lewy body disease, frontotemporal degeneration, and vascular disorders. In clinical practice, particularly in aging populations, cognitive complaints often arise in the context of mixed neurological processes, requiring careful integration of cognitive and non-cognitive findings. Despite this, there remains limited clarity regarding the respective roles of neurologists and clinical neuropsychologists and the distinction between cognitive and neuropsychological assessments, terms that are often used interchangeably despite important differences in methodology and scope. This lack of a shared framework has practical consequences. Cognitive test results, when interpreted in isolation for diagnosis, may be misconstrued as comprehensive measures of brain function, particularly when non-cognitive neurological features such as motor, cerebellar, or vestibular abnormalities should have been considered (but were not). Methods: In this narrative review, we synthesize clinical guidelines, consensus statements, regulatory sources, and representative empirical literature to articulate a competence-based framework in which cognitive assessment is a medically integrated process incorporating history, functional evaluation, neurological examination, and the targeted use of standardized neuropsychological instruments. Results: Neurologists are trained to establish medical diagnoses and integrate cognitive findings into the context of neurological disease, while neuropsychologists contribute detailed psychometric characterization, culturally and demographically informed interpretation, cognitive phenotyping, functional characterization, and validity assessment in complex clinical and medicolegal contexts. Although neuropsychologists are qualified to diagnose neurocognitive disorders using standardized diagnostic criteria, attribution to specific neurological etiologies requires a comprehensive medical evaluation that extends beyond cognitive testing alone. Conclusions: We outline a tiered approach to evaluation that aligns assessment methods with clinical questions and supports accurate diagnosis, interdisciplinary collaboration, and patient-centered care.},
}

@article {pmid42194973,
year = {2026},
author = {Agirbasli, D and Agirbasli, M and Cakir, ME and Muftuoglu, M},
title = {Association of VTN Genotype with Plasminogen Activator Inhibitor-1 Activity in Late-Onset Alzheimer's Disease.},
journal = {Genes},
volume = {17},
number = {5},
pages = {},
doi = {10.3390/genes17050516},
pmid = {42194973},
issn = {2073-4425},
mesh = {Humans ; *Alzheimer Disease/genetics/blood/pathology ; *Plasminogen Activator Inhibitor 1/genetics/blood ; Female ; *Vitronectin/genetics ; Male ; Aged ; Genotype ; Apolipoproteins E/genetics ; Polymorphism, Single Nucleotide ; Aged, 80 and over ; Case-Control Studies ; Age of Onset ; Genetic Predisposition to Disease ; },
abstract = {BACKGROUND/OBJECTIVES: Late-onset Alzheimer's disease (LOAD) is a multifactorial neurodegenerative disorder involving the interaction of genetic and environmental factors. Dysregulation of the fibrinolytic system, particularly an increase in plasminogen activator inhibitor-1 (PAI-1) levels, may contribute to Alzheimer's pathology. Vitronectin (VTN) regulates fibrinolysis by stabilizing PAI-1. This study investigated the relationships between plasma PAI-1 activity and VTN, SERPINE1 (PAI-1), and APOE gene variants in nineteen LOAD patients (>65 years) and ten cognitively normal age-matched control groups.

METHODS: Targeted next-generation sequencing was used to analyze the VTN, APOE, and SERPINE1 genes in 19 LOAD patients and ten controls. Additionally, plasma PAI-1 activity was measured in both groups.

RESULTS: Plasma PAI-1 activity was statistically significantly higher in LOAD patients compared to controls (p = 0.04). Targeted next-generation sequencing results showed that VTN 5'-UTR variants (rs7212814, rs1555584131, rs71135830, and rs11437594) were found in all patients and observed in 20% of controls (p = 0.0001). The VTN rs704 variant was detected in 84% of patients and 29% of controls (p = 0.001). VTN 5'-UTR variants showed Spearman correlation with PAI-1 activity (r = 1.0; p < 0.0001). SERPINE1 3'-UTR variants (rs11178, rs41423845) were found to be associated with the disease (p = 0.027; p = 0.0001). The APOEε3/ε4 genotype was present in 52.6% of patients and was not associated with PAI-1 activity. VTN variants showed an association with LOAD.

CONCLUSIONS: These findings suggest that VTN variants may contribute to LOAD pathogenesis by affecting PAI-1 and leading to fibrinolytic system dysregulation.},
}

Humans
*Alzheimer Disease/genetics/blood/pathology
*Plasminogen Activator Inhibitor 1/genetics/blood
Female
*Vitronectin/genetics
Male
Aged
Genotype
Apolipoproteins E/genetics
Polymorphism, Single Nucleotide
Aged, 80 and over
Case-Control Studies
Age of Onset
Genetic Predisposition to Disease

@article {pmid42195054,
year = {2026},
author = {Giannakis, A and Anyfantis, E and Litsou, E and Sioka, C and Konitsiotis, S},
title = {FDG-PET in the Evaluation of Primary Progressive Aphasia: A Narrative Review.},
journal = {Medicina (Kaunas, Lithuania)},
volume = {62},
number = {5},
pages = {},
doi = {10.3390/medicina62050800},
pmid = {42195054},
issn = {1648-9144},
mesh = {Humans ; *Aphasia, Primary Progressive/diagnostic imaging/diagnosis/physiopathology ; *Positron-Emission Tomography/methods ; *Fluorodeoxyglucose F18/therapeutic use ; },
abstract = {Background and Objectives: Primary progressive aphasia (PPA) and its variants-logopenic (lvPPA), semantic (svPPA), and nonfluent/agrammatic (nfvPPA)-are progressive neurocognitive syndromes characterized by predominant language impairment and associated with heterogeneous underlying neuropathologies. Accurate diagnosis remains challenging due to overlapping clinical features and complex pathobiological mechanisms. Fluorodeoxyglucose positron emission tomography (FDG-PET), which reflects regional cerebral glucose metabolism, may provide valuable insights into both the diagnosis and pathophysiological characterization of PPA. Materials and Methods: We reviewed the current literature and identified 48 original research articles that utilized FDG-PET in the evaluation of at least one PPA variant. Eight studies focused exclusively on lvPPA, six on svPPA, and two on nfvPPA, either alone or in comparison with other neurodegenerative diseases. Eighteen studies evaluated at least two PPA variants, while thirteen compared multiple PPA variants with other neurodegenerative disorders. Results: Most studies identified characteristic hypometabolic patterns for each PPA variant: left temporoparietal regions in lvPPA, bilateral anterior temporal regions with left predominance in svPPA, and left posterior frontal regions in nfvPPA. These variant-specific metabolic signatures may support differential diagnosis. Additionally, FDG-PET provided important insights into disease progression, including associations with worsening language impairment, evolution toward broader neurodegenerative syndromes, and correlations with specific neurocognitive deficits. These findings are largely consistent with other neuroimaging modalities and disease-specific biomarkers. However, limitations such as small sample sizes and the lack of autopsy confirmation in most studies limit the robustness of the results. Conclusions: FDG-PET appears to be a valuable tool for the diagnosis, differential diagnosis, and pathophysiological understanding of PPA. Nevertheless, large-scale, multicenter investigations incorporating pathologically confirmed cases to further validate its clinical utility are needed.},
}

Humans
*Aphasia, Primary Progressive/diagnostic imaging/diagnosis/physiopathology
*Positron-Emission Tomography/methods
*Fluorodeoxyglucose F18/therapeutic use

@article {pmid42195086,
year = {2026},
author = {André, Z and Kopániová, A and Gaštanová, B and Brandoburová, P and Režnáková, V and Fabian, M and Povinec, P and Hanes, J and Gmitterová, K},
title = {CSF Amyloid and Tau Biomarkers Distinguish Mixed from Vascular Dementia by Identifying Alzheimer's Disease Co-Pathology.},
journal = {Medicina (Kaunas, Lithuania)},
volume = {62},
number = {5},
pages = {},
doi = {10.3390/medicina62050833},
pmid = {42195086},
issn = {1648-9144},
mesh = {Humans ; Biomarkers/cerebrospinal fluid/analysis ; *Dementia, Vascular/cerebrospinal fluid/diagnosis ; *tau Proteins/cerebrospinal fluid/analysis ; *Alzheimer Disease/cerebrospinal fluid/diagnosis ; *Amyloid beta-Peptides/cerebrospinal fluid/analysis ; Female ; Male ; Aged ; Mixed Dementias ; Diagnosis, Differential ; Peptide Fragments/cerebrospinal fluid ; ROC Curve ; Aged, 80 and over ; Middle Aged ; },
abstract = {Background and Objectives: Vascular dementia (VaD) and mixed dementia (MD) represent prevalent causes of cognitive decline in the elderly, as they share similar pathological pathways and clinical features. Distinguishing between these two conditions remains a challenge, due to their frequent clinical and neuroimaging overlap. Nevertheless, it is important from a prognostic perspective. Materials and Methods: The study comprised 114 participants, including patients with VaD (n = 33), MD (n = 26), Alzheimer's disease (AD; n = 26), and 29 cognitively healthy controls (C). We evaluated routinely used cerebrospinal fluid (CSF) biomarkers (total tau, p-tau181, Aβ1-42) and their ratios to assess inter-group differences, diagnostic accuracy, and correlations with cognitive score. Results: Patients with MD demonstrated significantly higher levels of t-tau and p-tau181, and lower levels of Aβ1-42, compared to VaD (p < 0.004 for all analyses). With the exception of p-tau181/t-tau, all calculated ratios enabled differentiation between these groups. ROC analysis confirmed the high diagnostic accuracy of CSF Aβ1-42 and t-tau (AUC 0.82 and 0.79 respectively) for detecting AD pathology in dementia patients. Furthermore, the t-tau/Aβ1-42, p-tau181/Aβ1-42 ratios were the most effective in differentiating AD-related from vascular pathologies (AUC 0.78 and 0.80 respectively), and in differentiating MD from VaD (AUC 0.79 and 0.77 respectively). A significant correlation was observed between CSF biomarkers (especially tau markers) and cognitive impairment severity. Conclusions: CSF biomarkers effectively differentiate mixed from vascular dementia by identifying underlying AD pathology independent of the clinical phenotype. This supports the use of CSF biomarkers in clinical practice to reveal the neurodegenerative component in patients with cerebrovascular disease, which is of fundamental importance for emerging disease-modifying treatment strategies in mixed neuropathologies.},
}

