@article {pmid39835867,
year = {2025},
author = {Rongve, A and Årsland, D and Fladby, T and Øksengård, AR and Selbæk, G},
title = {[New era in the treatment and diagnosis of Alzheimer’s disease].},
journal = {Tidsskrift for den Norske laegeforening : tidsskrift for praktisk medicin, ny raekke},
volume = {144},
number = {1},
pages = {},
doi = {10.4045/tidsskr.24.0604},
pmid = {39835867},
issn = {0807-7096},
}

@article {pmid41653394,
year = {2026},
author = {Okuyama, C and Oishi, N and Ishizu, K and Hasegawa, H and Ito, M and Fujita, Y and Kusano, K and Okina, T and Kagawa, S and Watanabe, H and Higashi, T and Yamauchi, H and Ono, M},
title = {A new amyloid PET evaluation method using separated gray-matter histogram based on three-component model.},
journal = {Annals of nuclear medicine},
volume = {40},
number = {5},
pages = {564-574},
pmid = {41653394},
issn = {1864-6433},
support = {KAKENHI (JSPS Grant Number JP21K07635).//Japan Society for the Promotion of Science/ ; },
abstract = {OBJECTIVE: We have constructed a three-component model underlying amyloid PET accumulation and developed a new gray matter histogram evaluation method based on this model. This study aims to validate the utility of the new method compared with conventional visual and SUVR-based quantitative evaluation.

METHODS: A retrospective analysis was performed on amyloid PET/CT data from 63 participants (25 healthy volunteers, 38 patients with dementia or cognitive impairment) of previous study using [18]F-FPYBF-2. Subjects were visually classified into three groups: negative, borderline, and positive, and quantitatively evaluated using composed standardized uptake value (comSUVR) with a reference to cerebellar cortex. Histograms were generated for the whole-brain, gray matter (GM-histogram), and white matter (WM-histogram) based on probability-tissue maps. The GM-histogram was further decomposed into two Gaussian components: G1 and G2　using statistical software. Parameters of whole-brain histogram: skewness, mode-to-mean ratio (MMR), and parameters of GM-histogram: GM-kurtosis, µG2 (mean of G2), and πG2 (proportion of G2), were compared among visual groups and the correlation with comSUVR was evaluated.

RESULTS: The GM-histogram was sharply unimodal in visually negative group but showed a wide shape to bimodal patterns in visually positive cases. Visually border group showed significantly higher πG2 than negative group, and positive group showed significantly higher µG2 than border group. GM-kurtosis and µG2 showed stronger negative (p < 0.0001, R[2] = 0.7539) and positive (p < 0.0001, R[2] = 0.8589) correlations with ComSUVR, respectively than the correlations between whole-brain histogram parameters and ComSUVR.

CONCLUSION: Our proposed GM-histogram provides a visually comprehensive morphology and quantitative indicators that match conventional visual and SUVR-based assessments and may potentially detect even subtle amyloid accumulation. This method is considered promising as a complementary tool for early diagnosis and treatment monitoring of Alzheimer’s disease.},
}

@article {pmid42050008,
year = {2026},
author = {Gascón, E and Calvo, AC and Zaragoza, P and Osta, R},
title = {Unveiling an ALS Blood Transcriptomic Signature: A Machine Learning Classifier Distinct from Neurodegenerative Controls.},
journal = {Neuroinformatics},
volume = {24},
number = {2},
pages = {},
pmid = {42050008},
issn = {1559-0089},
abstract = {UNLABELLED: The absence of accessible and reliable biomarkers constitutes a critical barrier for the early diagnosis and stratification of neurodegenerative diseases. While peripheral blood offers a minimally invasive window into systemic pathophysiology, identifying molecular signatures that survive biological heterogeneity and technical noise remains an unresolved challenge. In this study, this issue was addressed through a comparative systemic transcriptomic analysis of Amyotrophic Lateral Sclerosis (ALS), Alzheimer’s disease (AD), and Parkinson’s disease (PD) in whole blood, implementing a comprehensive workflow integrating unsupervised network analysis and supervised machine-learning methods. By employing LASSO regression and cross-validation across independent external cohorts, a stable and specific transcriptomic signature for ALS was identified, comprising key crosstalk genes involved in systemic immune dysregulation and microglial function, including CTSS, PTEN, IL18, PTPRC, and CSF1R. In contrast, AD and PD exhibited weak transcriptomic signatures with poor predictive reproducibility, suggesting a distinctive systemic pathology in ALS. In addition, the study confirms the superiority of linear modeling for this genomic signature: while complex non-linear algorithms, specifically Radial Basis Function (RBF) kernel Support Vector Machine (SVM) and Random Forest, displayed high initial performance, they collapsed due to overfitting during external validation. Conversely, the linear LASSO model demonstrated superior robustness and generalizability (AUC 0.74). In conclusion, this study not only defines a unique systemic immunotranscriptomic signature for ALS, distinguishable from other neurodegenerative pathologies, but also establishes interpretability and linear simplicity as essential factors for developing reproducible blood-based biomarkers with clinical translational potential.

GRAPHICAL ABSTRACT: [Image: see text]

SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s12021-026-09780-7.},
}

@article {pmid42055644,
year = {2026},
author = {Dinakarapandian, DM and Watzlawik, JO and Sudarshan, TR and Rosenberry, TL and Paravastu, AK},
title = {How to prepare Alzheimer's amyloid-β(1-42) oligomer samples with sufficient quantity and quality for biophysical and solid-state NMR measurements.},
journal = {Methods in enzymology},
volume = {729},
number = {},
pages = {419-433},
doi = {10.1016/bs.mie.2026.02.002},
pmid = {42055644},
issn = {1557-7988},
mesh = {*Amyloid beta-Peptides/chemistry/isolation & purification ; *Peptide Fragments/chemistry/isolation & purification ; *Alzheimer Disease/metabolism ; Humans ; Chromatography, Gel/methods ; *Nuclear Magnetic Resonance, Biomolecular/methods ; Micelles ; Sodium Dodecyl Sulfate/chemistry ; Ultracentrifugation ; Protein Multimerization ; },
abstract = {This chapter outlines a protocol for preparing an oligomeric amyloid-β peptide (AβO) for solid-state NMR structural studies. This protocol was developed for the 42-amino acid isoform Aβ(1-42), which is a focus due to its pathological link to Alzheimer's disease (AD). This peptide is highly aggregation-prone and would rapidly form fibrils without special efforts to direct aggregation towards AβO. Our protocol includes separation of Aβ(1-42) monomers from fibril seeds that are typically present in synthetic preparations, exposure of monomers to detergent micelles of sodium dodecyl sulfate (SDS), and separation of oligomers from monomers. Separation of distinct aggregated states of Aβ(1-42) is performed using size-exclusion chromatography. Removal of SDS is performed by dialysis. Solid-state NMR rotors can be loaded via ultracentrifugation or lyophilization.},
}

*Amyloid beta-Peptides/chemistry/isolation & purification
*Peptide Fragments/chemistry/isolation & purification
*Alzheimer Disease/metabolism
Humans
Chromatography, Gel/methods
*Nuclear Magnetic Resonance, Biomolecular/methods
Micelles
Sodium Dodecyl Sulfate/chemistry
Ultracentrifugation
Protein Multimerization

@article {pmid42055645,
year = {2026},
author = {Jenkins, J and Gilbert, MAG and Fatima, N and O'Sullivan, TJ and Thompson, WG and Frank, RAW},
title = {In-tissue structural biology of the brain: A focus on Alzheimer's disease pathology.},
journal = {Methods in enzymology},
volume = {729},
number = {},
pages = {69-106},
doi = {10.1016/bs.mie.2026.02.001},
pmid = {42055645},
issn = {1557-7988},
mesh = {*Alzheimer Disease/pathology ; Humans ; *Cryoelectron Microscopy/methods/instrumentation ; *Brain/pathology/ultrastructure ; Electron Microscope Tomography/methods ; Microscopy, Fluorescence/methods ; Animals ; },
abstract = {The structure of biology spans length scales from meters to Ångstroms - from whole organisms to the atomic positions of macromolecules. Cryo-electron microscopy is well-established for determining the structures of individual macromolecules in isolation, including pathological aggregates from post-mortem donor Alzheimer's disease brain. Recent advances integrating cryo-fluorescence microscopy, sample preparation and cryo-electron tomography are revealing macromolecular structures in the context of cells and anatomically intact tissues. In this chapter, we describe experimental workflows for targeting the in-tissue structure of Alzheimer's disease pathology. We discuss associated practical considerations and limitations of fluorescence labelling, vitrification, sample thinning by cryo-ultramicrotomy and cryo-focused ion-beam scanning electron microscopy (cryoFIB-SEM), cryogenic correlated light and electron microscopy (cryoCLEM), cryo-electron tomography (cryoET) and in-tissue subtomogram averaging (STA). These experimental considerations may be useful and applicable to amyloids, diseases and fundamental structural biology research questions more broadly.},
}

