@article {pmid42107811,
year = {2026},
author = {Bell, TR and Pearce, RC and Puckett, OK and Hagler, DJ and Dale, A and Elman, JA and Fennema-Notestine, C and Franz, CE and Lyons, MJ and Panizzon, MS and Reynolds, CA and Kremen, WS and Eyler, LT and , },
title = {Association of C-reactive protein with brain micro- and macro-structure among older adult men.},
journal = {Brain, behavior, and immunity},
volume = {},
number = {},
pages = {106798},
doi = {10.1016/j.bbi.2026.106798},
pmid = {42107811},
issn = {1090-2139},
abstract = {BACKGROUND: The process by which aging leads to increased risk for Alzheimer's disease and related dementias is not entirely understood, but one hypothesized contributor is the occurrence of low-grade inflammation in older age. Associations between peripheral C-reactive protein (CRP), a marker of systemic inflammation, and brain structure have been widely studied, but fewer studies have examined CRP in relation to diffusion measures, particularly using newer techniques such as restriction spectrum imaging (RSI). In the current study, we examined how high sensitivity CRP (hsCRP) relates to diffusion metrics and global brain tissue volumes among a group of older adult men.

METHODS: We analyzed a sample of 372 cognitively unimpaired men from VETSA, who were assessed at average age 67 for plasma hsCRP and underwent diffusion and structural brain imaging. Linear mixed models examined associations of hsCRP with global and regional measures of restricted normalized directional (RND) and free normalized isotropic (FNI) diffusion in white matter and hindered normalized total diffusion (HNT) and FNI diffusion in gray matter derived from RSI. Similarly, the relationship of hsCRP to global and regional fractional anisotropy (FA) in white matter and mean diffusivity (MD) in white and gray matter was examined. Finally, we examined hsCRP relationships with global gray and white matter volumes as well as global abnormal white matter (AWM; white matter hyperintensities), to attempt quasi-replication of previous findings.

RESULTS: Higher hsCRP was associated with lower global white matter RND, with several tract-level associations. hsCRP was also associated with greater entorhinal cortex FNI. Conventional DTI metrics showed no associations with hsCRP. In structural analyses, higher hsCRP was associated with lower global gray matter volume but not white matter volume or abnormalities.

CONCLUSION: In this sample of older males, higher hsCRP was associated with differences in white matter microstructure measured using multi-shell RSI metrics and with lower global gray matter volume. Conventional DTI metrics showed few associations with hsCRP. These findings suggest that systemic inflammation may be reflected in subtle differences in brain microstructure and macrostructure and highlight the potential value of more sensitive multi-shell diffusion approaches for detecting inflammation-related brain differences in aging populations.},
}

@article {pmid42107892,
year = {2026},
author = {Chen, G and Zhao, C and Wang, C and Chen, G and Shi, J and Chen, H},
title = {Microglia crosstalk with T cells in neurodegenerative diseases: pathogenesis and treatment targets.},
journal = {International immunopharmacology},
volume = {182},
number = {},
pages = {116781},
doi = {10.1016/j.intimp.2026.116781},
pmid = {42107892},
issn = {1878-1705},
abstract = {Immune cells play a central role in driving inflammation and neurodegeneration across various neurological disorders. Central nervous system (CNS)-resident microglia and infiltrating T cells represent the innate and adaptive immune systems, respectively, and have been reported to contribute to the pathogenesis of neurodegenerative diseases individually. Growing evidence suggests that the encounter between activated microglia and infiltrating T cells amplifies their neurotoxic potential. In this review, we discussed alterations in microglial phenotype and function, and the contributions of different T cell subsets in neurodegenerative diseases including Alzheimer's disease (AD), Parkinson's disease (PD), Multiple sclerosis (MS), Amyotrophic lateral sclerosis (ALS) and glaucoma. We emphasized the crosstalk between microglia and T cells via antigen presentation, chemotactic signals, and pro-inflammatory mediators. We also explored emerging therapeutic strategies aimed at modulating T cell and microglial responses, as well as their interactions, for the treatment of neurodegenerative diseases.},
}

@article {pmid42107911,
year = {2026},
author = {Singh, M and Yu, J and Vanmierlo, T and Mulder, MT and Paul, SM and Cashikar, AG},
title = {The phytosterol 24(S)-saringosterol alters lipid homeostasis and inflammatory pathways in a cell-specific manner.},
journal = {Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie},
volume = {199},
number = {},
pages = {119506},
doi = {10.1016/j.biopha.2026.119506},
pmid = {42107911},
issn = {1950-6007},
abstract = {BACKGROUND: Neuroinflammation and disrupted cholesterol metabolism in microglia are key contributors to Alzheimer's disease (AD) pathogenesis. Liver X receptors (LXRα/β) regulate lipid metabolism and inflammation. Synthetic pan-LXR agonists, such as T0901317 and GW3965, exert neuroprotective effects by modulating lipid metabolism, making them promising therapeutic strategies for neurodegenerative disorders like Alzheimer's Disease (AD). However, their clinical use is limited by hepatic side effects, including hypertriglyceridemia and steatosis.

PURPOSE: To overcome these limitations, we investigated 24(S)-saringosterol, a phytosterol from Sargassum fusiforme, and its potential dissociating effect as a LXR agonist on myeloid cells vs hepatocytes.

METHOD: Using primary cultures of myeloid cells (microglia, bone marrow-derived macrophages) and hepatocytes, we performed transcriptomic and lipidomic analyses to assess the impact of 24(S)-saringosterol on lipid metabolism and inflammatory pathways.

RESULTS: 24(S)-saringosterol strongly activated LXR-regulated genes, upregulating cholesterol efflux transporter Abca1 in a dose-dependent manner. In myeloid cells, it reduced the expression of interferon-β pathway genes and promoted cholesterol efflux, mirroring GW3965's anti-inflammatory effects. Notably, 24(S)-saringosterol downregulated cholesterol biosynthesis (Dhcr24) and influx (Ldlr) via Srebp2 in both cell types, contrasting with GW3965, which increased lipid synthesis genes via Srebp1.

CONCLUSION: These findings suggest 24(S)-saringosterol acts as a selective LXR agonist in a cell-specific manner, retaining beneficial effects while minimizing hepatic risks. This compound represents a promising candidate for AD and other metabolic or inflammatory disorders.},
}

@article {pmid42107929,
year = {2026},
author = {Connon, P and McKenna, MC and Black, SE and Masellis, M},
title = {Blood-based biomarkers for Alzheimer's disease. 'Treat the test, not the patient?'; are we ready to defy Osler?.},
journal = {Expert review of molecular diagnostics},
volume = {},
number = {},
pages = {1-5},
doi = {10.1080/14737159.2026.2669646},
pmid = {42107929},
issn = {1744-8352},
}

@article {pmid42108258,
year = {2026},
author = {Sheng, J and Ahn, JY and Yang, L and Wan, Z and Qi, S and Yu, X and Xu, Z and Cao, Y and Vasquez, M and Irfan, A and Zhu, Y and Zhao, H and Yin, Z and Zhu, Y and Ding, Y and Faridar, A and Wang, L and Liu, F and Wang, H and Ji, Z and Mao, D and Chan, M and Kermany, D and Dong, W and Kim, DY and Zhang, XH and Wong, STC},
title = {iS2C2: a cointelligent platform for mechanistic discovery of disease cellular crosstalk.},
journal = {Signal transduction and targeted therapy},
volume = {11},
number = {1},
pages = {},
pmid = {42108258},
issn = {2059-3635},
mesh = {Humans ; *Cell Communication/genetics ; *Alzheimer Disease/genetics/pathology/metabolism ; *Algorithms ; *Single-Cell Analysis ; *Neoplasms/genetics/pathology/metabolism ; *Computational Biology/methods ; Transcriptome/genetics ; },
abstract = {Large language models (LLMs) have demonstrated impressive capabilities in summarization, reasoning, and content generation, yet their inability to directly interpret large-scale omics data has limited their utility in data-driven hypothesis generation-particularly in mechanism discovery that demands the integration and interpretation of multimodal datasets, heterogeneous models, and deep domain expertise. Conversely, traditional computational algorithms excel at quantitative analysis of omics data but often rely heavily on labor-intensive, expert-driven interpretation to extract biologically meaningful insights. Here, we introduce (cointelligent single-cell spatial cell‒cell communication: iS2C2), a novel cointelligent platform that synergizes mathematically rigorous computational algorithms with the contextual reasoning capabilities of LLMs to automatically generate biologically interpretable hypotheses from single-cell RNA-seq and spatial transcriptomics data. The iS2C2 platform incorporates a transparent and reproducible cell-cell communication analysis pipeline built upon mathematically rigorous algorithms designed to enhance interpretability for integration with LLMs that contextualize algorithmic outputs or predictions using domain-specific knowledge and literature-derived evidence. When applied to Alzheimer's disease and cancer datasets, iS2C2 generated accurate, reproducible, and expert-validated hypotheses, unveiling previously unrecognized signaling pathways and mechanistic insights in disease microenvironments. This cointelligent approach bridges the gap between structured computational analysis and generative reasoning, heralding a paradigm shift toward fully automated, interpretable biological discovery and advancing the frontiers of next-generation precision medicine and systems biology.},
}

Humans
*Cell Communication/genetics
*Alzheimer Disease/genetics/pathology/metabolism
*Algorithms
*Single-Cell Analysis
*Neoplasms/genetics/pathology/metabolism
*Computational Biology/methods
Transcriptome/genetics

@article {pmid42108320,
year = {2026},
author = {Tokdar, A and Agarwal, L and Chatterjee, S and Sukriti, },
title = {A deep hybrid CNN-BiLSTM-BiGRU architecture with explainability for mild cognitive impairment detection using EEG.},
journal = {Brain informatics},
volume = {},
number = {},
pages = {},
doi = {10.1186/s40708-026-00302-4},
pmid = {42108320},
issn = {2198-4018},
abstract = {Accurate detection of Mild Cognitive Impairment (MCI) is critical for timely intervention and for slowing progression to Alzheimer's disease. Electroencephalography (EEG) offers a non-invasive and cost-effective measure of brain activity; however, its complex, non-linear dynamics limit conventional analysis. We propose a CNN-Res-SE-BiLSTM-BiGRU framework for the automated detection of MCI directly from raw EEG. Convolutional and residual blocks capture local temporal structure, bidirectional recurrent layers model long-range dependencies, and Squeeze-and-Excitation (SE) modules provide channel-wise attention. Predicted probabilities are calibrated using temperature scaling, and operating thresholds are selected on the validation set using Youden's J statistic. The model is evaluated using five-fold cross-validation under both subject-dependent and strict subject-independent protocols on a primary resting-state dataset, with additional subject-independent validation on an odor EEG dataset. Under subject-independent evaluation on the odor dataset, the proposed model achieved an accuracy of 0.956 ± 0.051, with ROC-AUC of 0.971 ± 0.051 and PR-AUC of 0.934 ± 0.132. UMAP-based visualization and explainable AI analyses (SHAP and LIME) provide interpretable insight into the learned spatiotemporal patterns and sample-specific decisions. These results demonstrate robust, interpretable EEG-based MCI detection with potential clinical utility.},
}

@article {pmid42108381,
year = {2026},
author = {Chao, Y and Chen, Y and Chadwick, TA and Harrison, TM and Iaccarino, L and Heinsen, H and Ushizima, D and Tosun, D and Jagust, WJ and Grinberg, LT},
title = {Correlation between in vivo [18]F-flortaucipir PET and whole-brain postmortem histological tau signals in Alzheimer's disease.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {22},
number = {5},
pages = {e71453},
doi = {10.1002/alz.71453},
pmid = {42108381},
issn = {1552-5279},
support = {NCT02350634//Avid Radiopharmaceuticals/ ; R01AG070826/GF/NIH HHS/United States ; //BrightFocus Foundation/ ; /AG/NIA NIH HHS/United States ; },
mesh = {Humans ; *Alzheimer Disease/pathology/diagnostic imaging/metabolism ; *tau Proteins/metabolism ; *Positron-Emission Tomography/methods ; *Carbolines ; *Brain/pathology/diagnostic imaging/metabolism ; Male ; Female ; Aged ; Autopsy ; Aged, 80 and over ; Radiopharmaceuticals ; Immunohistochemistry ; },
abstract = {INTRODUCTION: Clinicopathological studies offer crucial interpretations of [18]F-flortaucipir (FTP) tau positron emission tomography (PET) signal but are limited by methods. We leveraged whole-brain, quantitative immunohistochemical (IHC) Alzheimer's Disease (AD) tau density maps to comprehensively evaluate the FTP tracer.

METHODS: We generated IHC maps for three AD-tau antibodies-AT8, AT100, and MC1-using two human brains histologically staged at Braak IV and VI. FTP-PET scans were acquired 6 and 10 weeks prior to death. Using region-wise and voxelwise methods, we correlated FTP-PET with IHC signals.

RESULTS: Only AT8 (p-tau Ser202/Thr205; neuronal and neuritic tau pathology) showed a notable correlation with FTP standardized uptake value ratios (SUVRs) in the Braak VI case (Spearman's rank correlation coefficient [rs] = 0.461, p < 0.001). FTP SUVRs failed to capture medial temporal lobe (MTL) tau burden, whereas neocortical regions showed lower IHC burden but more variability in FTP uptake.

DISCUSSION: Although FTP signals correlate well with AT8-positive tau in the more advanced case, they underestimate the severity of MTL burden, potentially confounding assessments of tau-targeted therapies.},
}

Humans
*Alzheimer Disease/pathology/diagnostic imaging/metabolism
*tau Proteins/metabolism
*Positron-Emission Tomography/methods
*Carbolines
*Brain/pathology/diagnostic imaging/metabolism
Male
Female
Aged
Autopsy
Aged, 80 and over
Radiopharmaceuticals
Immunohistochemistry

@article {pmid42108385,
year = {2026},
author = {Miller, ZA and Miller, BL and Rabinovici, GD and Gorno-Tempini, ML},
title = {Response to rethinking Alzheimer's disease susceptibility and heterogeneity. Comment on Miller et al.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {22},
number = {5},
pages = {e71454},
doi = {10.1002/alz.71454},
pmid = {42108385},
issn = {1552-5279},
support = {//Bluefield Project/ ; //Guilford Press/ ; //Cambridge University Press/ ; //Johns Hopkins Press/ ; P30 AG062422/AG/NIA NIH HHS/United States ; P01 AG019724/AG/NIA NIH HHS/United States ; R01 AG057234/AG/NIA NIH HHS/United States ; T32 AG023481/AG/NIA NIH HHS/United States ; AG045611/AG/NIA NIH HHS/United States ; //Eli Lilly/ ; //GE Healthcare/ ; //Life Molecular Imaging/ ; //Axon Neurosciences/ ; //Genentech/ ; //Johnson & Johnson/ ; //F. Hoffman-La Roche/ ; NS050915/NS/NINDS NIH HHS/United States ; DC015544/DC/NIDCD NIH HHS/United States ; },
}

@article {pmid42108387,
year = {2026},
author = {Pandya, K and Jaisinghani, LS and Tripathi, A and Kumar, D and Saraf, SK and Sahoo, J and Kumar, D},
title = {Rational Design and Optimisation of CRISPR-Cas9 Delivery Systems for Targeted Genomic Transformation.},
journal = {The journal of gene medicine},
volume = {28},
number = {5},
pages = {e70095},
doi = {10.1002/jgm.70095},
pmid = {42108387},
issn = {1521-2254},
support = {EMDR/SG/11/2023-5582//Indian Council of Medical Research/ ; },
mesh = {Humans ; *CRISPR-Cas Systems/genetics ; Genetic Vectors/genetics ; *Gene Editing/methods ; Animals ; Genetic Therapy/methods ; *Gene Transfer Techniques ; Blood-Brain Barrier/metabolism ; Dependovirus/genetics ; Alzheimer Disease/genetics/therapy ; },
abstract = {The CRISPR-Cas9 genome-editing technique offers a promising therapeutic strategy for genetic disorders, including neurodegenerative diseases like Alzheimer's disease (AD), characterised by inherited susceptibility and progressive cognitive decline, as well as other hallmarks such as amyloid beta (Aβ1-42) plaques and neurofibril tangles (NFTs). However, the blood-brain barrier (BBB) poses a significant challenge to the effectiveness of gene editing components in the affected brain region and impedes clinical translation. This comprehensive review compares various CRISPR-Cas9 delivery vectors, viral, nonviral and physical, with a focus on their efficacy in neurological diseases such as AD. Viral vectors viz., adeno-associated viruses (AAVs) and lentiviruses (LVs) demonstrate high transduction efficiency and BBB permeability. AAVs are preferred for their low immunogenicity, minimal toxicity, high neuronal tropism and episomal persistence, enabling sustained expression without insertional mutagenesis. LVs offer larger genetic payloads but raise concerns about genomic integration and potential oncogenesis, though integration-defective variants mitigate these risks. Nonviral vectors, including peptide and polymer-based nanoparticles, lipid nanoparticles (LNPs) and Inorganic carriers such as gold and silver nanoparticles, are less immunogenic and easier to handle but require further optimisation for in vivo BBB crossing and endosomal escape. Physical methods such as electroporation and microinjection are suitable for in vitro/ex vivo use, while novel CNS-targeted strategies, such as RVG-tagged particles, TfR-directed LNPs and engineered AAV variants, enhance brain penetration via receptor-mediated transcytosis. These preclinical studies show that these technologies can successfully edit genes and provide therapeutic benefits, including amyloid reduction and cognitive improvement in AD models. Yet off-target effects, immune responses and regulatory hurdles persist. Overall, continuous innovation in delivery vector design and safety profile-targeting strategies is crucial for advancing CRISPR-Cas9 towards clinical therapies for AD-based therapies and related neurological disorders.},
}

Humans
*CRISPR-Cas Systems/genetics
Genetic Vectors/genetics
*Gene Editing/methods
Animals
Genetic Therapy/methods
*Gene Transfer Techniques
Blood-Brain Barrier/metabolism
Dependovirus/genetics
Alzheimer Disease/genetics/therapy

@article {pmid42108388,
year = {2026},
author = {Frijo, A and Mazzeo, S and Filippi, M and Salsone, M},
title = {Rethinking Alzheimer's disease susceptibility and heterogeneity. Comment on Miller et al.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {22},
number = {5},
pages = {e71456},
doi = {10.1002/alz.71456},
pmid = {42108388},
issn = {1552-5279},
support = {//Italian Ministry of University and Research/ ; },
}

@article {pmid42108391,
year = {2026},
author = {Yu, G and Thorpe, A and Zeng, Q and Wang, E and Goate, A and Cai, D and Wang, M and Zhang, B},
title = {Single-cell transcriptomic analysis reveals APOE genotype-dependent sex differences in Alzheimer's disease.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {22},
number = {5},
pages = {e71463},
doi = {10.1002/alz.71463},
pmid = {42108391},
issn = {1552-5279},
support = {RF1AG054014/NH/NIH HHS/United States ; R56AG058655/NH/NIH HHS/United States ; RF1AG074010/NH/NIH HHS/United States ; UO1AG046170/NH/NIH HHS/United States ; RF1AG057440/NH/NIH HHS/United States ; RO1AG057907/NH/NIH HHS/United States ; R21AG077168/NH/NIH HHS/United States ; RF1AG077828/NH/NIH HHS/United States ; AARG-22-928419/ALZ/Alzheimer's Association/United States ; },
mesh = {Humans ; *Alzheimer Disease/genetics ; Female ; Male ; *Apolipoproteins E/genetics ; *Single-Cell Analysis ; Genotype ; *Sex Characteristics ; *Transcriptome/genetics ; Gene Expression Profiling ; Brain/metabolism/pathology ; Sex Factors ; Aged ; },
abstract = {INTRODUCTION: Alzheimer's disease (AD) is the most common form of dementia, with approximately two-thirds of AD patients being female. Basic and clinical research studies provide strong evidence that sex-specific differences contribute to AD complexity. Additionally, sex-specific interactions between apolipoprotein E (APOE) 𝜀4, the primary genetic risk factor of AD, and AD-associated neurodegenerative processes are well documented. However, there has been no comprehensive investigation into the interplay between sex and APOE genotypes at the single-cell level.

METHODS: In this study, we systematically explore sex- and APOE-associated differences in single-cell transcriptomics in AD.

RESULTS: Our work provides a high-resolution landscape of sex and APOE genotype-specific transcriptomic changes across 54 high-resolution cell types in AD and highlights genes and brain cell populations that show significant sex- and APOE-specific differences in AD.

DISCUSSION: This study lays the groundwork for understanding the complex molecular mechanisms of AD and informs the development of targeted sex- and APOE-stratified interventions for AD.},
}

Humans
*Alzheimer Disease/genetics
Female
Male
*Apolipoproteins E/genetics
*Single-Cell Analysis
Genotype
*Sex Characteristics
*Transcriptome/genetics
Gene Expression Profiling
Brain/metabolism/pathology
Sex Factors
Aged

@article {pmid42108496,
year = {2026},
author = {Zhu, Y and Wang, A and Wu, Y and Yang, L and Duan, Y and Zhao, Y and Zhao, X and Hu, W and Qun, S and , },
title = {Influence of local spontaneous activity and hippocampal volume on the relationship between APOE genotype, ATN biomarkers, and cognitive function across the Alzheimer's disease spectrum.},
journal = {Chinese medical journal},
volume = {},
number = {},
pages = {},
pmid = {42108496},
issn = {2542-5641},
}

@article {pmid42108553,
year = {2026},
author = {Zhao, Q and Du, J and Zhou, M and Wang, XW and Sun, Q and Chen, C},
title = {PEARL: Integrative multi-omics classification and omics feature discovery via deep graph learning.},
journal = {Bioinformatics (Oxford, England)},
volume = {},
number = {},
pages = {},
doi = {10.1093/bioinformatics/btag253},
pmid = {42108553},
issn = {1367-4811},
abstract = {MOTIVATION: Integrating multi-omics data provides valuable insights into biological processes by capturing information across multiple molecular layers, enabling a comprehensive understanding of complex diseases and driving advancements in precision medicine. However, existing computational methods for multi-omics integration face significant challenges, such as low reliability and poor generalizability, due to the high dimensionality and low sample size nature of omics data.

RESULTS: To address these challenges, we present PEARL (Pearson-Enhanced spectrAl gRaph convoLutional networks), a novel deep graph learning method for biomedical classification and functional important omics features identification. PEARL leverages a simple yet effective learning architecture to achieve superior and robust performance in high-dimensional, low-sample-size multi-omics settings. Our results demonstrate that PEARL significantly outperforms existing state-of-the-art methods on both synthetic and real biomedical datasets. Furthermore, applied to Alzheimer's disease (AD) brain multi-omics data, features prioritized by PEARL lead to functionally important genes that demonstrate significant enrichment in AD-related pathways. These findings highlight PEARL's practical utility in biomedical research and its potential to enhance biological interpretability in multi-omics studies.