Humans
Biomarkers/cerebrospinal fluid/analysis
*Dementia, Vascular/cerebrospinal fluid/diagnosis
*tau Proteins/cerebrospinal fluid/analysis
*Alzheimer Disease/cerebrospinal fluid/diagnosis
*Amyloid beta-Peptides/cerebrospinal fluid/analysis
Female
Male
Aged
Mixed Dementias
Diagnosis, Differential
Peptide Fragments/cerebrospinal fluid
ROC Curve
Aged, 80 and over
Middle Aged

@article {pmid42195382,
year = {2026},
author = {Testa, C and Palmese, F and Boni, S and Domenicali, M and Lauretani, F},
title = {Clinical Trajectories of Neurodegenerative Diseases in Older Adults: A Three-Sphere Framework for Precision Geriatric Neurology.},
journal = {Life (Basel, Switzerland)},
volume = {16},
number = {5},
pages = {},
doi = {10.3390/life16050827},
pmid = {42195382},
issn = {2075-1729},
abstract = {Neurodegenerative diseases are among the most consequential disorders of later life, not only because of their increasing prevalence, rising from approximately 1-2% at age 65 to over 30% by age 85, but also because they develop within the broader clinical context of ageing, multimorbidity, frailty, and polypharmacy. In older adults, these conditions rarely present as isolated and static diagnostic entities; rather, they unfold as dynamic clinical trajectories involving the progressive interaction of cognitive decline, behavioural-neuropsychiatric symptoms, and extrapyramidal-motor dysfunction. In this review, we propose a trajectory-based framework for the interpretation and management of major neurodegenerative disorders in later life, including Alzheimer's disease, frontotemporal dementia, Parkinson's disease and Parkinson's disease dementia, dementia with Lewy bodies, and vascular cognitive impairment. Building on a conceptual model organized around three major symptom spheres: cognitive, behavioural-neuropsychiatric, and extrapyramidal-motor, we argue that each disorder can be understood according to the relative predominance and temporal evolution of these domains. Alzheimer's disease is typically cognition-led, frontotemporal dementia behaviour-led, and Parkinsonian syndromes motor-led, whereas dementia with Lewy bodies shows early multidomain convergence across all three spheres simultaneously. Vascular and mixed dementias follow more heterogeneous trajectories shaped by lesion burden, network disruption, and copathology. This framework has direct implications for diagnosis, prognostic stratification, and treatment selection, because interventions targeting one sphere may destabilize another and generate prescription cascades, delirium, or functional decline. We further discuss how biomarker-based diagnosis, disease-modifying therapies, non-pharmacological interventions, multidisciplinary care, deprescribing strategies, and palliative planning can be integrated within a trajectory-based approach. Interpreting neurodegeneration through clinical trajectories rather than diagnostic labels alone offers a more realistic and therapeutically useful model for precision geriatric neurology across the full course of disease.},
}

@article {pmid42195415,
year = {2026},
author = {Stanciu, GD and Costachescu, I and Gogu, RM and Tamba, BI},
title = {Pain in Alzheimer's Disease: Disrupted Multilevel Integration of Nociception, Affective Processing and Clinical Expression Across Clinical and Preclinical Evidence.},
journal = {Life (Basel, Switzerland)},
volume = {16},
number = {5},
pages = {},
doi = {10.3390/life16050860},
pmid = {42195415},
issn = {2075-1729},
support = {PN-IV-P2-2.1-TE-2023-0879, within PNCDI IV.//This work was supported by a grant of the Ministry of Research, Innovation and Digitization, CNCS-UEFISCDI, project number PN-IV-P2-2.1-TE-2023-0879, within PNCDI IV./ ; },
abstract = {Pain is a multidimensional experience arising from the integration of nociceptive signals with affective, cognitive and behavioral processes. In Alzheimer's disease (AD), pain assessment remains challenging, as reduced self-reported pain is frequently observed despite exposure to potentially painful conditions, suggesting altered processing rather than its absence. Emerging evidence indicates that pain in AD is characterized by a disruption of coordination among sensory detection, affective experience and clinical expression. Within this framework, nociceptive input may remain partially preserved, while its integration into emotionally meaningful and behaviorally coherent responses is compromised. Clinical studies report reduced self-report alongside observable indicators of discomfort, including agitation, withdrawal and affective disturbances. In parallel, preclinical models demonstrate preserved reflexive responses but altered affective-motivational processing. These alterations are associated with neuroinflammatory processes, synaptic dysfunction, large-scale network disconnection and changes in neuromodulatory systems involved in affective pain regulation, ultimately disrupting the integration of nociceptive signals within limbic and cortical networks. Taken together, this review integrates clinical and preclinical evidence to characterize pain in AD as a disruption of multilevel integration linking nociception, affective processing and clinical expression, with important implications for pain assessment strategies that extend beyond self-report to incorporate behavioral and translational approaches.},
}

@article {pmid42195987,
year = {2026},
author = {Yu, J and Jiang, Y and Li, Y and Fan, B and Lu, C and Tang, M and Luo, W and Yang, Y and Wang, F and Wang, Q},
title = {The Effect of Polysaccharides and Saponins from Polygonatum kingianum on Cognitive Dysfunction in an AlCl3-Induced Alzheimer's Disease Zebrafish Model.},
journal = {Foods (Basel, Switzerland)},
volume = {15},
number = {10},
pages = {},
doi = {10.3390/foods15101785},
pmid = {42195987},
issn = {2304-8158},
support = {2024YFD1600603//Chinese Academy of Agricultural Sciences/ ; 2025PIPK005//Chinese Academy of Agricultural Sciences/ ; },
abstract = {Polygonatum kingianum (PK), a plant with established medicinal and nutritional applications, has shown potential neuroprotective activity in Alzheimer's disease (AD). Nevertheless, the effects of its major bioactive fractions remain unclear. This study examined the neuroprotective effects of PK polysaccharides (PKPs) and saponins (PKSs) using an AlCl3-induced zebrafish model. Chemical analyses revealed that PKP was dominated by a low-molecular-weight fraction (1890 Da, 83.8%), whereas LC-MS analysis detected 13 tentatively identified steroidal saponins within PKS, including diosgenin. Furthermore, behavioral assessments demonstrated that both PKP and PKS improved locomotor and cognitive functions. PKP exhibited a stronger effect on the cholinergic system; its acetylcholinesterase (AChE) inhibitory activity at 60 μg/mL was comparable to that of donepezil under the experimental conditions. Histopathological analysis indicated that PKP showed a stronger effect in reducing neuronal apoptosis, resulting in a 68% reduction in the number of apoptotic cells. Conversely, PKS displayed a greater effect on amyloid pathology, reducing amyloid-beta (Aβ) aggregation by 62%. These findings suggest that PKP and PKS showed different neuroprotective profiles in the zebrafish model. Specifically, PKP was more closely associated with cholinergic regulation and neuronal survival, whereas PKS showed a stronger effect on Aβ aggregation. This study provides experimental support for the potential use of PK-derived fractions as food-derived bioactive components for alleviating AD-related pathological changes.},
}

@article {pmid42196209,
year = {2026},
author = {Mouaimi, M and Metaxas, A and Kourti, M},
title = {The Emerging Role of Dimethyl Fumarate in Alzheimer's Disease-A Systematic Review of Available Preclinical Studies.},
journal = {International journal of molecular sciences},
volume = {27},
number = {10},
pages = {},
doi = {10.3390/ijms27104227},
pmid = {42196209},
issn = {1422-0067},
mesh = {*Dimethyl Fumarate/therapeutic use/pharmacology ; *Alzheimer Disease/drug therapy/metabolism ; Animals ; Humans ; NF-E2-Related Factor 2/metabolism ; Oxidative Stress/drug effects ; Antioxidants/pharmacology/therapeutic use ; Disease Models, Animal ; Amyloid beta-Peptides/metabolism ; tau Proteins/metabolism ; },
abstract = {Dimethyl fumarate (DMF), a fumaric acid ester, is approved for psoriasis and multiple sclerosis due to its antioxidant and anti-inflammatory properties mediated via Nrf2 activation. Nrf2 regulates genes that protect cells from oxidative stress, a key factor in neurodegenerative diseases such as Alzheimer's disease (AD), which is characterized by amyloid-β and tau accumulation and lipid peroxidation. This systematic review aimed to evaluate preclinical evidence for DMF as a potential therapeutic agent in AD models through Nrf2 activation. A comprehensive literature search of PubMed and Scopus (last search: December 2025) identified in vitro, in vivo, and combined preclinical studies assessing DMF in AD models. Studies were screened using predefined inclusion and exclusion criteria, and methodological quality was assessed using established tools. Results were synthesized narratively. Eighteen studies were ultimately included in the analysis. Across the included studies, DMF consistently activated the Nrf2 pathway, enhancing antioxidant and anti-inflammatory gene expression. DMF treatment reduced amyloid-β and tau protein levels, mitigated oxidative stress, and improved cognitive performance in animal models. However, the evidence is limited by heterogeneity in experimental models and methodological variability. In conclusion, preclinical evidence suggests DMF is a promising candidate for AD treatment by targeting oxidative stress and neuroinflammation via Nrf2 activation. Further preclinical studies, particularly on ferroptosis mechanisms, and well-designed clinical studies are warranted to clarify its full therapeutic potential. This review was not registered and the authors received no funding.},
}

*Dimethyl Fumarate/therapeutic use/pharmacology
*Alzheimer Disease/drug therapy/metabolism
Animals
Humans
NF-E2-Related Factor 2/metabolism
Oxidative Stress/drug effects
Antioxidants/pharmacology/therapeutic use
Disease Models, Animal
Amyloid beta-Peptides/metabolism
tau Proteins/metabolism