*Alzheimer Disease/pathology
Humans
*Cryoelectron Microscopy/methods/instrumentation
*Brain/pathology/ultrastructure
Electron Microscope Tomography/methods
Microscopy, Fluorescence/methods
Animals

@article {pmid42055793,
year = {2026},
author = {Caíña López, S and Portela Sotelo, A and Vázquez-Gómez, S},
title = {Drug repositioning in Alzheimer's disease: a vascular perspective targeting the NO-cGMP pathway.},
journal = {European journal of hospital pharmacy : science and practice},
volume = {},
number = {},
pages = {},
doi = {10.1136/ejhpharm-2026-005089},
pmid = {42055793},
issn = {2047-9956},
}

@article {pmid42055956,
year = {2026},
author = {Ivanidze, J and Gardella, J and Olson, A and Sun, SM and Thomas, C and Wong, OL and Intorcia, B and Moirano, J and Tanavde, V and Gershon, B and Pahlajani, S and Roytman, M and Nordvig, A and Lin, M and Hamed, M and Alport, A and Salgado, M and Keil, S and O'Dwyer, E and Lantos, J and Huicochea Castellanos, S and Ebani, EJ and Agee, M and Fink, ME and Osborne, JR and Chiang, GC and Blum, S},
title = {PET-guided Assessment of Amyloid Clearance and Outcomes in a Real-World Cohort of Patients with Alzheimer Disease undergoing Anti-Amyloid Therapy.},
journal = {AJNR. American journal of neuroradiology},
volume = {},
number = {},
pages = {},
doi = {10.3174/ajnr.A9387},
pmid = {42055956},
issn = {1936-959X},
abstract = {BACKGROUND AND PURPOSE: Beta-amyloid (Aβ)-PET is central to confirming Alzheimer disease (AD) before treatment with anti-amyloid monoclonal antibody therapies (AAT), however its role in treatment response monitoring in routine clinical practice remains unclear. This study aimed to evaluate longitudinal Aβ-PET changes following AAT and their association with clinical and safety outcomes in a real-world cohort.

MATERIALS AND METHODS: We conducted a retrospective single-center study of patients with mild cognitive impairment (MCI) or mild dementia due to AD who underwent Aβ-PET before and after treatment with AAT (lecanemab or donanemab). Aβ-PET scans were assessed using visual interpretation and quantitative measures including Centiloid level (CL) and regional Z-scores. Treatment-related amyloid clearance (TRAC) was determined based on magnitude of CL changes (ΔCL). Associations between Aβ-PET changes and baseline Fazekas score, amyloid-related imaging abnormalities (ARIA) and APOE-ε4 carrier status were examined. Associations between ΔCL and cognitive performance from baseline to post-AAT as assessed per Mini-Mental State Examination (ΔMMSE) were examined using multivariable linear regression models incorporating baseline CL and adjusting APOE-ε4 status and occurrence of ARIA. Region-specific multivariable analyses evaluated associations between regional Z-score changes and ΔMMSE.

RESULTS: Thirty-two patients met inclusion criteria (lecanemab, N=15; donanemab, N=17). Significant Aβ reduction was observed across the cohort (median ΔCL 59.11; p < 0.001) as well as within each treatment group. Most patients meeting TRAC criteria achieved full or partial TRAC (26/29, 89.7%). Baseline Aβ burden, as well as cognitive outcomes, did not differ significantly across TRAC categories (p = 0.25). ΔCL was not significantly associated with APOE-ε4 status or ARIA occurrence. In adjusted analyses, greater global CL reduction was associated with greater MMSE improvement, particularly at lower baseline burden. Region-specific analyses demonstrated marked, highly significant decrease in Z-scores across all regions.

CONCLUSIONS: Longitudinal Aβ-PET demonstrated substantial Aβ clearance following AAT in routine clinical practice. Aβ reduction was not significantly associated with baseline Aβ burden, ARIA, APOE-ε4 status. In adjusted analyses, greater Aβ reduction was associated with greater MMSE improvement. Our findings support Aβ-PET as a sensitive biomarker of biological treatment effect, while highlighting the complexity of linking Aβ clearance to short-term cognitive outcomes.},
}

@article {pmid42056071,
year = {2026},
author = {Giménez, S and Vaqué-Alcázar, L and Clos, S and Benejam, B and Carmona-Iragui, M and Maure-Blesa, L and Videla, L and Zhu, N and Altuna, M and Arranz, J and Barroeta, I and Rodríguez-Baz, Í and Bejanin, A and Bueno, A and Fernandez, S and Del Hoyo Soriano, L and Pertierra, L and Alcolea, D and Miller, B and Grinberg, LT and Ruiz, J and Lisgaras, CP and Wu, HT and Lleó, A and Osorio, RS and Blessing, EM and Fortea, J},
title = {Characterizing circadian rest-activity rhythm patterns across Alzheimer's disease continuum in Down syndrome.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {22},
number = {5},
pages = {e71409},
pmid = {42056071},
issn = {1552-5279},
support = {//Instituto de Salud Carlos III/ ; R01 AG056850/NH/NIH HHS/United States ; R21 AG056974/NH/NIH HHS/United States ; R01 AG061566/NH/NIH HHS/United States ; R01 AG081394/NH/NIH HHS/United States ; R61AG066543/NH/NIH HHS/United States ; 1RF1AG080769-01/NH/NIH HHS/United States ; GBHI_ALZ-18-543740//Global Brain Health Institute/ ; 1913 cycle 2019B//Jérôme Lejeune Foundation/ ; GBHI_ALZ-23-971107//Jérôme Lejeune Foundation/ ; 1801 Cycle 2020//Jérôme Lejeune Foundation/ ; IIBSP-DOW-2020-151//Fundación Tatiana Pérez de Guzmán el Bueno/ ; H2020-SC1-BHC-2018-2020//European Union/ ; 23S06157-001//Fundació La Caixa/ ; K24AG053435/GF/NIH HHS/United States ; U54 NS123746/GF/NIH HHS/United States ; R01 AG075802-04/GF/NIH HHS/United States ; R01 AG060477-01/GF/NIH HHS/United States ; R21AG086880/AG/NIA NIH HHS/United States ; R21AG086880/AG/NIA NIH HHS/United States ; R21 AG-086880/AG/NIA NIH HHS/United States ; R21AG086880/AG/NIA NIH HHS/United States ; R21AG086880/AG/NIA NIH HHS/United States ; R21 AG-086880/AG/NIA NIH HHS/United States ; Grant #1466036//CURE Epilepsy/ ; //New York State Office of Mental Health/ ; 23S06157-001//Fundación Bancaria Caixa d'Estalvis i Pensions de Barcelona/ ; H2020-SC1-BHC-2018-2020//HORIZON EUROPE Framework Programme/ ; (#1913 cycle 2019B//Fondation Jérôme Lejeune/ ; GBHI_ALZ-18-543740//University of California Global Health Institute/ ; PI20/00836//Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas/ ; AARG-22-923680/ALZ/Alzheimer's Association/United States ; },
mesh = {Humans ; *Down Syndrome/physiopathology/complications ; Male ; Female ; *Alzheimer Disease/physiopathology/complications ; *Circadian Rhythm/physiology ; Actigraphy ; Middle Aged ; Aged ; *Rest/physiology ; Disease Progression ; Adult ; Sleep Wake Disorders/physiopathology ; },
abstract = {INTRODUCTION: Sleep and circadian rest-activity rhythm (RAR) disruption may bidirectionally relate to Alzheimer's disease (AD). Down syndrome (DS), the most common genetic cause of AD, presents sleep disorders, yet RAR patterns across the DS-associated AD continuum remain uncharacterized.

METHODS: We analyzed 7-day wrist actigraphy in 140 adults with DS (108 asymptomatic; 32 AD dementia) and 41 unimpaired controls. General linear models, adjusted for age, sex, sleep efficiency, and obstructive sleep apnea (OSA) severity, tested group differences, with interaction terms included to evaluate group-specific associations.