The source code of our computational framework is available at https://github.com/zqq121017/PEARL.},
}

@article {pmid42108615,
year = {2026},
author = {Igarashi, A and Azuma-Kasai, M and Tani, M and Utsumi, T and Shibahara, H and Inoue, S and Rothwell, S and Kamanaka, G and Sakata, Y and Hiyoshi, H and Tomita, K},
title = {The social value of lecanemab for patients with early Alzheimer's disease in Japan.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261447312},
doi = {10.1177/13872877261447312},
pmid = {42108615},
issn = {1875-8908},
abstract = {BackgroundLecanemab is the first approved disease-modified therapy in Japan for patients with mild cognitive impairment (MCI) due to Alzheimer's disease (AD) or mild AD dementia (AD-D).ObjectiveThis study aims to evaluate the social value of lecanemab in Japan.MethodsThe social value was evaluated using a cost-effectiveness model. The intervention was lecanemab added to the standard of care (SOC), and the comparator was SOC alone. The effect of lecanemab was determined based on the phase III trial and subsequent long-term follow-up observation studies. Health outcomes were quantified in life years and quality-adjusted life years (QALYs). Both patient and caregiver utilities were considered by summing the absolute values of utility for both the caregiver and patient. The base-case analysis was conducted from the public healthcare and long-term care payer's perspectives.ResultsLecanemab extended the time spent in early AD, thereby maintaining quality of life (QOL), reducing caregiver burden, and medical and long-term care resource usage. The incremental QALYs were 1.31 QALYs for MCI due to AD and 0.85 QALYs for mild AD-D, and the incremental cost-effectiveness ratios (ICERs) were JPY 8.5 million /QALY and JPY 7.9 million /QALY ($1 = JPY 150), respectively.ConclusionsThe value-based price or the ICER of lecanemab varied greatly depending on the perspectives and the methods of reflecting caregiver QOL. In AD, where the progression of the illness spans a long period and had a significant impact on families and society, narrowly defined value assessments were not sufficient, indicating the need to consider broader social value.},
}

@article {pmid42108759,
year = {2026},
author = {Meng, Q and Li, J and Xu, G and Zhang, W and Cao, R and Cai, K},
title = {Ginsenoside Rh2 Alleviates Alzheimer Disease Models via Effects on Ferroptosis-Related Neuroinflammation.},
journal = {Journal of biochemical and molecular toxicology},
volume = {40},
number = {5},
pages = {e70860},
doi = {10.1002/jbt.70860},
pmid = {42108759},
issn = {1099-0461},
support = {YKK23216//Nanjing Health Science and Technology Development Special Fund/ ; ST222102//Major Sports Research Projects of Jiangsu Provincial Sports Bureau/ ; LKZ2025004//Jiangsu Elderly Health Scientific Research Project/ ; },
mesh = {Animals ; *Ginsenosides/pharmacology/therapeutic use ; *Alzheimer Disease/drug therapy/metabolism/pathology ; Mice ; Mice, Transgenic ; Disease Models, Animal ; *Ferroptosis/drug effects ; *Neuroinflammatory Diseases/drug therapy/metabolism/pathology ; Amyloid beta-Peptides/metabolism ; Cell Line, Tumor ; Male ; Oxidative Stress/drug effects ; Peptide Fragments ; },
abstract = {Ginsenosides are the primary active constituents derived from the dried roots of ginseng, a staple in traditional Chinese medicine. This study aimed to evaluate the therapeutic efficacy of the Ginsenoside Rh2 (Rh2) monomer in both in vitro and in vivo models of Alzheimer disease (AD). An in vivo AD cell model was established by stimulating N2a mouse neuroblastoma cells with β-amyloid (Aβ) 1-42, while APP/PS1 transgenic mice served as the in vivo model. In vitro, Aβ1-42-stimulated N2a cells were co-incubated with 40 or 80 μM Rh2 for 24 h. In vivo, APP/PS1 mice received daily intraperitoneal injections of Rh2 (20 mg/kg) for 5 weeks. Our results demonstrated that Rh2 treatment significantly enhanced the viability of N2a cells and ameliorated mitochondrial membrane potential dysregulation. Furthermore, Rh2 attenuated oxidative stress by reducing reactive oxygen species production and decreasing malondialdehyde levels. It also suppressed the hypersecretion of pro-inflammatory mediators, including nitric oxide, interleukin-1β (IL-1β), and IL-6, in Aβ-treated cells. Mechanistically, Rh2 exerted potent anti-ferroptotic and anti-inflammatory effects via the activation of the Nrf2/GPX4 signaling pathway, which ultimately translated to improved spatial learning and memory in APP/PS1 mice. These findings elucidate a novel mechanistic paradigm for Rh2, highlighting its potential as a therapeutic candidate for AD drug development.},
}

Animals
*Ginsenosides/pharmacology/therapeutic use
*Alzheimer Disease/drug therapy/metabolism/pathology
Mice
Mice, Transgenic
Disease Models, Animal
*Ferroptosis/drug effects
*Neuroinflammatory Diseases/drug therapy/metabolism/pathology
Amyloid beta-Peptides/metabolism
Cell Line, Tumor
Male
Oxidative Stress/drug effects
Peptide Fragments

@article {pmid42108964,
year = {2026},
author = {Zhang, P},
title = {Commentary on "Peripheral Insulin Resistance and Alzheimer's Disease: Possible Mediators Including Extracellular Vesicles".},
journal = {Geriatrics & gerontology international},
volume = {26},
number = {5},
pages = {e70529},
doi = {10.1111/ggi.70529},
pmid = {42108964},
issn = {1447-0594},
}

@article {pmid42109046,
year = {2026},
author = {Nilsson, MH and Lindh-Rengifo, M and Rochester, L and Van Westen, D and Smith, R and Palmqvist, S and Stomrud, E and Mattsson-Carlgren, N and Hansson, O},
title = {Turning as a single and dual task-associations with alzheimer's and vascular pathologies in cognitively healthy older people.},
journal = {The journals of gerontology. Series A, Biological sciences and medical sciences},
volume = {},
number = {},
pages = {},
doi = {10.1093/gerona/glag114},
pmid = {42109046},
issn = {1758-535X},
abstract = {BACKGROUND: Turning performance is an important and challenging motor activity, with potential relevance in several brain diseases. This study aimed to determine how Alzheimer's and vascular pathologies are associated with turning (360° while standing and 180° while walking) both as a single task and during dual-tasking in cognitively healthy older people.

METHODS: Cognitively healthy older people (n = 297, mean age 77.7 years, 61.6% women) were included. A 180° turn was assessed using a wearable sensor; a 360° turn was assessed both clinically and using a sensor. Dual-tasking included a simultaneous subtraction task. Alzheimer's pathologies (Aβ and tau) were assessed using positron emission tomography. Vascular pathology (white matter hyperintensities, WMH) was assessed using magnetic resonance imaging. Logistic and linear regression analyses were used.

RESULTS: Aβ and tau pathologies were significantly associated with being unstable while dual-tasking and turning 360°. When including both Aβ and tau in the model, only tau remained significantly associated with being unstable (OR 22.42, 95% CI 1.43, 349.88, p = 0.027). WMH were associated with impaired turning as a single task, i.e., an increased turn duration (360°) and a decreased peak angular velocity (180°: B -1.27, 95% CI -2.33, -0.21], p = 0.018).

CONCLUSIONS: This study suggests that early Alzheimer's pathologies are associated with an instability while turning 360° and dual-tasking, whereas WMH seem to be associated with impaired turning as a single task in cognitively healthy older people. Turning assessments seem promising for investigating motor aspects in very early stages of Alzheimer's disease and vascular brain disease.},
}

@article {pmid42109080,
year = {2026},
author = {Mattar, YA and Refaat, O and El-Makawi, S and Medhat, E and Khalifa, D},
title = {The interplay of APOE genotype, plasma levels, and cognitive functions in middle-aged adults with a parental history of Alzheimer's disease.},
journal = {The world journal of biological psychiatry : the official journal of the World Federation of Societies of Biological Psychiatry},
volume = {},
number = {},
pages = {1-14},
doi = {10.1080/15622975.2026.2666647},
pmid = {42109080},
issn = {1814-1412},
abstract = {BACKGROUND: Family history and APOE ε4 carriage represent the strongest non-modifiable Alzheimer's disease (AD) risk factors after advancing age. Early identification of cognitive markers in individuals at risk is essential for effective intervention strategies.

OBJECTIVES: To assess global cognition and its executive function subset in middle-aged offspring of AD patients versus controls, and to examine the influence of the Apolipoprotein E (APOE) ε4 allele and the potential of plasma APOE levels as a peripheral biomarker for cognitive health.

METHODS: In this case-control study, 80 clinically asymptomatic subjects (40 offspring of AD patients and 40 matched controls with no parental history of dementia) underwent comprehensive cognitive and executive function assessments, APOE genotyping, and plasma level measurements.

RESULTS: Offspring scored significantly lower on the Montreal Cognitive Assessment (MoCA), indicating early cognitive impairments despite being clinically asymptomatic. The APOE ε4 allele was more prevalent in the offspring group, although plasma APOE levels did not differ significantly between groups. A positive correlation was observed between plasma APOE levels and cognitive performance.

CONCLUSION: Middle-aged offspring of AD patients exhibit early cognitive vulnerabilities and a higher prevalence of the APOE4 genotype. These findings emphasise the importance of early monitoring and potential interventions for individuals at genetic risk for AD.},
}

@article {pmid42109151,
year = {2026},
author = {Siegel, K and Cabán, M and Wetmore, JB and Ottman, R},
title = {Latinos' appraisals of and responses to memory problems.},
journal = {Journal of health psychology},
volume = {},
number = {},
pages = {13591053261442545},
doi = {10.1177/13591053261442545},
pmid = {42109151},
issn = {1461-7277},
abstract = {Interest in finding early markers or risk factors for Alzheimer's disease (AD) has increased along with intervention options. Subjective memory complaints (SMC), the perception of cognitive decline in individuals with normal cognition, have been one area of focus. SMC are common among older adults and may be more prevalent among Latinos, among whom AD cases will grow rapidly. Fifty-four Latinos (ages 40-64) in a study of the impact of receiving information about one's AD risk reported current SMC and completed semi-structured qualitative interviews. They discussed the SMC's causes and consequences, their coping responses, and whether they had sought medical help. Most offered benign or normalizing explanations for their SMC. Many employed compensatory coping strategies that lessened the problem's practical and emotional consequences. Few discussed the problem with a physician. The findings provide novel insights regarding Latinos' illness behavior in response to SMC.},
}

@article {pmid42109539,
year = {2026},
author = {Osei, GN and Kpelle, L and Appiah, F and Nartey, K and Adu, AM and Simpong, DL and Afrifa, J},
title = {Peripheral oxidative stress related biomarkers in Alzheimer's disease: A systematic review of their implications for diagnosis and disease monitoring.},
journal = {Alzheimer's & dementia (Amsterdam, Netherlands)},
volume = {18},
number = {},
pages = {e70354},
pmid = {42109539},
issn = {2352-8729},
abstract = {Alzheimer's disease (AD) is a progressive neurodegenerative disorder in which oxidative stress drives amyloid beta accumulation and neuronal damage. Fluid-based oxidative stress-related biomarkers offer promising, minimally invasive platforms for early detection, with this review evaluating their diagnostic potential. Following Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines, a systematic search of PubMed, Scopus, and Google Scholar identified human studies published between 2000 and 2025 examining fluid-based oxidative stress-related biomarkers in individuals with AD. Elevated lipid peroxidation markers (malondialdehyde, 4-hydroxynonenal, and 1-palmitoyl-2-[5'-oxovaleroyl]-sn-glycero-3-phosphocholine) were consistently linked to AD and cognitive decline. Antioxidant enzymes (superoxide dismutase, glutathione [GSH] peroxidase, and catalase) showed reductions, while GSH and the GSH:oxidized GSH ratio emerged as robust indicators of redox imbalance in AD. Urinary 8-hydroxyguanosine demonstrated compartment-specific sensitivity. Altered trace elements (low selenium, iron, uric acid, and high copper) reflected systemic disruption in AD. Peripheral oxidative stress-related biomarkers offer scalable, minimally invasive avenues for AD diagnosis and monitoring, supporting improved clinical decision making.},
}

@article {pmid42109582,
year = {2026},
author = {Vashishath, Y and Pijani, BA and Goud Baddam, N and Saeed, F and Bozdag, S and , },
title = {Predicting progression of Alzheimer's disease using blood-based multi-omics data.},
journal = {Bioinformatics advances},
volume = {6},
number = {1},
pages = {vbag085},
pmid = {42109582},
issn = {2635-0041},
abstract = {MOTIVATION: Early prediction of Alzheimer's disease (AD) progression from mild cognitive impairment (MCI) remains a major challenge, particularly when relying on non-invasive biomarkers. Identifying individuals with progressive MCI (pMCI) before conversion to AD could improve intervention strategies and clinical management. In this study, we developed a machine learning (ML) framework integrating blood-based multi-omics and demographic data to distinguish pMCI from stable MCI (sMCI).

RESULTS: We trained ML models using combinations of single nucleotide polymorphism (SNP), DNA methylation, gene expression, lipid, and bile acid metabolite data using both early and late data integration strategies. Late integration consistently outperformed early integration, with the L1-regularized logistic regression model achieving the highest F1 score of 90.7% when combining SNP and lipid data. Feature interpretability analyses using LIME and SHAP identified reproducible biomarkers across omic layers, including SNPs in MYH11, FOXP1, MAPK10, and SYN3; methylation changes in CDX2 and DHX58; and altered ceramide lipid CER.D19.1.24.0 levels, all previously associated with AD-related pathology. These findings demonstrate that combining multi-omics and demographic data can improve early prediction of AD progression and support the feasibility of blood-based, interpretable biomarkers for precision diagnostics.

The data analyzed in this study were obtained from the Alzheimer's Disease Neuroimaging Initiative (ADNI) database (https://adni.loni.usc.edu/) and are available to qualified researchers upon application. The code used in this study, together with instructions and a toy dataset, is available at: https://github.com/bozdaglab/AD_sMCI_vs_pMCI.},
}

@article {pmid42109888,
year = {2026},
author = {Wu, H and Zhang, T and Ma, J and Yin, J and Liu, J and Lin, H and Yu, Y and He, Y and Cheng, W and Song, Z and Chang, C},
title = {Noninvasive Terahertz Wave Binocular Stimulation Improves Cognition in Amyloid-β-Related Dementia.},
journal = {Research (Washington, D.C.)},
volume = {9},
number = {},
pages = {1268},
pmid = {42109888},
issn = {2639-5274},
abstract = {Terahertz (THz) waves occupy a unique spectral region where they can resonantly interact with collective vibrational modes of biomolecules, thereby modulating protein conformation and subsequently affecting neural signaling. However, whether noninvasive THz wave stimulation can be extended to Alzheimer's disease and related dementias (ADRD) remains unknown. Here, we demonstrate that 14 d of noninvasive THz wave binocular stimulation (33 THz) effectively restores cognitive performance and neural homeostasis in Aβ1-42-induced dementia mice, a widely used experimental model of ADRD with the features including neuroinflammation and cognitive decline. Behavioral assessments revealed a marked restoration of spatial learning and memory ability, with a 53.1% ± 22.0% improvement compared with untreated dementia mice. Furthermore, THz wave stimulation reduced sleep fragmentation and restored physiological sleep-wake dynamics, indicating improved neural homeostasis. In the hippocampus, binocular stimulation attenuated microglial activation and normalized the levels of pro-inflammatory cytokines including interleukin-1β and tumor necrosis factor-α. Concurrently, THz wave stimulation activated hippocampal cyclic adenosine monophosphate (cAMP)-cAMP-response element binding protein (CREB)-brain-derived neurotrophic factor (BDNF) signaling, promoting neurotrophic support and re-establishing cholinergic functional integrity. Our findings demonstrate that THz wave binocular stimulation is a noninvasive approach capable of improving cognitive function in a dementia mouse model, offering a potential strategy to restore brain function in neurodegenerative diseases.},
}

@article {pmid42109911,
year = {2026},
author = {Choi, S and Park, S and Jung, YH and Oh, MS and Yu, KH and Lee, BC and Lee, M},
title = {Comparative risk of dementia between direct oral anticoagulants and warfarin after atrial fibrillation related ischemic stroke.},
journal = {Frontiers in aging neuroscience},
volume = {18},
number = {},
pages = {1718536},
pmid = {42109911},
issn = {1663-4365},
abstract = {INTRODUCTION: Direct oral anticoagulants (DOAC) have been associated with a reduced risk of dementia compared to warfarin in patients with atrial fibrillation (AF) without prior stroke. However, the impact of DOAC on dementia risk in AF-related ischemic stroke survivors is unclear.

METHODS: We conducted a retrospective, nationwide cohort study using the Korean National Health Insurance Service database. We identified patients with newly diagnosed ischemic stroke and concurrent AF who began DOAC or warfarin therapy within one month after stroke. Incidence of all-cause dementia, Alzheimer's dementia (AD), and vascular dementia (VaD) was compared between groups using multivariable Cox models with inverse probability of treatment weighting.

RESULTS: A total of 3,112 patients (mean age 70.6 ± 9.5 years; 66.6% male) were analyzed, including 2,919 DOAC users and 193 warfarin users. Over a mean follow-up of 3.63 years, 673 all-cause dementia cases (538 AD, 168 VaD) occurred. After IPTW, DOAC use was associated with higher risks of all-cause dementia (HR 1.16, 95% CI 1.04-1.30) and AD (HR 1.85, 95% CI 1.62-2.13) but a lower risk of VaD (HR 0.54, 95% CI 0.45-0.66) compared to warfarin.

DISCUSSION: In this retrospective nationwide cohort of AF-related ischemic stroke survivors, DOAC use was associated with a higher incidence of all-cause dementia and Alzheimer's dementia, but a lower incidence of vascular dementia, compared with warfarin. These observational findings suggest that anticoagulant type may be differentially associated with subsequent dementia subtypes in this high-risk population and should be interpreted with caution.},
}

@article {pmid42109913,
year = {2026},
author = {Sharoar, MG and Singh, N and Hu, XY},
title = {Editorial: Unravelling Aβ toxicity: implications for Alzheimer's cognitive and behavioral deficits.},
journal = {Frontiers in aging neuroscience},
volume = {18},
number = {},
pages = {1848776},
pmid = {42109913},
issn = {1663-4365},
}

@article {pmid42109914,
year = {2026},
author = {Fu, X and Huang, J and Liu, Y and Li, H and Zhang, Y},
title = {Unraveling the anti-neuroinflammatory mechanisms of Cervus cucumis polypeptide injection in Alzheimer's disease: insights from network pharmacology, molecular docking, molecular dynamics simulation, and experimental validation.},
journal = {Frontiers in aging neuroscience},
volume = {18},
number = {},
pages = {1797302},
pmid = {42109914},
issn = {1663-4365},
abstract = {OBJECTIVE: Alzheimer's disease (AD) is a progressive neurodegenerative disorder with increasing global prevalence, in which neuroinflammation serves as a critical pathological driver exacerbating cognitive decline. While current therapies offer limited symptomatic relief, multi-target strategies are urgently needed. Cervus cucumis polypeptide injection (CCPI), a traditional Chinese medicine (TCM) formulation, has demonstrated anti-inflammatory properties; however, its mechanisms of action against AD remain unclear. This study aimed to elucidate the anti-AD potential mechanisms of CCPI using an integrated approach combining network pharmacology, molecular docking, molecular dynamics (MD) simulation, and experimental validation.

METHODS: Active components and corresponding targets of CCPI were retrieved from the TCMSP database, while AD-related targets were collected from Genecards, OMIM, and DrugBank. Potential therapeutic targets were identified by intersecting drug and disease targets, followed by protein-protein interaction (PPI) network construction, Gene Ontology (GO), and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses. Molecular docking and MD simulations were performed to evaluate interactions between potential active components and key targets. In vitro experiments were conducted on Aβ25-35-induced BV2 microglial cells to assess cell viability (CCK-8 assay), inflammatory cytokine levels (ELISA), and protein expression (Western blot) related to the neuroinflammation pathway and microglial polarization.

RESULTS: A total of 28 active components and 50 common targets of CCPI for AD treatment were identified. Linoleic acid (LA) was determined to be a potential active component, with IL-6 as the key target based on PPI network topology. Molecular docking and MD simulation confirmed a stable binding affinity between LA and IL-6. KEGG analysis revealed significant enrichment in the HIF-1 signaling pathway, particularly the IL-6/STAT3/VEGF signaling pathway. In vitro, CCPI treatment significantly enhanced cell viability and attenuated the pro-inflammatory response, as evidenced by reduced levels of IL-6, IL-1β, and TNF-α, decreased the expression of the pro-inflammatory marker iNOS. Concurrently, it elevated the expression of the anti-inflammatory/repair-associated marker CD206. Western blot analysis further verified that CCPI suppressed IL-6/STAT3 activation while upregulating VEGF expression. Additionally, LA alone significantly reduced IL-6 levels and STAT3 phosphorylation, decreased the expression of iNOS, and increased the expression of CD206, with therapeutic efficacy comparable to CCPI.

CONCLUSION: CCPI exerts neuroprotective effects in AD models by regulating the IL-6/STAT3/VEGF pathway, downregulating the expression of the inflammation-related iNOS protein, upregulating the expression of the CD206 protein associated with anti-inflammatory and reparative functions, remodeling the functional state of microglia, inhibiting their pro-inflammatory responses, and enhancing their reparative functions. Its potential active component, LA, likely mediates this effect by stably binding to and inhibiting IL-6, thus suppressing the downstream STAT3 phosphorylation that drives inflammatory activation.},
}

@article {pmid42110324,
year = {2026},
author = {Karamacoska, D and Yu, K and Liang, J and Phung, M and Rahman, T and Nguyen, A and Caballero, G and Dadich, A and DiGiacomo, M and Steiner-Lim, GZ and Raman, R and Siette, J},
title = {A scoping review of dementia education programs for Chinese, Japanese, Korean, Filipino, and Vietnamese communities.},
journal = {Alzheimer's & dementia (Amsterdam, Netherlands)},
volume = {18},
number = {2},
pages = {e70295},
pmid = {42110324},
issn = {2352-8729},
abstract = {This scoping review explored characteristics and impacts of community-based dementia education programs developed for East and Southeast Asian diaspora, including Chinese, Japanese, Korean, Filipino, and Vietnamese communities. Studies involving community-dwelling adults and people impacted by dementia were identified through several databases. Data on study characteristics, program design, implementation, and impact were extracted. Of the 3431 records screened, 26 met inclusion criteria: 11 targeted general community members and 15 involved caregivers. Only 10 programs engaged individuals living with dementia or caregivers in their development. Community-focused initiatives improved literacy and attitudes, while caregiver-focused programs showed feasibility and preliminary effectiveness in reducing caregiver burden. Most initiatives were at the pilot stage and required cultural tailoring. To address gaps in dementia awareness, stigma, and accessibility, culturally tailored education, developed with meaningful community involvement, will be essential for strengthening dementia care and support within Asian diaspora populations.},
}

@article {pmid42110549,
year = {2026},
author = {Wang, Y and Wang, Q and Xie, H and Liu, X and Ju, Y and Liu, X and Sun, S},
title = {Efficacy and possible mechanism of Kai-xin-san in animal models of Alzheimer's disease: a systematic review and meta-analysis of preclinical studies.},
journal = {Frontiers in pharmacology},
volume = {17},
number = {},
pages = {1806181},
pmid = {42110549},
issn = {1663-9812},
abstract = {CONTEXT: Alzheimer's disease (AD) is the most common neurodegenerative disorder, which is associated with impaired cognition. Kai-xin-san (KXS), a classic Chinese herbal formula, has been widely used to treat cognitive disorders.

OBJECTIVES: This study aimed to investigate the therapeutic potential and underlying mechanisms of KXS for AD.

METHODS: A systematic search of 7 databases was conducted from inception to October 2025, with language restrictions in both Chinese and English. Behavior and biomarkers were assessed as measures of efficacy and mechanism. The risk of bias was assessed by the SYRCLE's risk of bias tool. The meta-analysis was performed by STATA version 15.0 software packages and RevMan 5.4 software. Subgroup, meta-regression, and sensitivity analyses were used to ascertain the robustness of primary analyses, Egger's test and funnel plots were used to assess potential publication bias, and the evidence of evidence was assessed by the modified GRADE approach.

RESULTS: This study included 44 studies, involving a total of 2,681 animals, 3 behavioral tests, such as Morris water maze (MWM), novel object recognition (NOR), Y maze, and 9 biomarkers, such as β-amyloid peptide (Aβ), tau protein, tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β), and interleukin-6 (IL-6), malondialdehyde (MDA), superoxide dismutase (SOD), acetylcholinesterase (AchE), and acetylcholine (ACh). KXS could significantly shorten escape latency from the target quadrant, and elevate entry frequency into the target quadrant and time spent in the target quadrant in MWM; meanwhile, KXS could also significantly enhance the relative recognition index in NOR, and improve spontaneous alternation performance in Y-maze. Moreover, KXS could decrease Aβ, tau and AchE in the hippocampus, and TNF-α, IL-1β, IL-6, and MDA in both serum and hippocampus, while increase ACh in the hippocampus and SOD in both serum and hippocampus.

CONCLUSION: These findings suggest that KXS may alleviates cognitive deficits in AD animal models, which may be attributed to its modulation of multiple mechanisms, including Aβ and tau pathology, inflammation, oxidative stress, and cholinergic function. However, due to the high risk of bias, indicating that the true effects of KXS may be smaller than those reported. Therefore, high-quality preclinical studies are essential before clinical efficacy can be considered.},
}

@article {pmid42110595,
year = {2026},
author = {Białecka, M and Białecka, M and Machoy-Mokrzyńska, A and Malinowski, D and Rać, M},
title = {The importance of TNF-α signaling: a potential risk factor in neurodegenerative and cardiovascular diseases.},
journal = {Archives of medical science : AMS},
volume = {22},
number = {1},
pages = {27-44},
pmid = {42110595},
issn = {1734-1922},
abstract = {Cytokines are small, membrane-bound, protein-based cell signaling molecules that aid cell-to-cell communication in physiological and pathological processes. TNF-α is a pleiotropic cytokine that is regarded as a principal cytokine in the acute and chronic phases of the immune and inflammatory responses. TNF-α has been demonstrated to play a role in neuroplasticity and myelination, as well as excitotoxicity, neuroinflammation, and damage to the blood-brain barrier. The involvement of TNF-α in the etiology of Parkinson's disease, both in its early and late stages, Alzheimer's disease, multiple sclerosis, and coronary artery disease has been substantiated using both experimental models and clinical studies. TNF also plays a key role in cardiovascular disease, initiating a cascade of inflammatory and vascular responses. The aim of this study was to clarify the molecular mechanisms of TNF action and the effects of its secretion in selected diseases.},
}

@article {pmid42110765,
year = {2026},
author = {Ertuğrul Uygun, HD and Demir, MN},
title = {Rapid Detection of Amyloid β1-42 via PAMAM G4 Supported Molecularly Imprinted Sensor.},
journal = {ACS omega},
volume = {11},
number = {17},
pages = {25960-25968},
pmid = {42110765},
issn = {2470-1343},
abstract = {In this research, a novel sensor system was prepared for the rapid and selective determination of Amyloid β1-42 (Aβ1-42), a key biomarker in the early recognition of Alzheimer's disease. A screen-printed gold electrode (AuE) was used as the base for a self-assembled monolayer (SAM)-based molecularly imprinted polymer (MIP). The electrode was modified by sequential incubation in 100 mM cysteamine, 5% glutaraldehyde, and PAMAM G4 dendrimer. Electropolymerization was performed using pyrrole-3-carboxylic acid and Aβ1-42. Desorption was achieved using 500 mM HCl to remove the template molecule, generating specific recognition sites. The sensor's performance was determined by electrochemical impedance spectroscopy (EIS) and cyclic voltammetry (CV), with additional surface characterization via SEM, XPS, and FT-IR. The nonimprinted polymer (NIP) showed no response to Aβ1-42, confirming the selectivity of the MIP. Selectivity tests using Tau protein showed minimal interference. The quantification limit (LOQ) and the limit of detection (LOD) were found to be 0.42 and 0.14 ng/mL, respectively. In diagnostic applications, the proposed sensor shows promise as a quick, sensitive, and selective way to detect Aβ1-42.},
}

@article {pmid42110915,
year = {2026},
author = {Huang, Z and Kong, W and Wang, S},
title = {Leveraging Hamiltonian neural flow for robust single-cell multi-omics integration: application to Alzheimer's disease.},
journal = {Frontiers in genetics},
volume = {17},
number = {},
pages = {1795752},
pmid = {42110915},
issn = {1664-8021},
abstract = {Alzheimer's disease (AD) progression involves complex molecular interactions across multiple biological layers, yet integrating high-dimensional single-cell multi-omics data remains computationally challenging. While Graph Convolutional Networks (GCNs) effectively model cell-gene interaction topologies, they face three critical limitations: over-smoothing in deep architectures, instability under data perturbations, and lack of mechanistic interpretability-obstacles that impede clinical translation. The Hamiltonian Graph Convolutional Network (HGCN), a physics-inspired framework integrating symplectic dynamics with graph-based learning, is proposed in this study, which incorporates energy-conserving Hamiltonian mechanics to address these limitations through: (1) geometric constraints that prevent over-smoothing, (2) stable gradient propagation via symplectic integration, and (3) interpretable phase space representations of cellular states. To validate the effectiveness of the HGCN model, it was evaluated on three single-cell multi-omics datasets: an AD prefrontal cortex dataset, and peripheral blood benchmarks. Meanwhile, differential analysis emerged as the most effective feature extraction strategy in the evaluated experimental setting through systematic preprocessing comparisons. On the AD composite classification task requiring simultaneous prediction of cell type and disease state, HGCN achieved 92.28% accuracy and 0.9228 F1-score, significantly outperforming baseline GCN (88.59% accuracy, 0.8860 F1-score). Phase space visualization revealed biologically meaningful patterns: Inhibitory neurons exhibited heterogeneous subtype structures, while disease states showed symmetric geometric organization suggesting cell-type-invariant pathological mechanisms. Robustness experiments on citation networks demonstrated superior resilience to both feature and structural perturbations compared to standard GCN, with performance advantages increasing under higher perturbation intensities. These results establish HGCN as a robust, interpretable framework for multi-omics integration in complex disease analysis, with potential applications in precision medicine.},
}

@article {pmid42111079,
year = {2026},
author = {Türkegün Şengül, M and Nemutlu Samur, D},
title = {Glial biomarkers improve classification of cognitive impairment: an explainable artificial intelligence study using CSF biomarkers.},
journal = {Frontiers in neurology},
volume = {17},
number = {},
pages = {1787915},
pmid = {42111079},
issn = {1664-2295},
abstract = {BACKGROUND: Alzheimer's disease (AD) is increasingly recognized as a disorder involving not only amyloid and tau pathology but also glial activation and neuroinflammation. Biomarkers reflecting these processes may improve the classification of clinical cognitive impairment. This study evaluated the diagnostic value of glial biomarkers, alongside cerebrospinal fluid (CSF) biomarkers, for distinguishing cognitively normal individuals from those with clinical dementia rating scale (CDR)-defined very mild or mild dementia.