@article {pmid42196212,
year = {2026},
author = {Jóźwiak-Bębenista, M and Stasiak, A and Sienkiewicz, M and Kwiatkowski, P and Kowalczyk, E},
title = {Psilocybin in Older Adults: Therapeutic Opportunities in Inflammation-Driven Disorders of Aging-From Depression to Neurodegeneration.},
journal = {International journal of molecular sciences},
volume = {27},
number = {10},
pages = {},
doi = {10.3390/ijms27104229},
pmid = {42196212},
issn = {1422-0067},
support = {503/1-108-01/503-11-001//Medical University of Lodz/ ; },
mesh = {Humans ; *Aging/drug effects ; *Inflammation/drug therapy ; *Neurodegenerative Diseases/drug therapy ; *Depression/drug therapy ; *Psilocybin/therapeutic use/pharmacology ; Animals ; Aged ; *Hallucinogens/therapeutic use/pharmacology ; },
abstract = {Aging is associated with chronic, low-grade inflammation ("inflammaging"), which contributes to neuropsychiatric and neurodegenerative disorders such as depression, Alzheimer's disease, and Parkinson's disease. Conventional pharmacotherapies often provide limited benefit in older adults and are further complicated by polypharmacy and drug-drug interactions. Psilocybin, a serotonergic psychedelic acting primarily as a partial agonist at the 5-HT2A receptor and currently undergoing accelerated clinical development, has emerged as a potential multimodal therapeutic agent addressing these challenges. Acting via its active metabolite psilocin, 5-HT2A receptor-mediated signaling modulates cortical glutamatergic transmission, enhances tropomyosin receptor kinase B/brain-derived neurotrophic factor (TrkB/BDNF) pathways, and modulates neuroimmune cascades (includingnuclear factor kappa B (NF-κB), with convergent systems-level effects such as reorganization of the default mode network. Human studies report acute reductions in TNF-α with variable effects on IL-6 and CRP, consistent with an immunomodulatory profile. Pharmacokinetically, psilocybin shows properties advantageous in geriatric care: rapid onset, short half-life, and predominant phase-II glucuronidation, reducing interaction risk. Controlled studies demonstrate rapid antidepressant and anxiolytic effects in major depressive disorder, treatment-resistant depression, and existential distress, with emerging feasibility signals in neurodegeneration. Together, these findings support the hypothesis that a time-limited, mechanism-based intervention may improve mood and cognition while attenuating inflammation. This review integrates current evidence on psilocybin's neuroimmune and pharmacokinetic mechanisms relevant to aging, outlining its potential role in inflammation-related disorders and highlighting the need for targeted studies in older adults, who remain underrepresented in psychedelic research.},
}

Humans
*Aging/drug effects
*Inflammation/drug therapy
*Neurodegenerative Diseases/drug therapy
*Depression/drug therapy
*Psilocybin/therapeutic use/pharmacology
Animals
Aged
*Hallucinogens/therapeutic use/pharmacology

@article {pmid42196227,
year = {2026},
author = {Kasprzak, A},
title = {Somatostatin in Aging: Correlations with Selected Central Nervous System and Gastrointestinal Tract Diseases.},
journal = {International journal of molecular sciences},
volume = {27},
number = {10},
pages = {},
doi = {10.3390/ijms27104244},
pmid = {42196227},
issn = {1422-0067},
mesh = {Humans ; *Aging/metabolism ; *Somatostatin/metabolism ; Animals ; *Gastrointestinal Diseases/metabolism ; *Central Nervous System/metabolism ; },
abstract = {The hypothalamic-pituitary-somatotropic (HPS) axis, which includes growth hormone (GH) and insulin-like growth factor 1 (IGF-1), is one of three endocrine systems that show a decline in hormone concentration with age. Among the hypothalamic hormones involved in the aging process, GH-releasing hormone (GHRH) and somatostatin (SST) are most affected, resulting in several age-related changes. The pathophysiology of GH decline in the aging process is unclear, specifically, whether it results from decreased GHRH or increased SST levels. Similarly, it is not known whether quantitative changes in hypothalamic peptides (including SST) precede or follow age-related pathological behavioral changes. SST is produced mainly by cells of the central nervous system (CNS) and the gastrointestinal (GI) tract, which are functionally interconnected systems that undergo significant changes during aging. The physical changes in the aging organism are considered physiological, and experimental evidence indicates that a large proportion of these changes are the result of declining hormonal activity (including the SST system). It is particularly important to understand the role of SST in diseases of old age, which affect both cognitive processes and memory (e.g., Alzheimer's and Parkinson's diseases) and the proper functioning of the GI tract and pancreas (e.g., obesity, type 2 diabetes mellitus, and colorectal cancer). This narrative review discusses systemic and peripheral changes in SST production and secretion observed in aging individuals and their potential association with selected diseases of old age, especially CNS and GI tract diseases. Understanding the role of SST expression with age will enable the better application of this neuropeptide in the diagnosis and treatment of diseases of old age (including cancers).},
}

Humans
*Aging/metabolism
*Somatostatin/metabolism
Animals
*Gastrointestinal Diseases/metabolism
*Central Nervous System/metabolism

@article {pmid42196249,
year = {2026},
author = {Sheikh, AM and Yano, S and Tabassum, S and Bhuiya, J and Nagai, A},
title = {Protein Modifications and Quality Control System: Target for Alzheimer's Disease Therapy.},
journal = {International journal of molecular sciences},
volume = {27},
number = {10},
pages = {},
doi = {10.3390/ijms27104266},
pmid = {42196249},
issn = {1422-0067},
mesh = {Humans ; *Alzheimer Disease/metabolism/therapy/pathology/drug therapy ; *Protein Processing, Post-Translational ; tau Proteins/metabolism ; Amyloid beta-Peptides/metabolism ; Animals ; Phosphorylation ; Proteostasis ; Ubiquitination ; },
abstract = {Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by memory loss and cognitive decline. Its main pathological features are extracellular plaques composed of aggregated amyloid-β (Aβ) peptides and intracellular neurofibrillary tangles formed by hyperphosphorylated tau. The Aβ hypothesis proposes that Aβ accumulation is a key driver of AD, influencing tau pathology, neuroinflammation, and neurodegeneration. However, therapies that reduce Aβ have shown limited clinical benefits. This suggests that the mechanisms underlying peptide-mediated modulation of AD pathology are much more complex. Both Aβ and tau undergo various post-translational modifications (PTMs) that affect their structure, aggregation, and toxicity. In addition, these abnormal proteins are not efficiently cleared in AD, indicating dysfunction of the protein quality control (PQC) system that maintains proteostasis. Such abnormal PTMs and impaired PQC likely work together to drive disease progression, which may explain the limited success of Aβ-reduction therapies. In this review, we describe how major PTMs, including phosphorylation, ubiquitination, acetylation, glycosylation, and oxidation, regulate the pathological behavior of Aβ and tau. We also discuss the role of the PQC systems in the pathology of AD. We propose that dysregulation of PTMs and PQC constitutes a convergent mechanism underlying AD pathogenesis. Therapeutic strategies targeting these processes may provide more effective and sustained disease modification than approaches focused solely on Aβ reduction.},
}

Humans
*Alzheimer Disease/metabolism/therapy/pathology/drug therapy
*Protein Processing, Post-Translational
tau Proteins/metabolism
Amyloid beta-Peptides/metabolism
Animals
Phosphorylation
Proteostasis
Ubiquitination

@article {pmid42196255,
year = {2026},
author = {Liao, Y and Zhao, L and Zhu, Y and Ye, S and Huang, J and Niu, Z and Zhang, L and Lei, N and Guo, P and Xie, Y},
title = {Fluid Biomarkers of Cognitive Impairments Following Traumatic Brain Injury: A Systematic Review and Meta Analysis.},
journal = {International journal of molecular sciences},
volume = {27},
number = {10},
pages = {},
doi = {10.3390/ijms27104274},
pmid = {42196255},
issn = {1422-0067},
support = {No.202501AS070139//Yunnan Province Science and Technology Department/ ; },
mesh = {Humans ; *Brain Injuries, Traumatic/complications/metabolism ; *Biomarkers/cerebrospinal fluid ; *Cognitive Dysfunction/etiology/metabolism/diagnosis ; tau Proteins ; Glial Fibrillary Acidic Protein ; Neurofilament Proteins ; },
abstract = {Traumatic brain injury (TBI), a major cause of persistent cognitive impairment (CI), increases the long-term risk of developing dementia, including Alzheimer's disease (AD). To elucidate this association, we systematically reviewed fluid biomarkers linked to post-TBI cognitive outcomes. A comprehensive search of the PubMed, Embase, and Cochrane Library databases was performed. A total of 29 clinical studies were included, reporting on several biomarkers related to neural injury and repair, AD-like pathology, and inflammation. Among these, neurofilament light chain (NfL), ubiquitin C-terminal hydrolase L1, total tau, and glial fibrillary acidic protein (GFAP) were consistently associated with CI and brain atrophy across various TBI severities and stages. Notably, certain biomarkers assessed during the acute phase (within 7 days post-injury), such as brain-derived neurotrophic factor, neuron-specific enolase, and interleukin-1β, showed significant correlations with CI. In contrast, elevated levels of GFAP and NfL measured during the recovery phase (6 months to 8 years post-injury) were significantly associated with TBI-related CI (TBI-CI). The findings also highlighted that axonal injury, glial activation, neuroinflammation, neuronal damage, and degeneration drive TBI-CI, with tau pathology and synaptic dysfunction emerging as potential bridges from TBI to AD. This review underscores the critical temporal dynamics of fluid biomarkers in TBI-CI, revealing that stage-specific biomarker profiles mirror distinct underlying pathophysiological processes. Future longitudinal studies should focus on well-characterized patient subgroups, adopt standardized diagnostic criteria, and integrate fluid biomarkers with neuroimaging and genetic data.},
}

Humans
*Brain Injuries, Traumatic/complications/metabolism
*Biomarkers/cerebrospinal fluid
*Cognitive Dysfunction/etiology/metabolism/diagnosis
tau Proteins
Glial Fibrillary Acidic Protein
Neurofilament Proteins

@article {pmid42196306,
year = {2026},
author = {Schulten, W and Czaniera, NJ and Fazel, M and Kaltschmidt, B and Kaltschmidt, C},
title = {APOE4 Alters Early Transcriptional Programs and Inflammatory Signaling in Human Induced Pluripotent Stem Cells.},
journal = {International journal of molecular sciences},
volume = {27},
number = {10},
pages = {},
doi = {10.3390/ijms27104325},
pmid = {42196306},
issn = {1422-0067},
mesh = {Humans ; *Induced Pluripotent Stem Cells/metabolism/cytology ; *Apolipoprotein E4/genetics/metabolism ; *Signal Transduction ; Cell Differentiation/genetics ; *Transcription, Genetic ; *Inflammation/genetics/metabolism ; Gene Expression Regulation ; Alzheimer Disease/genetics/metabolism ; Genotype ; SOXB1 Transcription Factors/metabolism/genetics ; Apolipoprotein E3/genetics ; Protein Interaction Maps ; },
abstract = {The APOE4 allele represents the strongest genetic risk factor for late-onset Alzheimer's disease (AD), yet its influence on early cellular programs remains poorly understood. In this study, we investigated transcriptional differences between human induced pluripotent stem cells (iPSCs) carrying the APOE3 or APOE4 genotype. RNA sequencing revealed pronounced genotype-dependent transcriptional changes, with enrichment of genes associated with neural development and metallothioneins in APOE4 cells, while genes related to extracellular matrix organization and cell adhesion were downregulated. Protein-protein interaction network analysis confirmed the presence of clusters linked to neurodevelopmental processes and cellular stress responses in APOE4 cells. Increased expression and nuclear localization of the early neural marker SOX1 further suggest a shift towards early neural lineage commitment in APOE4 cells. In addition, altered expression of early growth response (EGR) transcription factors and reduced TNFR2 protein levels indicated genotype-specific differences in stress and inflammatory signaling pathways. Together, these findings suggest that APOE genotype-dependent alterations in transcriptional regulation, stress responses, and inflammatory signaling may already emerge in pluripotent cells and potentially influence early differentiation programs.},
}