RESULTS: DS showed lower relative amplitude and higher nocturnal activity, already in asymptomatic individuals. Rhythm strength declined further with AD progression, while regularity and phase timing remained preserved until dementia. Findings were independent of sleep duration and OSA.

DISCUSSION: Adults with DS showed early RAR disturbance that progressed across the AD continuum, paralleling sporadic AD. Circadian RAR features may be scalable biomarkers of AD progression.},
}

Humans
*Down Syndrome/physiopathology/complications
Male
Female
*Alzheimer Disease/physiopathology/complications
*Circadian Rhythm/physiology
Actigraphy
Middle Aged
Aged
*Rest/physiology
Disease Progression
Adult
Sleep Wake Disorders/physiopathology

@article {pmid42056392,
year = {2026},
author = {Henríquez, F and Riquelme, P and Forno, G and Migeot, J and Henríquez, R and Lillo, P and Thumala-Dockendorff, D and Okuma, C and Campo, CG and Hornberger, M and Aboitiz, F and Slachevsky, A},
title = {Activities of daily living and their neural correlates across the Alzheimer's disease continuum: Evidence from a Latin American cohort.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {22},
number = {5},
pages = {e71445},
pmid = {42056392},
issn = {1552-5279},
support = {ALZ-RWD-26-1466627/ALZ/Alzheimer's Association/United States ; SG-20-725707/ALZ/Alzheimer's Association/United States ; 21211340//ANID Doctoral Scholarship/ ; 1231839//ANID/FONDECYT regular/ ; 15150012//ANID/FONDAP/ ; CIN250068//ANID/CIN/ ; R01AG057234/AG/NIA NIH HHS/United States ; R01AG075775/AG/NIA NIH HHS/United States ; R01AG083799/AG/NIA NIH HHS/United States ; //Bluefield Project to Cure Frontotemporal Dementia GRANT: Building Capacity for Frontotemporal Dementia Trial in ReDLat/ ; //TAU Consortium and Rainwater Charitable Foundation, GRANT: Multi-Partner Consortium for Dementia Research in Latin America/ ; },
mesh = {Humans ; *Alzheimer Disease/pathology/psychology/physiopathology ; *Activities of Daily Living ; Female ; Male ; Aged ; Magnetic Resonance Imaging ; *Cognitive Dysfunction/pathology ; Disease Progression ; Cohort Studies ; Latin America ; Neuropsychological Tests ; Aged, 80 and over ; *Brain/pathology/diagnostic imaging ; *Gray Matter/pathology/diagnostic imaging ; Surveys and Questionnaires ; },
abstract = {INTRODUCTION: Functional decline in activities of daily living (ADL)-advanced (AADL), instrumental (IADL), and basic (BADL)-is a hallmark of Alzheimer's disease (AD). However, integrated clinical-neuroanatomical evidence on progression across the AD continuum remains limited, particularly in Latin American populations.

METHODS: We studied 138 older adults with subjective cognitive complaints (SCCs), mild cognitive impairment (MCI), and Alzheimer's disease dementia (ADD). ADL domains were assessed using the Technology-Activities of Daily Living Questionnaire. Structural magnetic resonance imaging data were analyzed using voxel-based morphometry (VBM) to identify gray matter (GM) correlates of ADL performance.

RESULTS: A hierarchical decline from AADL to IADL to BADL differentiated clinical stages. SCC and MCI differed mainly in AADL performance, whereas ADD showed decline across all domains. VBM revealed GM correlates consistent with this hierarchy, with distinct but partially overlapping substrates for each ADL domain.

DISCUSSION: These findings underscore a diagnostically informative and anatomically organized progression of ADL decline.},
}

Humans
*Alzheimer Disease/pathology/psychology/physiopathology
*Activities of Daily Living
Female
Male
Aged
Magnetic Resonance Imaging
*Cognitive Dysfunction/pathology
Disease Progression
Cohort Studies
Latin America
Neuropsychological Tests
Aged, 80 and over
*Brain/pathology/diagnostic imaging
*Gray Matter/pathology/diagnostic imaging
Surveys and Questionnaires

@article {pmid42056639,
year = {2026},
author = {Vazquez-Guajardo, M and Mimenza-Alvarado, AJ and Martinez-Zamora, CA and Lee, A and Padilla Solis, OAJ and Parodi, JF and Custodio Capuñay, NS and Aguilar-Navarro, SG},
title = {Bibliometric analysis of Alzheimer's and dementia research in Latin America.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {22},
number = {5},
pages = {e71395},
pmid = {42056639},
issn = {1552-5279},
mesh = {*Bibliometrics ; Humans ; Latin America ; *Dementia ; *Alzheimer Disease ; *Biomedical Research/statistics & numerical data ; },
abstract = {INTRODUCTION: Dementia is increasing rapidly in Latin America and the Caribbean (LAC), but research output remains limited. Tracking publication trends, themes, and collaborations is key to guiding regional research and policy.

METHODS: Bibliometric analysis was conducted on dementia-related publications from 21 LAC countries (1990 to 2024) using Scopus. Thirteen keywords identified relevant articles, classified into themes through artificial intelligence (AI)-assisted and manual review. Bibliometrix and VOSviewer assessed publication trends, country and institutional output, and collaboration networks.

RESULTS: Of 201,939 worldwide publications, 6003 (3%) included at least one LAC-affiliated author. Brazil produced 49.9% of all dementia publications, followed by Argentina and Mexico. Clinical scenarios (15%) and basic science (14%) dominated thematic output. Mexico, Argentina, and Chile led regional collaboration efforts.

DISCUSSION: Despite growth, dementia research in LAC remains concentrated in a few countries, with major thematic gaps and uneven collaboration. Strengthening cross-country partnerships, broadening research themes, and increasing investment in applied and policy-focused studies are essential.},
}

*Bibliometrics
Humans
Latin America
*Dementia
*Alzheimer Disease
*Biomedical Research/statistics & numerical data

@article {pmid42056645,
year = {2026},
author = {Rani, S and Khatri, A and Devi, S and Mahesh, KV and Sandhir, R and Prabhakar, N},
title = {Electrochemical detection of miRNA-128 in Alzheimer's disease using (3-aminopropyl) triethoxysilane and citrate-capped green-synthesized silver nanoparticles.},
journal = {Mikrochimica acta},
volume = {193},
number = {5},
pages = {},
pmid = {42056645},
issn = {1436-5073},
support = {201610127295//University Grants Commission/ ; 13(9268-A/2024-Pool//Human Resource Development Centre, Council of Scientific And Industrial Research/ ; },
}

@article {pmid42056682,
year = {2026},
author = {Song, Z and Huang, X and Jannu, AJ and Johnson, TS and Zhang, J and Huang, K},
title = {Identification of Alzheimer's disease subtypes and biomarkers from human multi-omics data using subspace merging algorithm.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {22},
number = {5},
pages = {e71292},
pmid = {42056682},
issn = {1552-5279},
support = {5U54AG065181//National Institutes of Health (NIH)/ ; R21AG075541//National Institutes of Health (NIH)/ ; },
mesh = {Humans ; *Alzheimer Disease/genetics/classification/pathology ; *Algorithms ; *Biomarkers ; Quantitative Trait Loci/genetics ; Male ; Female ; Brain/pathology/metabolism ; Aged ; Cohort Studies ; Genome-Wide Association Study ; Phenotype ; Transcriptome ; Multiomics ; },
abstract = {INTRODUCTION: Alzheimer's disease (AD) is a heterogeneous disease with diverse disease progression trajectories and brain pathology. Identifying AD subtypes is essential for understanding AD etiology, heterogeneity, and developing precise treatment.

METHODS: We applied a subspace-merging algorithm to integrate multi-omics data from brain tissues of three large AD cohorts and identify data-driven AD subtypes. Within each cohort, we performed multiple analyses to characterize subtype-specific biology. A Phenome-wide Association Study (PheWAS) of expression quantitative trait loci (eQTLs) targeting differentially expressed genes (DEGs) was conducted to link molecular differences to disease phenotypes.

RESULTS: We identified AD subtypes that differed in cognitive and pathological phenotypes in three cohorts. Further analyses highlighted synaptic and neurotransmission pathways, and the PheWAS revealed significant associations with disease phenotypes.