METHODS: Data from 333 adults aged ≥60 years were obtained from the Knight Alzheimer's Disease Research Center's longitudinal, open-access dataset. Seven multimodal models integrating CSF biomarkers, glial biomarkers, and clinical features were developed using machine-learning approaches. A hybrid model incorporating feature selection was applied, and model interpretability was assessed. Classification performance was evaluated using AUC, accuracy, recall, precision, and F1-score.

RESULTS: Incorporating all biomarkers, the model achieved the highest performance (AUC = 0.959; accuracy = 0.912), followed by a parsimonious hybrid model (clustering, cystatin C, age, tau, Aβ42, sex) with comparable performance (AUC = 0.951; accuracy = 0.868; p = 0.309). According to SHAP analysis, tau and cystatin C were the most influential features in both models for clinical impairment classification.

CONCLUSION: Glial biomarkers significantly enhance diagnostic classification of CDR-defined clinical cognitive impairment beyond core CSF biomarkers. Parsimonious and interpretable machine-learning models achieve performance comparable to more complex approaches, supporting their potential use in clinical stratification frameworks.},
}

@article {pmid42111182,
year = {2026},
author = {Dakhel, A and Mothes, T and Eltom, K and Michno, WP and Erlandsson, A},
title = {Exposure to fibrillar proteins leads to widespread infiltration but only mild tau pathology in cortical organoids.},
journal = {iScience},
volume = {29},
number = {5},
pages = {115819},
pmid = {42111182},
issn = {2589-0042},
abstract = {Alzheimer's disease (AD) and Parkinson's disease (PD) are the most common neurodegenerative disorders, both characterized by accumulation of aggregated proteins. In AD, the pathological deposits consist predominantly of amyloid-beta (Aβ) and tau, while alpha-synuclein (αSYN) forms inclusions in PD. However, cross-seeding often generates mixed pathologies. Emerging evidence suggests a role of astrocytes in disease spreading, but the underlying mechanisms remain unclear, partly due to limitations of mouse models in replicating early human disease. To address this, we developed a human cerebral organoid platform to study early sporadic AD/PD events. We introduced fibrillar aggregates of αSYN, Aβ, and tau directly into organoids or via astrocytes pre-exposed to the aggregates. All proteins successfully penetrated the organoids with distinct morphology and distribution patterns. Twelve weeks post-exposure, organoids exposed to Aβ or αSYN-containing astrocytes showed the highest insoluble tau levels, but none developed robust tau pathology, highlighting limitations in organoid modeling of tau pathology.},
}

@article {pmid42111249,
year = {2026},
author = {Yan, T and Vaquer, J and Springer, W and Fiesel, FC},
title = {The modifier matrix: emerging roles of ubiquitin-like proteins in Alzheimer's disease.},
journal = {Molecular neurodegeneration advances},
volume = {2},
number = {1},
pages = {18},
pmid = {42111249},
issn = {3059-4944},
abstract = {Ubiquitin and ubiquitin-like proteins (UBLs) have emerged as critical regulators of protein homeostasis and cellular signaling, processes that are increasingly recognized as central to the pathogenesis of Alzheimer's disease (AD). This review explores the expanding roles of UBL modifiers, including SUMO, NEDD8, ISG15, UFM1, and ATG8/ATG12, in the development and progression of AD. We discuss how these post-translational modifications influence key pathological features of AD such as amyloid-beta accumulation and neurofibrillary tangles formation, as well as their impact on neuronal function, proteostasis, and neuroinflammation. Recent advances in our understanding of the enzymatic machinery mediating these modifications, and the interplay between different UBL proteins, offer new insights into the molecular mechanisms underlying AD. Furthermore, we highlight emerging therapeutic strategies targeting UBL pathways, which may provide novel avenues for intervention in AD. By integrating current findings, this review underscores the significance of UBL proteins in AD and identifies future directions for research aimed at unraveling their complex roles in neurodegeneration.},
}

@article {pmid42111521,
year = {2026},
author = {Guo, B and Wang, J and Lou, F and Yuan, B and Chen, Z and Tang, C and Chen, W and Yi, F and Jiang, J and Hu, G and Cong, C and Lu, Y},
title = {Graphene field-effect transistor based multiplexed sensing platform for simultaneous detection of multiple Alzheimer's disease biomarkers.},
journal = {RSC advances},
volume = {16},
number = {26},
pages = {23937-23944},
pmid = {42111521},
issn = {2046-2069},
abstract = {Simultaneous detection of multiple biomarkers for one disease using a single drop of body fluid is challenging yet critical to confirm symptoms in the early stage. This study presents the development of a graphene field-effect transistor (GFET)-based multiplexed sensing platform designed for overcoming this obstacle. The platform utilizes a hexamethyldisilazane (HMDS) blocking layer as a hydrophobic treatment to enable recognition element (probe/aptamer) modifications within a small chip area (3 × 3 mm[2]), and this further enables simultaneous detection of multiple targets (multi-targets) in complex biological samples. The optimized aptamer/probe functionalization also enhances the specificity, sensitivity, and accuracy of the sensor. The technology was demonstrated with Alzheimer's disease (AD) biomarkers as a case study. Two distinctive biomarkers, hsa-miR-125b and Aβ42, are detected simultaneously with distinguishable signatures, and the lowest tested concentration is 1 fM. The cross-check experiments also show the effectiveness of the multi-target detection capability. This concise platform paves the way for accurate detection of early-stage diseases when the simultaneous identification of multiple biomarkers is required.},
}

@article {pmid42111637,
year = {2026},
author = {Lucà, F and Picano, E and Aschieri, D and Battistoni, I and Bilato, C and Di Fusco, SA and Geraci, G and Ad, VG and Iacovoni, A and Mabritto, BMT and Milli, M and Scicchitano, P and Troisi, F and Vigorito, F and Gabrielli, D and Gulizia, MM and Colivicchi, F and Oliva, F and Nardi, F and Grimaldi, M},
title = {Occupational Hazards in Cardiac Catheterization Laboratories: Radiation and Beyond-ANMCO Position Paper Update 2026.},
journal = {European heart journal supplements : journal of the European Society of Cardiology},
volume = {28},
number = {Suppl 6},
pages = {vi304-vi314},
pmid = {42111637},
issn = {1520-765X},
abstract = {Interventional cardiology has profoundly transformed the management of cardiovascular disease; however, working within the cardiac catheterization laboratory exposes healthcare professionals to substantial occupational hazards. Four principal risks can be identified: (i) malignancy and non-malignant sequelae related to chronic exposure to ionizing radiation; (ii) musculoskeletal injury associated with prolonged use of heavy radioprotective equipment; (iii) exposure to blood-borne pathogens and other infectious agents; and (iv) work-related psychological strain. Among these, cumulative radiation exposure remains the most consequential and historically under-recognized threat. Although the radiation dose which operators receive during a single procedure is markedly lower than that delivered to patients, healthcare professionals are subjected to repeated, lifelong exposure. For a high-volume interventional cardiologist, the annual effective dose may substantially exceed that of other radiation-exposed professionals, including nuclear industry workers and diagnostic radiologists. Importantly, unlike radiologists, many cardiologists receive limited formal training in radiation physics and radiobiology, which may lead to limited awareness of dose-optimization strategies and stochastic risk. Contemporary epidemiological evidence has refined our understanding of the biological effects of chronic low-dose and low-dose-rate radiation. Risk estimates for malignancy have progressively increased as follow-up durations have lengthened and methodological approaches have improved. Moreover, emerging data suggest that sustained low-dose exposure may confer an elevated risk of cardiovascular disease, thereby extending concern beyond oncological endpoints. Occupational exposure varies greatly depending on the location: doses to the head can be several times higher than doses to the chest, with a predominance on the left side attributable to the position of the operator in relation to the X-ray source. In addition to the well-established association with posterior subcapsular cataracts, observational studies have reported potential links between long-term occupational exposure and neurodegenerative disorders, including Alzheimer's and Parkinson's diseases, although causality remains to be definitively established. Mitigation of these risks necessitates a paradigm shift towards a rigorous culture of radiation safety. Institutional commitment is essential, encompassing advanced shielding systems, ceiling-suspended protection, real-time dosimetry with immediate feedback, and systematic optimization of imaging protocols. Ultimately, the future of the field may depend on the progressive adoption of radiation-sparing and radiation-free technologies, including intracardiac and intracoronary ultrasound, electro anatomical mapping systems, and non-fluoroscopic navigation platforms. In parallel, robot-assisted procedures enable remote manipulation of the catheter promise to reduce the operator's direct exposure. The pursuit of a zero-radiation environment in the workplace should not be considered an ambitious ideal but a strategic priority to safeguard the next generation of interventional cardiologists.},
}

@article {pmid42111940,
year = {2026},
author = {Ismail Al-Khaleel, R and Kalenahalli, Y and Hemalatha, S and Baker, S and Raj, SN and Rangappa, KS and Gowda, S and Siddaiah, C},
title = {Metabolomic analysis of Pennisetum glaucum seed extracts using advanced LC-MS/MS and Q-TOF technology.},
journal = {Journal of food science and technology},
volume = {63},
number = {5},
pages = {962-970},
pmid = {42111940},
issn = {0022-1155},
abstract = {UNLABELLED: Pearl millet (Pennisetum glaucum) is a cereal widely cultivated and grown in Africa and the Indian subcontinent for centuries. The present investigation aims to use LC-MS/MS to analyze the secondary metabolites present in pearl millet seeds using different solvents such as methanol, hexane, chloroform, and ethyl acetate. METLIN software was used to identify the metabolites. The analysis revealed the presence of 650 metabolites, among which 145 were commonly found in all the solvent extracts. The major classes of identified metabolites are terpenoids, flavonoids, sterols, amino acids, fatty acids, glycoconjugates, and carbohydrates. 80% methanolic extract and ethyl acetate extract yielded the highest concentrations of terpenoid (23%) and flavonoid (17%). The enrichment analysis was performed to statistically examine and identify the metabolites present in the metabolomic library dataset. In the hexane extract, notable metabolites such as quercetin and rutin were identified, which possess potential for the management of Alzheimer's disease due to their neuroprotective effects (p < 4e-35). In the methanol extract, metabolites like gallic acid and caffeic acid were associated with uremia treatment due to their antioxidant activity (p < 5e-37). Overall, the present study provides an overview of the metabolites present in the pearl millet seeds and the nutritive as well as therapeutic potential of these millets in the management of human diseases.

SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s13197-025-06328-6.},
}

@article {pmid42112106,
year = {2026},
author = {Itkyal, VS and LaGrow, TJ and Jensen, KM and Iraji, A and Calhoun, VD},
title = {Investigating white matter functional network connectivity across the Alzheimer's disease spectrum using resting-state fMRI.},
journal = {Frontiers in neuroimaging},
volume = {5},
number = {},
pages = {1796824},
pmid = {42112106},
issn = {2813-1193},
abstract = {White matter (WM) has traditionally been considered structurally important but functionally inert in fMRI research. However, growing evidence indicates that WM exhibits meaningful BOLD fluctuations and participates in functional connectivity. Here, we investigate alterations in WM functional network connectivity (FNC) across the Alzheimer's disease (AD) spectrum using resting-state fMRI data from the Alzheimer's Disease Neuroimaging Initiative (ADNI; 415 cognitively normal (CN), 283 mild cognitive impairment (MCI), 91 AD). We applied a guided independent component analysis (ICA) approach based on a combined multiscale template including 202 intrinsic connectivity networks [ICNs; 97 WM, 105 gray matter (GM)] to estimate subject-specific timecourses and compute FNC. Group differences in WM-WM, GM-GM, and WM-GM functional network connectivity (AD-CN, AD-MCI, MCI-CN) were evaluated using two-sample t-tests on residual FNC values for age, sex, and mean framewise displacement. Multiple comparisons across edges were controlled using false discovery rate correction (q < 0.05), and effect sizes were quantified using Hedges' g. Results showed robust alterations in WM-WM and WM-GM connectivity in AD, particularly involving WM subcortical, frontal, sensorimotor, and occipitotemporal networks. Several WM-GM interactions with cerebellar and hippocampal GM networks were also disrupted, including reduced GM-cerebellar: WM-frontal coupling and increased GM-hippocampal: WM-frontal connectivity. Notably, MCI already showed WM-GM dysconnectivity relative to CN, suggesting that functional disruption of WM circuits emerges prior to overt dementia. These findings provide converging evidence that WM functional connectivity is both measurable and selectively altered across the AD continuum. Our findings support WM FNC as a candidate biomarker to GM-based measures for staging and monitoring AD. Together, these results position WM-GM dysconnectivity as an important systems-level signature of the AD continuum and support WM functional network connectivity as a promising complement to established GM-based measures for understanding disease progression.},
}

@article {pmid42112371,
year = {2026},
author = {Gera, R and Mocci, G and Tambaro, S and Vanlandewijck, M and Nilsson, P and Eriksdotter, M and Mitra, S},
title = {Nerve growth factor responsive elements modulate immune cell inflammation and are dysregulated in an Alzheimer's disease mouse model.},
journal = {Frontiers in immunology},
volume = {17},
number = {},
pages = {1722477},
pmid = {42112371},
issn = {1664-3224},
mesh = {Animals ; *Alzheimer Disease/immunology/metabolism/pathology ; Mice ; Disease Models, Animal ; *Nerve Growth Factor/metabolism/immunology ; *Inflammation/immunology/metabolism ; Receptors, Nerve Growth Factor/metabolism ; Receptor, trkA/metabolism ; Mice, Inbred C57BL ; Immunity, Innate ; },
abstract = {Inflammation is a crucial regulator of body's defense mechanism primarily modulated by the immune system. Context dependent immune activation (e.g., pathogen) requires acute inflammatory reactions followed by efficient resolution of inflammation. Impaired resolution may lead to chronic inflammation, often associated with several pathological processes, including dementia disorders. At present, the mechanisms of inflammation resolution are poorly understood. High levels of the neurotrophin nerve growth factor (NGF) are evident at the site of inflammation, however the effect of NGF on immune cells is debated, ranging from proinflammatory to anti-inflammatory. Thus, identifying the immune cells which possess NGF responsive receptors is crucial to understand how NGF can modulate immune function of those specific immune cells. Utilizing multi-color flow cytometry, we mapped across various immune cell subtypes including adaptive and innate immunity landscape from unchallenged mouse spleen for the presence of NGF receptors (TrkA and p75). Although NGF receptors were previously reported in some immune cell types, we report comprehensive cell-type dependent expression of NGF receptors on immune cells including dendritic cells, macrophage, natural killer (NK) cell as well as various subsets of lymphocytes (T and B cells). Since NGF is the upstream regulator of cholinergic signaling, we employed single cell RNA sequencing (scRNA-seq) and observed heterogenous neurotrophin-cholinergic landscape among various immune sub-sets, and report discordance between RNA and protein level expression. Interestingly, we found that differential activation methods ex-vivo could increase TrkA and p75 protein levels differently, a crucial regulator of NGF downstream signaling. Furthermore, we report that NGF supplementation reduced inflammatory cytokine production in activated T- and B-cells significantly. Using a mouse model of AD, we show age-dependent alterations in TrkA and p75 in immune cells, indicating altered NGF-immune coupling in AD. In conclusion, this study identifies that immune cells are direct recipient of NGF signaling by expressing its associated receptors and the existence of a novel inflammation regulatory mechanism mediated through NGF-receptors. The NGF responsive elements get hampered in the immune cells in an AD mouse model which may have pathogenic implications in the resolution of chronic inflammatory response. Thus, NGF associated mechanisms constitute novel regulatory potential in immune cells which can be targeted for inflammatory immune disorders.},
}

Animals
*Alzheimer Disease/immunology/metabolism/pathology
Mice
Disease Models, Animal
*Nerve Growth Factor/metabolism/immunology
*Inflammation/immunology/metabolism
Receptors, Nerve Growth Factor/metabolism
Receptor, trkA/metabolism
Mice, Inbred C57BL
Immunity, Innate

@article {pmid42112453,
year = {2025},
author = {Usman, M and Ashebir, S and Okey-Mbata, C and Yun, Y and Kim, S},
title = {Neuroengineering Frontiers: A Selective Review of Neural Interfaces, Brain-Machine Interactions, and Artificial Intelligence in Neurodegenerative Diseases.},
journal = {Applied sciences (Basel, Switzerland)},
volume = {15},
number = {21},
pages = {},
pmid = {42112453},
issn = {2076-3417},
abstract = {Neurodegenerative diseases, including Alzheimer's disease (AD) and Parkinson's disease (PD), present a growing public health challenge globally. Recent advancements in neurotechnology and neuroengineering have significantly enhanced brain-computer interfaces, artificial intelligence, and organoid technologies, making them pivotal instruments for diagnosis, monitoring, disease modeling, treatment development, and rehabilitation of various diseases. Nonetheless, the majority of neural interface platforms focus on unidirectional control paradigms, neglecting the need for co-adaptive systems where both the human user and the interface continually learn and adapt. This selected review consolidates information from neuroscience, artificial intelligence, and organoid engineering to identify the conceptual underpinnings of co-adaptive and symbiotic human-machine interaction. We emphasize significant shortcomings in the advancement of long-term AI-facilitated co-adaptation, which permits individualized diagnostics and progression tracking in Alzheimer's disease and Parkinson's disease. We concentrate on incorporating deep learning for adaptive decoding, reinforcement learning for bidirectional feedback, and hybrid organoid-brain-computer interface platforms to mimic disease dynamics and expedite therapy discoveries. This study outlines the trends and limitations of the topics at hand, proposing a research framework for next-generation AI-enhanced neural interfaces targeting neurodegenerative diseases and neurological disorders that are both technologically sophisticated and clinically viable, while adhering to ethical standards.},
}

@article {pmid42112454,
year = {2026},
author = {Fang, C and Lei, Z and Han, Y and Tang, P and Yu, G and Sun, J and Wang, B and Xu, Y},
title = {Inhibitory effect of non-alcoholic compounds from spontaneously fermented beverage on Helicobacter pylori.},
journal = {Frontiers in cellular and infection microbiology},
volume = {16},
number = {},
pages = {1742545},
pmid = {42112454},
issn = {2235-2988},
mesh = {*Helicobacter pylori/drug effects/growth & development ; *Helicobacter Infections/microbiology/drug therapy ; Gastrointestinal Microbiome/drug effects ; Animals ; Humans ; *Anti-Bacterial Agents/pharmacology ; Cytokines/metabolism ; Fermentation ; Mice ; China ; Lactic Acid/pharmacology ; Alcoholic Beverages ; Fermented Foods ; Disease Models, Animal ; },
abstract = {Global public health has long been threatened by H. pylori infection associated diseases. Spontaneously fermented beverage contains significant quantities of antibacterial and anti-inflammatory compounds. Here in this study, we demonstrated that the non-alcoholic compounds (NACs) of Baijiu, a traditional spontaneous fermented alcoholic beverage of China, have significant H. pylori inhibitory activity. It can ameliorate H. pylori infection-induced inflammation both in vitro and in vivo. Furthermore, NACs intervention reverses H. pylori infection-induced alteration of gut microbiota, especially boosting colonization of the beneficial gut commensal Lactobacillus, Akkermansia, Eisenbergiella, Ruminococss, and Bifidobacterium. Prediction of gut microbiota function indicated that NACs reversed the increase in a series of metabolic pathways induced by H. pylori infection, including those associated with Alzheimer's disease, pathways in cancer etc. The non-targeted metabolomic analysis reveals 384 compounds in NAC, including 142 organic acids. Amongst these compounds, the content of lactic acid is as high as 1.26 g/L. Lactic acid at such concentration effectively inhibited the growth of H. pylori, reduced urease activity and transcript levels virulence genes (VacA, CagA), and decreased H. pylori infection-induced increase of cytokines (IL-6, IL-1β) in GES-1 cells. Our work proposes that Baijiu NAC could serve as a candidate for the supportive eradication of H. pylori. More importantly, it expands upon the existing limited knowledge of the impact of H. pylori infection on gut microbiota.},
}

*Helicobacter pylori/drug effects/growth & development
*Helicobacter Infections/microbiology/drug therapy
Gastrointestinal Microbiome/drug effects
Animals
Humans
*Anti-Bacterial Agents/pharmacology
Cytokines/metabolism
Fermentation
Mice
China
Lactic Acid/pharmacology
Alcoholic Beverages
Fermented Foods
Disease Models, Animal

@article {pmid42112546,
year = {2026},
author = {Shi, Y and Li, S},
title = {Mediation Analysis of Failure Time Data Under Interval Censoring.},
journal = {Statistics in medicine},
volume = {45},
number = {10-12},
pages = {e70583},
doi = {10.1002/sim.70583},
pmid = {42112546},
issn = {1097-0258},
support = {12471251//National Natural Science Foundation of China/ ; 2025A03J3083//Science and Technology Program of Guangzhou of China/ ; 2025A1515012851//Nature Science Foundation of Guangdong Province of China/ ; },
mesh = {Humans ; Alzheimer Disease/genetics ; Likelihood Functions ; Computer Simulation ; Proportional Hazards Models ; *Mediation Analysis ; Disease Progression ; Survival Analysis ; Apolipoproteins E/genetics ; Models, Statistical ; },
abstract = {Motivated by disentangling the direct and indirect genetic effects on the Alzheimer's disease progression, we propose a mediation approach for analyzing interval-censored failure time data. Under the counterfactual framework with sequential ignorability, generalized linear and spline-based proportional hazards (PH) models are employed to depict path-specific effects (PSEs) of an exposure on the interested failure time mediated through multiple mediators. In particular, the PSEs are derived on the basis of both survival probability and restricted mean survival time, bypassing the restrictive rare outcome assumption inherent in the PH model. A sieve maximum likelihood method is proposed to estimate all unknown parameters in the PH model. Simulation studies demonstrate the satisfactory empirical performances of the proposed mediation method. A real-world data analysis quantifies the mediation effects of Apolipoprotein E- ϵ $$ \epsilon $$ 4 allele on the risk of developing the Alzheimer's disease.},
}

Humans
Alzheimer Disease/genetics
Likelihood Functions
Computer Simulation
Proportional Hazards Models
*Mediation Analysis
Disease Progression
Survival Analysis
Apolipoproteins E/genetics
Models, Statistical