Humans
*Induced Pluripotent Stem Cells/metabolism/cytology
*Apolipoprotein E4/genetics/metabolism
*Signal Transduction
Cell Differentiation/genetics
*Transcription, Genetic
*Inflammation/genetics/metabolism
Gene Expression Regulation
Alzheimer Disease/genetics/metabolism
Genotype
SOXB1 Transcription Factors/metabolism/genetics
Apolipoprotein E3/genetics
Protein Interaction Maps

@article {pmid42196318,
year = {2026},
author = {Maciel, P and Lamas, CB and Araújo, AC and Chagas, EFB and Guiguer, EL and Curi, R and Pithon-Curi, TC and Almeida, MCDS and Sloan, KCP and Sloan, LA and Souza, ALDM and Rubira, CJ and Mendes, CG and Rocha, MG and Valenti, VE and Barbalho, SM},
title = {Physical Exercise Counteracts Impaired Cognition by Improving Mitochondrial Function.},
journal = {International journal of molecular sciences},
volume = {27},
number = {10},
pages = {},
doi = {10.3390/ijms27104337},
pmid = {42196318},
issn = {1422-0067},
mesh = {Humans ; *Mitochondria/metabolism ; Animals ; Oxidative Stress ; *Exercise/physiology ; *Cognitive Dysfunction/metabolism/therapy/physiopathology ; Energy Metabolism ; Reactive Oxygen Species/metabolism ; },
abstract = {Mitochondrial dysfunction is a key contributor to cognitive impairment, directly affecting neuronal viability, synaptic function, and energy metabolism. In the central nervous system, where energy demand is particularly high, disturbances in mitochondrial dynamics, including impaired oxidative phosphorylation (OxPhos), increased reactive oxygen species (ROS) production, and reduced ATP availability, can compromise synaptic transmission and accelerate cognitive decline. These alterations are commonly observed in neurodegenerative diseases such as Alzheimer's (AD) and Parkinson's (PD), in which mitochondrial dysfunction is closely associated with oxidative stress and neuroinflammatory processes. This review aims to investigate the role of mitochondrial dysfunction in cognitive impairment and the effects of physical exercise as a non-pharmacological strategy to mitigate these alterations. Current evidence indicates that exercise promotes mitochondrial biogenesis through activation of the AMPK/PGC-1α pathway, enhances oxidative metabolism, and improves mitochondrial efficiency. Furthermore, exercise reduces oxidative stress and inflammation while stimulating the release of neurotrophic factors, such as brain-derived neurotrophic factor which support neurogenesis, synaptic plasticity, and neuronal survival. Overall, these findings reinforce the importance of mitochondrial integrity in maintaining cognitive function and highlight physical exercise as a promising strategy to counteract mitochondrial dysfunction and delay the progression of neurodegenerative diseases.},
}

Humans
*Mitochondria/metabolism
Animals
Oxidative Stress
*Exercise/physiology
*Cognitive Dysfunction/metabolism/therapy/physiopathology
Energy Metabolism
Reactive Oxygen Species/metabolism

@article {pmid42196321,
year = {2026},
author = {Venetsanaki, V and Pardali, EC and Cholevas, C and Grammatikopoulou, MG and Goulis, DG and Theoharides, TC},
title = {Natural Molecules for Brain Health and Resilience.},
journal = {International journal of molecular sciences},
volume = {27},
number = {10},
pages = {},
doi = {10.3390/ijms27104343},
pmid = {42196321},
issn = {1422-0067},
mesh = {Humans ; *Brain/drug effects/metabolism ; Animals ; *Neuroprotective Agents/pharmacology/therapeutic use ; *Dietary Supplements ; Oxidative Stress/drug effects ; *Neurodegenerative Diseases/drug therapy/metabolism ; Flavonoids/pharmacology ; Antioxidants/pharmacology/therapeutic use ; *Biological Products/pharmacology/therapeutic use ; },
abstract = {The global rise in cognitive decline and neurodegenerative disorders has intensified the search for safe and accessible strategies to support brain health. In recent years, nutraceuticals have gained considerable attention as potential modulators of neurological function due to their antioxidant, anti-inflammatory, and neuroprotective properties. Increasing evidence suggests that oxidative stress, neuroinflammation, mitochondrial dysfunction, and impaired neurovascular integrity play central roles in the pathogenesis of several neurodegenerative diseases, namely Alzheimer's, Parkinson's disease and autism spectrum disorder, among others. This narrative review provides an integrated overview of selected nutraceuticals with potential relevance to brain-related disorders, including biotin, folinic acid, flavonoids (apigenin, diosmin, luteolin, naringin, pycnogenol, and quercetin), huperzine A, Lion's mane, olive oil polyphenols, oleuropein and palmitoylethanolamide. Rather than presenting a purely descriptive summary, we considered both mechanistic and clinical evidence, highlighting differences in the strength, consistency, and quality of available data across compounds. Among the reviewed compounds, huperzine A, specific flavonoids-particularly luteolin-and olive oil polyphenols demonstrated relatively stronger and more consistent support across experimental models and emerging clinical studies, mainly through modulation of cholinergic signaling, neuroinflammatory pathways, and oxidative stress responses. In contrast, evidence for other agents remains limited, heterogeneous, or primarily at the preclinical level. Overall, this review aims to provide a clearer and more structured synthesis of the current literature on neuronutrition, identifying compounds with the most promising profiles while outlining key limitations and research gaps that need to be addressed to better define their role in brain health.},
}

Humans
*Brain/drug effects/metabolism
Animals
*Neuroprotective Agents/pharmacology/therapeutic use
*Dietary Supplements
Oxidative Stress/drug effects
*Neurodegenerative Diseases/drug therapy/metabolism
Flavonoids/pharmacology
Antioxidants/pharmacology/therapeutic use
*Biological Products/pharmacology/therapeutic use

@article {pmid42196404,
year = {2026},
author = {Wang, SB and Chou, KN and Chiu, YL},
title = {Integrated Transcriptomic and Spatial Analyses Associate M2-like Myeloid Signatures with Neuroimmune Remodeling in Alzheimer's Disease.},
journal = {International journal of molecular sciences},
volume = {27},
number = {10},
pages = {},
doi = {10.3390/ijms27104430},
pmid = {42196404},
issn = {1422-0067},
support = {NSTC-111-2314-B-016-019-MY3//National Science and Technology Council/ ; NSTC-112-2813-C-016-022-B//National Science and Technology Council/ ; MND-MAB-D-114166//Ministry of National Defense/ ; MND-MAB-D-113103//Ministry of National Defense/ ; },
mesh = {*Alzheimer Disease/immunology/genetics/pathology/metabolism ; Humans ; *Transcriptome ; *Macrophages/metabolism/immunology ; *Myeloid Cells/metabolism/immunology ; Spatial Transcriptomics ; Gene Expression Profiling ; Signal Transduction ; *Neuroimmunomodulation ; },
abstract = {Alzheimer's disease (AD) is characterized by progressive neurodegeneration and prominent neuroimmune remodeling, but the contribution of macrophage and myeloid states across disease severity remains incompletely defined. We integrated bulk transcriptomic, single-cell RNA sequencing (RNA-seq), and spatial transcriptomic datasets to characterize AD-associated myeloid immune changes across Braak stage and disease status. Across datasets, M2-like macrophage and myeloid signatures showed progressive enrichment with increasing neuropathological severity and were accompanied by pathway changes related to macrophage proliferation, TGF-β signaling, and myeloid homeostasis. Immune-feature-based classifiers identified macrophage-related variables among the informative features distinguishing AD from controls. CellChat analyses further inferred that M2-like myeloid populations occupied communication-enriched positions in single-cell and spatial interaction networks, including apolipoprotein E (ApoE), CX3C chemokine signaling, and fibronectin 1 (FN1)-associated signaling contexts. Collectively, these findings indicate that M2-like myeloid programs are consistently associated with AD severity and neuroimmune network remodeling. Rather than establishing a causal disease driver, this study highlights M2-like myeloid signatures as candidate neuroimmune components that warrant experimental validation in human-relevant systems.},
}

*Alzheimer Disease/immunology/genetics/pathology/metabolism
Humans
*Transcriptome
*Macrophages/metabolism/immunology
*Myeloid Cells/metabolism/immunology
Spatial Transcriptomics
Gene Expression Profiling
Signal Transduction
*Neuroimmunomodulation