DISCUSSION: Our developed integration algorithm successfully merged different data modalities into a common subspace for patient clustering and identified data-driven subtypes. The identified transcriptomic signatures provide valuable insights into the molecular mechanisms underlying AD heterogeneity, paving the way for personalized AD treatment.},
}

Humans
*Alzheimer Disease/genetics/classification/pathology
*Algorithms
*Biomarkers
Quantitative Trait Loci/genetics
Male
Female
Brain/pathology/metabolism
Aged
Cohort Studies
Genome-Wide Association Study
Phenotype
Transcriptome
Multiomics

@article {pmid42057007,
year = {2026},
author = {He, Z and Xing, Y and Gu, J and Xu, D and He, P and Lin, X and Cui, W and Lv, H and Ding, H and Sui, K and Hao, W and Zheng, Y and Yang, X and Huang, X and Yin, K and He, C and Zheng, K and Yu, Y and Pan, W},
title = {PTP1B in astrocytes drives pathogen-induced neurodegeneration.},
journal = {Journal of neuroinflammation},
volume = {},
number = {},
pages = {},
doi = {10.1186/s12974-026-03837-9},
pmid = {42057007},
issn = {1742-2094},
support = {202410313045Y//Training Programs of Innovation and Entrepreneurship for College Students in Jiangsu Province/ ; 202510313019//the Training Programs of Innovation and Entrepreneurship for College Students in Jiangsu Province/ ; No. 82302557//National Natural Science Foundation of China/ ; No. BK20201459//Natural Science Foundation of Jiangsu Province/ ; No. QL-YB022//the XZHMU-QL Joint Research Fund/ ; },
abstract = {Mounting evidence implicates pathogen infections in the pathogenesis of Alzheimer's disease (AD), yet the cellular mechanisms underlying infection-induced neurodegeneration remain poorly understood. Central to this process is the dysfunction of astrocyte-neuron interactions, which are critical for maintaining neuroinflammatory balance and synaptic homeostasis. Here, we demonstrate that astrocytic protein tyrosine phosphatase 1B (PTP1B) acts as a key regulator of astrocyte reactivity during infection, leading to impaired neuroglial communications and cognitive decline. In a murine model of chronic Toxoplasma gondii (T. gondii) infection, elevated PTP1B levels in astrocytes were closely associated with neuroinflammation and cognitive impairments. Conditional deletion of astrocytic PTP1B or its pharmacological inhibition mitigated neuroinflammation, restored synaptic integrity, and rescued cognitive function. Mechanistically, astrocytic PTP1B induced the polarization of A1-like neurotoxic reactive astrocytes, enhanced glutamate-mediated excitotoxicity, and triggered neuronal senescence, collectively contributing to synaptic damage and cognitive deficits. Notably, elevated levels of PTP1B, GAFP and cellular senescence markers were observed in the serum samples from T. gondii IgG-seropositive individuals and in hippocampal transcriptomes from AD patients, underscoring the translational relevance. Together, our findings reveal that PTP1B-mediated disorder of astrocyte-neuron crosstalk represents a novel mechanism of pathogen-driven neurodegeneration.},
}

@article {pmid42057058,
year = {2026},
author = {Yang, D and Ke, Z and Chen, N and Yue, L and Chen, S and Jiang, M and Hu, Z and Xie, C and Zhu, W and Xu, J and Yu, L and Tang, L and Zhao, H and Dong, J and Li, C and Chen, G and Luo, B and Zhang, J and Xu, Y},
title = {Performance of plasma pTau217, pTau181 and their ratios to Aβ42 in detecting Aβ pathology using a China-developed direct chemiluminescence assay.},
journal = {Alzheimer's research & therapy},
volume = {},
number = {},
pages = {},
doi = {10.1186/s13195-026-02058-9},
pmid = {42057058},
issn = {1758-9193},
support = {2022ZD0211800//the STI2030-Major Projects/ ; 82130036//the National Natural Science Foundation of China/ ; ZDXK202216//Jiangsu Province Key Medical Discipline/ ; },
abstract = {BACKGROUND: Increasing evidence indicates that blood-based biomarkers, particularly phosphorylated tau (pTau) 217 and the pTau217/amyloid‑β (Aβ) 42 ratio, demonstrate strong diagnostic performance for Alzheimer's disease (AD) and may offer a minimally invasive alternative to cerebrospinal fluid (CSF) assays and Aβ PET imaging. There is an urgent need to develop local plasma pTau217 and pTau217/Aβ42 ratio assay and to establish population-appropriate diagnostic cutoffs tailored to Chinese populations.

METHODS: This study included 831 individuals from a community-based memory screening cohort and 301 patients from a hospital-based cohort with confirmed Aβ pathology. Plasma pTau217, pTau181, and their ratios to Aβ42 were measured using a high-sensitivity direct chemiluminescence (DCL) immunoassay incorporating proprietary China-developed antibodies. Data-driven Gaussian mixture modeling (GMM) was applied to the community cohort to derive biomarker cutoffs; the diagnostic performance of these cutoffs was validated in the patients with confirmed Aβ pathology. A two-cutoff approach was established in the hospital-based cohort. Multivariate regression analysis was performed to assessed potential confounding effects from routine blood biochemical parameters.

RESULTS: GMM identified cutoffs of 4.380 pg/mL for pTau217 and 0.670 for the pTau217/Aβ42 ratio. These values closely matched cutoffs derived from the maximum Youden index (4.296 pg/mL for pTau217 and 0.706 for pTau217/Aβ42) and achieved high diagnostic accuracy (up to 89%) for Aβ pathology in the hospital-based cohort with confirmed Aβ pathology, outperforming pTau181-based measures. Only the pTau217/Aβ42 ratio was unaffected by routine plasma biochemistry. Using a two-cutoff workflow, pTau217 or the pTau217/Aβ42 ratio definitively classified approximately 90% of patients as positive or negative, leaving an intermediate-risk zone of < 10%.

CONCLUSIONS: The China-developed DCL immunoassay reliably measures plasma pTau217 and the pTau217/Aβ42 ratio with high diagnostic accuracy for detecting Aβ pathology. The biochemical stability of the pTau217/Aβ42 ratio supports its potential as a practical, less invasive alternative to CSF or PET testing in Chinese populations.},
}

@article {pmid42057258,
year = {2026},
author = {Yi, Y and Jia, P and Xie, P and Peng, X and Zhu, X and Yin, S and Yan, C and Yu, G},
title = {Natural Products for Alzheimer's Disease: A New Twist Impacting Ferroptosis.},
journal = {The American journal of Chinese medicine},
volume = {},
number = {},
pages = {1-25},
doi = {10.1142/S0192415X26500266},
pmid = {42057258},
issn = {1793-6853},
abstract = {Alzheimer's disease (AD) is a neurodegenerative disorder characterized by progressive cognitive decline. Despite significant advances in AD research, effective disease-modifying therapies remain unavailable. In recent years, ferroptosis has gained increasing attention for its potential role in the pathogenesis of AD. Accumulating evidence indicates that substantial iron accumulation, dysregulation of anti-oxidant defense systems, and elevated levels of lipid peroxidation are present in the brains of AD patients. These alterations create a conducive environment for ferroptosis and are closely associated with neuronal death and cognitive dysfunction. Therefore, targeting ferroptosis-related signaling pathways holds promise as a novel strategy to delay or halt the progression of AD. Natural products, such as flavonoids, phenolic compounds, and terpenoids, have become a focus of research in the intervention of neurodegenerative diseases due to their structural diversity, broad biological activities, and relatively low toxicity. Increasing studies have demonstrated that various herbal medicines, including Rhodiola rosea, Polygala tenuifolia, Ginkgo biloba, and Poria cocos, can effectively suppress ferroptosis through multiple mechanisms. These mechanisms include scavenging free radicals, enhancing anti-oxidant capacity, modulating iron metabolism, and restoring the function of key regulators like GPX4 or system Xc[-], to thereby ameliorate AD-related neural damage. This review systematically summarizes recent advances in understanding the role of ferroptosis in AD and highlights the therapeutic potential of natural products that target ferroptotic pathways. We aim to provide theoretical support and candidate molecules for the development of novel AD treatment strategies based on ferroptosis regulation, and thus offer valuable insights for future research into new ferroptosis inhibitors.},
}