@article {pmid42112640,
year = {2026},
author = {Bertrand, F and Gaudiez, A and Valadoux, AS and Delbeuck, X and Deramecourt, V and Lebouvier, T},
title = {[Late-onset frontotemporal degenerations].},
journal = {Geriatrie et psychologie neuropsychiatrie du vieillissement},
volume = {24},
number = {1},
pages = {42-58},
doi = {10.1684/pnv.2026.1278},
pmid = {42112640},
issn = {2115-7863},
mesh = {Humans ; *Frontotemporal Lobar Degeneration/diagnosis/epidemiology/psychology/genetics/pathology ; Aged ; Age of Onset ; Alzheimer Disease/diagnosis ; Aged, 80 and over ; },
abstract = {Frontotemporal lobar degeneration (FTLD) encompasses a heterogeneous group of neurodegenerative disorders, including a wide range of clinical, neuropathological, and genetic entities, whose late-onset forms remain underdiagnosed in clinical practice. Although FTLD is less frequent than Alzheimer's disease (AD) in older adults, recent epidemiological studies indicate that its incidence increases with age, peaking around the seventh decade, thereby challenging the traditional view of FTLD as a disorder predominantly affecting younger individuals. In older patients, diagnostic accuracy is reduced by the frequent absence of typical early-onset features. Late-onset FTLD often presents with less characteristic clinical phenotypes, including attenuated behavioural symptoms, misleading memory impairment suggestive of AD, and subtle motor or language manifestations, all of which contribute to delayed recognition. From a neuropathological perspective, late-onset FTLD displays distinct features compared with earlier-onset forms, including less pronounced frontotemporal atrophy, a higher frequency of mixed pathologies, and the presence of age-related lesions, which may influence clinical expression. In clinical practice, the identification of FTLD in older adults relies on a multimodal approach integrating detailed clinical and neuropsychological evaluation with structural or functional neuroimaging. In the absence of FTLD-specific biomarkers, cerebrospinal fluid biomarkers of AD are frequently used to support the diagnostic process, primarily to identify or exclude concomitant AD pathology, although their interpretation requires caution in this age group. Genetic analyses may also contribute to the diagnostic assessment, particularly in presentations compatible with the behavioural variant of FTLD, including late-onset cases. Overall, integrating clinical, neuropsychological, imaging, biomarker, and genetic data is essential to improve the recognition of late-onset FTLD and optimize patient management in this population.},
}

Humans
*Frontotemporal Lobar Degeneration/diagnosis/epidemiology/psychology/genetics/pathology
Aged
Age of Onset
Alzheimer Disease/diagnosis
Aged, 80 and over

@article {pmid42112644,
year = {2026},
author = {Laflamme, E and Rioux, É and Breton, C and Brizard, N and Desjardins, S and Gagnon, S and Laplante, A and Pépin, É and Boller, B and Vallet, GT},
title = {[Preliminary validation of the Quebec French version of the Memory Binding Test: Comparison with the Rey Auditory Verbal Learning Test in adults aged 55 and older].},
journal = {Geriatrie et psychologie neuropsychiatrie du vieillissement},
volume = {24},
number = {1},
pages = {90-101},
doi = {10.1684/pnv.2026.1275},
pmid = {42112644},
issn = {2115-7863},
mesh = {Humans ; Aged ; Male ; Female ; Middle Aged ; Quebec ; *Verbal Learning ; *Neuropsychological Tests ; Reproducibility of Results ; *Memory and Learning Tests ; Aged, 80 and over ; Alzheimer Disease/diagnosis/psychology ; Memory, Episodic ; },
abstract = {Early detection of Alzheimer's disease (AD) requires cognitive tools that are both sensitive to subtle memory impairments and specific to the disease. The Memory Binding Test (MBT) was designed for this purpose, targeting episodic memory binding through structured, semantically cued encoding, thereby reducing executive demands. Although a French adaptation of the MBT has been validated, no version has yet been developed for the Quebec French population, despite known linguistic and cultural differences that may affect verbal memory performance. This study aimed (1) to validate a Quebec French adaptation of the MBT derived from the French version developed in France, and (2) to assess its convergent validity with the Rey Auditory Verbal Learning Test (RAVLT), a widely used but more executive-dependent episodic memory task. Materials and methods. Fifty-two participants aged 55 years and older, all professionals or executives, completed both tests in a remote cognitive assessment setting. Moderate to strong correlations were observed between MBT free recall and RAVLT recall scores, increasing across RAVLT learning trials. However, no significant correlation was found for recognition scores, likely due to methodological differences and ceiling effects in the RAVLT. Paired comparisons showed significantly higher free recall performance in the MBT than in RAVLT trial 1, but lower than after five trials, reflecting the MBT's structured encoding advantage versus the cumulative learning effect in the RAVLT. Recognition scores were significantly lower in the MBT, consistent with its higher cognitive demands (i.e., source memory). Overall, these findings support the convergent validity and clinical relevance of the Quebec MBT, particularly for detecting subtle episodic memory deficits in aging. Its structure makes it less reliant on executive strategies, positioning it as a complementary tool to traditional memory tests such as the RAVLT for the early detection of AD-related memory decline in cognitively high-functioning individuals.},
}

Humans
Aged
Male
Female
Middle Aged
Quebec
*Verbal Learning
*Neuropsychological Tests
Reproducibility of Results
*Memory and Learning Tests
Aged, 80 and over
Alzheimer Disease/diagnosis/psychology
Memory, Episodic

@article {pmid42112660,
year = {2026},
author = {Kasper, E and Lehto, A and Jürs, A and Nordmann, N and Peters, O and Hellmann, J and Priller, J and Spruth, EJ and Petzold, GC and Voigt, I and Weydt, P and Bernsen, S and Dinter, E and Falkenburger, B and Günther, R and Düzel, E and Glanz, W and Synofzik, M and Beichert, L and Spottke, A and Wagner, M and Brosseron, F and Schmid, MC and Halle, A and Herms, J and Schneider, A and Teipel, S and Prudlo, J and Neumann, M and Hermann, A},
title = {Alzheimer's Disease Co-Pathology and Cognitive Impairment in Amyotrophic Lateral Sclerosis.},
journal = {Annals of neurology},
volume = {},
number = {},
pages = {},
doi = {10.1002/ana.78227},
pmid = {42112660},
issn = {1531-8249},
abstract = {OBJECTIVES: Amyotrophic lateral sclerosis (ALS) and Alzheimer's disease (AD) share neuropathological features, including tau, amyloid, and TDP-43 pathology. This study investigated whether AD-related pathological changes are associated with cognitive impairment ALS.

METHODS: Cerebrospinal fluid (CSF total-tau, phosphorylated-tau, beta-amyloid) and plasma biomarkers (TDP-43; neurofilament light chain [NfL]) were analyzed in 192 individuals with ALS or ALS with frontotemporal dementia (ALS-FTD) and 100 healthy controls. Cognitive performance was assessed using the Edinburgh Cognitive and Behavioral ALS Screen (ECAS). Group comparisons and regression analyses examined associations between biomarker profiles and cognitive status. Autopsy data were available for a subset of participants.

RESULTS: Compared with healthy controls, patients with ALS - particularly those with cognitive impairment (ALSci) or ALS-FTD - showed elevated AD-related biomarkers. Significant differences in beta-amyloid levels were observed between healthy controls (HCs) and patients with ALSci, but not between controls and cognitively unimpaired patients. CSF p-tau and total-tau levels were strongly associated with domain-specific cognitive performance. In contrast, plasma extracellular vesicle TDP-43 and NfL showed weak or no association with cognition. In vivo biomarkers alone reliably distinguished cognitive impairment only in ALSci and ALS-FTD. Postmortem analyses showed no strong association between ABC scores or overall TDP-43 burden and cognitive state; however, temporal and hippocampal TDP-43 burden was associated with cognitive dysfunction.

INTERPRETATION: Our findings suggest that tau-related CSF biomarkers, particularly p-tau and total-tau, are associated with cognitive deficits in ALS, indicating that AD-related pathology might be associated to cognitive decline in ALS. However, postmortem data showed even stronger relation of TDP43 pathology to cognitive deficits in ALS. ANN NEUROL 2026 ANN NEUROL 2026.},
}

@article {pmid42112683,
year = {2026},
author = {Zhang, D and Huang, D and He, J and Shen, Y and Dai, L and Shi, L},
title = {Corneal Immune Cell Alterations and Tau Pathology in a Mouse Model of Alzheimer's Disease.},
journal = {Investigative ophthalmology & visual science},
volume = {67},
number = {5},
pages = {20},
doi = {10.1167/iovs.67.5.20},
pmid = {42112683},
issn = {1552-5783},
mesh = {Animals ; *Alzheimer Disease/metabolism/pathology/immunology ; Disease Models, Animal ; Mice ; *Cornea/immunology/pathology/metabolism ; *tau Proteins/metabolism ; Female ; Male ; Mice, Transgenic ; *Dendritic Cells/pathology/immunology ; Mice, Inbred C57BL ; Phosphorylation ; Humans ; Amyloid beta-Protein Precursor/genetics/metabolism ; },
abstract = {PURPOSE: Early diagnosis of Alzheimer's disease (AD) remains a formidable challenge. Although retinal markers are extensively studied, the cornea-the eye's primary transparent window-presents a potential but poorly understood platform for biomarker discovery. This study systematically characterized AD-associated corneal pathological evolution using the 5 × FAD mouse model.

METHODS: Corneas from wild-type (WT) and 5 × FAD mice (ages 3, 5, 7, and 10 months; both sexes included) were analyzed using multimodal approaches: whole-mount immunostaining with 3D reconstruction, immunoblotting, RNA sequencing, and mass spectrometry proteomics.

RESULTS: Although local human APP production was absent, a defined temporal cascade emerged selectively in the peripheral cornea. Dendritic cell (DC) morphological simplification (reduced perimeter and branching) occurred as early as 3 months, preceding significant DC expansion at 5 months and CD3⁺ T cell infiltration at 7 months. Tau hyperphosphorylation (Thr181) surfaced at 7 months, coinciding with heightened GSK3β activity (reduced pGSK3β Ser9). By 10 months, significant peripheral subbasal nerve plexus and superficial nerve terminals loss were observed, with residual fibers exhibiting markedly elevated phosphorylated tau burden. Multi-omics at 7 months validated this pro-inflammatory state, identifying upregulated adhesion molecules (ICAM1 and ITGB2) and the T cell chemoattractant IL-16.

CONCLUSIONS: Corneal neuro-immune remodeling-manifesting as early DC dysfunction followed by T cell recruitment and tau pathology-precedes overt nerve degeneration. These findings suggest the cornea as a potential, noninvasively accessible site for monitoring AD progression.},
}

Animals
*Alzheimer Disease/metabolism/pathology/immunology
Disease Models, Animal
Mice
*Cornea/immunology/pathology/metabolism
*tau Proteins/metabolism
Female
Male
Mice, Transgenic
*Dendritic Cells/pathology/immunology
Mice, Inbred C57BL
Phosphorylation
Humans
Amyloid beta-Protein Precursor/genetics/metabolism

@article {pmid42112871,
year = {2026},
author = {Tekade, A and Shinde, R and Nimbalkar, J and Kadam, P and Aswar, M and H N, S},
title = {Development and Evaluation of Intranasal Nanostructured Lipid Carriers Encapsulating Donepezil HCl and Caesalpinia bonduc Seed Extract for Targeting Alzheimer's Disease: in vitro and in vivo evaluation.},
journal = {Journal of drug targeting},
volume = {},
number = {},
pages = {1-26},
doi = {10.1080/1061186X.2026.2671309},
pmid = {42112871},
issn = {1029-2330},
abstract = {Alzheimer's disease (AD) is a progressive neurodegenerative disorder marked by memory loss and cognitive decline. This study aimed to develop and optimize an intranasal nanostructured lipid carrier (NLC) system co-loaded with Donepezil Hydrochloride (DPZ) and Caesalpinia bonduc seed extract (CBSE) to enhance therapeutic outcomes. LC-MS/MS profiling identified a CBSE bioactive compound with 93.16% structural similarity to neostigmine, suggesting synergistic cholinergic activity. NLCs were prepared using high-pressure homogenization and ultrasonication, optimized using Design of Experiments (DoE). The optimized NLCs exhibited an average particle size of 144.3 ± 1.78 nm, polydispersity index of 0.245 ± 0.025, and a zeta potential of -42.13 ± 2.14 mV, indicating uniformity and stability. TEM confirmed spherical morphology and particle size. The formulation showed high entrapment efficiency (67.27 ± 2.32%) with drug loading (16.81 ± 3.59%) and sustained drug release (72.43 ± 4.78%) over 5 h, following Zero-Order kinetics with Super Case II transport. Ex vivo nasal permeation studies showed significantly higher permeability (p < 0.05) than control, while histological analysis confirmed nasal mucosal safety. In vivo behavioral studies on AD-induced rats demonstrated significantly improved memory and cognition (p < 0.05) following nasal NLC administration. The DPZ-CBSE NLCs present a promising, safe, and non-invasive strategy for effective AD management.},
}

@article {pmid42112907,
year = {2026},
author = {Rasmussen, J},
title = {Perspectives in dementia risk reduction - food for thought.},
journal = {Neurodegenerative disease management},
volume = {},
number = {},
pages = {1-12},
doi = {10.1080/17582024.2026.2669599},
pmid = {42112907},
issn = {1758-2032},
abstract = {Diet and specific nutritional factors, alone and in combination with other lifestyle approaches, have an important role in decreasing the risk for dementia. Protective factors for dementia risk reduction are important in early as well as late adult life, since pathological processes underlying dementia begin years before clinical symptoms appear. Decreased levels of nutrients, such as B vitamins and omega-3 fatty acids, exacerbate pathological processes contributing to cognitive impairment. Initial work using specific diets, including the MIND diet (which combines elements of the Mediterranean and DASH diets), has shown potential to reduce the risk of cognitive decline and/or improve cognitive function, but further research is required. Although the benefits of single-agent nutrient supplementation are unclear, the LipiDiDiet trial has indicated that multinutrient supplementation with Fortasyn Connect may have the potential to improve cognitive function and decrease disease progression in individuals with prodromal Alzheimer's disease. The worldwide FINGER studies are assessing the potential benefits of multidomain lifestyle-based interventions in the prevention of cognitive decline, including dietary interventions. Evidence for the importance of nutrition in combination with lifestyle approaches in maintaining a healthy brain indicates that public health policy must consider nutrition and diet when targeting dementia risk reduction and healthy aging.},
}

@article {pmid42113045,
year = {2026},
author = {Vitali, R and Tanno, B and Casciati, A and Palone, F and Pieroni, L and Morotti, M and Santoro, M and Fratini, E and Pazzaglia, S and Podda, MV and Mancuso, M},
title = {Fecal miRNome and Proteome Profiling Uncovers Stage-Specific Biomarkers of Alzheimer's Disease in 3×Tg-AD Mice.},
journal = {Cellular and molecular neurobiology},
volume = {},
number = {},
pages = {},
doi = {10.1007/s10571-026-01735-5},
pmid = {42113045},
issn = {1573-6830},
abstract = {Reliable, minimally invasive biomarkers for Alzheimer's disease (AD) remain a critical unmet need. Considering mounting evidence for gut-brain interactions in AD, we explored whether fecal samples contain host-derived molecular signals that reflect disease-related changes and could serve as accessible biomarkers. Fecal small RNA sequencing and quantitative proteomics were performed in symptomatic 15-month-old 3×Tg-AD mice and controls. Pathway and network analyses identified key dysregulated molecules. Selected miRNAs and proteins were validated by qPCR or Western blotting in independent pre-symptomatic, early symptomatic, and severe cohorts. To assess whether fecal signals mirrored tissue alterations, colon samples were analyzed for tight-junction proteins, inflammatory markers, epigenetic regulation, and expression of selected miRNAs and proteins. Multi-omics identified 31 miRNAs and 81 proteins modulated in AD fecal sample, revealing a distinct AD-associated fecal signature involving pathways linked to neuroinflammation, synaptic dysfunction, vascular imbalance, and metabolism. Several miRNAs- including miR-322-5p, miR-194-1 and miR-223-3p were significantly altered and validated across disease stages (3-,7-,15-old months mice, respectively). Notably, miR-146b-5p expression is inversely correlated with AD severity, exhibiting a stepwise decline from asymptomatic individuals to those with mild and severe stages. IgKappa and Ela3B emerged as the strongest protein candidates, showing opposite and progressive modulation. Notably, IgKappa and miR-146b showed the most consistent trajectories. Colon analyses uncovered reduced Claudin-7, strong IgKappa upregulation driven by enhancer hypomethylation, and partial overlap between fecal and tissue miRNA profiles, indicating that fecal signals reflect subtle epithelial and immune perturbations associated with AD. Multi-omics at severe stage and a stage specific validation support fecal miRNAs and proteins as promising, host-derived biomarkers for AD. Fecal profiling offers a practical, repeatable, and low-cost approach with translational potential for early detection and longitudinal monitoring in neurodegeneration.},
}

@article {pmid42113090,
year = {2026},
author = {Li, N and Chen, Y and Chen, G},
title = {The NLRP3 Inflammasome: A Central Mediator in Sevoflurane-Induced Neurotoxicity and A Potential Target for Neuroprotection.},
journal = {Molecular neurobiology},
volume = {63},
number = {1},
pages = {},
pmid = {42113090},
issn = {1559-1182},
mesh = {*Sevoflurane/adverse effects/toxicity ; *NLR Family, Pyrin Domain-Containing 3 Protein/metabolism ; Humans ; Animals ; *Inflammasomes/metabolism ; *Neuroprotection/drug effects ; *Neuroprotective Agents/pharmacology ; },
abstract = {The neurological influence of the widely used inhalational anesthetic sevoflurane presents a context-dependent paradox, manifesting as either neurotoxicity or neuroprotection. The NOD-like receptor family pyrin domain containing 3 (NLRP3) inflammasome, a central mediator of neuroinflammation and pyroptosis, has emerged as a key molecular underlying these divergent outcomes. This review integrates current evidence on the role of the NLRP3 inflammasome in the bidirectional effects of sevoflurane, offering a mechanistic framework to guide neuroprotective strategies in perioperative medicine. Analysis reveals that in vulnerable states such as Alzheimer's disease and postoperative cognitive dysfunction, sevoflurane-induced activation of the NLRP3 inflammasome contributes to neurotoxicity and cognitive decline. This process engages multiple CNS cell types, with microglia serving as the primary source of inflammasome-dependent pyroptosis, astrocytes amplifying the inflammatory response, and neurons representing the ultimate targets of injury. Key upstream triggers include mitochondrial dysfunction, oxidative stress, impaired autophagy, and disruption of ion homeostasis, with blood-brain barrier breakdown and gut microbiota dysbiosis further reinforcing this pathological cascade. Conversely, under specific pathological conditions, including cerebral ischemia and neuropathic pain, sevoflurane can suppress NLRP3 activation, indicating that its ultimate effect is determined by the host cellular stress landscape and the net balance of concurrently engaged signaling pathways. Pharmacological inhibition of the NLRP3 pathway demonstrates robust neuroprotective efficacy in preclinical models. Nevertheless, a substantial translational gap remains due to challenges in drug specificity, blood-brain barrier penetration, and safety concerns associated with prolonged suppression of innate immunity. In conclusion, the NLRP3 inflammasome serves as a pivotal integrator of sevoflurane context-dependent neurological effects. The current research landscape remains fragmented and predominantly correlative, relying on heterogeneous experimental models. Future studies should shift from descriptive phenomenology toward identifying decisive molecular switches that govern NLRP3 activation or suppression following sevoflurane exposure. Such insights are indispensable for developing context-dependent combinatorial therapeutic strategies and for bridging the translational gap through validated biomarkers and clinically relevant models, thereby advancing the objective of precision anesthesiology.},
}

*Sevoflurane/adverse effects/toxicity
*NLR Family, Pyrin Domain-Containing 3 Protein/metabolism
Humans
Animals
*Inflammasomes/metabolism
*Neuroprotection/drug effects
*Neuroprotective Agents/pharmacology

@article {pmid42113295,
year = {2026},
author = {Godino, L and Battistuzzi, L and Turchetti, D and Varesco, L and Gentili, V and Chiari, P and Palese, A},
title = {Learning about the genetic risk in my family: Preferences of Italian nurses.},
journal = {Journal of community genetics},
volume = {17},
number = {3},
pages = {},
pmid = {42113295},
issn = {1868-310X},
abstract = {This study explores Italian nurses' preferences and views regarding the disclosure and sharing of genetic risk information within families, focusing on their genetic literacy and responsibility, and comparing these perspectives with laypeople. A nested cross-sectional online survey, originally designed for the general population, included three hypothetical scenarios of inherited genetic risk (Cystic Fibrosis, Hereditary Cancer Syndromes, and early-onset Alzheimer's disease) and items assessing genetic literacy (awareness), family cohesion, disclosure preferences, and responsibility. Quantitative data were analyzed descriptively and inferentially, and qualitative responses were analyzed inductively using Reflexive Thematic Analysis. Among the 1,302 respondents, 501 were healthcare professionals (HCPs), including 315 nurses. Their genetic literacy was modest (mean 2.5/4), higher than laypeople's, with no differences by age or education. Nearly all (94.9%) wished to be informed of genetic risk for at least one condition, with 75.9% preferring to be informed for all three, similar to laypeople (78.1%). Most (97.8%) would undergo genetic testing if informed (95.6% of laypeople). Responsibility for disclosure was viewed as shared between relatives and HCPs (39.1%) or by everyone involved (themselves, relatives and HCPs) (25.1%), echoing laypeople's views. Qualitative findings from the few who did not wish to be informed (n = 16) emphasized anxiety, psychological self-protection, and scepticism toward predictive medicine, similar to laypeople. Italian nurses expressed views and preferences similar to laypeople. While they valued receiving genetic risk information and HCP involvement in family communication, limited familiarity with clinical applications of genetic testing highlights a gap in nursing education and practice, with implications for targeted training.},
}

@article {pmid42113315,
year = {2026},
author = {Mishra, R and Upadhyay, A},
title = {Exosomes in Amyloid Propagation-Roles in Neurodegeneration.},
journal = {Molecular neurobiology},
volume = {63},
number = {1},
pages = {},
pmid = {42113315},
issn = {1559-1182},
mesh = {*Exosomes/metabolism ; Humans ; Animals ; *Neurodegenerative Diseases/metabolism/pathology ; *Amyloid/metabolism ; },
abstract = {Extracellular vesicle (EVs)-mediated cell-to-cell communication is crucial for cell growth, signaling, and metabolism. Exosomes are a subtype of EVs originating from endosomal cellular machinery and have a relatively smaller size (30-150 nM). They carry nucleic acids, proteins, miRNA, lipids, metabolites, and growth factors, making them an exciting research tool for understanding the pathophysiology of complex human diseases. Different brain cells also communicate with themselves by the release of exosomes which helps in overall brain growth and in cell signaling. Recent studies have highlighted the importance of exosomes in neurodegenerative diseases (NDDs) of Alzheimer's disease (AD), Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), prion, and Huntington's disease (HD). Exosomes are involved in the spread of amyloid-like protein aggregates formed in these diseases, but a comprehensive understanding of this spread mechanism is limited. In this article, we have analyzed the roles of exosomes in the spread of amyloid protein aggregates in the NDDs. Furthermore, we have discussed possible measures to address several gaps in our current understanding of cross talks between exosomes and protein aggregates in neurodegenerative disorders (NDDs). We have also discussed the therapeutic opportunities to delay or prevent pathogenic amyloid aggregate spread by exploiting exosomal transport. Overall, the review will contribute to develop a better understanding vesicular transport of amyloids and will help contend their propagation in different NDDs.},
}

*Exosomes/metabolism
Humans
Animals
*Neurodegenerative Diseases/metabolism/pathology
*Amyloid/metabolism

@article {pmid42113316,
year = {2026},
author = {Teles, C and Durães, J and Faustino, P and Baldeiras, I and Gens, H and Pereira, MT and Almeida, MR and Santana, I},
title = {Spastic paraparesis linked to a rare presenilin-1 mutation.},
journal = {Neurogenetics},
volume = {27},
number = {1},
pages = {},
pmid = {42113316},
issn = {1364-6753},
mesh = {Humans ; Female ; *Paraparesis, Spastic/genetics ; *Presenilin-1/genetics ; Adult ; Mutation ; Alzheimer Disease/genetics ; },
abstract = {Familial Alzheimer's disease (FAD) accounts for < 1% of AD cases and is mainly associated with pathogenic variations in presenilin 1 (PSEN1), PSEN2 and the amyloid precursor protein [1]. Most patients present with an earlier onset classic amnestic syndrome [2]. We report a 37-year-old female with progressive spastic paraparesis (SP), wheelchair-dependent at 40-years-old and bedridden at 43yo. She developed mild cognitive complaints at 41yo. Multigene panel revealed a rare probably pathogenic heterozygous PSEN1 variant (p.Pro433Ser). CSF was consistent with pathological Alzheimer continuum. This highlights the importance of considering AD in SP of undetermined cause, showing a novel clinical association between PSEN1 p.Pro433Ser and SP.},
}

Humans
Female
*Paraparesis, Spastic/genetics
*Presenilin-1/genetics
Adult
Mutation
Alzheimer Disease/genetics