@article {pmid42196496,
year = {2026},
author = {Agnello, L and Dominici, R and Gambino, CM and Scazzone, C and Ciaccio, M},
title = {Analytical Methods for Fluid Biomarkers in Alzheimer's Disease from Discovery to Clinical Implementation.},
journal = {International journal of molecular sciences},
volume = {27},
number = {10},
pages = {},
doi = {10.3390/ijms27104518},
pmid = {42196496},
issn = {1422-0067},
mesh = {*Alzheimer Disease/cerebrospinal fluid/diagnosis/blood/metabolism ; Humans ; *Biomarkers/cerebrospinal fluid/blood ; Proteomics/methods ; Amyloid beta-Peptides/cerebrospinal fluid ; Immunoassay/methods ; Enzyme-Linked Immunosorbent Assay/methods ; Animals ; tau Proteins/cerebrospinal fluid ; },
abstract = {Alzheimer's disease (AD) is increasingly recognized as a biological continuum characterized by early neuropathological and molecular changes that precede the onset of clinical symptoms. Fluid biomarkers have transformed the diagnostic landscape by enabling the in vivo detection of core AD pathologies, particularly amyloid-β deposition and tau-related neurodegeneration. Despite the rapid expansion of candidate biomarkers, however, only a limited number have successfully translated into clinical practice. Discovery-phase approaches, primarily driven by mass spectrometry-based proteomics, enable the unbiased identification of novel biomarker candidates across multiple biological pathways. Research-phase methods, including immunoassays such as enzyme-linked immunosorbent assay (ELISA), electrochemiluminescence immunoassays (ECLIA), microfluidic platforms, and ultrasensitive technologies such as single-molecule array (SIMOA), support analytical and clinical validation in well-characterized cohorts. Clinical implementation has been advanced by fully automated platforms, including Lumipulse and Elecsys, which have obtained regulatory approval for cerebrospinal fluid biomarkers and, more recently, blood-based biomarkers. These developments represent a paradigm shift toward minimally invasive and scalable diagnostic strategies that may reduce dependence on neuroimaging techniques. Nevertheless, major challenges remain, including assay standardization, inter-platform variability, demonstration of clinical utility, and barriers to widespread clinical adoption. This review provides a comprehensive overview of analytical methods used to measure AD fluid biomarkers in cerebrospinal fluid and plasma, structured according to the biomarker development pipeline from discovery to clinical implementation. Overall, the review highlights a fit-for-purpose approach to biomarker development and emphasizes the complementary roles of diverse analytical technologies across the different phases of biomarker translation.},
}

*Alzheimer Disease/cerebrospinal fluid/diagnosis/blood/metabolism
Humans
*Biomarkers/cerebrospinal fluid/blood
Proteomics/methods
Amyloid beta-Peptides/cerebrospinal fluid
Immunoassay/methods
Enzyme-Linked Immunosorbent Assay/methods
Animals
tau Proteins/cerebrospinal fluid

@article {pmid42196498,
year = {2026},
author = {Bianchi, VE and Visbal, LC and Devesa, J},
title = {Growth Hormone and Brain Regeneration: Evidence from Clinical Studies in Dementia, Traumatic Brain Injury, and Stroke: A Systematic Review.},
journal = {International journal of molecular sciences},
volume = {27},
number = {10},
pages = {},
doi = {10.3390/ijms27104521},
pmid = {42196498},
issn = {1422-0067},
mesh = {Humans ; *Brain Injuries, Traumatic/drug therapy/metabolism/physiopathology ; *Stroke/drug therapy/metabolism/physiopathology ; *Dementia/drug therapy/metabolism ; *Growth Hormone/therapeutic use/metabolism/pharmacology ; Animals ; *Brain/drug effects/physiology/metabolism ; Insulin-Like Growth Factor I/metabolism ; *Regeneration/drug effects ; },
abstract = {Growth hormone (GH) and insulin-like growth factor 1 (IGF-1) play essential roles in the brain, influencing neuronal and dendritic growth, as well as neurotransmission. These effects persist throughout life. Numerous studies in animals and humans have demonstrated the beneficial effects of GH therapy on memory and cognitive function, as well as on the restoration of neuronal function following injury. All nerve cells, including neurons, glia, endothelial, epithelial, and perivascular cells, are affected by the actions of GH/IGF-1. IGF-1, in particular, has been associated with cognitive function. The GH-IGF-1 axis increases the proliferation of neuronal progenitor cells and the formation of new neurons, oligodendrocytes, and astrocytes. In this study, we searched databases such as PubMed, Google Scholar, and Embase for human clinical trials evaluating the effect of growth hormone (GH) therapy on dementia, Alzheimer's disease (AD), post-traumatic brain injury (PTI), and stroke. The following search terms were used: "GH and dementia," "GH and Alzheimer's disease," "GH and TBI," and "GH and stroke." Inclusion criteria were all randomized controlled trials and observational studies. Exclusion criteria included the lack of cognitive and memory assessments. We found 28 articles. Most studies show the beneficial effects of GH therapy on memory and recovery of brain function after traumatic injury and stroke; however, consistent data are still lacking. The limited number of clinical trials, the small number of patients, and the lack of data on plasma levels of sex hormones that clearly contribute to brain function are limiting factors. This is the case, for example, with androgens. Other critical factors are dosage and treatment duration. Prolonged administration and supraphysiological doses are more effective in inducing positive clinical changes. Growth hormone (GH) therapy is a very promising intervention for preventing and treating dementia and early-stage Alzheimer's disease, and it contributes significantly to the recovery of brain function in patients after traumatic injury and stroke. Further studies with more robust methodologies are needed to confirm these results.},
}

Humans
*Brain Injuries, Traumatic/drug therapy/metabolism/physiopathology
*Stroke/drug therapy/metabolism/physiopathology
*Dementia/drug therapy/metabolism
*Growth Hormone/therapeutic use/metabolism/pharmacology
Animals
*Brain/drug effects/physiology/metabolism
Insulin-Like Growth Factor I/metabolism
*Regeneration/drug effects

@article {pmid42196534,
year = {2026},
author = {He, J and Li, J and Huo, J and Pang, Y and Sun, K and Zhu, H and He, Y and Ren, Z and Cheng, X and Ao, S and Peng, Y},
title = {Network Pharmacology Reveals the Therapeutic Potential of BBB-Permeable Compounds from Lonicera caerulea for Alzheimer's Disease and Lipid Metabolism Disorders.},
journal = {International journal of molecular sciences},
volume = {27},
number = {10},
pages = {},
doi = {10.3390/ijms27104556},
pmid = {42196534},
issn = {1422-0067},
support = {GZ20040050//the Key Research and Development Program of Heilongjiang Province/ ; JJ2025XQ0159//the Industry-University Co-operation Project of the Natural Science Foundation of Heilongjiang Province/ ; GJB1425362//Key Project of "14th Five-Year" Plan for Heilongjiang Provincial Educational Science Research in 2025/ ; N/A//Special Support Program for "Excellent Physician Training Research" of Harbin Medical Univer-sity in 2025/ ; 2022YFD1600500//Key R&D Program of China/ ; },
mesh = {*Alzheimer Disease/drug therapy/metabolism ; *Blood-Brain Barrier/metabolism/drug effects ; Humans ; Molecular Docking Simulation ; *Lonicera/chemistry ; Molecular Dynamics Simulation ; Network Pharmacology/methods ; *Lipid Metabolism Disorders/drug therapy/metabolism ; Lipid Metabolism/drug effects ; *Plant Extracts/pharmacology/chemistry ; },
abstract = {Although risk factors for Alzheimer's disease (AD) involve obesity and elevated low-density lipoprotein (LDL) cholesterol levels, and Lonicera caerulea has been reported to improve lipid metabolism disorders (LMDs), it remains unknown whether Lonicera caerulea can simultaneously modulate the progression of both AD and LMDs. In this study, an integrative strategy combining network pharmacology, Mendelian randomization (MR), molecular docking, and molecular dynamics simulations was employed to explore potential targets, pathways, and causal relationships. Network pharmacology and molecular docking results revealed that several blood-brain barrier (BBB)-permeable active components of Lonicera caerulea, including Naringenin and Palmatine, may be associated with targets involved in the lipid and atherosclerosis pathway, such as HSP90AA1, SRC and TNF. These associations indicate a potential link between the modulation of lipid metabolism and AD-related processes, although further validation is required. Molecular dynamics simulations were conducted to support the stability of key docking complexes. Given that elevated LDL is a central feature of LMDs and a key indicator of cholesterol imbalance, MR analysis was conducted to assess its causal relationship with AD. The results provided genetic evidence supporting a causal role of elevated LDL in AD risk, reinforcing the epidemiological link between lipid metabolism and neurodegeneration. These findings imply that BBB-permeable constituents of Lonicera caerulea may exert multi-target effects relevant to AD and LMDs. Enrichment analysis further indicates a possible involvement of pathways associated with lipid and atherosclerosis, supporting its potential as a dietary strategy for at-risk populations.},
}

*Alzheimer Disease/drug therapy/metabolism
*Blood-Brain Barrier/metabolism/drug effects
Humans
Molecular Docking Simulation
*Lonicera/chemistry
Molecular Dynamics Simulation
Network Pharmacology/methods
*Lipid Metabolism Disorders/drug therapy/metabolism
Lipid Metabolism/drug effects
*Plant Extracts/pharmacology/chemistry

@article {pmid42196596,
year = {2026},
author = {Hasan, I and Tang, X and Xu, J},
title = {Glial Cells in Behavioral and Psychological Symptoms of Alzheimer's Disease.},
journal = {International journal of molecular sciences},
volume = {27},
number = {10},
pages = {},
doi = {10.3390/ijms27104621},
pmid = {42196596},
issn = {1422-0067},
support = {82173798//National Natural Science Foundation of China/ ; },
mesh = {Humans ; *Alzheimer Disease/psychology/pathology/metabolism ; *Neuroglia/metabolism/pathology ; Animals ; Microglia/metabolism/pathology ; Astrocytes/metabolism/pathology ; Oligodendroglia/metabolism/pathology ; },
abstract = {Behavioral and psychological symptoms of dementia (BPSD) affect the majority of patients with Alzheimer's disease (AD), substantially increasing caregiver burden and the likelihood of institutionalization. The clinical management of BPSD remains challenging because of its poorly understood pathogenesis, the limited efficacy of conventional interventions, and significant safety concerns associated with current treatments. These limitations underscore the urgent need to identify novel therapeutic targets and develop glia-centered treatment strategies. As essential components of the central nervous system, glial cells maintain neural homeostasis, regulate neurotransmission, and mediate neuroinflammatory responses. Increasing evidence suggests that glial dysfunction contributes to the development of BPSD, thereby linking AD neuropathology and neuropsychiatric symptoms. Aberrant microglial activation, astrocytic dysfunction, and oligodendrocyte injury collectively compromise neural circuit integrity, disrupt neurotransmitter balance, and impair neuron-glia communication, ultimately promoting the progression of diverse BPSDs. Given the critical role of glial cells in regulating neurotransmitter systems, the dysregulation of which is closely associated with BPSD, this review summarizes the involvement of glial cells in BPSD, elucidates the underlying molecular mechanisms, and discusses recent advances in glia-based therapeutic strategies, thereby providing insights into the pathogenesis of BPSD in AD.},
}

Humans
*Alzheimer Disease/psychology/pathology/metabolism
*Neuroglia/metabolism/pathology
Animals
Microglia/metabolism/pathology
Astrocytes/metabolism/pathology
Oligodendroglia/metabolism/pathology