@article {pmid42057270,
year = {2026},
author = {Halpin, SN},
title = {Interviewing People Living with Cognitive Impairment: A Conversation Analysis of Supportive Interactional Practices.},
journal = {The Gerontologist},
volume = {},
number = {},
pages = {},
doi = {10.1093/geront/gnag062},
pmid = {42057270},
issn = {1758-5341},
abstract = {Effective qualitative interviews with individuals with cognitive impairment require careful conversational strategies to maintain dignity, support engagement, and enable meaningful narrative co-construction. Despite recognition of these challenges, practical guidance on interviewer talk in dementia research remains limited. This study applies conversation analysis (CA) to examine interviewer practices used in interviews with individuals with mild cognitive impairment (MCI) or Alzheimer's disease (AD). Analysis of 17 interviews identified five recurring practices: (1) scaffolding memory retrieval through subtle prompts, (2) normalizing cognitive lapses using humor and affiliative talk, (3) echoing and affirming responses to sustain narrative coherence, (4) managing caregiver co-participation to preserve participant voice, and (5) repairing emotional disclosures to support dignity. These practices shaped participants' experiences by validating emotions, affirming partial successes, and maintaining autonomy, thereby enhancing both ethical and empirical quality. This study addresses a key methodological gap by offering concrete, interactionally grounded strategies to improve qualitative interviews with cognitively impaired populations. Future research should examine these practices across more diverse populations and multimodal data sources.},
}

@article {pmid42057407,
year = {2026},
author = {Lee, M and Kim, M},
title = {Donepezil increases angiogenic potential in patients with Alzheimer's disease.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261444020},
doi = {10.1177/13872877261444020},
pmid = {42057407},
issn = {1875-8908},
abstract = {BackgroundAlzheimer's disease (AD) is the leading cause of dementia in the elderly. Acetylcholinesterase inhibitors are the mainstay of symptomatic treatment, and vascular dysfunction is increasingly recognized as a key contributor to AD pathophysiology. While donepezil is a standard AD treatment, its effects on the vascular system remain poorly understood despite known neurovascular interactions.ObjectiveTo investigate whether donepezil treatment influences endothelial progenitor cell (EPC) populations and differentiation capacity in patients with AD.MethodsEPCs were evaluated in healthy controls and patients with AD (n = 20 per group; N = 80 total): controls (Ctrl), patients initiating donepezil 5 mg (Dp_Start), patients receiving donepezil 5 mg for ≥6 months (Dp_5 mg), and patients escalated to 10 mg after ≥6 months of 5 mg treatment (Dp_10 mg). Peripheral blood samples were collected at baseline, 12 weeks, and 24 weeks. Circulating EPCs were quantified by flow cytometry, and EPC differentiation capacity was assessed by counting early and late EPC colony-forming units (CFUs).ResultsAt baseline, EPC differentiation capacity was reduced in AD patients compared with controls. Circulating EPC levels did not show significant changes across groups or treatment durations. In contrast, both early and late EPC CFU counts were significantly increased in AD patients receiving donepezil, particularly during the first 12 weeks of treatment. This effect was pronounced in patients initiating donepezil therapy.ConclusionsDonepezil enhanced EPC differentiation into early and late populations without altering circulating EPC levels. These findings suggest that donepezil improves EPC functional competence and vascular regenerative capacity beyond its established cognitive effects.},
}

@article {pmid42057546,
year = {2026},
author = {Jha, NK and Chauhan, P and Abomughaid, MM and Avinash, D and Almutary, AG and Lakhanpal, S and Singh, A and Sulaimani, GM and Al-Kuraishy, HM and Mohammed, HA and Misra, J and Thakur, K and Kumar, D},
title = {mTOR Signalling in Neurodegenerative Disorders: Unveiling Key Factors, Mechanistic Insights, and Possible Therapeutic Interventions.},
journal = {Cellular physiology and biochemistry : international journal of experimental cellular physiology, biochemistry, and pharmacology},
volume = {60},
number = {2},
pages = {136-174},
doi = {10.33594/000000858},
pmid = {42057546},
issn = {1421-9778},
mesh = {*TOR Serine-Threonine Kinases/metabolism/antagonists & inhibitors ; Humans ; *Signal Transduction/drug effects ; *Neurodegenerative Diseases/metabolism/pathology/drug therapy ; Animals ; Phosphatidylinositol 3-Kinases/metabolism ; Proto-Oncogene Proteins c-akt/metabolism ; AMP-Activated Protein Kinases/metabolism ; Alzheimer Disease/metabolism/pathology/drug therapy ; Autophagy ; },
abstract = {Neurodegenerative diseases (NDDs) are defined by the gradual degeneration of neuronal cells, wherein the accumulation of misfolded proteins can lead to memory impairments, motor dysfunctions, and other deteriorations. Despite the widespread impact, there are currently no viable pharmaceuticals to treat these disorders. The mTOR protein is a crucial regulator of cell survival, growth, autophagy, and apoptosis. Targeted modulation of mTOR signaling holds promise for mitigating neurodegeneration in Alzheimer's, Huntington's, ALS, and Parkinson's disease. Understanding its interactions with pathways such as PI3K/Akt, AMPK, and SIRT1 is essential for developing effective therapeutics.},
}

*TOR Serine-Threonine Kinases/metabolism/antagonists & inhibitors
Humans
*Signal Transduction/drug effects
*Neurodegenerative Diseases/metabolism/pathology/drug therapy
Animals
Phosphatidylinositol 3-Kinases/metabolism
Proto-Oncogene Proteins c-akt/metabolism
AMP-Activated Protein Kinases/metabolism
Alzheimer Disease/metabolism/pathology/drug therapy
Autophagy

@article {pmid42057585,
year = {2026},
author = {Ramírez-Márquez, CD and López-López, E and Medina-Franco, JL},
title = {Constellation Plots in KNIME: An Automated Scaffold-Based Workflow for Interactive Chemical Space Visualization.},
journal = {Molecular informatics},
volume = {45},
number = {5},
pages = {e70035},
pmid = {42057585},
issn = {1868-1751},
mesh = {Workflow ; *Software ; *Drug Discovery/methods ; Humans ; Algorithms ; tau Proteins/antagonists & inhibitors ; },
abstract = {Chemical space analysis is extensively used in different chemistry areas, ranging from the study of natural products to drug discovery projects. Its versatility stems from the ability to integrate continuous properties with molecular representations. This data is used to generate visualizations through dimensionality reduction algorithms. Constellation Plots have been proposed as a general approach to the visual representation of chemical space by encoding structural similarity, scaffold contents, frequency, and continuous properties into a single coordinate-based map. Thus, Constellation Plots provide a high-density visual representation of the chemical space of compound datasets with complex relations. Despite the versatility of Constellation Plots, there remains a significant lack of intuitive, user-friendly, or low-code protocols to automate the generation of these plots for non-computational experts. Herein, we present an interactive and automated scaffold-based Constellation Plot workflow developed within the open-source platform KNIME, facilitating chemical space visualization and analysis. To illustrate the application of the workflow, we used a dataset of 5,211 compounds that inhibit Tau protein, a key therapeutic target for Alzheimer's disease. The KNIME workflow is a general resource that can be used to analyze virtually any data set annotated with a property, including biological activity. The workflow is freely available at: https://github.com/Daniphantom99/KNIME_Constellation_plots.},
}

Workflow
*Software
*Drug Discovery/methods
Humans
Algorithms
tau Proteins/antagonists & inhibitors

@article {pmid42057743,
year = {2026},
author = {Radhakrishnan, A and Dutta, D and Saha, M and Venkatakrishnan, S and Kulkarni, A and Chandrachari, KP and Salins, PC and Suresh, A},
title = {Neuro-reparative potential of hyperbaric oxygen therapy in animal models of Alzheimer's and Parkinson's diseases: systematic review and meta-analysis.},
journal = {Neurodegenerative disease management},
volume = {},
number = {},
pages = {1-9},
doi = {10.1080/17582024.2026.2665357},
pmid = {42057743},
issn = {1758-2032},
abstract = {INTRODUCTION: This systematic review and meta-analysis explored the efficacy of Hyperbaric oxygen therapy (HBOT) in preclinical models of Alzheimer's disease (AD) and Parkinson's disease (PD).

METHODS: Data were extracted as per PRISMA guidelines using specific search criteria, with bias assessed using SYRCLE guidelines. Random-effect models were used for meta-analyses of key outcomes, and forest plots were generated. Outcomes assessed included cognitive and motor performance, neuroinflammation, oxidative stress, mitochondrial function, apoptosis, and dopaminergic neuron survival.