@article {pmid42113396,
year = {2026},
author = {S, T and Dwivedi, PSR and Mole, SS and U, N and Shastry, CS},
title = {The neuroprotective potential of diosgenin: an integrated in silico, in vitro, and in vivo approach in colchicine-induced Alzheimer's model.},
journal = {Journal of computer-aided molecular design},
volume = {40},
number = {1},
pages = {},
pmid = {42113396},
issn = {1573-4951},
mesh = {*Diosgenin/pharmacology/chemistry ; *Alzheimer Disease/drug therapy/chemically induced/metabolism/pathology ; Animals ; *Neuroprotective Agents/pharmacology/chemistry ; Colchicine ; Rats ; Oxidative Stress/drug effects ; Molecular Docking Simulation ; Disease Models, Animal ; Male ; Molecular Dynamics Simulation ; Antioxidants/pharmacology/chemistry ; Mice ; Humans ; Brain/drug effects/metabolism ; },
abstract = {Alzheimer's disease (AD) is a progressive neurodegenerative disorder associated with memory loss, spatial disorientation, and a marked decline in cognitive capacity. Colchicine, a microtubule-disrupting agent, is widely used to model cognitive dysfunction in animals. This study aimed to assess the therapeutic potential of Diosgenin against AD utilizing an integrated in silico, in vitro, and in vivo approach. The in silico analyses, molecular docking and molecular dynamics simulations demonstrated strong binding affinity of Diosgenin with key AD-associated proteins LRP5, MME, and NOS2, indicating modulation of oxidative stress, apoptosis, and neuroinflammation. Computational studies also indicated favourable pharmacokinetic properties, supporting its blood-brain barrier permeability. In vitro assays in BV2 microglial cells demonstrated the antioxidant potential of Diosgenin by reducing oxidative stress markers such as MDA while preserving key antioxidant enzymes SOD and GSH. In vivo studies in a colchicine-induced rat model of AD showed that Diosgenin significantly improved cognitive and memory functions, as evidenced by enhanced performance in radial arm maze and novel object recognition tasks. Brain tissue analysis showed that diosgenin improved cholinergic function by lowering AChE and BChE activity. It also enhanced the brain's antioxidant defence (SOD and GSH) and reduced lipid peroxidation (MDA), thereby limiting oxidative stress. Microscopic studies further confirmed fewer degenerating neurons, reduced plaques, and less inflammation. Taken together, these findings suggest that diosgenin offers multi-faceted protection in AD-supporting memory-related neurotransmission, reducing oxidative damage, and dampening inflammation. Nevertheless, further investigation into advanced formulation strategies to overcome its limited bioavailability is warranted to enable clinical translation.},
}

*Diosgenin/pharmacology/chemistry
*Alzheimer Disease/drug therapy/chemically induced/metabolism/pathology
Animals
*Neuroprotective Agents/pharmacology/chemistry
Colchicine
Rats
Oxidative Stress/drug effects
Molecular Docking Simulation
Disease Models, Animal
Male
Molecular Dynamics Simulation
Antioxidants/pharmacology/chemistry
Mice
Humans
Brain/drug effects/metabolism

@article {pmid42113447,
year = {2026},
author = {Xin, JY and Liu, J and Dong, HM and Yu, HL and Xiao, ZS and Hu, JN and Jiang, Q and Zhu, YP and Feng, L and Feng, Y and Jia, YJ and Yuan, ZY and Yu, ZY and Shi, AY and Zeng, GH and Wang, J and Wang, WY and Cheng, L and Vella, LJ and Li, FZ and Masters, CL and Wang, YJ},
title = {Proteomic comparison of human neural cell-derived extracellular vesicles and parental cells from Alzheimer's disease and cognitively normal individuals.},
journal = {Science China. Life sciences},
volume = {},
number = {},
pages = {},
pmid = {42113447},
issn = {1869-1889},
abstract = {Circulating brain-derived extracellular vesicles (BDEVs) have emerged as promising biomarkers for neurodegenerative diseases, including Alzheimer's disease (AD). However, it remains unclear to what extent extracellular vesicles (EVs) proteomes reflect the molecular states and disease-associated alterations of their parent brain cell types. Here, using a multi-line human induced pluripotent stem cell (hiPSC) platform derived from three AD and three cognitively normal (CN) donors, we generated neurons, astrocytes, microglia, and oligodendrocytes, and performed paired proteomic profiling of each cell type and its secreted EVs. We systematically compared protein profiles to evaluate cell-EV similarity, disease-associated features, and concordance with proteomic datasets from human AD brain tissue. Across all four lineages, EV proteomes showed extensive overlap with parent cells (>97% overlap; Jaccard index: 0.69-0.80) while also displaying lineage-specific functional biases. Under AD versus CN comparisons, EVs exhibited larger effect sizes and retained a higher number of differentially expressed proteins (DEPs) when applying the same fold-change criteria, yielding clearer AD-CN separation than their parent cells. Importantly, EV DEPs showed higher concordance with human AD brain proteomic signatures (EVs: 2,134 DEPs; cells: 816 DEPs). Finally, amyloid precursor protein (APP)-derived peptides, including amyloid-β (Aβ), were preferentially enriched in neuron- and oligodendrocyte-derived EVs, and AD EVs showed elevated Aβ42, p-Tau217 and p-Tau181 relative to CN EVs. Together, these data indicate that cell type-resolved EV proteomes largely recapitulate parent cell identity while sensitively capturing AD-relevant molecular alterations, supporting EV-based strategies for early diagnosis and monitoring of AD and potentially other neurodegenerative disorders.},
}

@article {pmid42113634,
year = {2026},
author = {Dahdah, A and de Silva, NH and Blanch, EW and Maniam, S},
title = {Spirooxindoles as Disruptors of Preformed Hen Egg White Lysozyme Fibrils as a Model for Neurodegenerative Diseases.},
journal = {ChemMedChem},
volume = {21},
number = {9},
pages = {e202501106},
doi = {10.1002/cmdc.202501106},
pmid = {42113634},
issn = {1860-7187},
support = {//RMIT University/ ; },
mesh = {*Muramidase/metabolism/chemistry/antagonists & inhibitors ; Animals ; *Neurodegenerative Diseases/metabolism/drug therapy ; *Spiro Compounds/chemistry/pharmacology/chemical synthesis ; *Oxindoles/chemistry/pharmacology ; Chickens ; Molecular Structure ; *Indoles/chemistry/pharmacology/chemical synthesis ; Spirooxindoles ; },
abstract = {Formation of fibrils from the misfolding of proteins has been associated with being the root cause of many neurodegenerative diseases. The highly ordered structure of fibrils formed from stacked β-sheet, makes the deposition of the structures and resultant development of neurodegeneration extremely difficult to treat. The importance of effective treatments against these conditions led to the highlighted study. Synthesized spirooxindole compounds labeled Hd-63, Hd-66, and Hd-74, indicated potent abilities to perturb the structure of hen egg white lysozyme (HEWL) fibrils. The spectroscopic analyses, centered around the use of Raman spectroscopy and the changes in key protein marker bands, known as the amide I and amide III bands, show that the addition of Hd-63, Hd-66, and Hd-74 to solutions of preformed HEWL fibrils leads to morphological changes that indicate a breakdown of the highly ordered β-sheet scaffold, and result in the formation of highly disordered aggregates, which do not suggest a fibril-like nature. The formation of these disordered aggregates suggests the progression in the mechanism of fibrillation away from the saturation of fibrils in solution and instead toward the formation of off-pathway oligomers.},
}

*Muramidase/metabolism/chemistry/antagonists & inhibitors
Animals
*Neurodegenerative Diseases/metabolism/drug therapy
*Spiro Compounds/chemistry/pharmacology/chemical synthesis
*Oxindoles/chemistry/pharmacology
Chickens
Molecular Structure
*Indoles/chemistry/pharmacology/chemical synthesis
Spirooxindoles

@article {pmid42113655,
year = {2026},
author = {Song, X and Wang, K and Li, M and Xu, S and Liu, Q},
title = {Structure-Semantic Guided MRI-to-PET Synthesis with Spatial-Frequency Discriminator.},
journal = {IEEE journal of biomedical and health informatics},
volume = {PP},
number = {},
pages = {},
doi = {10.1109/JBHI.2026.3692268},
pmid = {42113655},
issn = {2168-2208},
abstract = {Multi-modal medical imaging plays a vital role in clinical decision-making by providing complementary anatomical and functional information. In particular, the combination of Magnetic Resonance Imaging (MRI) and Positron Emission Tomography (PET) offers synergistic insights for early diagnosis and progression monitoring of Alzheimer's disease (AD). However, PET's clinical utility remains constrained by high cost, radiation exposure, and limited availability. To address these limitations, we propose a novel adversarial framework for synthesizing clinically plausible PET representations from structural T1-weighted MRI. Specifically, we design a Multi-scale Structural Representation Injection (MSRI) module to overcome structural misalignments in diagnostically sensitive regions, which is achieved by hierarchical anatomical encoding integrated with axis-aware attention. Building upon this foundation, the Adaptive Semantic Residual Fusion (ASRF) module bridge the semantic inconsistencies between locally extracted Res2Net features and globally encoded Transformer representations via dual-attention gating. Furthermore, the Direction-Aware Spatial-Frequency Discriminator (DASFD) ensures anatomical fidelity by incorporating reconstruction-guided priors and multi-domain discrimination across spatial, frequency, and patch-level pathways. Extensive experiments demonstrate that the proposed method consistently produces high-fidelity PET (SSIM: 90.66%, PSNR: 26.35 dB), surpassing existing methods in both quantitative accuracy and visual realism.},
}

@article {pmid42113681,
year = {2026},
author = {Wang, S and Yuan, X and Wang, T and Yang, M and Dong, P and Han, H},
title = {Mechanisms and Therapeutic Targeting of the GutMicrobiota-Immune-Brain Axis in Alzheimer's Disease.},
journal = {Immunological investigations},
volume = {},
number = {},
pages = {1-31},
doi = {10.1080/08820139.2026.2669375},
pmid = {42113681},
issn = {1532-4311},
abstract = {BACKGROUND: Alzheimer's disease (AD) is a highly prevalent neurodegenerative disease globally. The main pathological features of AD are amyloid-β (Aβ) deposition and tau hyperphosphorylation. Recent studies suggest that the gut microbiota-immunity-brain axis plays an important role in the onset and progression of AD. Gut microbiota dysbiosis may impair intestinal barrier integrity and promote the entry of pro-inflammatory mediators into the circulation. Pro-inflammatory signals in the bloodstream may further activate the central immune system, drive microglial polarization, and increase the release of inflammatory factors in the brain. The resulting neuroinflammatory cascade may aggravate Aβ accumulation, tau phosphorylation, and cognitive impairment, although this mechanism has not been conclusively established in humans.

METHODS AND RESULTS: Based on relevant literature on AD, gut microbiota, immunity, neuroinflammation, and the gut-brain axis, this article systematically reviews the mechanism of action of the microbiota-immunity-brain axis in AD. Current intervention strategies targeting this axis, including probiotics, fecal microbiota transplantation, dietary interventions, and traditional Chinese medicine, were also discussed. Such intervention measures have the potential to regulate the balance of the gut microbiota, reduce neuroinflammation, and slow the progression of AD pathology.

CONCLUSION: It is essential to integrate multi-omics approaches in future research to deepen the understanding of AD pathogenesis and support the development of more precise and personalized treatment strategies.},
}

@article {pmid42113787,
year = {2026},
author = {Sun, R and Wang, J and Liu, S and Tian, H and Wang, X and Zhang, Y},
title = {Imaging Strategies for Acupuncture Intervention in Alzheimer's Disease Model Mice.},
journal = {Journal of visualized experiments : JoVE},
volume = {},
number = {230},
pages = {},
doi = {10.3791/70998},
pmid = {42113787},
issn = {1940-087X},
mesh = {*Alzheimer Disease/therapy/diagnostic imaging/metabolism ; Animals ; Mice ; Disease Models, Animal ; *Positron-Emission Tomography/methods ; Amyloid beta-Peptides/metabolism/analysis ; Brain/diagnostic imaging/metabolism ; *Acupuncture Therapy/methods ; Mice, Transgenic ; *Electroacupuncture/methods ; },
abstract = {Alzheimer's disease (AD) is a neurodegenerative disorder primarily characterized by progressive cognitive dysfunction. One of its typical pathological features is the formation of senile plaques in the brain due to the deposition of β-amyloid (Aβ) proteins. Acupuncture has demonstrated potential in clinical practice for improving cognitive function in AD patients. However, its dynamic effects on Aβ pathology require objective elucidation through modern technological approaches. Micro-positron emission tomography (micro-PET) provides a powerful tool for in vivo, non-invasive observation of Aβ deposition in the brains of AD model mice. In this protocol, we detail an imaging strategy utilizing [18F]AV-45 micro-PET to assess the effects of electroacupuncture intervention, complemented by Morris Water Maze behavioral testing and Western blot molecular analysis. The integrated approach enables the visualization and quantification of Aβ pathological progression in the brains of AD model mice. This provides objective and quantitative evidence to explore the regulatory effect of acupuncture on Aβ deposition. By integrating traditional Chinese medicine principles with modern molecular imaging and molecular biology technologies.},
}

*Alzheimer Disease/therapy/diagnostic imaging/metabolism
Animals
Mice
Disease Models, Animal
*Positron-Emission Tomography/methods
Amyloid beta-Peptides/metabolism/analysis
Brain/diagnostic imaging/metabolism
*Acupuncture Therapy/methods
Mice, Transgenic
*Electroacupuncture/methods

@article {pmid42114333,
year = {2026},
author = {Orlof, W and Maciejczyk, M},
title = {Protein glycoxidation in neuropsychiatric disorders-from basic research to clinical practice.},
journal = {Redox biology},
volume = {94},
number = {},
pages = {104190},
doi = {10.1016/j.redox.2026.104190},
pmid = {42114333},
issn = {2213-2317},
abstract = {This review integrates current findings on protein glycation, glycoxidation, and carbonyl stress in selected neurodegenerative and neuropsychiatric disorders, with a particular focus on mechanistic pathways relevant to Alzheimer's disease (AD), Parkinson's disease (PD), schizophrenia, and depression, as well as on their potential clinical relevance, including biomarker development and antiglycation interventions. These processes are increasingly recognised as cross-cutting features in various neuropsychiatric conditions. Despite this mechanistic relevance, no neuropsychiatric drugs have been convincingly demonstrated to exert direct antiglycation activity in vivo. The majority of published findings concern indirect modulation of carbonyl stress, redox imbalance, and advanced glycation end products (AGEs) and their receptor (RAGE) signalling rather than direct inhibition of glycation. AGEs, particularly the lysine-derived adducts Nε-(carboxyethyl)lysine (CEL) and Nε-(carboxymethyl)lysine (CML), show potential as diagnostic and prognostic biomarkers in neurodegenerative diseases, although further clinical validation is required. Modulation of protein glycation, carbonyl stress, and AGE-RAGE signalling has emerged as a common mechanistic denominator in various therapeutic strategies explored in neuropsychiatric disorders.},
}

@article {pmid42114417,
year = {2026},
author = {Liu, D and Talevi, V and Tavares, JF and Wang, R and Imtiaz, MA and Melas, K and Teumer, A and Wittfeld, K and Hillary, RF and Vojinovic, D and Beekman, M and Armstrong, NJ and Estrada, S and Völzke, H and Bülow, R and Royle, NA and Wardlaw, JM and Wen, W and Sachdev, PS and Mather, KA and Slagboom, PE and Cox, SR and Grabe, HJ and Yang, Q and Aziz, NA and Breteler, MMB},
title = {DNA methylation signatures of bilateral hippocampal volume, asymmetry and atrophy: a cross-omics analysis in the general population.},
journal = {EBioMedicine},
volume = {128},
number = {},
pages = {106289},
doi = {10.1016/j.ebiom.2026.106289},
pmid = {42114417},
issn = {2352-3964},
abstract = {BACKGROUND: Left-right hippocampal volumetric asymmetry and atrophy are implicated in neurodegenerative and neuropsychiatric disorders, yet their molecular basis in healthy adults remains poorly understood.

METHODS: We conducted a meta-analysis of epigenome-wide association studies across six population-based cohorts (n = 8156; 53% women; mean age = 60.7 years) to identify DNA methylation signatures associated with left and right hippocampal volumes (LHCV, RHCV) and hippocampal asymmetry (i.e, differences between left and right volumes divided by their sums).

FINDINGS: We identified five CpGs and 262 differentially methylated regions associated with LHCV, nine CpGs and 246 regions with RHCV, one CpG and 16 regions with asymmetry. Cross-omics integration uncovered 15 LHCV-related and 13 RHCV-related methylation-gene expression pairs, with five overlapping genes primarily involved in immune regulation. LHCV-specific genes were involved in cellular signalling, and Mendelian randomisation (MR) analyses supported a potential causal association between brain expression of DIP2C and increased risk of major depressive disorder. RHCV-specific genes were involved in neuronal differentiation pathways, with MR analyses suggesting that brain-tissue expression of BAIAP2, MACF1, SLC16A5, and CORO1B was associated with neuropsychiatric disorders. We also identified sex-specific patterns with hippocampal asymmetry. Notably, baseline methylation at these sites predicted hippocampal atrophy rates, explaining >10% of the variation. Associations with multiple healthy dietary patterns suggest modifiable influences on hippocampal structure.

INTERPRETATION: These findings highlight distinct methylation profiles as potential biomarkers or therapeutic targets for neuropsychiatric and neurodegenerative conditions.

FUNDING: Institutional funds, Federal Ministry of Education and Research of Germany, Alzheimer's Association.},
}

@article {pmid42103698,
year = {2026},
author = {Gerónimo-Olvera, C and Scheeler, SM and Aguirre, CG and Vega-Hormazabal, G and Garcia, D and Wu, L and Murad, N and Schneider, K and Wilson, KA and Markov, NT and Song, S and Simons, J and Gerencser, AA and Parlan, E and Mooney, SD and Verdin, E and Campisi, J and Tracy, TE and Furman, D and Melov, S and Ellerby, LM},
title = {Exceptional Longevity Modifying Allele APOE2 Promotes DNA Signaling Pathways Resisting Cellular Senescence in Human Neurons.},
journal = {Aging cell},
volume = {25},
number = {5},
pages = {e70494},
pmid = {42103698},
issn = {1474-9726},
support = {1RO1AG061879/AG/NIA NIH HHS/United States ; 5P01AG066591/AG/NIA NIH HHS/United States ; T32 AG000266/AG/NIA NIH HHS/United States ; //Paul F. Glenn Center for Biology of Aging/ ; //CatalystX award from Alex and Bob Griswood/ ; },
mesh = {Humans ; *Apolipoprotein E2/genetics/metabolism ; *Cellular Senescence/genetics ; *Signal Transduction/genetics ; *Longevity/genetics ; *Neurons/metabolism ; Alleles ; Animals ; DNA Damage ; Mice ; Induced Pluripotent Stem Cells/metabolism ; Apolipoprotein E4/genetics ; DNA Repair ; Alzheimer Disease/genetics ; },
abstract = {Genome-wide association studies (GWAS) have identified APOE2 allele as linked to exceptional longevity, with carriers exhibiting a reduced risk of Alzheimer's disease (AD). Apolipoprotein E (APOE), a glycoprotein involved in lipid transport, has three major alleles. However, alterations in lipid metabolism alone do not fully explain APOE2's protective effects. In contrast, APOE4 is the strongest genetic risk factor for AD. To investigate how APOE2 promotes neuronal longevity and confers neuroprotection, we generated human isogenic APOE iPSC-derived models of both inhibitory GABAergic and excitatory neurons. In GABAergic neurons, APOE alleles differentially influenced endogenous DNA damage, DNA repair, and neuronal motility. Single-cell RNA sequencing revealed APOE4-specific gene expression signatures associated with AD, whereas APOE2 GABAergic neurons were enriched for DNA repair and signaling pathways. Consistent with this, APOE2 neurons exhibited significantly lower levels of DNA damage. APOE4 GABAergic neurons exhibit increased expression of repetitive ribosomal RNA, which is associated with DNA damage and cellular senescence. To determine whether the effects extended to excitatory neurons, we used a separate human model of Ngn2-induced glutamatergic neurons, and found that APOE2 excitatory neurons were more resistant to cellular senescence and DNA damage than isogenic APOE3 and APOE4 neurons. Similarly, we found human APOE2-targeted replacement mice exhibited less nucleolar enlargement and increased nuclear Lamin A/C, Hmgb1, and H3K9me3 compared to APOE4 counterparts. Together, our findings identify DNA repair and suppression of senescence-associated processes as key mechanisms by which APOE2 is associated with neuronal resilience, providing mechanistic insight into its association with exceptional longevity and protection against AD.},
}

Humans
*Apolipoprotein E2/genetics/metabolism
*Cellular Senescence/genetics
*Signal Transduction/genetics
*Longevity/genetics
*Neurons/metabolism
Alleles
Animals
DNA Damage
Mice
Induced Pluripotent Stem Cells/metabolism
Apolipoprotein E4/genetics
DNA Repair
Alzheimer Disease/genetics

@article {pmid42104415,
year = {2026},
author = {Malorny, N and Chausse, B and Khodaie, B and Elgez, A and Söder, L and Lewen, A and Egorov, AV and Kann, O},
title = {TNF-α and IFN-γ impair neural oscillations and induce neurodegeneration by microglial nitric oxide, metabolic and oxidative stress.},
journal = {Journal of neuroinflammation},
volume = {},
number = {},
pages = {},
doi = {10.1186/s12974-026-03835-x},
pmid = {42104415},
issn = {1742-2094},
abstract = {BACKGROUND: The cytokine tumor necrosis factor-alpha (TNF-α) regulates inflammatory responses in infectious and neurodegenerative diseases and also affects neuronal function. The role of TNF-α in the activation of microglial cells (resident central nervous system macrophages), including the impact on neuronal survival, excitability, and synaptic transmission is incompletely defined, however. We explored the effects of chronic TNF-α exposure (72 h) on microglia and neurons in organotypic hippocampal slice cultures from male and female rats, i.e., postnatal cortex tissue lacking leukocyte invasion and adaptive immunity.

METHODS: We applied gene expression analysis, biochemical assays, immunohistochemistry, electrophysiology by extracellular (local field potential) and intracellular (intrinsic membrane properties) recordings, and pharmacological ablation of the microglial cell population. We mainly focused on carbachol-induced neural network oscillations (brain waves) in the gamma frequency band (30-70 Hz) that underlie higher cognitive functions such as perception, attention, and memory.

RESULTS: TNF-α induced microglial proliferation and upregulation of genes related to inflammation and oxidative stress such as Il6 (interleukin-6), Nos2 [inducible nitric oxide (NO) synthase, iNOS] and Sod2 (superoxide dismutase 2), which was accompanied by a decreased number of slices showing gamma oscillations in extracellular recordings. Notably, a fraction of slices presented neural bursting reflecting hyperexcitability in the tissue. Neuronal dysfunction was absent during acute TNF-α exposure (30 min). When paired with the lymphocyte cytokine interferon-gamma (IFN-γ), TNF-α induced an amplified neuroinflammation response dominated by bursting or loss of electrical activity. In intracellular recordings, neurons showed a brief burst of action potentials followed by slowing of spiking with pronounced afterhyperpolarization (switch from regular to burst firing behavior) during depolarizing current injection. Notably, the impairments could be attenuated by inhibition of iNOS and NADPH oxidase, glucose supplementation, microglial depletion or blockade of TNF receptor 1 (TNFR1) signaling with small molecule drugs, RIPA-56 and ICCB-19.

CONCLUSIONS: Our data provide mechanistic insight into TNF-α- and IFN-γ-induced neuronal impairments mediated by microglial NO, metabolic and oxidative stress, and demonstrate functional neuroprotection by pharmacology. Our study extends the pathophysiological understanding of diseases such as sepsis, multiple sclerosis, Alzheimer's disease, depression and schizophrenia featuring activated microglia, infiltrating monocytes and T cells, and/or blood-brain barrier leakage.},
}

@article {pmid42104459,
year = {2026},
author = {Comas-Albertí, A and Lladó, A and Esteller-Gauxax, D and Borrego-Écija, S and Falgàs, N and Dakterzada, F and Pérez-Millan, A and Puey, R and Collet-Romà, T and Guillén, N and Massons, M and Tort-Merino, A and Augé, JM and Fernandez-Villullas, G and Bosch, B and Ruiz-García, R and Naranjo, L and Balasa, M and Piñol-Ripoll, G and Antonell, A and Sánchez-Valle, R},
title = {Proteomic analysis in Alzheimer's disease and other dementias: a focus on sex-specific differences.},
journal = {Alzheimer's research & therapy},
volume = {},
number = {},
pages = {},
doi = {10.1186/s13195-026-02068-7},
pmid = {42104459},
issn = {1758-9193},
support = {PI23/00173//Instituto de Salud Carlos III/ ; JR22/00014//Instituto de Salud Carlos III/ ; Joan Rodés-Josep Baselga grant//Fundación BBVA/ ; polAris project//Fundació Rosa Maria Vivar/ ; polAris project//Fundació Rosa Maria Vivar/ ; SGR 2021-01126//Generalitat de Catalunya/ ; },
abstract = {BACKGROUND: Fluid protein studies in cerebrospinal fluid (CSF) and plasma have provided important insights into neurodegenerative dementias; however, there is a limited investigation of sex-related differences and cross-biofluid relationships. In Alzheimer's disease (AD), Lewy body dementia (LBD), and frontotemporal dementia (FTD), large-scale, sex-stratified analyses of paired CSF and plasma samples remain scarce. Using the multiplex and ultrasensitive capabilities of NULISAseq™ technology, this study aims to characterize sex- and disease-specific proteomic alterations associated with Central Nervous System (CNS) pathology to explore underlying mechanisms.

METHODS: CSF and plasma samples from 359 individuals with AD, LBD, FTD, and cognitively healthy controls were analyzed using the NULISAseq™ CNS Disease Panel 120. Differential protein expression analyses were conducted across diagnoses and stratified by sex, adjusting for relevant covariates. Spearman's correlation analyses were performed to assess concordance between CSF and plasma protein levels. All statistical analyses were conducted in R v4.4.3.

RESULTS: Differential protein expression analyses across diagnoses revealed two potential transdiagnostic biomarkers: ICAM1 in CSF and ANXA5 in plasma, showing consistent increases across AD, LBD, and FTD. Sex-stratified analyses in CSF showed modest changes, including higher CCL26, ANXA5, and IL10 in females with AD, and higher IL9, PRDX6, and CX3CL1 in males with AD. In LBD, females exhibited upregulation of ACHE, SFRP1, POSTN in both CSF and plasma. NPTX1 was identified as a potential CSF biomarker for FTD, showing downregulation particularly in males. In contrast, analyses stratified by sex in plasma displayed a larger number of proteins across all dementias, with females showing a higher number of upregulated inflammation-related proteins predominantly involved in cytokine signaling. Overall cross-fluid correlations were restricted to a small subset of proteins, indicating compartment-specific regulation.