@article {pmid42196607,
year = {2026},
author = {Wind-Mark, K and Kunze, LH and Willem, M and Palumbo, G and Giudici, C and Nuscher, B and Boening, G and Gildehaus, FJ and Lindner, S and Werner, RA and Franzmeier, N and Gnörich, JS and Brendel, M and Zatcepin, A},
title = {Tracking of Neuroinflammation Dynamics During Combined Anti-β-Amyloid Therapy (AAT) and Immunomodulation in a Preclinical Alzheimer's Disease Model.},
journal = {International journal of molecular sciences},
volume = {27},
number = {10},
pages = {},
doi = {10.3390/ijms27104632},
pmid = {42196607},
issn = {1422-0067},
support = {EXC 2145 SyNergy - ID 390857198//German Research Foundation/ ; Medical & Clinician Scientist Program (MCSP)//Ludwig Maximilian University of Munich/ ; },
mesh = {Animals ; *Alzheimer Disease/drug therapy/immunology/diagnostic imaging/metabolism ; *Amyloid beta-Peptides/immunology/antagonists & inhibitors ; Mice ; Positron-Emission Tomography ; Disease Models, Animal ; Pioglitazone/pharmacology/therapeutic use ; *Neuroinflammatory Diseases/drug therapy/diagnostic imaging ; Receptors, GABA/metabolism ; *Antibodies, Monoclonal/pharmacology/therapeutic use ; *Immunomodulation/drug effects ; PPAR-gamma Agonists ; Mice, Transgenic ; Microglia/metabolism/drug effects ; Brain ; },
abstract = {Neuroinflammation is increasingly recognized as a key modulator of therapeutic response and adverse events in Alzheimer's disease (AD), especially during anti-amyloid-β (Aβ) monoclonal antibody (Aβ-mAb) treatment. We applied longitudinal translocator protein (TSPO) positron emission tomography (PET) to evaluate TSPO-associated neuroinflammatory responses to chronic Aβ-mAb therapy and their modulation by the peroxisome proliferator-activated receptor γ (PPARγ) agonist pioglitazone. App[NL-G-F] knock-in mice underwent TSPO-PET and Aβ-PET imaging at 5, 7.5, and 10 months of age across four treatment arms: placebo, Aβ-mAb, pioglitazone, and combination therapy. TSPO-PET detected early and progressive neuroinflammatory responses to Aβ-mAb that appeared lower with pioglitazone co-treatment. Both mono- and combination therapy were associated with altered temporal and spatial dynamics of the TSPO-PET signal. In addition, we applied a previously validated microglia desynchronization index based on TSPO-PET connectivity, which captured individual variation in regional TSPO-PET organization and correlated with cognitive performance. Together, TSPO-PET and its regional synchronicity can quantify longitudinal, region-specific treatment effects, which may help differentiate harmful from adaptive neuroinflammatory responses. These findings highlight the potential of TSPO-PET as a stratification biomarker to optimize therapeutic interventions. TSPO-PET therefore enables in vivo tracking of treatment-associated neuroinflammatory responses during anti-Aβ immunotherapy and provides a non-invasive framework for evaluating combination strategies targeting amyloid pathology and immune regulation in AD.},
}

Animals
*Alzheimer Disease/drug therapy/immunology/diagnostic imaging/metabolism
*Amyloid beta-Peptides/immunology/antagonists & inhibitors
Mice
Positron-Emission Tomography
Disease Models, Animal
Pioglitazone/pharmacology/therapeutic use
*Neuroinflammatory Diseases/drug therapy/diagnostic imaging
Receptors, GABA/metabolism
*Antibodies, Monoclonal/pharmacology/therapeutic use
*Immunomodulation/drug effects
PPAR-gamma Agonists
Mice, Transgenic
Microglia/metabolism/drug effects
Brain

@article {pmid42196628,
year = {2026},
author = {Lo Vecchio, F and la Torre, A and Gravina, C and D'Onofrio, G and Greco, A},
title = {Molecular Mechanisms Underlying Alzheimer's Disease Pathogenesis: Comprehensive Overview.},
journal = {International journal of molecular sciences},
volume = {27},
number = {10},
pages = {},
doi = {10.3390/ijms27104651},
pmid = {42196628},
issn = {1422-0067},
mesh = {Humans ; *Alzheimer Disease/metabolism/pathology/etiology/genetics ; Animals ; Amyloid beta-Peptides/metabolism ; Neurofibrillary Tangles/metabolism/pathology ; },
abstract = {Alzheimer's disease (AD) is a progressive, multifactorial neurodegenerative disorder ranking first as cause of dementia in the elderly. It is characterized by the progressive deterioration of the central nervous system, leading to impaired cognitive function and reduced ability to perform daily activities. Pathological hallmarks of AD include the accumulation of β-amyloid plaques and neurofibrillary tangles which ultimately cause neuronal death and synaptic loss. The vast majority of AD cases are sporadic, with aging representing the primary non-modifiable risk factor contributing to disease susceptibility and progression. However, several factors encompassing genetic predisposition, systemic inflammation, chronic diseases, infections, traumatic brain injury, lifestyle factors, and environmental exposures may affect AD onset. This work aims to describe and discuss the main molecular pathways involved in AD pathophysiology and to examine how these mechanisms cross-interact in promoting neurodegeneration and disease progression.},
}

Humans
*Alzheimer Disease/metabolism/pathology/etiology/genetics
Animals
Amyloid beta-Peptides/metabolism
Neurofibrillary Tangles/metabolism/pathology

@article {pmid42197117,
year = {2026},
author = {Hryniewicka, A and Pawelski, D and Plonska-Brzezinska, ME},
title = {Design, Synthesis, and Biological Evaluation of Highly Functionalized Tetrahydro-β-carboline-imidazolium Hybrids Targeting Cholinesterases.},
journal = {Molecules (Basel, Switzerland)},
volume = {31},
number = {10},
pages = {},
doi = {10.3390/molecules31101563},
pmid = {42197117},
issn = {1420-3049},
mesh = {*Cholinesterase Inhibitors/chemistry/pharmacology/chemical synthesis ; *Carbolines/chemistry/chemical synthesis/pharmacology ; Molecular Docking Simulation ; *Imidazoles/chemistry/pharmacology/chemical synthesis ; Structure-Activity Relationship ; *Drug Design ; Acetylcholinesterase/chemistry/metabolism ; Humans ; Butyrylcholinesterase/chemistry/metabolism ; Molecular Structure ; Animals ; Catalytic Domain ; Alzheimer Disease/drug therapy ; },
abstract = {A novel series of hybrid tetrahydro-β-carboline (THβC)-imidazolium (IM) salts incorporating a fused diketopiperazine scaffold was designed, synthesized, and evaluated as cholinesterase inhibitors for potential application in Alzheimer's disease. The molecular design integrates a π-conjugated THβC core with a cationic IM moiety to promote dual-site interactions within the acetylcholinesterase (AChE) active-site gorge. All compounds exhibited micromolar inhibitory activity against AChE and butyrylcholinesterase (BChE), with a pronounced preference for AChE. The most active derivative, 12d, showed an IC50 value of 0.72 μM toward AChE, while compound 12c demonstrated the highest selectivity (SI = 8.4). Structure-activity relationship studies revealed that both stereochemistry and N-alkyl chain length are critical determinants of activity, with S,S-configured derivatives consistently outperforming their R,R-configured analogs. In silico ADMET analysis indicated favorable physicochemical properties and predicted central nervous system permeability, although potential hepatotoxicity highlights the need for further optimization. Molecular docking studies suggested that the most promising compound adopts a dual-binding mode, interacting with both the peripheral anionic site and catalytic active site of AChE. These results identify THβC-IM hybrids as a structurally novel and promising scaffold for the development of selective cholinesterase inhibitors, providing a basis for further optimization toward multifunctional anti-Alzheimer agents.},
}

*Cholinesterase Inhibitors/chemistry/pharmacology/chemical synthesis
*Carbolines/chemistry/chemical synthesis/pharmacology
Molecular Docking Simulation
*Imidazoles/chemistry/pharmacology/chemical synthesis
Structure-Activity Relationship
*Drug Design
Acetylcholinesterase/chemistry/metabolism
Humans
Butyrylcholinesterase/chemistry/metabolism
Molecular Structure
Animals
Catalytic Domain
Alzheimer Disease/drug therapy

@article {pmid42197128,
year = {2026},
author = {Cui, X and Zhu, XC and Yao, SQ and Wang, R and Zhang, YX and Li, J and Wang, B and Deng, YR and Wu, CJ},
title = {Phytochemical Profiling of Mulberry Diels-Alder Adducts as Selective Butyrylcholinesterase Inhibitors: In Vitro Activity, Molecular Docking, and Molecular Dynamics Simulation.},
journal = {Molecules (Basel, Switzerland)},
volume = {31},
number = {10},
pages = {},
doi = {10.3390/molecules31101574},
pmid = {42197128},
issn = {1420-3049},
support = {245101610085//Henan Science and Technology Department/ ; 242102310430//Henan Science and Technology Department/ ; 2019YFC1711000//Ministry of Science and Technology of the People's Republic of China/ ; },
mesh = {*Molecular Docking Simulation ; *Cholinesterase Inhibitors/chemistry/pharmacology ; *Morus/chemistry ; *Butyrylcholinesterase/chemistry/metabolism ; Molecular Dynamics Simulation ; Humans ; *Phytochemicals/chemistry/pharmacology ; Plant Extracts/chemistry/pharmacology ; Molecular Structure ; Structure-Activity Relationship ; Cycloaddition Reaction ; },
abstract = {Alzheimer's disease (AD) is a common neurodegenerative disorder linked to cholinergic dysfunction, with butyrylcholinesterase (BChE) being a key therapeutic target for moderate-severe AD. Cortex Mori Radicis, a traditional Chinese medicinal herb, is rich in Diels-Alder adducts with potential neuroprotective effects; here, eighteen Diels-Alder adducts (four new: morusalbanol B-E, 1-4) were isolated and identified from its 80% ethanol extract. Their cholinesterase inhibitory activities were assessed via Ellman's method, with enzyme kinetics and molecular docking performed for active compounds. Most compounds showed selective BChE inhibition, with kuwanon X (14) being the most potent (IC50 = 2.3 μM). morusalbanol B (1), cathayanon A (8), and kuwanon G (12) acted as noncompetitive inhibitors, while Morusalbanol C (2) and kuwanon X (14) were mixed competitive inhibitors. Molecular docking suggested that potent inhibitors occupied the BChE active pocket via hydrogen bonds, π-π stacking, and hydrophobic interactions with Trp82, His438, and Phe329. MD simulations and MM-GBSA binding free energy analysis further verified that all three representative complexes (1, 8, and 14) achieved favorable thermodynamic and structural stability, with binding driven primarily by van der Waals forces. Residue decomposition revealed that Trp82 and Phe329 served as core binding hotspots for all tested inhibitors. Structure-activity analysis indicated that a cis-trans methylcyclohexene configuration, shorter aliphatic ester chains, and more prenyl groups enhanced BChE inhibition. This study provides new lead compounds and a systematic molecular mechanism basis for developing novel anti-AD BChE inhibitors from natural products.},
}