RESULTS: The PRISMA search yielded 8 studies (AD: 3; PD: 5) from a total of 8261 articles identified. A total of 308 animals were reported across the studies; however, 182 were included in the meta-analysis, as only animals from relevant treatment and corresponding control groups with extractable outcome data were eligible for quantitative analysis. HBOT significantly improved cognitive function (reduced escape latency, Standardized Mean Difference; SMD: -2.13), improved spatial memory, and reduced compensatory locomotor activity (decreased distance traveled, SMD: -6.94). The markers of neuroinflammation (lower TNF-α, higher IL-10), oxidative stress (SOD, MDA), mitochondrial biogenesis (SIRT1, PGC-1α, TFAM, VDAC), and anti-apoptotic markers (higher Bcl-xl, lower Bax) showed differences in post-HBO treatment. HBOT also preserved dopaminergic neurons in PD models.

CONCLUSIONS: These preclinical findings support HBOT as a potential complementary neuroprotective therapy for AD and PD, warranting further clinical validation.},
}

@article {pmid42057932,
year = {2026},
author = {Kanazawa, M and Hatakeyama, M and Imamura, T and Kobayashi, T},
title = {Chronic rhinosinusitis and posterior cingulate hypoperfusion on SPECT in dementia diagnosis.},
journal = {Frontiers in neurology},
volume = {17},
number = {},
pages = {1777862},
pmid = {42057932},
issn = {1664-2295},
abstract = {INTRODUCTION: Single-photon emission computed tomography (SPECT) is widely used in dementia clinics to evaluate regional cerebral blood flow (rCBF). Posterior cingulate cortex (PCC) hypoperfusion is a supportive, though not definitive, marker for Alzheimer's disease (AD). Magnetic resonance imaging (MRI)-defined sinus inflammation has been associated with systemic inflammation and altered brain connectivity; therefore, we aimed to determine whether MRI-defined chronic rhinosinusitis (CRS) is associated with differences in PCC perfusion patterns on SPECT among patients with cognitive impairment.

METHODS: We retrospectively reviewed 54 patients with cognitive impairment who had undergone brain MRI and SPECT. CRS was defined using MRI-based modified Lund-Mackay scores. SPECT findings were analyzed using the easy Z-score Imaging System (eZIS), focusing on PCC severity, extent, and ratio. Comparisons were performed between patients with and without CRS.

RESULTS: Ten patients (18.5%) had CRS. The frequency of AD was higher in patients with CRS than in patients without CRS (p = 0.028). Compared with patients without CRS (n = 44), those with CRS showed significantly greater PCC hypoperfusion: eZIS severity (1.7 ± 0.5 vs. 1.2 ± 0.4, p = 0.026), extent (26.1 ± 13.4% vs. 15.1 ± 14.3%, p = 0.196), and ratio (5.0 ± 2.8 vs. 2.0 ± 1.7, p = 0.013). No differences were observed in the cingulate island sign score (CIScore; p = 0.215). Moreover, in the subgroup of patients clinically diagnosed with AD, those with CRS showed significantly greater PCC hypoperfusion than those without CRS (1.8 ± 0.3 vs. 1.4 ± 0.5; p = 0.023). PCC hypoperfusion in CRS overlapped with canonical AD patterns but was not observed in non-AD dementias.

CONCLUSION: Our exploratory findings suggest that MRI-defined CRS may be associated with differences in SPECT-derived PCC perfusion patterns in patients with cognitive impairment. Awareness of CRS as a common incidental MRI finding may help neurologists interpret SPECT results more cautiously in memory clinic settings.},
}

@article {pmid42058034,
year = {2026},
author = {Hong, BV and Liu, Y and Oloumi, A and K Agus, J and Bouchibti, Y and Jin, LW and Maezawa, I and Harvey, DJ and Lebrilla, CB and Zivkovic, AM},
title = {LOESS-based normalization workflow for targeted HDL glycoproteomics in an Alzheimer's disease cohort.},
journal = {RSC advances},
volume = {16},
number = {24},
pages = {22252-22260},
pmid = {42058034},
issn = {2046-2069},
abstract = {High-density lipoprotein (HDL) carries proteins and glycoproteins involved in lipid metabolism and inflammatory regulation, yet quantitative characterization of HDL-associated peptides in Alzheimer's disease (AD) cohorts remains challenging due to small biological effect sizes superimposed on substantial technical variability. We applied a Locally Estimated Scatterplot Smoothing (LOESS)-based drift correction and internal-standard-guided normalization workflow to targeted multiple reaction monitoring (MRM) glycoproteomic data generated from HDL isolates collected from 194 participants spanning the cognitive spectrum. Of the 164 transitions originally targeted, 59 features passed quality control (QC), and 21 HDL-associated peptide and glycopeptide features showed consistent signal across all 194 samples; these 21 analytes were used for analysis. Normalization improved analytical reproducibility, reducing median HDL pooled QC coefficients of variation from 69.1% to 55.2%. APOE genotype analyses identified six peptides with statistically significant differences between APOE3/E3 and APOE3/E4 carriers, five of which remained statistically significant after false-discovery rate correction, and all six of which remained significant in covariate-adjusted models, whereas disease-related differences within APOE3/E3 carriers were modest and did not remain statistically significant after covariate adjustment. These findings demonstrate that LOESS-based drift correction combined with feature-specific internal-standard selection stabilizes quantitative HDL glycoproteomic measurements and support downstream comparisons. This workflow provides a practical framework for QC-informed normalization in targeted glycoproteomics and highlights APOE-associated variation in HDL peptides within an aging clinical cohort.},
}

@article {pmid42058326,
year = {2026},
author = {Han, S and Liu, M and Zhao, S and Yan, W and Lu, Z and Huang, X},
title = {Development of Free Testosterone Chemiluminescence Detection Kit and Its Clinical Application.},
journal = {Journal of analytical methods in chemistry},
volume = {2026},
number = {},
pages = {5165899},
pmid = {42058326},
issn = {2090-8865},
abstract = {BACKGROUND: Free testosterone (FT), the bioactive form comprising 1%-2% of total testosterone, directly enters cells. Unlike total testosterone, FT levels are less affected by sex hormone-binding globulin and better reflect biological activity. Accurate serum FT measurement is crucial for diagnosing conditions like male hypogonadism, PCOS, metabolic syndrome, osteoporosis, and Alzheimer's. However, existing methods suffer from inadequate sensitivity, complexity, and high cost, necessitating improved detection technologies. We developed and evaluated a chemiluminescence assay kit for FT.

METHODS: FT was quantified using a competitive immunoassay where sample FT competes with acridinium ester-labeled testosterone derivatives for binding to biotinylated antitestosterone antibodies on magnetic beads. Key parameters (magnetic bead concentration, biotinylation, labeling, and antibody/derivative concentrations) were optimized. Kit performance was rigorously assessed for linearity, limit of blank (LoB), accuracy, precision, stability, specificity, and clinical relevance. FT levels were measured in 1615 male and 2035 female patient samples to analyze clinical significance.

RESULTS: The assay demonstrated excellent linearity (r > 0.99), low LoB (0.021 pg/mL), high accuracy (deviation < 5%), precision (CV < 5%), and 12-month stability. Specificity testing showed no cross-reactivity. Method comparison with 392 clinical samples yielded a strong correlation (r = 0.9941). Analysis of patient samples revealed significant FT level differences among males with various diagnoses: lower levels in prostate cancer patients and higher levels in conditions like hair loss.

CONCLUSION: The developed chemiluminescence FT assay kit exhibits superior performance, low cost, and high automation, fully meeting clinical requirements. FT measurement provides a valuable reference for diagnosing and assessing specific diseases, aiding improved clinical management.},
}

@article {pmid42058506,
year = {2026},
author = {Rabaneda-Lombarte, N and Ferrari-Souza, JP and Celedon, J and Zimmer, ER and Dickerson, BC and Arnold, SE and Kivisäkk, P and Serrano-Pozo, A},
title = {Real-world comparison of brain [[18]F]FDG-PET imaging with CSF Alzheimer's disease biomarkers in a tertiary memory clinic setting.},
journal = {EClinicalMedicine},
volume = {95},
number = {},
pages = {103910},
pmid = {42058506},
issn = {2589-5370},
abstract = {BACKGROUND: [[18]F]FDG-PET brain scan remains widely used in the evaluation of cognitive decline worldwide, however data on its diagnostic performance against gold-standard CSF Alzheimer's disease (AD) biomarkers are scarce. We aimed to assess the agreement between [[18]F]FDG-PET findings and CSF AD biomarkers in a real-world tertiary memory clinic setting.