CONCLUSIONS: This study represents a large-scale, sex-stratified proteomic analysis of CSF and plasma across major neurodegenerative dementias using NULISAseq™ technology. The findings highlight sex-dependent biomarker patterns, particularly in plasma, and underscore the importance of incorporating sex as a biological variable in dementia research. Future studies should validate candidate proteins in independent cohorts, investigate their functional and mechanistic roles, and assess their utility for biomarker development and sex-tailored therapeutic strategies.},
}

@article {pmid42104633,
year = {2026},
author = {Martínez-Tazo, P and Mejias-Ortega, M and López-López, V and Bhojwani-Cabrera, AM and Saxton, E and Canals, S and Hardingham, G and Gutierrez, A and Lopez-Atalaya, JP and De Santis, S},
title = {Multiscale Approximations to Understand the Complex Role of Microglia in Alzheimer's Disease.},
journal = {The European journal of neuroscience},
volume = {63},
number = {9},
pages = {e70536},
pmid = {42104633},
issn = {1460-9568},
support = {2023-1296//Fundacion Pasqual Maragall/ ; PI24/00274//Instituto de Salud Carlos III/ ; PROMETEO 2020/007//Generalitat Valenciana/ ; CIESGT/2025/06//Generalitat Valenciana/ ; CIDEGENT/2021/015//Generalitat Valenciana/ ; CIPROM/2022/15//Generalitat Valenciana/ ; PID2021-129053OB-I00//Ministerio de Ciencia e Innovación/ ; PID2021-128909NA-I00//Ministerio de Ciencia e Innovación/ ; CNS2023-144883//Ministerio de Ciencia e Innovación/ ; RTI2018-102260-B-I00//Ministerio de Ciencia e Innovación/ ; PID2021-128158NB-C21//Ministerio de Ciencia e Innovación/ ; PID2024-162400OB-C21//Ministerio de Ciencia e Innovación/ ; PCI2024-153491//Ministerio de Ciencia e Innovación/ ; //UK Dementia Research Institute/ ; CTS950-G-FEDER//Junta de Andalucía/ ; CEX2021-001165-S//Programa para Centros de Excelencia en I+D Severo Ochoa/ ; FPU20/05737//Spanish Ministry/ ; },
mesh = {*Microglia/pathology/metabolism/immunology/physiology ; *Alzheimer Disease/pathology/immunology/metabolism ; Humans ; Animals ; *Brain/pathology/immunology ; },
abstract = {Microglia, the resident innate immune cells of the central nervous system, play a pivotal role in the pathogenesis of Alzheimer's disease (AD). Microglia are now recognized as a highly dynamic and heterogeneous population whose molecular and functional states vary with spatial context, disease stage, and genetic background. Recent discoveries across multiple scales from genetics, molecular and cellular biology, to systems-level imaging and epidemiology have underscored the complex and context-dependent contributions of microglia to the AD cascade. Together, these findings highlight the need for integrative, multiscale approaches that bridge molecular, cellular, and systemic perspectives to elucidate the diverse roles of microglia and their impact on disease progression. This mini-review discusses recent advances in understanding microglial biology across these dimensions and outlines current challenges toward achieving a more unified and therapeutically oriented framework for studying microglia in AD.},
}

*Microglia/pathology/metabolism/immunology/physiology
*Alzheimer Disease/pathology/immunology/metabolism
Humans
Animals
*Brain/pathology/immunology

@article {pmid42104655,
year = {2026},
author = {Sharmin, T and Doecke, JD and Chatterjee, P and Pedrini, S and Sohrabi, HR and Ashton, NJ and Zetterberg, H and Garg, ML and Blennow, K and Martins, RN},
title = {Circulating Sphingomyelins Correlate With Plasma T-Tau in Cognitively Unimpaired Older Adults at Risk of Developing Alzheimer's Disease.},
journal = {Journal of neurochemistry},
volume = {170},
number = {5},
pages = {e70436},
pmid = {42104655},
issn = {1471-4159},
support = {2018-02532//MQ Research Seeding Grant, Macquarie University/ ; 681712//MQ Research Seeding Grant, Macquarie University/ ; 201809-2016862//MQ Research Seeding Grant, Macquarie University/ ; 2017-00915//MQ Research Seeding Grant, Macquarie University/ ; FO2017-0243//MQ Research Seeding Grant, Macquarie University/ ; JPND2019-466-236//MQ Research Seeding Grant, Macquarie University/ ; //Macquarie University HDR Fund, Macquarie University/ ; 101053962//European Union's Horizon Europe research and innovation programme/ ; 2019-02397//Swedish Research Council/ ; },
mesh = {Humans ; Female ; Aged ; *tau Proteins/blood ; Male ; *Alzheimer Disease/blood/diagnostic imaging/psychology ; *Sphingomyelins/blood ; Cross-Sectional Studies ; Positron-Emission Tomography ; Aged, 80 and over ; Biomarkers/blood ; Amyloid beta-Peptides/metabolism ; Cognition/physiology ; Cohort Studies ; },
abstract = {Alterations in plasma sphingomyelin (SM) levels have been reported in Alzheimer's disease (AD), pointing to disturbances in lipid metabolism that may contribute to disease pathogenesis. Neuronal damage in early AD triggers tau release into central and peripheral systems. Despite influence from peripheral contributions, alterations in plasma total-tau (T-tau) remain valuable in indicating AD-related neurodegeneration. Investigating relationships between SM metabolism and tau release during preclinical AD may uncover important biochemical processes and support advancing early non-invasive detection and treatment approaches. This cross-sectional study investigated cognitively unimpaired (CU) older adults from the KARVIAH cohort, grouped by cortical amyloid-β (Aβ) status through positron emission tomography (PET) imaging (CU Aβ- and CU Aβ+) and utilised a Biocrates-targeted metabolomic platform and Single-molecule array (Simoa) technology to quantify plasma levels of SMs and T-tau, respectively. Associations between circulating SMs and T-tau were examined within each group, with T-tau-associated SMs further evaluated for their association with cognitive performance and cortical Aβ burden and their potential to discriminate CU Aβ+ from CU Aβ- individuals. Significant positive correlations were observed between SMs and T-tau levels exclusively in CU Aβ+ individuals, suggesting connections between SM-mediated biochemical pathways and tau release from early neurodegeneration in preclinical AD. Lower SM levels were associated with weaker working memory and executive function, as well as poorer global cognition, indicating their potential predictive value for weaker cognitive performance. Moreover, SMs were also inversely associated with cortical Aβ load in CU Aβ+ individuals, possibly reflecting early SM-mediated neuroprotective responses against AD pathogenesis. Receiver operating characteristic analysis further revealed the significant potential of the SM panel in distinguishing cortical PET-Aβ status and enhancing the predictive performance of plasma T-tau in CU individuals. Therefore, circulating T-tau-associated SMs may serve as promising early biomarkers of lipid-mediated processes in CU older adults with cortical amyloid pathology and tau-related neurodegeneration.},
}

Humans
Female
Aged
*tau Proteins/blood
Male
*Alzheimer Disease/blood/diagnostic imaging/psychology
*Sphingomyelins/blood
Cross-Sectional Studies
Positron-Emission Tomography
Aged, 80 and over
Biomarkers/blood
Amyloid beta-Peptides/metabolism
Cognition/physiology
Cohort Studies

@article {pmid42104711,
year = {2026},
author = {Hao, X and Jiao, B and Wang, Y and Xu, T and Yang, Q and Zhu, Y and Liu, Y and Zhang, C and Liang, X and Zhou, Y and Liao, X and Luo, S and Tang, B and Li, J and Xiao, X and Shen, L},
title = {Association of mitochondrial genome variants with Alzheimer's disease in a Chinese population.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261442231},
doi = {10.1177/13872877261442231},
pmid = {42104711},
issn = {1875-8908},
abstract = {BackgroundResearch on the mitochondrial genome variants of Alzheimer's disease (AD) in Chinese populations is lacking.ObjectiveThe study aimed to identify mitochondrial DNA (mtDNA) variants associated with AD risk and explore the relationship between mtDNA variants and plasma biomarkers in AD patients.MethodsWhole genome sequencing was performed in 1509 AD patients and 2010 controls from the Chinese population. mtDNA variants were called according to GATK's best practice mitochondrial pipeline. We evaluated the association of AD risk with mtDNA variants and mitochondrial haplogroup. Common variant (MAF≥0.01) based association analysis and gene-based tests of rare variants (MAF<0.01) were carried out with PLINK 1.9 and SKAT-O, respectively. Spearman correlation analysis was performed to assess the association between the burden of mtDNA variants and plasma biomarker levels.ResultsThe frequency of mitochondrial haplogroup G in AD group was nominally higher than control group (p = 0.019, OR = 1.48). Rare variants of MT-CYB gene were significantly enriched in controls compared to AD patients (p = 2.81 × 10[-4], OR = 0.886). Besides, the control group exhibited considerably lower mRNA expression of MT-CYB in brain regions compared to AD patients in GEO database. Furthermore, the number of mtDNA indel variants per individual correlated positively with plasma Aβ42 levels.ConclusionsMitochondrial haplogroup G may serve as a risk factor for AD, while rare variants of MT-CYB gene acted as protective factor against AD in mainland China. Moreover, mtDNA variants were related to AD plasma biomarker levels. Our findings highlighted the role of mitochondrial genome variants in the pathogenesis of AD.},
}

@article {pmid42104715,
year = {2026},
author = {Tang, Q and Liu, J and Fan, C and Zhang, X and Zhang, C and Qi, H},
title = {Early diagnosis of Alzheimer's disease through handwriting analysis and deep learning: A review.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261446573},
doi = {10.1177/13872877261446573},
pmid = {42104715},
issn = {1875-8908},
abstract = {Alzheimer's disease (AD) is one of the most prevalent neurodegenerative disorders worldwide, requiring early identification for timely intervention and to slow disease progression. However, existing diagnostic approaches, while effective at later stages, remain limited in detecting early-stage AD. Handwriting analysis has recently emerged as a non-invasive, cost-effective, and ecologically valid digital behavioral biomarker that reflects neurocognitive impairment. This review examines the role of handwriting as a neurocognitive marker for AD, focusing on integrating deep learning methodologies to enhance early diagnostic accuracy. It also elucidates the neurocognitive mechanisms linking handwriting behavior and AD, addressing current methodological and translational challenges. We performed a PRISMA-informed structured literature search and narrative synthesis of handwriting- and drawing-based studies for detecting AD/mild cognitive impairment (MCI), including offline handwriting images and online pen-stroke kinematics captured by digital devices. Task paradigms, data dimensions, preprocessing pipelines, modeling strategies (traditional machine learning and deep learning), evaluation practices, and translational considerations were summarized, and studies were organized by detection purpose and analytic approach. Our findings show that handwriting-based models generally discriminate AD/MCI from healthy controls with accuracy exceeding 80%, while deep learning models (e.g., convolutional neural network and multimodal Transformer fusion) approach 90% in structured tasks like clock drawing and figure copying. Online kinematic markers (e.g., reduced velocity, prolonged in-air time, increased pausing, and pressure instability) recur across studies, and multimodal integration with speech, gait, or facial signals can further improve sensitivity and ecological validity, although most studies are small and single-center.},
}

@article {pmid42104723,
year = {2026},
author = {Keret, O and Xia, T and Wilkins, S and Ncube, LNL and Smaw, B and Xiong, Y and Gandy, S and Pereira, A and Georges, N and Elahi, FM},
title = {Real-world clinical profile of individuals with cerebrospinal fluid Aβ[-]/pTau181.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261445561},
doi = {10.1177/13872877261445561},
pmid = {42104723},
issn = {1875-8908},
abstract = {BackgroundCerebrospinal fluid (CSF) pTau181 is used to support Alzheimer's disease (AD) diagnosis but can also rise in amyloid-negative individuals. This CSF profile (Aβ[-]/pTau181[+]) lies outside the AD continuum and complicates real-world etiologic diagnosis of neurocognitive disorders.ObjectiveTo determine the prevalence and clinical phenotype associated with the Aβ[-]/pTau181[+] CSF biomarker profile in a real-world memory clinic population.MethodsWe screened the Mount Sinai Hospital database (2015-2024) for patients who underwent ADmark CSF biomarker testing. An Aβ[-]/pTau181[+] group was classified using assay cutoffs (Amyloid-Total-Tau Index>1.2, pTau181 > 54 pg/mL) and compared to an Aβ[+] group (Amyloid-Total-Tau Index<0.8) matched for pTau181 and total-Tau. Clinical variables were extracted via chart review, limited to notes preceding CSF and blinded to CSF results.ResultsThe Aβ[-]/pTau181[+] group included 25 individuals (10.1% of the cohort) and had equally impaired cognition but fewer episodic memory complaints. Diagnosis was more often Lewy body or frontotemporal dementia. On neuroimaging, Aβ[-]/pTau181[+] exhibited less white matter hyperintensity burden and temporoparietal atrophy.ConclusionsCSF Aβ[-]/pTau181[+] is frequent in real-world evaluations of cognitive impairment and presents with fewer AD phenotypic features. Further research is required to clarify Aβ[-]/pTau181[+] underlying biology and clinical trajectory.},
}

@article {pmid42104729,
year = {2026},
author = {Si, K and Sun, C and Guo, H and Shi, C and Wang, Y},
title = {Association between the Dietary Index for Gut Microbiota and cognitive function among older adults in the United States.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261449420},
doi = {10.1177/13872877261449420},
pmid = {42104729},
issn = {1875-8908},
abstract = {BackgroundThe Dietary Index for Gut Microbiota (DI-GM) is a novel index reflecting diet quality relative to gut microbiota health.ObjectiveThe study aims to investigate the relationship between DI-GM and cognitive function in older adults.MethodsData were obtained from 2629 participants aged ≥60 years in the National Health and Nutrition Examination Surveys (NHANES) (2011-2014). Cognitive function was assessed using the Consortium to Establish a Registry for Alzheimer's Disease (CERAD), the Animal Fluency Test (AFT), the Digit Symbol Substitution Test (DSST), and a global z score. Multivariable linear regression, restricted cubic splines (RCS), and subgroup analysis were performed. Predictive utility of DI-GM was assessed via the receiver operating characteristic (ROC) analysis against a baseline model. Mediation analysis examined relationships among DI-GM, the Dietary Inflammatory Index (DII), and cognitive outcomes.ResultsHigher DI-GM was associated with higher AFT, DSST, and the global z scores (p < 0.001). After full adjustment, participants with DI-GM (≥ 6) showed higher AFT score (β = 1.11, 95% CI 0.46∼1.75), DSST score (β = 4.95, 95% CI 3.05∼6.86) and z score (β = 0.19, 95% CI 0.10∼0.28), compared to those with DI-GM (0-3). No significant direct association was observed with CERAD (β = 0.45, 95% CI -0.29∼1.18, p = 0.233). RCS indicated linear relationships between DI-GM and cognitive function scores. DI-GM had excellent predictive performances based on the ROC. No significant interactions were detected by subgroup analysis. Furthermore, DII partly mediated the relationship between DI-GM and cognitive function.ConclusionsThe DI-GM showed a linear positive correlation with cognitive function in older adults.},
}

@article {pmid42104730,
year = {2026},
author = {Panigrahi, B},
title = {A novel synaptic compartmentalization failure framework for neurodegeneration.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261449379},
doi = {10.1177/13872877261449379},
pmid = {42104730},
issn = {1875-8908},
abstract = {Synaptic plasticity relies on precise spatial and temporal compartmentalization of signaling within dendritic spines, presynaptic terminals, and axonal domains. This compartmentalization is usually reinforced through activity-dependent remodeling of spine geometry, cytoskeletal scaffolds, calcium handling, and local protein synthesis, allowing plasticity signals to remain localized and terminate appropriately. Here, a unifying framework is proposed in which neurodegenerative diseases emerge when the capacity to maintain and renew these compartments declines. Ageing and glial dysregulation may act as major biological drivers of this process by altering dendritic spine structure, calcium homeostasis, metabolic support, neurotransmitter clearance, and activity-dependent synaptic remodeling. In this state, plasticity induction remains largely preserved, but signaling becomes spatially diffuse and temporally prolonged, imposing chronic structural and energetic stress on synapses and axons. Proteins such as tau and alpha synuclein, which normally support cytoskeletal organization and dynamic phase separated assemblies, may become destabilized under these conditions leading to pathological aggregation. This framework provides an explanation for early synaptic dysfunction, selective neuronal vulnerability, long presymptomatic phases, network-level disease propagation, the protective effects of education and cognitive engagement, and the limited efficacy of proteinopathy centric therapeutic strategies. Neurodegeneration may be conceptualized as a failure of synaptic compartmentalization, with protein aggregation arising downstream of this primary vulnerability.},
}

@article {pmid42104731,
year = {2026},
author = {Tsotsoros, CE and Centeno Román, CA and Clark, AL and De Anda-Duran, I and Ajrouch, KJ and Vega, IE},
title = {Cognitive function in immigrants from Mexico and Latin America: The role of age at migration.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261446976},
doi = {10.1177/13872877261446976},
pmid = {42104731},
issn = {1875-8908},
abstract = {BackgroundLatino immigrants in the United States represent diverse national origins, with Mexicans comprising the largest group. Cognitive health disparities among Latino immigrants may reflect differences in migration experiences, including age at migration, socioeconomic differences, and acculturation. Whether Mexican immigrants differ from Latin American immigrants in cognitive outcomes remains unclear.ObjectiveThis study examined the independent and interactive effects of Mexican origin and age at migration on cognitive levels and decline compared to other Latin American immigrants. We also test whether socioeconomic and acculturation factors help explain differences in cognitive outcomes.MethodsData came from 2077 Latino immigrants in the Health and Retirement Study (2014-2020). Cognition was assessed using the Telephone Interview for Cognitive Status. Mixed-effects models evaluated the main and interaction effects of origins and age at migration on age-related decline, controlling for demographic, health-related, socioeconomic, and acculturation covariates.ResultsMexican immigrants had significantly lower cognitive levels than Latin American immigrants. However, after adjusting for socioeconomic indicators and language acculturation, Mexican immigrants demonstrated higher cognitive scores. Among Mexicans, late-life migration was associated with significantly poorer cognitive levels, which persisted after accounting for socioeconomic and acculturation factors. No significant differences were observed in rates of cognitive decline by origin or age at migration.ConclusionsLate-life migration is associated with poorer cognitive outcomes among Mexican immigrants. Findings indicate that socioeconomic and acculturation factors mask underlying differences in cognitive performance between Mexican and Latin American immigrants, underscoring the need to consider both migration experiences and social context when evaluating cognitive disparities.},
}

@article {pmid42104858,
year = {2026},
author = {He, Y and Xue, H and Bi, S and Wang, Y and Liu, X and Li, Y and Chen, Z and Rong, D and Cui, B and Ma, J and Yan, S and Lu, J},
title = {Correspondence of Basal Forebrain Resting-State Functional Connectivity and Cerebral Glucose Metabolism Alterations With Neurotransmitter Maps in Alzheimer's Disease.},
journal = {CNS neuroscience & therapeutics},
volume = {32},
number = {5},
pages = {e70901},
doi = {10.1002/cns.70901},
pmid = {42104858},
issn = {1755-5949},
support = {82394434//National Natural Science Foundation of China/ ; 62333002//National Natural Science Foundation of China/ ; HZ2025PYDTR006//Xuanwu Hospital Talent Convergence Program/ ; },
mesh = {Humans ; Male ; *Alzheimer Disease/metabolism/diagnostic imaging ; Female ; Aged ; *Glucose/metabolism ; *Neurotransmitter Agents/metabolism ; Positron-Emission Tomography ; Magnetic Resonance Imaging ; *Basal Forebrain/metabolism/diagnostic imaging ; Middle Aged ; Rest ; Aged, 80 and over ; },
abstract = {AIMS: To investigate alterations in basal forebrain (BF) subregional functional connectivity (FC), cerebral glucose metabolism, and their spatial correspondence with atlas-based neurotransmitter distributions in Alzheimer's disease (AD).

METHODS: Forty-two Aβ-PET-positive AD patients and forty-one matched healthy controls (HC) underwent simultaneous PET/MRI. We analyzed resting-state FC of BF subregions (Ch1-3, Ch4) and measured cerebral glucose metabolism using [18]F-FDG PET standardized uptake value ratio (SUVR). Spatial correlations with neurotransmitter maps were assessed using the JuSpace toolbox.

RESULTS: Compared with HC, AD patients showed decreased FC between the left Ch4 and hippocampus/posterior cingulate gyrus, and increased FC between the right Ch4 and precentral/postcentral gyrus. Additionally, AD patients showed increased FC between the left Ch1-3 and superior temporal gyrus/insula, decreased FC between the right Ch1-3 and the orbitofrontal gyrus, and increased FC between the right Ch1-3 and the left temporal lobe (voxel-level p < 0.001, cluster-level p < 0.05, GRF correction). These FC changes were spatially correlated with serotonergic (5HT1a, 5HT4, SERT) and dopaminergic (D1, D2, DAT) receptor distributions (p < 0.05, FDR corrected). Widespread cerebral hypometabolism in temporoparietal and frontal regions was spatially correlated with serotonin, dopamine, GABA, glutamate, and kappa-opioid systems (p < 0.05, FDR corrected).

CONCLUSION: The FC of BF and cerebral metabolic changes in AD show distinct spatial correspondence with specific neurotransmitter systems, highlighting the crucial involvement of serotonin and dopamine in AD pathophysiology.},
}

Humans
Male
*Alzheimer Disease/metabolism/diagnostic imaging
Female
Aged
*Glucose/metabolism
*Neurotransmitter Agents/metabolism
Positron-Emission Tomography
Magnetic Resonance Imaging
*Basal Forebrain/metabolism/diagnostic imaging
Middle Aged
Rest
Aged, 80 and over

@article {pmid42104909,
year = {2026},
author = {Kramarczyk, D and Ballard, C and Corbett, A and Da Silva, MV and Mcleish, KI and Cummings, J and Khan, Z},
title = {Racial and Ethnic Representation in Dementia Clinical Trials Registered on ClinicalTrials.gov in the United States, United Kingdom, and Canada.},
journal = {International journal of geriatric psychiatry},
volume = {41},
number = {5},
pages = {e70211},
doi = {10.1002/gps.70211},
pmid = {42104909},
issn = {1099-1166},
support = {//National Institute for Health and Care Research HealthTech Research Center in Brain Health./ ; },
mesh = {Humans ; United Kingdom ; United States ; Canada ; *Dementia/ethnology/therapy ; Male ; Female ; *Ethnicity/statistics & numerical data ; Aged ; *Clinical Trials as Topic/statistics & numerical data ; Patient Selection ; Aged, 80 and over ; *Racial Groups/statistics & numerical data ; Alzheimer Disease/therapy/ethnology ; Middle Aged ; },
abstract = {OBJECTIVE: To evaluate racial and ethnic representation and temporal trends in phase II-IV dementia clinical trials conducted in the United States, United Kingdom, and Canada.

METHODS: We interrogated ClinicalTrials.gov for interventional dementia and Alzheimer's disease (AD) trials completed since 2000. Data on age, gender, and ethnicity were extracted from 163 eligible trials. Representation was compared across two time periods (2000-2015 and 2016-2019) to assess progress in diversity.

RESULTS: Of the 163 trials, 58.9% (n = 96) reported ethnicity data. Among the 12,900 participant records in these trials, 80.6% were Caucasian. Since 2016, despite improved reporting standards (100% of recent trials reported ethnicity), actual diversity declined: Asian participant representation dropped from 4.9% to 1.2%, and Hispanic/Latino representation fell from 2.2% to 0.7%. No ethnic minority group showed an increase in participation over the study period.

CONCLUSIONS: Diverse ethnic groups remain significantly underrepresented in dementia clinical trials, with diversity metrics stagnating or declining over the last decade. Greater inclusivity in trial design and recruitment is urgently required to ensure that emerging dementia treatments are safe and effective for all populations.},
}

Humans
United Kingdom
United States
Canada
*Dementia/ethnology/therapy
Male
Female
*Ethnicity/statistics & numerical data
Aged
*Clinical Trials as Topic/statistics & numerical data
Patient Selection
Aged, 80 and over
*Racial Groups/statistics & numerical data
Alzheimer Disease/therapy/ethnology
Middle Aged

@article {pmid42105113,
year = {2026},
author = {Kaya, M and Konukoglu, O and Genç, H and Cindemir, E and Onay, M},
title = {Differentiation of normal pressure hydrocephalus from alzheimer's and Parkinson's Diseases using the splenial angle measured on brain CT: diagnostic performance and reliability study.},
journal = {Neuroradiology},
volume = {},
number = {},
pages = {},
pmid = {42105113},
issn = {1432-1920},
abstract = {BACKGROUND: Although MRI and diffusion tensor imaging (DTI) based studies have evaluated the Splenial Angle (SA) in distinguishing normal pressure hydrocephalus (NPH), its reproducibility and diagnostic utility on CT remain untested.

OBJECTIVE: To assess the diagnostic performance and intra/inter-observer repeatability of CT-derived SA measurements for differentiating NPH from Alzheimer's and Parkinson's diseases.