*Molecular Docking Simulation
*Cholinesterase Inhibitors/chemistry/pharmacology
*Morus/chemistry
*Butyrylcholinesterase/chemistry/metabolism
Molecular Dynamics Simulation
Humans
*Phytochemicals/chemistry/pharmacology
Plant Extracts/chemistry/pharmacology
Molecular Structure
Structure-Activity Relationship
Cycloaddition Reaction

@article {pmid42197282,
year = {2026},
author = {Ali Agha, ASA and Khaleel, S and Abdelaziz, HMA and Alzweiri, M and Qinna, NA and AlDabet, G and El Khassawna, T and Aburjai, T},
title = {Toward a Molecular Framework of Systemic Multi-Organ Toxicity Induced by Chronic Aluminum Chloride Exposure.},
journal = {Molecules (Basel, Switzerland)},
volume = {31},
number = {10},
pages = {},
doi = {10.3390/molecules31101728},
pmid = {42197282},
issn = {1420-3049},
support = {1878//University of Jordan/ ; },
mesh = {*Aluminum Chloride/toxicity ; Animals ; Humans ; Oxidative Stress/drug effects ; *Aluminum Compounds/toxicity ; Organ Specificity/drug effects ; },
abstract = {Aluminum chloride (AlCl3) is widely used in experimental toxicology, particularly in rodent models of neurodegeneration, where its effects have been studied primarily in the central nervous system. However, experimental findings also indicate that chronic exposure is associated with changes across multiple peripheral organs, although these observations are often considered separately. In this review, we bring together evidence from different organ systems to examine aluminum toxicity from a broader perspective. Rather than focusing on isolated tissue-specific effects, we consider the extent to which reported findings may reflect overlapping molecular disturbances expressed across physiological systems. Within this context, organ-level outcomes are discussed as potentially related manifestations of shared underlying processes, while acknowledging variability in experimental conditions and model interpretation. To structure this synthesis, we outline a conceptual framework that links recurring molecular responses, system-level regulatory influences, and tissue-specific patterns of injury. This approach is intended to provide a more integrated way of organizing existing data rather than to establish a single unifying mechanism. Importantly, the pathological alterations discussed throughout this review are interpreted as experimentally observed toxicological manifestations of chronic AlCl3 exposure rather than evidence that aluminum constitutes a definitive etiological cause of Alzheimer's disease. Overall, this review aims to complement existing neuro-focused interpretations of the AlCl3 model by situating it within a multi-organ context and highlighting areas where further integrative investigation may be warranted.},
}

*Aluminum Chloride/toxicity
Animals
Humans
Oxidative Stress/drug effects
*Aluminum Compounds/toxicity
Organ Specificity/drug effects

@article {pmid42197288,
year = {2026},
author = {Mu, Q and Ma, Y and Zhang, T and Cong, F and Jin, J and Jin, Q and Wang, X},
title = {Odd-Chain Fatty Acids-Enriched Algal Oil Improves Locomotor Function and Modulates Metabolic Pathways in Caenorhabditis elegans Model of Alzheimer's Disease.},
journal = {Molecules (Basel, Switzerland)},
volume = {31},
number = {10},
pages = {},
doi = {10.3390/molecules31101734},
pmid = {42197288},
issn = {1420-3049},
support = {No. SKLF-ZZB-202509//State Key Laboratory of Food Science and Technology/ ; 32402082//National Natural Science Foundation of China/ ; 2662024SPQD001//Fundamental Research Funds for the Central Universities/ ; ZYSP2025KF036//Open Research Fund of the Food Laboratory of Zhongyuan/ ; },
mesh = {Animals ; *Caenorhabditis elegans/drug effects/metabolism ; *Alzheimer Disease/metabolism/drug therapy ; *Fatty Acids/pharmacology/chemistry ; Disease Models, Animal ; *Metabolic Networks and Pathways/drug effects ; Metabolomics/methods ; *Locomotion/drug effects ; Neuroprotective Agents/pharmacology/chemistry ; *Plant Oils/pharmacology/chemistry ; },
abstract = {Alzheimer's disease (AD) is a common age-related neurodegenerative disorder with extremely low drug development success rates, making nutritional intervention a promising strategy. Cerebral energy metabolism dysfunction is a core pathological feature of AD. Odd-chain fatty acids (OCFAs) can generate propionyl-CoA via β-oxidation to replenish the impaired tricarboxylic acid (TCA) cycle. This study characterized the lipid composition of OCFAs-enriched algal oil by UPC[2]-Q-TOF-MS, evaluated its neuroprotective effects on Caenorhabditis elegans (C. elegans) models with AD, Parkinson's disease (PD), and Huntington's disease (HD), and explored the metabolic mechanism of its key component pentadecanoic acid (C15:0) using untargeted metabolomics. Results showed that triglycerides (TAGs) represented the predominant lipid class, accounting for 97.3% of the total lipid content in the algal oil. Among all the identified TAG molecular species, TAGs containing C15:0/C17:0 accounted for more than 90%. OCFAs-enriched algal oil exhibited disease-selective neuroprotection. It significantly improved locomotor function in AD nematodes, moderately ameliorated PD-related deficits, whereas showed no efficacy in HD nematodes. Metabolomics revealed that C15:0 produced propionyl-CoA to rescue TCA cycle dysfunction and energy deficits, upregulated membrane phospholipids to repair membrane integrity, and reduced abnormal metabolites to restore metabolic homeostasis. KEGG analysis confirmed that C15:0 globally regulated core metabolic pathways including amino acid, cofactor, nucleotide, and carbon metabolism. OCFAs-enriched algal oil exerted selective anti-AD effects by repairing energy metabolism, remodeling membrane phospholipids, and restoring metabolic homeostasis, providing a novel nutritional candidate for AD intervention.},
}

Animals
*Caenorhabditis elegans/drug effects/metabolism
*Alzheimer Disease/metabolism/drug therapy
*Fatty Acids/pharmacology/chemistry
Disease Models, Animal
*Metabolic Networks and Pathways/drug effects
Metabolomics/methods
*Locomotion/drug effects
Neuroprotective Agents/pharmacology/chemistry
*Plant Oils/pharmacology/chemistry

@article {pmid42197293,
year = {2026},
author = {Shin, SH and Kim, J and Moon, H and Sheshashena Reddy, T and Choi, MS},
title = {Porphyrin-Based Fluorescent Probe for Nanomolar Detection of Cu[2+] and Ni[2+] Ions.},
journal = {Molecules (Basel, Switzerland)},
volume = {31},
number = {10},
pages = {},
doi = {10.3390/molecules31101739},
pmid = {42197293},
issn = {1420-3049},
support = {2024//Konkuk University/ ; 20026593 and 00418987//Ministry of Trade, Industry and Energy/ ; },
mesh = {*Copper/analysis/chemistry ; *Porphyrins/chemistry ; *Nickel/analysis ; *Fluorescent Dyes/chemistry ; Spectrometry, Fluorescence ; Fluorescent Chemosensor Compounds ; Ions ; Amines ; Picolinic Acids ; },
abstract = {Copper is an indispensable trace element for maintaining metabolic homeostasis; however, the dysregulation and subsequent accumulation of Cu[2+] are critically linked to neurodegenerative pathologies, including Alzheimer's disease in humans. Consequently, the development of robust analytical tools for Cu[2+] monitoring is of paramount importance. Here, we report a 2,2'-dipicolylamine porphyrin (DPAP)-based fluorescent sensor designed for the precise detection of metal cations. Photophysical investigations reveal that DPAP operates via a rapid turn-off fluorescence mechanism, achieving high-performance sensing in the parts-per-million range. Notably, the probe demonstrates exceptional sensitivity with detection limits of 26.3 nM for Cu[2+] and 34.8 nM for Ni[2+]. Interference studies demonstrated the selectivity of DPAP for Cu[2+] over a diverse range of competing metal ions such as Na[+], Ag[+], Ni[2+], Cr[3+], Pb[2+], Al[3+], Fe[2+], Cd[2+], and Zn[2+]. These results indicate that DPAP is a sensitive and selective probe suitable for copper ion detection.},
}

*Copper/analysis/chemistry
*Porphyrins/chemistry
*Nickel/analysis
*Fluorescent Dyes/chemistry
Spectrometry, Fluorescence
Fluorescent Chemosensor Compounds
Ions
Amines
Picolinic Acids

@article {pmid42197618,
year = {2026},
author = {Elshafie, HS and Camele, I},
title = {From Chemotaxonomy to Green Biocides: An Overview of New Studies on the Composition and Functional Properties of Some Plant Essential Oils.},
journal = {Plants (Basel, Switzerland)},
volume = {15},
number = {10},
pages = {},
doi = {10.3390/plants15101484},
pmid = {42197618},
issn = {2223-7747},
abstract = {In recent years, the search for sustainable, bio-based alternatives to synthetic chemicals has intensified, positioning plant essential oils (EOs) at the forefront of applied phytochemical research. The following collection of ten articles from different geographical regions, published in Plants as part of the Special Issue "Plant Essential Oil with Biological Activity: 3rd Edition," covers various aspects of recent scientific research on plant EOs, ranging from chemotaxonomy to green biocides, with particular emphasis on chemical composition and functional properties. Further attention is given to specific predominant single constituents and their bio-selectivity, modes of action, and innovative applications in the medical and pharmaceutical sectors, particularly against major diseases such as cancer and Alzheimer's.},
}