METHODS: Cross-sectional study of Mass General Brigham patients with cognitive concerns and available [[18]F]FDG-PET imaging and CSF AD biomarkers between 01/01/2013 and 06/30/2025. [[18]F]FDG-PET brain scan findings were categorized as "Normal," "Abnormal Inconclusive," "Abnormal Not AD-like," or "Abnormal AD-like," based on the narrative report. The CSF AD biomarker panel was classified as "Not AD," "Equivocal," or "Consistent with AD" following the lab report. [[18]F]FDG-PET was compared with gold-standard CSF AD biomarkers using kappa agreement test and regression models.

FINDINGS: Among 360 eligible individuals, 151 had a CSF profile "Consistent with AD," 136 "Equivocal," and 73 "Not Consistent with AD." The [[18]F]FDG-PET showed an AD-like pattern in 73/151 (48.3%) of subjects with CSF "Consistent with AD" and was normal in 30/73 (41.1%) of those with CSF "Not Consistent with AD." However, 19/151 (12.6%) of individuals with a CSF profile "Consistent with AD" had normal [[18]F]FDG-PET scans (false negatives) whereas 8/73 (11.0%) of those with a CSF profile "Not Consistent with AD" had an AD-like [[18]F]FDG-PET pattern (false positives), resulting in 0.48 sensitivity, 0.84 specificity, and 0.66 AUC of [[18]F]FDG-PET report vs. gold-standard CSF AD biomarkers, and a fair agreement between both tests (κ = 0.334). An AD-like [[18]F]FDG-PET pattern was strongly associated with a CSF "Consistent with AD" (OR = 4.81, p < 0.0001) and a lower Amyloid-Tau Index (ATI; β = -0.43, p < 0.0001). By region, posterior cingulate gyrus glucose hypometabolism predicted both an AD-like [[18]F]FDG-PET result (OR = 6.41, p < 0.0001) and a CSF profile "Consistent with AD" (OR = 2.48, p = 0.0003), whereas frontal hypometabolism predicted a Not AD-like [[18]F]FDG-PET result (OR = 5.90, p < 0.0001) but also lower odds of a CSF "Not Consistent with AD" (OR = 0.41, p = 0.0016).

INTERPRETATION: [[18]F]FDG-PET imaging demonstrated high specificity but limited sensitivity to identify AD as defined by CSF biomarker criteria. Although a report of a typical AD-like [[18]F]FDG-PET pattern of glucose hypometabolism predicted a positive CSF AD biomarker panel, the agreement between [[18]F]FDG-PET report and CSF AD biomarker results was only fair.

FUNDING: NR-L was supported by a Research Fellowship from the Fundación Ramón Areces, Madrid (Spain). JC, BCD, SEA, PK, and AS-P were supported by the Massachusetts Alzheimer's Disease Research Center (NIH/NIA P30AG062421).},
}

@article {pmid42058736,
year = {2026},
author = {Xu, B and Wan, H and Liu, P and Zhao, Z and Xie, Y and Meng, J and Qin, Y},
title = {Application of Photostimulation Therapy in Cognitive Function of Alzheimer's Disease Patients: A Scoping Review.},
journal = {Clinical interventions in aging},
volume = {21},
number = {},
pages = {600468},
pmid = {42058736},
issn = {1178-1998},
mesh = {Humans ; *Alzheimer Disease/therapy/psychology ; *Cognition ; *Phototherapy/methods ; Quality of Life ; *Cognitive Dysfunction/therapy ; },
abstract = {BACKGROUND: Alzheimer's disease patients often experience cognitive decline during disease progression, impacting their quality of life. Photostimulation therapy, as a non-invasive neuromodulation method, has been increasingly used in the adjunctive management of Alzheimer's patients in recent years. Despite the increasing number of related studies, a systematic review and comprehensive evaluation are still lacking.

OBJECTIVE: This review systematically summarizes the current application of photostimulation therapy in Alzheimer's disease patients, outlines its implementation characteristics, outcome indicators, intervention effects and mechanisms of action in cognitive function intervention, and identifies evidence gaps in current research.

METHODS: Relevant studies were systematically retrieved from PubMed, Web of Science, Cochrane Library, Embase, CINAHL, CNKI, CBM, WanFang Database, and VIP Database from their inception to January 5, 2026. Data from the included literature were extracted and analyzed.

RESULTS: A total of 21 studies were included. Photostimulation therapy primarily includes light stimulation, 40 Hz rhythm-related light stimulation, photobiological modulation and their combined therapies, as well as transcatheter intracranial laser therapy. This therapy has potential value in improving cognitive function or delaying cognitive decline and may affect sleep/rhythm and behavioral symptoms. Its potential mechanisms involve neural oscillation modulation, circadian rhythm reconstruction, and improvement of synaptic plasticity. However, existing evidence exhibits significant heterogeneity in study design, sample size, intervention parameters, and outcome indicators.

CONCLUSION: Photostimulation therapy has shown promising potential in cognitive function intervention for Alzheimer's disease patients, but current evidence is still largely in the exploratory stage. Future research should focus on multi-center, large-sample, and standardized studies to determine the optimal parameter combinations for different stages and scenarios, and to optimize individualized intervention protocols to improve clinical efficacy.},
}

Humans
*Alzheimer Disease/therapy/psychology
*Cognition
*Phototherapy/methods
Quality of Life
*Cognitive Dysfunction/therapy

@article {pmid42059026,
year = {2026},
author = {Yoo, SS and Gu, SM and Nam, KT and Choi, JS and Lee, YS and Yeo, IJ and Yu, JE and Kim, S and Lee, DW and Ham, HJ and Chang, JY and Yun, J and Son, DJ and Han, SB and Hong, JT},
title = {Stress Accelerates Depressive-Like Behaviors through Increase of Notch2 Expression in N141I Mutation Presenilin-2 Transgenic Mice.},
journal = {Biomolecules & therapeutics},
volume = {34},
number = {3},
pages = {544-555},
doi = {10.4062/biomolther.2025.246},
pmid = {42059026},
issn = {1976-9148},
abstract = {Alzheimer's disease (AD) is characterized by progressive cognitive deterioration and significant depression. However, the mechanisms linking depression to AD pathology remain unclear. Here, we investigated whether Notch2 signaling mediates depression-like behaviors in presenilin-2 (PS2) N141I mutant mice, an early-onset AD model. PS2 wild-type (WT) and mutant (MT) mice aged 12-15 months were subjected to unpredictable chronic mild stress (UCMS) for 4 weeks, followed by sucrose preference, tail-hanging, and forced swimming tests. Behavioral assessments showed that UCMS exacerbated anhedonia and immobility only in PS2 MT mice. Molecular analysis revealed concomitant increases in plasma corticosterone, hippocampal γ-secretase activity, and Notch2 expression, and elevated total and phosphorylated glucocorticoid receptor levels in PS2 MT-UCMS mice. Gene expression profiling of human hippocampal datasets confirmed upregulation of NOTCH2 in Alzheimer's disease and depression. Pharmacological inhibition of γ-secretase and Notch signaling with DAPT normalizes depressive behavior, reduces corticosterone release, attenuates GR phosphorylation, and inhibits Notch2 signaling in PS2 MT mice. These findings identify Notch2 as a pivotal mediator linking chronic stress to molecular changes associated with depression and AD, and suggest that targeting Notch2 signaling may provide therapeutic benefits for comorbid mood and neurodegenerative disorders.},
}