MATERIALS AND METHODS: This retrospective study included 325 individuals: 87 with NPH, 71 with Alzheimer's disease, 66 with Parkinson's disease, and 101 healthy controls. Evans Index (EI), Callosal Angle (CA), and SA were measured on brain CT images. Two radiologists assessed intra- and inter-observer repeatability. Continuous variables were analyzed using ANOVA, categorical variables using Chi-square tests, and Receiver Operating Characteristic (ROC) analysis determined diagnostic performance.

RESULTS: EI, CA, and SA differed significantly between the NPH group and the other groups (p < 0.001). The SA showed the highest diagnostic accuracy for NPH (AUC = 0.999; cut-off = 49.5°; sensitivity = 0.996; specificity = 0.989; LR + = 86.63; LR- = 0.004). The CA also demonstrated strong performance (AUC = 0.993; cut-off = 87.5°). The EI achieved high accuracy (AUC = 0.928) but was less specific. In the Alzheimer's and Parkinson's groups, these measurements had limited discriminatory ability. Intra- and inter-observer agreement was high for all three parameters, with the SA showing the greatest repeatability.

CONCLUSION: The SA can be used as a reliable CT-based marker to help distinguish NPH from neurodegenerative diseases, serving as a supportive imaging parameter in clinical assessment.},
}

@article {pmid42105174,
year = {2026},
author = {Lai, L and Tang, Y and Song, G and Long, Y and Chen, C and Chen, C and Li, W},
title = {Lipid metabolism, neuroinflammation, and oxidative stress in Alzheimer disease: an integrated mechanistic review.},
journal = {Acta neurologica Belgica},
volume = {},
number = {},
pages = {},
pmid = {42105174},
issn = {2240-2993},
abstract = {Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterised by the accumulation of amyloid-β plaques, tau tangles, and extensive synaptic and neuronal loss. Increasing evidence suggests that the condition develops through the combined effects of protein misfolding, lipid dysregulation, oxidative stress, and chronic neuroinflammation. Among these processes, the APOE ε4 allele has a central role by linking disrupted lipid metabolism to impaired amyloid clearance, abnormal tau phosphorylation, and heightened neuronal vulnerability. This relationship highlights lipidopathy as a potential upstream driver of disease progression rather than a secondary feature. Advances in biomarker research, including cerebrospinal fluid and plasma assays, molecular imaging, and microRNA profiles, now enable detection of AD pathology years before clinical symptoms become evident and allow patient stratification based on molecular signatures. Despite these advances, currently available symptomatic and disease-modifying therapies remain limited in their ability to halt or reverse cognitive decline. This review synthesises recent findings across amyloid, tau, and lipid-driven mechanisms, while providing a comparative analysis of therapeutic strategies and their limitations. A lipid-focused, multi-target framework is proposed in which correcting metabolic imbalance enhances the effectiveness of amyloid- and tau-directed interventions. Such an approach may strengthen precision medicine and offer a realistic path toward improved outcomes in AD.},
}

@article {pmid42105291,
year = {2026},
author = {Sandhu, JK and Tanha, J and Arbabi-Ghahroudi, M},
title = {Targeting the NLRP3 inflammasome with antibody-based Therapeutics for chronic neurodegenerative diseases.},
journal = {Expert opinion on therapeutic targets},
volume = {},
number = {},
pages = {},
doi = {10.1080/14728222.2026.2671675},
pmid = {42105291},
issn = {1744-7631},
abstract = {INTRODUCTION: The NLRP3 inflammasome is a central regulator of innate immunity that becomes aberrantly activated by amyloid-β, hyperphosphorylated tau, and α-synuclein aggregates in chronic neurodegenerative diseases such as Alzheimer's (AD) and Parkinson's disease (PD). Sustained activation drives neuroinflammation, synaptic dysfunction, and neuronal loss, making NLRP3 a compelling therapeutic target in chronic neurodegeneration.

TOPICS COVERED: This review summarizes current insights into NLRP3 inflammasome biology in AD and PD, with emphasis on antibody-based interventions. Emerging delivery approaches, such as receptor-mediated transcytosis, nanoparticles, adeno-associated viral vectors, and magnetic resonance-guided focused ultrasound are also examined for their potential to enhance central nervous system (CNS) delivery of NLRP3-targeting antibodies.

EXPERT OPINION: Antibody-based inhibitors of the NLRP3 inflammasome offer high specificity and favorable safety profile compared with small-molecular-weight inhibitors; however, limited blood-brain barrier (BBB) penetration remains a major challenge. Advances in antibody engineering, modular bi-/multi-specific designs, and targeted CNS delivery platforms may soon enable the development of first-in-class antibodies capable of directly modulating neuroinflammation. To realize this potential, the field should prioritize: (1) developing BBB-penetrant antibody constructs; (2) integrating delivery technologies with target biology; and (3) accelerating translation toward first-in-human studies. Successful implementation could transform therapeutic strategies for AD and PD and extend antibody-based interventions across a broader spectrum of neuroinflammatory disorders.},
}

@article {pmid42105317,
year = {2026},
author = {Balwant Patil, K and Sugunan, S and Padiyar, A and Mishra, AK and Jain, S},
title = {Neuroprotective role of phenolic acids: mechanistic insights into cognitive decline and neurodegenerative disorder.},
journal = {Nutritional neuroscience},
volume = {},
number = {},
pages = {1-25},
doi = {10.1080/1028415X.2026.2669234},
pmid = {42105317},
issn = {1476-8305},
abstract = {BACKGROUND: Age-associated cognitive deterioration and neurodegenerative conditions, including Alzheimer's disease (AD) and Parkinson's disease (PD), are predominantly influenced by oxidative stress, neuroinflammation, mitochondrial dysfunction, and abnormal protein aggregation. Dietary phenolic acids, prevalent in plant-based foods, have demonstrated potential neuroprotective and cognitive-enhancing effects in recent studies.

PURPOSE: This review seeks to thoroughly assess the neuroprotective mechanisms of phenolic acids and to consolidate existing evidence from human and preclinical studies concerning their potential efficacy in alleviating cognitive impairment and neurodegeneration.

STUDY DESIGN: Narrative and evidence-based literature review.

METHODS: Recent experimental, clinical, and epidemiological studies examining significant phenolic acids - such as caffeic, chlorogenic, ferulic, gallic, rosmarinic, sinapic, ellagic, protocatechuic, p-coumaric, and tannic acids - in relation to AD, PD, and cognitive functions were retrieved from electronic databases. We put together the most important information about molecular mechanisms and treatment.

RESULTS: Preclinical studies show that phenolic acids have antioxidant, anti-inflammatory, anti-apoptotic, and anti-aggregation effects by changing important signaling pathways like Nrf2/HO-1, NF-κB, and PI3 K/Akt. These actions protect dopaminergic neurons, lower the toxicity of amyloid-beta and α-synuclein, and make behavior better in disease models. Human studies suggest that increased dietary consumption of phenolic acids, especially hydroxycinnamic acids such as caffeic and chlorogenic acid, is associated with enhanced cognitive performance and a diminished risk of cognitive decline, although results are not uniform.

CONCLUSION: Phenolic acids are secure, readily accessible neuroprotective compounds that can alter various pathological pathways associated with cognitive decline and the progression of neurodegenerative diseases.},
}

@article {pmid42105452,
year = {2026},
author = {Uehara, MA and Bretecher, CA and Teschuk, JM and Verot, A and Saha, C and Fitzgerald, PB and Koski, L and Millikin, C and Moussavi, Z},
title = {Examining adverse effects in a large clinical trial of rTMS application as a treatment for Alzheimer's disease.},
journal = {Psychiatry research},
volume = {362},
number = {},
pages = {117212},
doi = {10.1016/j.psychres.2026.117212},
pmid = {42105452},
issn = {1872-7123},
abstract = {BACKGROUND: Repetitive transcranial magnetic stimulation (rTMS) has several advantages compared to other interventions for neurological and psychological disorders. However, various adverse effects have been reported in rTMS research, and little is known about who is most susceptible to rTMS adverse effects, or how they can be minimized.

AIMS: We aimed to identify risk factors for adverse effects reported in a recent clinical trial examining rTMS as a treatment for Alzheimer's disease (AD). We hypothesized that higher stimulation intensity would be associated with experiencing unspecified pain/discomfort, dental pain, headache, jaw pain, and muscle contractions, but not be associated with other adverse effects.

METHODS: Using detailed notes from treatment sessions, 10 adverse effects were identified. Spearman correlations were conducted to assess relationships between the highest applied stimulation intensity and normalized frequency of each adverse effect amongst those who experienced that adverse effect. Demographic information, cognitive scores, and withdrawal status were compared between the binarized groups of participants who experienced adverse effects versus those who did not. Spearman correlations were also conducted on the binarized adverse effects and the highest applied stimulation intensity. Logistic regressions were conducted to identify potential risk factors.

RESULTS: In both the sham and active treatment groups, unspecified pain/discomfort was the most common adverse effect, followed by muscle contractions and dizziness. In both the active and sham treatment groups, stimulation intensity was positively associated with muscle contractions, but was not significantly related to any other adverse effect. In evaluating groups with/without adverse effects, we found there was a significantly higher proportion of males reporting adverse effects in both the active treatment group and the sham treatment group compared to females.

CONCLUSION: The findings of this study are a step toward understanding how researchers can minimize such adverse effects, and thereby, create a less aversive experience for rTMS participants.},
}

@article {pmid42105723,
year = {2026},
author = {Sambuco, N and Scaramuzzi, GF and Gasparre, D and Cornacchia, E and Bonvino, A and Antonucci, LA and Pergola, G and Taurisano, P},
title = {Baseline brain volumes predict cognitive decline more robustly than atrophy rates: Evidence for brain reserve.},
journal = {Cortex; a journal devoted to the study of the nervous system and behavior},
volume = {200},
number = {},
pages = {200-215},
doi = {10.1016/j.cortex.2026.03.022},
pmid = {42105723},
issn = {1973-8102},
abstract = {The concept of brain reserve offers a framework for understanding the mechanisms of cognitive resilience in later life. This study investigated whether a static measure of brain structure, a proxy for accumulated reserve, or a dynamic measure of atrophy is a more powerful predictor of future cognitive changes. Using Alzheimer's disease (AD) as a model of accelerated cognitive aging, we investigated this question across the neurocognitive continuum. We analyzed longitudinal structural MRI and neuropsychological data from 75 Alzheimer's Disease Neuroimaging Initiative (ADNI) participants (Healthy, MCI, Dementia) using LASSO regularization and logistic regression to identify associations with cognitive change and model MCI conversion. Baseline brain volumes were robust predictors of cognitive decline, significantly outperforming short-term volumetric changes (atrophy rate). Specifically, larger lateral ventricles and smaller hippocampal and thalamic volumes, particularly in the anterior and medial thalamic nuclei, were associated with greater impairment in memory and executive function. Importantly, while APOE ϵ4 carrier status was high across the MCI group (∼56%), it did not differentiate converters from non-converters, indicating that genetic risk alone does not account for divergent clinical trajectories. Our model, based on these baseline volumes, predicted MCI conversion with good accuracy (AUC = .82). These findings highlight the importance of structural brain reserve, as a proxy for the resilience of integrated neural networks against neurodegeneration. Our results underscore the clinical utility of a single baseline MRI scan for identifying individuals at risk and advancing a network-based understanding of neurodegeneration.},
}

@article {pmid42105724,
year = {2026},
author = {Karalı, FS and Tosun, S and Çınar, N and Gerwien, J},
title = {Macro-event processing in Alzheimer's disease, mild cognitive impairment, and healthy aging: Evidence from a Turkish sample.},
journal = {Cortex; a journal devoted to the study of the nervous system and behavior},
volume = {200},
number = {},
pages = {216-236},
doi = {10.1016/j.cortex.2026.04.016},
pmid = {42105724},
issn = {1973-8102},
abstract = {Understanding everyday events requires integrating individual event units (micro-events) into coherent higher-level representations (macro-events). Cognitive decline may disrupt this ability, contributing to difficulties in comprehension, prediction, and goal inference. We investigated macro-event processing in Turkish-speaking healthy older adults, individuals with mild cognitive impairment (MCI), and individuals with Alzheimer's disease (AD) across two experiments. Participants recognized and labeled macro-events from sets of component micro-events. In Experiment 1, participants arranged micro-events into the correct temporal order. In half of the trials, the macro-event name was provided to test whether verbal cueing improved ordering performance; in the other half, participants named the macro-event after uncued ordering. A subsample completed a second administration to assess response stability. In Experiment 2, participants identified macro-events from incrementally presented micro-events, allowing assessment of how much information was required before recognition. Across experiments, we observed graded impairment with increasing cognitive decline. Naming accuracy reliably distinguished AD from the other groups, whereas differences between MCI and healthy controls were less consistent. Non-verbal measures, including temporal ordering, response stability, and the amount of information sampled before responding, revealed more robust group differences. These findings support macro-event processing as a core mechanism of event cognition that is progressively disrupted in MCI and AD, and indicate that non-verbal measures may provide sensitive markers of impairment beyond naming accuracy.},
}

@article {pmid42105801,
year = {2026},
author = {Hoyer-Kimura, C and Hay, M},
title = {Neurovascular unit dysfunction in vascular cognitive impairment: Mechanisms, biomarkers, and translational strategies.},
journal = {Experimental neurology},
volume = {},
number = {},
pages = {115815},
doi = {10.1016/j.expneurol.2026.115815},
pmid = {42105801},
issn = {1090-2430},
abstract = {Vascular cognitive impairment and dementia (VCID) encompasses a heterogeneous spectrum of cognitive disorders driven by cerebrovascular pathology and represents a major contributor to late-life cognitive decline. VCID is highly prevalent and frequently coexists with Alzheimer's disease pathology. Despite this, it remains poorly defined in clinical practice and lacks approved disease-modifying therapies. Therapeutic development has been hindered by biological heterogeneity, challenges in patient stratification, and a historical emphasis on neurodegenerative targets that inadequately address vascular mechanisms. Increasing evidence implicates dysfunction of the neurovascular unit-including small vessel disease, chronic hypoperfusion, blood-brain barrier disruption, and neuroinflammation-as a central driver of vascular-mediated cognitive impairment and a unifying therapeutic target across diverse VCID phenotypes. In this review, we synthesize current understanding of VCID pathobiology with a focus on neurovascular unit dysfunction and emerging mechanism-based strategies aimed at restoring vascular and neurovascular homeostasis. We further examine translational considerations for targeting neurovascular signaling pathways, including endothelial stabilization, modulation of vascular inflammation, and preservation of blood-brain barrier integrity. As an illustrative example, we discuss preclinical evidence supporting Mas receptor agonism, including the glycosylated angiotensin-(1-7) analogue PNA5, as a potential approach to address vascular-mediated cognitive impairment. Finally, we explore implications for biomarker selection, patient enrichment, and early clinical trial design. Together, this framework highlights neurovascular dysfunction as a tractable therapeutic target in VCID and underscores the need for mechanism-driven approaches to address a substantial unmet clinical need.},
}

@article {pmid42105904,
year = {2026},
author = {Guo, M and Zou, Y and Wang, T and Wu, H and Ji, Y and Liu, S and Xu, G and Wang, P},
title = {Spatiotemporal reconfiguration of functional networks by transcranial magnetic stimulation in Alzheimer's disease.},
journal = {Neuroscience},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.neuroscience.2026.05.002},
pmid = {42105904},
issn = {1873-7544},
abstract = {Alzheimer's disease (AD) is associated with impaired connectivity in critical functional networks. This study investigated the effects of 20 Hz transcranial magnetic stimulation (TMS) on brain network mechanisms in 25 patients with AD, including 17 in the TMS group and 8 in the sham group. We analyzed resting-state functional magnetic resonance imaging data, using the amplitude of low-frequency fluctuations (ALFF) and fractional ALFF (fALFF) to quantify neural activity and identify regions of interest. Subsequently, changes in static and dynamic functional connectivity were analyzed based on these regions. The results showed that: (1)In the TMS group, significant increases in ALFF/fALFF were observed specifically in the right dorsolateral superior frontal gyrus (SFGdor.R) and the left anterior cingulate gyrus (ACG.L); (2)Enhanced static functional connectivity between the SFGdor.R and the right middle temporal gyrus was positively correlated with improvements in Montreal Cognitive Assessment scores, while reduced static functional connectivity between the ACG.L and the left inferior temporal gyrus was associated with gains in Boston Naming Test scores; (3)Improvements in both Montreal Cognitive Assessment scores and Mini Mental State Examination scores were linked to decreased dynamic functional connectivity variability between the ACG.L and the middle occipital gyrus. These findings suggest that TMS improves cognitive and behavioral performance in patients with AD through multiscale regulatory effects, and that this improvement may be associated with alterations in functional integration among brain regions as well as reduced variability of abnormal network dynamics, providing new insights into the mechanism of action of TMS in AD.},
}

@article {pmid42105919,
year = {2026},
author = {Barough, SS and Ohno, S and Bilgel, M and Moghekar, A and Sair, HI and Luciano, MG and Moghekar, A},
title = {Disproportionately Elevated Sulcal Index (DESI): An automatically driven index representing disproportionate subarachnoid space enlargement in brain MRI scans.},
journal = {Brain research bulletin},
volume = {},
number = {},
pages = {111928},
doi = {10.1016/j.brainresbull.2026.111928},
pmid = {42105919},
issn = {1873-2747},
abstract = {INTRODUCTION: Idiopathic normal pressure hydrocephalus (iNPH) is frequently underdiagnosed due to non-specific symptoms and the risks of invasive testing. While disproportionately enlarged subarachnoid space hydrocephalus (DESH) is a hallmark imaging feature, manual assessment is subjective and qualitative. We developed the Disproportionately Elevated Sulcal Index (DESI), a fully automated deep learning-based volumetric biomarker, to objectively quantify these morphological changes.

METHODS: We trained a U-Net model with an EfficientNet-B0 encoder on T1-weighted MRI scans from the Baltimore Longitudinal Study of Aging and Johns Hopkins Clinic (n=1,248) to segment Sylvian fissures and superior sulcal spaces. DESI was defined as the volumetric ratio of the Sylvian fissure to superior sulci within an AC-PC aligned wedge. The model was externally validated on the multi-site PENS trial dataset (n=94), comparing NPH patients against healthy controls and participants with Alzheimer's disease and vascular dementia.

RESULTS: In external validation, DESI demonstrated high diagnostic accuracy. The index distinguished NPH patients with DESH features from non-DESH NPH cases with an Area Under the Curve (AUC) of 0.97. When differentiating NPH with DESH from a pooled group of healthy controls and neurodegenerative mimics, DESI achieved an AUC of 0.99 (sensitivity 98%, specificity 100%). In a broad comparison of all NPH cases versus all non-NPH groups, DESI maintained an AUC of 0.94.

CONCLUSIONS: DESI provides a robust, fully automated quantification of sulcal disproportion that effectively differentiates iNPH from normal aging and neurodegenerative mimics. This continuous, non-invasive metric offers a scalable tool for accurate iNPH screening and patient stratification in clinical settings.},
}

@article {pmid42105933,
year = {2026},
author = {Pourzal, R and Agarwal, P and Leurgans, SE and McCarthy, SM and Hall, DJ and McDevitt, CA and Ganio, K and Ayton, S and Bush, AI and Grodstein, F and James, B and Agrawal, S and Hallab, NJ and Bennett, DA and Schneider, JA and Jacobs, JJ},
title = {Cobalt and titanium levels in the brain are associated with Alzheimer's disease pathology but not cognition: A study of older adults with and without total joint replacement.},
journal = {Acta biomaterialia},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.actbio.2026.05.006},
pmid = {42105933},
issn = {1878-7568},
abstract = {Alzheimer's disease (AD) and total joint arthroplasty are prevalent and often concomitant in older adults, but an etiologic link is debated. Since wear particles are an inevitable side product of total joint arthroplasty (TJA), we hypothesized that older adults with TJA agglomerate higher-than-normal concentrations of implant alloy elements caused by the dissemination of debris from the implants, resulting in a pathological reaction. A cross-sectional analysis was conducted among 701 autopsied participants of an ongoing longitudinal cohort (Memory and Aging Project (MAP)) of whom postmortem neuropathologic data was available and implant-related metals (cobalt, titanium) were quantified in four brain regions by inductively coupled mass-spectrometry. MAP participants are enrolled without known dementia at baseline and followed annually for cognitive assessments using 19-test battery. In the analytical sample, 229 had TJA (total hip arthroplasty, total knee arthroplasty, and total shoulder arthroplasty) and n=472 had no total joint. Due to a higher likelihood of cobalt release in total hip arthroplasty, the TJA group was subdivided into a hip (n=146) and a knee/shoulder (n=83) group. We used regression and linear mixed-effects models, adjusted for demographics and apolipoprotein E ε4 status, to examine associations between metals, AD pathology and cognitive decline. Cobalt content of brain tissue was 8.9% higher in the total hip arthroplasty group than in the no-TJA group (p=0.003). Cobalt-containing particles were identified within brain tissue using scanning electron microscopy. In the inferior temporal cortex, cobalt was positively associated (p=0.0004) and titanium was negatively associated (p=0.038) with amyloid-beta load, but had no association with cognition. These results warrant monitoring the potential impact of metal implant debris on brain health. STATEMENT OF SIGNIFICANCE: This study is of great clinical significance because Alzheimer's disease (AD) and total joint arthroplasty (TJA)-the end-stage treatment of osteoarthritis-affect large and overlapping groups in our aging population. There is limited knowledge about the relationship between the prominent TJA implant metals cobalt and titanium and the pathogenesis of AD. This study shows that Co28Cr6Mo and Ti6Al4V implant alloy particles-most likely from a subset of total hip replacements with accelerated wear or tribocorrosion-can disseminate to the brain and be associated with increased cobalt and titanium concentrations. Cobalt was associated with greater AD pathology in the inferior-temporal cortex, even after correction for other known AD risk factors. However, there was no correlation with cognitive decline. Titanium was negatively associated with AD pathology, but titanium oxide appeared to be abundant in the brain from sources other than joint replacements.},
}

@article {pmid42105996,
year = {2026},
author = {Bashir, MA and Ullah, I and Aara, G and Khan, AU and Shah, SUA},
title = {Multitarget Pharmacological Effects of Lawsone in Mitigating Alzheimer's Disease.},
journal = {European journal of pharmacology},
volume = {},
number = {},
pages = {178920},
doi = {10.1016/j.ejphar.2026.178920},
pmid = {42105996},
issn = {1879-0712},
abstract = {Alzheimer's disease (AD) is a multifactorial neurodegenerative disorder characterized by progressive neuronal loss, cognitive impairment, oxidative stress, neuroinflammation, and aggregation of abnormal proteins, including amyloid precursor protein (APP), amyloid-beta (Aβ), and hyper phosphorylated Tau (p-Tau). Developing therapies that simultaneously target multiple pathogenic pathways remains a major therapeutic challenge. Lawsone (LW), a naturally occurring naphthoquinone derived from the leaf of henna plant (Lawsonia inermis), was investigated for its therapeutic potential in AD. Computational studies were performed to evaluate binding affinities and stability of the compound against key AD-related molecular targets. Sprague-Dawley rats were randomly assigned to five groups: vehicle control, Scopolamine (SCP), donepezil (DNZ), and two groups treated with LW at doses of 2.5 and 5mg/kg. Morris water Maze and Y Maze tests were employed to validate the behavioral performance. Oxidative stress markers were measured biochemically, tissue histopathology was evaluated using hematoxylin-eosin and Congo red staining. Expression of the proinflamatory markers, nuclear factor kappa β (NF-κβ), c-Jun N terminal kinase (c-JNK), Tumor necrosis factor-α (TNF-α) and Alzheimer's associated proteins APP, Aβ1-42, and Tau were assessed through real time polymerase chain reaction (qPCR), enzyme linked immunosorbent assay (ELISA). Computational evaluation showed strong binding to NF-κβ, c-JNK, acetylcholinestrase (AChE), butyrylcholinestrase (BuChE) and TNF-α, supporting its multi-target potential. LW demonstrated neuropharmacological efficacy through preservation of neuronal structure, suppression of Aβ pathology, enhancement of cognitive function, restoration of antioxidant defenses, downregulation of proinflamatory, amyloidogenic, and tauopathic markers. These findings featured its potential as a multi target therapeutic agent for the management of AD.},
}

@article {pmid42106150,
year = {2026},
author = {Xiang, J and Xu, J and Zhang, Y and Liu, X},
title = {Urolithin A: potential to enhance autophagic clearance and mitigate neuroinflammation in Alzheimer's disease.},
journal = {Ageing research reviews},
volume = {},
number = {},
pages = {103157},
doi = {10.1016/j.arr.2026.103157},
pmid = {42106150},
issn = {1872-9649},
abstract = {Alzheimer's disease (AD) is the most common neurodegenerative disorder worldwide and the leading cause of dementia in older adults. The presence of extracellular β-amyloid (Aβ) plaques and intracellular neurofibrillary tangles (NFTs) constitutes the two principal neuropathological features of AD. However, current therapies targeting only Aβ or tau remain suboptimal, likely due to intrinsic neuronal and glial dysfunction in affected brain regions. Urolithin A (UroA) is a widely recognized mitophagy activator with potent antioxidant and anti-inflammatory properties. Current clinical studies confirm UroA's safety in humans and its broad benefits for mitochondrial health. Preclinical data show enhanced lysosomal and mitochondrial quality in neurons and glia during AD progression. Given current AD pathology insights, UroA shows significant therapeutic promise. The AMPK/SIRT/mTOR signaling axis regulates cellular adaptation to metabolic stress and energy balance, and is significantly dysregulated in AD progression. This review comprehensively evaluates the structural and biological characteristics of UroA, with a focus on its role in enhancing mitophagy, promoting lysophagy, and mitigating neuroinflammation in the context of AD. However, current research has not clarified how UroA enhances mitochondrial and lysosomal function while suppressing neuroinflammation. This report further investigates the potential interplay between UroA and the AMPK/SIRT/mTOR signaling pathway, elucidating a plausible mechanism through which UroA regulates the autophagic-lysosomal system and mitigates neuroinflammation via modulation of this axis.},
}