@article {pmid42198082,
year = {2026},
author = {Suffian, M and Ieracitano, C and Mammone, N and Pascarella, A and Ferlazzo, E and Morabito, FC},
title = {An EEG-Based Edge-AI Framework for Alzheimer's and Creutzfeldt-Jakob Disease Classification.},
journal = {Sensors (Basel, Switzerland)},
volume = {26},
number = {10},
pages = {},
doi = {10.3390/s26103274},
pmid = {42198082},
issn = {1424-8220},
mesh = {Humans ; *Creutzfeldt-Jakob Syndrome/diagnosis/classification/physiopathology ; *Alzheimer Disease/diagnosis/classification/physiopathology ; *Electroencephalography/methods ; *Artificial Intelligence ; Convolutional Neural Networks ; Signal Processing, Computer-Assisted ; Algorithms ; Deep Learning ; Neural Networks, Computer ; Female ; },
abstract = {Electroencephalography (EEG) has emerged as a promising non-invasive tool for the diagnosis of neurodegenerative disorders, and artificial intelligence (AI) has shown significant potential in this domain, as demonstrated by recent studies. However, strong inter-subject variability remains a major challenge, limiting the ability of AI-based models to learn disease-specific features that generalize across individuals, thereby hindering the development of clinically deployable subject-independent systems. In this work, we propose a cross-subject, AI-based EEG classification framework to distinguish between Alzheimer's disease (AD), Creutzfeldt-Jakob disease (CJD), and healthy control subjects using clinical EEG data collected from a local hospital. A lightweight hybrid deep learning model is developed, combining a two-layer one-dimensional convolutional neural network with a two-layer Transformer encoder to capture both local temporal patterns and long-range dependencies in EEG signals. The proposed model achieves an average classification accuracy of 97%, representing a 3% improvement over a baseline model evaluated on a cohort of 36 subjects. To assess deployment feasibility in real-time clinical settings, the trained model is implemented and evaluated on an edge-AI platform (NVIDIA Jetson AGX Orin), demonstrating energy efficiency for the inference with a compact model footprint. These results indicate that the proposed approach provides an accurate, efficient, and practically deployable solution for subject-independent EEG-based classification of neurological disorders.},
}

Humans
*Creutzfeldt-Jakob Syndrome/diagnosis/classification/physiopathology
*Alzheimer Disease/diagnosis/classification/physiopathology
*Electroencephalography/methods
*Artificial Intelligence
Convolutional Neural Networks
Signal Processing, Computer-Assisted
Algorithms
Deep Learning
Neural Networks, Computer
Female

@article {pmid42198235,
year = {2026},
author = {Souza, IFF and Placido, RV and Placido, MJ and Rocha, LC and Bonfilio, R and Boralli, VB and Ruela, ALM and Pereira, GR},
title = {Nanostructured Lipid Carriers Loaded with Donepezil for Nose-to-Brain Targeting.},
journal = {Pharmaceutics},
volume = {18},
number = {5},
pages = {},
doi = {10.3390/pharmaceutics18050541},
pmid = {42198235},
issn = {1999-4923},
support = {001//the Coordenação de Aperfeiçoamento de Pessoal de Nível Superior, Brazil (CAPES)/ ; },
abstract = {Background/Objectives: The oral administration of donepezil has been shown to have common side effects due to systemic drug delivery, with fluctuations in blood and brain donepezil concentrations. Therefore, we obtained nanostructured lipid carriers loaded with donepezil (donepezil-NLC) for nose-to-brain targeting. Methods: The obtained NLCs were characterized by measurements of particle size, the polydispersity index, zeta potential, encapsulation efficiency, atomic force microscopy, Differential Scanning Calorimetry, Fourier transform infrared spectroscopy, X-ray diffraction, and in vitro release studies. Plasma and brain pharmacokinetic studies in Wistar rats were carried out to determine brain targeting. Results: Donepezil-NLC showed low polydispersity and nanometric size, high zeta potential, and high drug entrapment efficiency. Microscopy images showed spherical particles with regular surfaces. Thermal analysis, X-ray diffraction, and FTIR-ATR suggested the formation of an amorphous lipid matrix and the incorporation of donepezil molecularly dispersed within the lipid matrix. In vitro drug release studies demonstrated a biphasic drug release pattern with an initial burst followed by sustained release, with results better fitted to the Korsmeyer-Peppas model (n-value > 0.5). Following the nasal administration of donepezil-NLC, brain pharmacokinetic studies in Wistar rats demonstrated a significant improvement in bioavailability. Compared to the intravenous injection of donepezil, the AUC[0-ꝏ] value was 10.5-fold higher. Drug targeting efficiency and direct transport percentage showed extremely higher values, suggesting nose-to-brain targeting after donepezil-NLC intranasal administration. Conclusions: Donepezil-NLC has proven to be an efficient drug delivery system for the nose to the brain, which may reduce systemic toxicity and improve Alzheimer's therapy with low doses of donepezil and fewer adverse effects.},
}

@article {pmid42198279,
year = {2026},
author = {Garofalide, S and Pricop, DA and Olteanu, E and Pricop, SE and Brinza, I and Boiangiu, RS and Cocean, A and Bulai, G and Ursu, EL and Motrescu, I and Cocean, I and Hritcu, L and Gurlui, S},
title = {Neuroprotective Effects of a Composite Based on Irradiated Gold Nanoparticles and Lipid Vesicles in a Zebrafish Model.},
journal = {Pharmaceutics},
volume = {18},
number = {5},
pages = {},
doi = {10.3390/pharmaceutics18050585},
pmid = {42198279},
issn = {1999-4923},
abstract = {Background: In this work, gold nanoparticles synthesized by the chemical method were exposed to natural green light, then associated with a lipid layer of phosphatidylcholine by physical adsorption, without excluding their partial encapsulation. Methods: A suspension of lipid vesicles grafted with irradiated nanoparticles (Au(ir)L) was obtained that showed improved colloidal stability, evidenced by a higher negative ζ potential (-23.8 mV compared to -17.08 mV for AuL), an increased hydrodynamic size, and a higher lipid coverage, suggesting improved nanoparticle-membrane electrostatic interactions. The biological effects of these vesicles were evaluated in a zebrafish model of scopolamine-induced cognitive impairment. Behavioral and biochemical analyses were conducted to assess their impact on anxiety-like behavior, memory, and oxidative stress, using galantamine as a reference compound. Results: Under non-induced conditions, no significant behavioral differences were observed between the control and nanoparticle-treated groups, supporting the biocompatibility of the formulations. In scopolamine-treated zebrafish, both AuL and Au(ir)L showed partial improvements in behavioral parameters; however, these effects were not consistently statistically significant across all endpoints. Notably, more consistent effects were observed at the biochemical level, where both formulations, particularly Au(ir)L, significantly modulated acetylcholinesterase activity and reduced markers of oxidative stress, including lipid peroxidation. Conclusions: Overall, these findings suggest that lipid-grafted gold nanoparticles, especially in their irradiated form, exhibit moderate neuroprotective potential, primarily supported by biochemical outcomes and accompanied by partial behavioral improvements.},
}

@article {pmid42198335,
year = {2026},
author = {Lu, H and Yu, Y and Yang, Y and Li, H and Li, Y and Yu, T and Wang, S and Li, F and Cheng, X},
title = {Ginsenoside Rg1 Ameliorates the Learning and Memory Deficits of 5xFAD Mice by Inhibiting CCR3 Activity: Insights from In Vivo and In Vitro Investigations.},
journal = {Pharmaceuticals (Basel, Switzerland)},
volume = {19},
number = {5},
pages = {},
doi = {10.3390/ph19050661},
pmid = {42198335},
issn = {1424-8247},
support = {No.82374062//National Natural Science Foundation of China/ ; YDZX2023003//Central government-guided special fund project for local scientific and technological development/ ; KYZK2024Q24//Shandong University of Traditional Chinese Medicine Youth Science Research Fund Project/ ; },
abstract = {Background/Objectives: Alzheimer's disease (AD) is characterized by amyloid-beta accumulation and neuroinflammation, yet the molecular target of Ginsenoside Rg1 remains elusive. This study aimed to elucidate the neuroprotective mechanism of Ginsenoside Rg1, specifically investigating its interaction with C-C motif chemokine receptor 3 (CCR3). Methods: We utilized 5xFAD transgenic mice and CCR3-overexpressing BV2 microglial cells. Behavioral assessments, enzyme-linked immunosorbent assays, quantitative real-time polymerase chain reaction, molecular docking, and surface plasmon resonance were employed to evaluate cognitive function and molecular pathways. Results: Ginsenoside Rg1 treatment significantly ameliorated spatial learning and memory deficits. Quantitatively, Rg1 reduced cortical amyloid-beta 1-40 levels (p < 0.05) and bound directly to CCR3 with a dissociation constant of 3.599 × 10[-5] mol/L. This inhibition suppressed neuroinflammation and restored neurotrophic factors, including Brain-derived neurotrophic factor. Conclusions: CCR3 is a novel pharmacological target for Ginsenoside Rg1, providing a precise molecular basis for its neuroprotective effects. Future research should focus on clarifying the pharmacokinetic profile and brain bioavailability of Ginsenoside Rg1 to facilitate clinical translation.},
}

@article {pmid42198353,
year = {2026},
author = {Skroban, J and Kruk-Słomka, M and Popiołek, Ł},
title = {Exploring Acylhydrazones' Properties Against Neurodegenerative Diseases and Other Clinical Applications: A Review.},
journal = {Pharmaceuticals (Basel, Switzerland)},
volume = {19},
number = {5},
pages = {},
doi = {10.3390/ph19050679},
pmid = {42198353},
issn = {1424-8247},
abstract = {Neurodegenerative diseases are a serious problem for modern society, and their treatment remains an important issue discussed by the scientific community. One of the promising potential directions for modulating neurodegenerative processes is the use of acylhydrazones, a class of compounds that combine different bioactive fragments linked by an acylhydrazone moiety. So far, the biological properties of these compounds have been proven. They show antibacterial, antiviral, antifungal, antiparasitic, anticancer, anti-inflammatory and antioxidant activity. Many research papers focus on designing acylhydrazones that will find use in the treatment of neurodegenerative diseases by inhibiting the enzymatic activity of acetylcholinesterase (AChE), butyrylcholinesterase (BuChE), β-secretase 1 (BACE1) and monoamine oxidase (MAO), as well as inhibiting β-amyloid aggregation, exhibiting metal chelation and antioxidant properties. Recent studies have described the acylhydrazone-based dual (multi-target) inhibitors, which have demonstrated encouraging outcomes during in vitro evaluations. This review covers recent articles published in the years 2020-2025 and offers a comprehensive overview of the biological properties of the acylhydrazones and their multifunctional derivatives on neurodegenerative processes and/or neuroprotection, while emphasizing their universal nature, structural versatility and role as leading structures in the search for new drugs.},
}