@article {pmid42106151,
year = {2026},
author = {Sharma, P and Kaur, N and Vasal, N and Solanki, K and Sunkaria, A},
title = {The Mitochondria-Synapse Axis in Alzheimer's Disease: Lost Coordination in Early Stages.},
journal = {Ageing research reviews},
volume = {},
number = {},
pages = {103168},
doi = {10.1016/j.arr.2026.103168},
pmid = {42106151},
issn = {1872-9649},
abstract = {Synaptic dysfunction emerges early in Alzheimer's disease, often years before the appearance of clinical symptoms, and is among the most reliable predictors of subsequent cognitive decline. Despite its importance, the cellular events that trigger this early synaptic vulnerability remain poorly defined. Growing evidence points to a critical failure at the interface between neuronal energy metabolism and synaptic signalling, commonly referred to as the mitochondria-synapse axis, suggesting that its disruption may occur well before the accumulation of classical amyloid and tau pathology. In this Review, we combine findings from human neuronal models, multi-omics analyses, and in vivo studies to show how amyloid-β oligomers (Aβ oligomers) induce subtle yet consequential defects in mitochondrial trafficking, calcium handling, redox homeostasis, and local ATP supply. Together, these changes undermine the precise coordination between mitochondrial metabolism and calcium-dependent signalling that is essential for synaptic plasticity. As a result, affected neural circuits lose the capacity to meet the energetic demands of sustained information processing. We propose that this early uncoupling of energy availability from synaptic demand represents a leading contributor to neuronal vulnerability rather than a secondary consequence of protein aggregation, based on converging evidence from iPSC-derived cortical neurons, human neuronal cultures, and transgenic mouse models, with human in vivo validation still emerging. Finally, we highlight emerging therapeutic strategies aimed at restoring mitochondrial quality control, axonal transport, and metabolic communication. By re-aligning bioenergetic support with synaptic function, such approaches may open a critical window for intervention before irreversible circuit degeneration takes hold.},
}

@article {pmid42106438,
year = {2026},
author = {Aydin, AG and Manoj, P and Ramadan, F and Rajan, S and Youssef, E and Torres, EB and Bieszczad, KM},
title = {Sound-evoked auditory neurophysiological signals are a window into prodromal functional differences in a preclinical model of Alzheimer's disease.},
journal = {Scientific reports},
volume = {},
number = {},
pages = {},
doi = {10.1038/s41598-026-51854-8},
pmid = {42106438},
issn = {2045-2322},
support = {Career Continuation Award//Nancy Lurie Marks Family Foundation/ ; DC018561/DC/NIDCD NIH HHS/United States ; },
abstract = {Hearing is the largest modifiable mid-life risk factor for Alzheimer's disease (AD), yet its link to dementia remains unclear. We identified a neurophysiological biomarker of AD risk using the non-invasive, rapidly acquired, and clinically translatable auditory brainstem response (ABR) in normal hearing knock-in rats (Swedish familial AD risk variant to Amyloid precursor protein, App[S]; male and female). Human ABRs have been proposed as a biomarker for AD and related dementias. The novel metric reported here is derived from multidimensional parametric feature extraction on the distribution statistics of repeated single-trial ABR traces. We report accurate prediction of genetic risk for AD risk in young and aged rats: App[S] separate clearly from healthy humanized (App[H]) in sex- and age-dependent manners. Notably, auditory learning during young adulthood shifted the App[S] ABR signature towards a healthy App[H]-like state that maintained over time into older age. Altogether the findings support the utility of the ABR to track disease state, progression, and effects of intervention, and point to a central neural generator of auditory dysfunction related to AD risk. ABRs could provide a very early biomarker for detection of AD risk and used to test the synergy of auditory and cognitive functions in human dementia.},
}

@article {pmid42106468,
year = {2026},
author = {Santos, ACC and Corrêa, JL and Duarte, RMF and Malta, SM and Rodrigues, TS and de Oliveira Santos, D and de Faria, PR and do Prado Mascarenhas, FNA and Zanon, RG and Cassemiro, NS and Carollo, CA and Espindola, FS and Martins, MM and Mendes-Silva, AP and Bonetti, AM and Dos Santos, AR and Ueira-Vieira, C},
title = {Bacterial polar metabolites modulate β-amyloid toxicity and cholinergic dysfunction in models of Alzheimer's disease.},
journal = {Scientific reports},
volume = {},
number = {},
pages = {},
doi = {10.1038/s41598-026-52291-3},
pmid = {42106468},
issn = {2045-2322},
support = {APQ-00269-22//Fundação de Amparo à Pesquisa do Estado de Minas Gerais/ ; 403193/2022-2//Conselho Nacional de Desenvolvimento Científico e Tecnológico/ ; APQ-03613-17; APQ-02766-17//Fundação de Amparo à Pesquisa do Estado de Minas Gerais , Brasil/ ; },
abstract = {Alzheimer's disease is characterized by progressive neurodegeneration driven by β-amyloid (Aβ) toxicity, oxidative stress, and cholinergic dysfunction. In this study, we investigated whether polar metabolites derived from a cultivable bacterial isolate could modulate Aβ-associated neurodegenerative phenotypes in complementary experimental models. A bioactivity-guided approach identified an aqueous fraction with high antioxidant capacity in DPPH, FRAP, and ORAC assays. In a transgenic Drosophila melanogaster model expressing human Aβ, treatment with this fraction significantly reduced amyloid accumulation and attenuated neurodegenerative histopathological alterations. In human SH-SY5Y neuronal cultures, the metabolites improved cell viability under therapeutic, but not preventive, conditions following exposure to aggregated Aβ. The aqueous fraction also exhibited significant inhibitory activity against acetylcholinesterase and butyrylcholinesterase. Whole-genome sequencing assigned the bioactive isolate to the genus Providencia, with comparative genomic analyses suggesting its placement within a distinct taxonomic lineage. Metabolomic profiling by LC-ESI-MS/MS revealed a diverse set of polar metabolites, including metabolites putatively annotated based on spectral matching, previously associated with neuroprotective and cholinesterase-modulating activities. Collectively, these findings demonstrate that bacterial polar metabolites can modulate key pathological features of Alzheimer's disease, supporting their relevance for mechanistic studies of Aβ toxicity and cholinergic dysfunction.},
}

@article {pmid42106823,
year = {2026},
author = {Yin, C and Nelen, I and Harms, A and Hartman, R and Bos, S and Nijgh-van Kooij, C and Hankemeier, T and Kindt, A and de Lange, E},
title = {Longitudinal metabolomic profiling of biogenic amines in plasma and CSF, and their correlation, reveals sex-specific and age changes in TgF344 Alzheimer's disease transgenic and wildtype rats.},
journal = {Fluids and barriers of the CNS},
volume = {},
number = {},
pages = {},
doi = {10.1186/s12987-026-00811-8},
pmid = {42106823},
issn = {2045-8118},
support = {175.2019.032//Nederlandse Organisatie voor Wetenschappelijk Onderzoek/ ; },
abstract = {BACKGROUND: Alterations in amine metabolism have been implicated in Alzheimer's disease (AD), but the relationships between plasma and cerebrospinal fluid (CSF) amine levels remain insufficiently understood.

AIM: To investigate longitudinal changes in amines in plasma and CSF, as well as their cross-matrix correlations, in male and female TgF344-AD transgenic rats compared with wild-type (WT) controls.

METHOD: LC-MS-based targeted metabolomics was used to quantify 60 plasma amines and 55 CSF amines in male and female TgF344-AD and WT rats at 12, 25, 50 and 85 weeks of age. Generalized linear models, Pearson correlations, and Fisher's r-to-z transformation were applied for statistical analysis.

RESULTS: In plasma, age- and sex-associated differences were observed. At 25 weeks, three amines (4-hydroxy-proline, homocitrulline, and hydroxylysine) showed significantly increased levels in male TgF344-AD rats after multiple-testing correction. Additional trend-level changes were observed at 12, 50, and 85 weeks. In CSF, no amines passed the significance threshold after multiple-testing correction, although descriptive age- and sex-associated patterns were observed, with earlier changes in males and later-stage trends in females. CSF-plasma correlations tended to be stronger in TgF344-AD rats than in WT rats, with relatively strong correlations for alpha-aminobutyric acid, citrulline, N6,N6,N6-trimethyl-lysine, and putrescine.

CONCLUSIONS: Body fluid, age- and sex-dependent amine alterations in CSF and plasma of TgF344-AD rats compared to WT controls provide important insights into AD disease processes and may aid early diagnosis and therapeutic targeting.},
}

@article {pmid42107073,
year = {2026},
author = {Xiong, L and Sun, D and Guo, HH and Lee, D and Liu, Z and Mei, L and Xiong, WC},
title = {A Skull Bone Marrow-to-Brain Axis Links Osteoblastic Activity to Myeloid Cell Trafficking, Cerebral Blood Flow, and Cognition in Alzheimer's Progression.},
journal = {Advanced science (Weinheim, Baden-Wurttemberg, Germany)},
volume = {},
number = {},
pages = {e75622},
doi = {10.1002/advs.75622},
pmid = {42107073},
issn = {2198-3844},
support = {AG051510/NH/NIH HHS/United States ; AG066526/NH/NIH HHS/United States ; },
abstract = {Patients with Alzheimer's disease (AD) often develop osteoporosis, but the role of bone remodeling in AD remains unclear. We previously showed that osteoblast-specific expression of APPswe induces bone loss, glial activation, and behavioral deficits, suggesting a bone-to-brain signaling axis. Here, we identify an altered skull bone marrow (SBM)-to-brain axis in AD. Early SBM changes, including reduced cellularity, increased density, and expanded vascular channels to the meninges, occur in multiple APPswe mouse models. These vascular changes facilitate migration of SBM-derived myeloid cells into the meninges and cortex, improving cerebral blood flow (CBF) and slowing cognitive decline. Notably, these effects are age-dependent, emerging at 6 months but diminishing by 12 months. Enhancing this axis via bone marrow transplantation improves CBF and cognitive function in aged mice, whereas disrupting it through osteoblastic deletion of ATP6AP2 impairs both. Together, these findings reveal a previously unrecognized SBM-to-brain axis that regulates immune, vascular, and cognitive functions, highlighting systemic contributions to AD pathogenesis.},
}

@article {pmid42107260,
year = {2026},
author = {Huang, Y and Wang, Y and Wang, Y and Cheng, H and Yang, H and Wang, C and Xu, Y},
title = {The design, synthesis and evaluation of the first carbon-11 positron emission tomography radiotracer for ASK1 imaging.},
journal = {Bioorganic chemistry},
volume = {178},
number = {},
pages = {109970},
doi = {10.1016/j.bioorg.2026.109970},
pmid = {42107260},
issn = {1090-2120},
abstract = {Apoptosis signal regulating kinase 1 (ASK1) plays a central role in the molecular pathogenesis of various neurological disorders by mediating inflammation, oxidative stress, and apoptosis. ASK1 has emerged as an important therapeutic target in a range of neurodegenerative and neuroinflammatory disorders, including Alzheimer's disease, Parkinson's disease, and multiple sclerosis. Herein, we describe the development and preclinical evaluation of [[11]C]HYF038 as the first positron emission tomography radiotracer for imaging ASK1. In vitro autoradiography, [[11]C]HYF038 performed good specific binding to the ASK1 proteins in the mice brain regions, data are expressed as the density light units per square millimeter (DLU/mm[2]) in the blocking group was reduced by 28%. In vivo PET imaging of [[11]C]HYF038 in rodent model demonstrated a certain blood-brain barrier (BBB) penetration with SUV = 0.5, the biodistribution result of [[11]C]HYF038 in different organs showed that [[11]C]HYF038 is mainly metabolized in the liver. These findings indicate that [[11]C]HYF038 can act as a promising lead for the further development of PET tracers to image ASK1 in neurodegenerative disease progression.},
}

@article {pmid42107267,
year = {2026},
author = {Wei, Y and Zhang, A and Qiu, W and Xiong, B and Song, Z and Zheng, N and Wu, Y and Zhang, C and Cao, Z and Wang, X and Xu, C and Zhao, Q and Wu, Y and Liu, Z and Chen, Y and Sun, H},
title = {Development of tacrine-based multitarget-directed ligands as dual AChE/EGFR inhibitors with neuroprotective activity.},
journal = {Bioorganic & medicinal chemistry},
volume = {139},
number = {},
pages = {118677},
doi = {10.1016/j.bmc.2026.118677},
pmid = {42107267},
issn = {1464-3391},
abstract = {Alzheimer's disease (AD) is a multifaceted neurodegenerative disease for which current therapies primarily rely on cholinesterase inhibitors (ChEIs). Tacrine was the first and potent ChEI, which was soon withdrawn due to hepatic side effects. Meanwhile, the epidermal growth factor receptor (EGFR) inhibitor gefitinib has shown anti-AD potential. Inspired by these findings, we designed a series of hybrid molecules by conjugating the tacrine and gefitinib pharmacophores to create dual AChE/EGFR inhibitors, aiming to ameliorate cognitive impairment. After the structure-activity relationship (SAR) studies, two lead compounds (S24-1008 and S24-1017) were identified with high target affinity. These optimized compounds exhibited moderate cytotoxicity across various neuronal cell lines. Compared to traditional EGFR inhibitors, they demonstrated superior blood-brain barrier (BBB) permeability. Furthermore, they conferred significant neuroprotection against H2O2- and glutamate-induced neuronal damage. In vivo studies confirmed that both S24-1008 and S24-1017 effectively reversed cognitive deficits and enhanced learning and memory in mice, with no significant change in body weight observed.},
}

@article {pmid42107310,
year = {2026},
author = {Xiao, P and Yu, J and Han, Y and Chen, X and Hu, Y and Huang, X},
title = {[1,3]Oxazine-based NIR molecular switches: Hydrochromic behavior, viscosity sensing, and targeted cell imaging.},
journal = {Spectrochimica acta. Part A, Molecular and biomolecular spectroscopy},
volume = {360},
number = {},
pages = {128046},
doi = {10.1016/j.saa.2026.128046},
pmid = {42107310},
issn = {1873-3557},
abstract = {Molecular switches based on [1,3] oxazine show distinctive properties between their ring-closed and ring-opened forms (RCF and ROF), differing in conjugation length, charge, hydrophilicity, and optical behavior. These features enable low background interference and organelle-selective targeting, which are highly valuable for intracellular fluorescence imaging. However, related studies remain scarce. In this work, two near-infrared (NIR) molecular switches, BOA-1 and BOA-2, were designed using [1,3] oxazine as the core scaffold. They exhibit excellent hydrochromic behavior with a 300 nm absorption red-shift, supporting applications in water-ink painting. BOA-1 shows a pKa of 8.78 and specific endoplasmic reticulum (ER) targeting in living cells. It also presents specific fluorescence activation toward viscosity, with two non-overlapping emission peaks separated by 230 nm, ensuring high anti-interference performance and quantitative ratiometric detection. Notably, BOA-1 shows great potential for Alzheimer's disease (AD) diagnosis and therapeutic monitoring. This work first reports the NIR fluorescent sensing of [1,3] oxazine derivative toward intracellular microenvironments, which provides a promising platform for disease diagnosis and further biological fluorescence sensing applications.},
}

@article {pmid42107415,
year = {2026},
author = {Stepanchuk, AA and Joseph, JT and Lashley, T and Stys, PK},
title = {Disentangling amyloid polymorphs in normal aging and Alzheimer's disease using dual-probe spectral imaging.},
journal = {Neurobiology of aging},
volume = {165},
number = {},
pages = {51-59},
doi = {10.1016/j.neurobiolaging.2026.04.009},
pmid = {42107415},
issn = {1558-1497},
abstract = {Variability in Alzheimer's disease (AD) clinical presentation complicates mechanistic studies and therapeutic outcome prediction. Brain protein aggregate load does not directly correlate with clinical symptoms; however, different subtypes of AD have been reported to exhibit structural variation (polymorphism) of aggregates. Little is known about the structural diversity of the deposits in cognitively normal aged brains. This study investigates the structural heterogeneity of amyloid aggregates in the hippocampus and their association with age- and disease-related pathology. Post-mortem hippocampal tissue from cognitively normal aged controls and AD patients was co-stained with the amyloid-sensitive dyes BSB and MCAAD-3 and imaged across various subregions using spectral fluorescence microscopy. Machine learning analysis of spectral data differentiated amyloid polymorphs between cognitively normal and Alzheimer's cases. Our analysis revealed distinct spectral features across the amyloid plaques, neurofibrillary tangles and the background tissue parenchyma associated with AD compared to those observed in cognitively normal aging, irrespective of overall aggregate load. This study underscores the importance of amyloid polymorphism in determining the clinical impact of protein pathology in AD. Our findings highlight that focusing on amyloid structure rather than total load can aid in advancing personalized approaches in the diagnosis and treatment of neurodegenerative diseases.},
}

@article {pmid42107515,
year = {2026},
author = {Verma, B and Singh, P and Goberdhan, DCI and Wilson, C},
title = {Defective Regulated Secretion: A Trigger for Alzheimer's Pathology?.},
journal = {Progress in neurobiology},
volume = {},
number = {},
pages = {102926},
doi = {10.1016/j.pneurobio.2026.102926},
pmid = {42107515},
issn = {1873-5118},
abstract = {Extracellular amyloid plaques formed from aggregated Amyloid-β (Aβ), a specific cleavage product of Amyloid Precursor Protein (APP), and intracellular tau-containing neurofibrillary tangles are the two key histopathological hallmarks of Alzheimer's Disease (AD). However, increasing evidence suggests that the trigger for neurodegeneration in AD involves intraneuronal defects in endolysosomes, which might be induced by both Aβ and tau. Recent high-resolution analysis of trafficking inside neuronal and non-neuronal cells suggests such defects may arise through aberrant compartmental maturation events during regulated secretion. These events bring together APP, secretory and endosomal compartments, and also the proteolytic secretases that generate Aβ. They may be initiated by the accumulation of Aβ and/or C-terminal fragments of APP, which interfere with endolysosomal trafficking and potentially induce tau pathology. They also lead to secretion of proteins from these Aβ-containing compartments, which can trigger endolysosomal phenotypes in other cells that endocytose them. By implicating regulated secretion in the initiation of AD, this new model highlights novel intracellular mechanisms that might drive neurodegeneration. Identifying suppressors of these pathways could suggest entry points for the development of novel therapies that target the earliest stages of AD pathology.},
}

@article {pmid42107604,
year = {2026},
author = {Shaheen, H and Melnik, R},
title = {Bayesian modelling of amyloid-beta dynamics and astrocyte influence in Alzheimer's disease.},
journal = {Journal of neuroscience methods},
volume = {},
number = {},
pages = {110785},
doi = {10.1016/j.jneumeth.2026.110785},
pmid = {42107604},
issn = {1872-678X},
abstract = {BACKGROUND: Alzheimer's disease (AD) is a complicated neurological condition defined by the deposition of amyloid-beta (Aβ) plaques. Despite extensive research, the dynamics of Aβ growth, particularly the role of astrocytes, remain poorly understood, limiting the development of effective treatments.

NEW METHOD: This study addresses this gap by introducing a Bayesian inference framework for modelling Aβ dynamics, incorporating both strong and weak astrocyte effects utilizing Alzheimer's Disease Neuroimaging Initiative (ADNI) clinical data.

RESULTS: Through a combination of stochastic growth models and approximate Bayesian computation (ABC), we evaluate how astrocyte concentrations influence Aβ accumulation in different disease stages. Our findings show that higher astrocyte levels can suppress Aβ growth, while lower levels promote it, suggesting that astrocyte-targeted interventions may alter disease progression.

This data-driven probabilistic approach not only captures the inherent biological variability but also provides a tractable method to estimate uncertain parameters.

CONCLUSIONS: The present research offers a valuable tool for therapeutic modelling and prediction in AD.},
}

@article {pmid42107617,
year = {2026},
author = {Tian, Y and Whitwell, JL},
title = {Advanced Diffusion MRI Tract Signatures in Alzheimer's Disease, Dementia with Lewy Bodies, and the FTD/PPA Spectrum.},
journal = {NeuroImage},
volume = {},
number = {},
pages = {121984},
doi = {10.1016/j.neuroimage.2026.121984},
pmid = {42107617},
issn = {1095-9572},
abstract = {Alzheimer's disease (AD), Dementia with Lewy bodies (DLB), frontotemporal dementia (FTD), and primary progressive aphasia (PPA) are heterogeneous neurodegenerative syndromes with overlapping clinical features and substantial societal burden. Their phenotypic diversity, including atypical AD variants and multiple PPA subtypes, poses major challenges for early diagnosis and disease monitoring. Sensitive, non-invasive imaging biomarkers remain limited. Diffusion magnetic resonance imaging (dMRI) has evolved beyond conventional diffusion tensor imaging (DTI) to include multi-shell models such as neurite orientation dispersion and density imaging (NODDI), free-water imaging (FWI), and fixel-based analysis (FBA), which offer increased microstructural specificity by probing neurite organization, extracellular water content, and fiber-specific degeneration. In this review of 54 dMRI studies spanning AD, DLB, FTD, and PPA spectrums, we identify both convergent microstructural patterns shared across techniques and disease-specific signatures revealed by advanced models. Canonical DTI findings demonstrate consistent syndrome-related alterations, including fornix and cingulum involvement in AD, widespread diffusivity increases in DLB, uncinate fasciculus degeneration in FTD, and arcuate fasciculus disruption in PPA. Advanced dMRI methods extend these observations by revealing disease-specific neurite and free-water alterations, associations with molecular imaging markers, and improved sensitivity to clinical severity, longitudinal cognitive decline, and microstructural progression. Across syndromes and subtypes, NODDI- and FBA-based metrics consistently outperform conventional DTI. Together, this review provides a comprehensive framework for interpreting advanced dMRI markers across the AD, DLB, and the FTD-PPA spectrum, and highlights their potential for refining disease characterization and tracking neurodegenerative progression.},
}

@article {pmid42107621,
year = {2026},
author = {Khattab, NA and El Kadeem, A and Goda, AE and El-Mahdy, NA and El-Shitany, N},
title = {Aluminum chloride in Alzheimer's disease: A dual focus on molecular mechanisms and rat experimental models.},
journal = {Experimental neurology},
volume = {},
number = {},
pages = {115814},
doi = {10.1016/j.expneurol.2026.115814},
pmid = {42107621},
issn = {1090-2430},
abstract = {Alzheimer's disease (AD) is a leading cause of dementia among middle-aged and elderly individuals globally. Animal models of AD are widely used to investigate disease mechanisms and evaluate potential treatments for disease modification. Among non-genetically modified models, aluminum (Al[3+]) induced neurotoxicity has been widely employed to mimic key features of AD, including neuroinflammation and cognitive decline. This review comprehensively elucidates current evidence on the molecular and cellular mechanisms underlying Al[3+]-induced AD-like pathology, including amyloid-β accumulation, tau protein hyperphosphorylation, oxidative stress, mitochondrial dysfunction, neuroinflammation, cholinergic system impairment, synaptic plasticity deficits, apoptosis, metal ion dyshomeostasis, and epigenetic alterations. This review critically discusses methodological variables that significantly influence experimental outcomes in Al[3+]-based models, including dosage, route of administration, exposure duration, and animal age and gender. Moreover, this review emphasizes the translational significance, advantages, and limitations of the Al[3+]-induced model by merging mechanistic insights with experimental design considerations, offering guidelines for its optimal application in AD research and treatment development.},
}

@article {pmid42107623,
year = {2026},
author = {Martínez-Drudis, L and Sheta, R and Musiol, D and Teixeira, M and Oueslati, A},
title = {The emerging role of polo-like kinase 2 in Alzheimer's disease.},
journal = {Experimental neurology},
volume = {},
number = {},
pages = {115806},
doi = {10.1016/j.expneurol.2026.115806},
pmid = {42107623},
issn = {1090-2430},
abstract = {Alzheimer's disease (AD) is a progressive neurodegenerative disorder marked by the accumulation of amyloid-β (Aβ) plaques and hyperphosphorylated Tau tangles. Protein phosphorylation is increasingly recognized as a key modulator of AD pathology, but the specific kinases involved remain incompletely characterized. Polo-like kinase 2 (PLK2), a serine/threonine kinase previously studied in Parkinson's disease, has recently emerged as a potential contributor to AD pathogenesis. This review explores the physiological and pathological roles of PLK2, emphasizing its expression in the brain, its regulation by neuronal activity, and its involvement in synaptic homeostasis. Evidence from postmortem brain studies, in vivo models, and cell-based experiments indicates that PLK2 is associated with AD through multiple mechanisms. PLK2 has been shown to modulate the amyloidogenic processing of amyloid precursor protein (APP), is associated with increased Aβ production, and can directly phosphorylates APP at critical sites. Elevated PLK2 levels have also been associated with reduced APP surface expression and increased endocytosis, changes that are consistent with enhanced Aβ generation. Although direct phosphorylation of Tau by PLK2 has not been clearly established, recent findings suggest that PLK2 activity can modulate Tau protein levels and influence its phosphorylation state, potentially through regulation of other kinases and phosphatases. Pharmacological inhibition of PLK2 has shown promising effects in transgenic mouse models of AD, including modulation of Aβ and Tau pathology and improvement in cognitive performance, with some sex-specific responses. While these findings support a contributory role for PLK2 in AD-relevant pathways, its precise position within the causal hierarchy of disease progression remains to be fully established.},
}