@article {pmid42059045,
year = {2026},
author = {Xie, K and Jiang, Y and Chen, T and Liu, S and Fang, Y and Chen, F and Shen, J and Zeng, X and Li, P and Qiu, T and Wang, J and Yu, L and Zang, X and Wang, N and Yuan, J and Pang, H and Zhang, W and Ni, Z and Gu, L and Guo, Y and Lu, R},
title = {A prospective, randomized, double-blind, placebo-controlled, multicenter study of thiamin plus folic acid in the treatment of cognitive impairment in patients undergoing maintenance hemodialysis.},
journal = {Renal failure},
volume = {48},
number = {1},
pages = {2658981},
doi = {10.1080/0886022X.2026.2658981},
pmid = {42059045},
issn = {1525-6049},
mesh = {Humans ; *Thiamine/administration & dosage/therapeutic use/blood/adverse effects ; *Folic Acid/administration & dosage/therapeutic use/blood/adverse effects ; Female ; Male ; Double-Blind Method ; *Renal Dialysis/adverse effects ; Middle Aged ; *Cognitive Dysfunction/drug therapy/etiology/blood ; Prospective Studies ; Adult ; Aged ; Treatment Outcome ; *Kidney Failure, Chronic/therapy/complications ; Vitamin B Complex ; Young Adult ; Homocysteine/blood ; Adolescent ; },
abstract = {This prospective, randomized, double-blind, placebo-controlled trial investigated the efficacy and safety of thiamin and folic acid for cognitive impairment in maintenance hemodialysis (MHD) patients. A total of 215 MHD patients aged 18-75 with cognitive impairment were randomized to receive either oral thiamin (90 mg/day) plus folic acid (30 mg/day) or a placebo for 96 weeks. The primary endpoint was the change in the Alzheimer's Disease Assessment Scale-Cognitive section (ADAS-Cog) score. After 96 weeks, the treatment group showed a significant improvement in ADAS-Cog scores (from 21.25 ± 9.2 to 15.07 ± 8.38, p < 0.001), whereas the placebo group showed a non‑significant improvement (from 24.53 ± 11.01 to 26.53 ± 14.43, p = 0.077). The treatment group also demonstrated significantly increased blood levels of thiamin (from 5.59 ± 0.95 to 18.21 ± 3.91 ng/mL) and folate (from 12.37 ± 4.62 to 63.33 ± 16.02 ng/mL), and a reduction in homocysteine levels (from 4709.06 ± 353.15 to 2962.68 ± 158.87 ng/mL, p < 0.001), with no significant changes in the placebo group. While mortality was similar between the two groups (12.1% vs. 12.0%, p = 0.978), the incidence of adverse events was significantly lower in the treatment group (31.8% vs. 62.0%, p = 0.0017), particularly cardiovascular and cerebrovascular events (13.1% vs. 25.9%, p = 0.001). The study concludes that combined thiamin and folic acid supplementation improves cognitive function in MHD patients with a favorable safety profile.},
}

Humans
*Thiamine/administration & dosage/therapeutic use/blood/adverse effects
*Folic Acid/administration & dosage/therapeutic use/blood/adverse effects
Female
Male
Double-Blind Method
*Renal Dialysis/adverse effects
Middle Aged
*Cognitive Dysfunction/drug therapy/etiology/blood
Prospective Studies
Adult
Aged
Treatment Outcome
*Kidney Failure, Chronic/therapy/complications
Vitamin B Complex
Young Adult
Homocysteine/blood
Adolescent

@article {pmid42059099,
year = {2026},
author = {Stephan, AT and Walton, A and Chai, HW and Martinez, V and Lewis-Harris, M and Weaver, C and Steele, T and Skrelja, J and McVey, A and Courtney, M and Phillips, CB and Gamaldo, AA and Ross, LA},
title = {Digital tools for cognitive healthcare: Exploring perceptions of an everyday function app among midlife and older adults.},
journal = {Applied psychology. Health and well-being},
volume = {18},
number = {3},
pages = {e70154},
pmid = {42059099},
issn = {1758-0854},
support = {//Prisma Health Upstate/ ; 5P30AG059294-05//Carolina Center on Alzheimer's Disease and Minority Research/ ; //South Carolina Alzheimer's Disease Research Center/ ; },
mesh = {Humans ; Aged ; Male ; Female ; Middle Aged ; *Mobile Applications ; *Cognitive Dysfunction/diagnosis ; *Activities of Daily Living ; South Carolina ; Aged, 80 and over ; Qualitative Research ; },
abstract = {Early detection of cognitive decline may be effective in reducing the adverse impacts of Alzheimer's disease and related dementias (ADRD). Given that functional declines precede ADRD evaluation and diagnosis, regular assessments of everyday function are an avenue for detecting cognitive performance changes. While app-based measures of everyday function and cognition are promising tools for early detection, perceptions of these tools' value remain unexamined. This study explored perceptions of an app-based measure of everyday function (i.e., comfort with sharing performance data and perceived utility in healthcare) with community-dwelling midlife and older adults in South Carolina, United States (N = 131, Mage = 67.08 years). Participants completed daily tasks through a mobile app objectively measuring everyday function then shared their feedback through a semi-structured interview. Our thematic analysis found that interest and confidence in utilizing this technology was connected to beliefs around the value of having real-time information about one's cognitive performance, experiences with healthcare providers, and trust in technology security and accuracy. Additionally, some adults have not thought critically about the role of these technologies in their healthcare. As health-tracking technology expands in cognitive healthcare, researchers and practitioners must be aware of midlife and older adults' perceptions and educate users on its potential function.},
}

Humans
Aged
Male
Female
Middle Aged
*Mobile Applications
*Cognitive Dysfunction/diagnosis
*Activities of Daily Living
South Carolina
Aged, 80 and over
Qualitative Research

@article {pmid42059217,
year = {2026},
author = {Lopes, LFF and Tolomeu, HV and Vieira, RP},
title = {A Perspective on Alzheimer's Therapeutics: A Multitarget Approach with Rho-associated Kinase and Histone Deacetylase Inhibitors.},
journal = {Medicinal chemistry (Shariqah (United Arab Emirates))},
volume = {},
number = {},
pages = {},
doi = {10.2174/0115734064452204260325102425},
pmid = {42059217},
issn = {1875-6638},
}

@article {pmid42059332,
year = {2026},
author = {Hodgson, NA and Latif, S and Talwar, S and Huang, L and Finegan, K and Stratton, L and Fazio, S and Moreno, M},
title = {Multi-State Implementation of the Alzheimer's Association Dementia Care Coordination (DCC) Program.},
journal = {Journal of the American Geriatrics Society},
volume = {},
number = {},
pages = {},
doi = {10.1111/jgs.70475},
pmid = {42059332},
issn = {1532-5415},
support = {/ALZ/Alzheimer's Association/United States ; },
abstract = {BACKGROUND: The Alzheimer's Association partnered with health systems in Illinois, Greater Missouri, and Washington to implement and evaluate the Knight Family dementia care coordination (DCC) program, a novel telephone-based care coordination service that bridged the gap between clinical care and community support. Healthcare providers were trained to systematically identify dementia caregivers and refer them to Alzheimer's Association care consultants who provided personalized education, resources, and support. This innovative model addressed critical care coordination gaps in dementia care delivery.

METHODS: A mixed-methods process evaluation assessed DCC implementation and caregiver outcomes. Caregivers completed validated surveys at baseline and follow-up, including the PROMIS Self-Efficacy for Managing Emotions scale and the general self-efficacy scale (GSE). Surveys also captured action plan uptake, resource utilization, and barriers to implementation. Health system employees completed surveys and structured interviews about program satisfaction and workflow integration. The Consolidated Framework for Implementation Research (CFIR) and the RE-AIM framework (Reach, Effectiveness, Adoption, Implementation, and Maintenance) guided identification of barriers, facilitators, and implementation outcomes.

RESULTS: Caregiver self-efficacy scores were mixed: approximately 44%-45% improved on the self-efficacy scales at follow-up, while a nearly equal proportion (42%-44%) worsened. Mean PROMIS scores showed no significant change (all p > 0.4), and mean GSE scores declined slightly but significantly at 3 months. Although improvements in self-efficacy were not consistently observed, caregivers demonstrated high program engagement: 70% completed action steps, 80% utilized community resources, and 90% demonstrated comprehension of their individualized action plans. Health system employees reported high program satisfaction, though clinician engagement remained a barrier.

CONCLUSIONS: This multi-state evaluation demonstrates the feasibility of implementing a telephone-based dementia care coordination program across diverse health systems and highlighted strong caregiver engagement with program resources. However, self-efficacy outcomes did not show consistent improvement. Controlled trials are needed to determine which caregivers benefit most and whether more intensive or targeted interventions are required.},
}

@article {pmid42059425,
year = {2026},
author = {Gómez-Morales, A and Bahrami, R},
title = {Secondary Caregiving in Alzheimer's Disease and Related Dementias: A Scoping Review of Their Challenges and Contributions.},
journal = {Research on aging},
volume = {},
number = {},
pages = {1640275261449482},
doi = {10.1177/01640275261449482},
pmid = {42059425},
issn = {1552-7573},
abstract = {The experiences, roles, key contributions, and support provided by secondary caregivers of people with dementia are underexplored when compared to primary caregivers. This scoping review mapped the existing literature on secondary caregivers. The review followed the PRISMA-ScR framework. Data was subtracted to focus on caregiving outcomes, and on thematic patterns across both qualitative and quantitative designs. Findings from the selected articles (N = 10) indicated that secondary caregivers provide emotional, logistical, and financial support. They also experienced psychological distress, guilt, role conflict, and communication challenges. Family dynamics, gender, and cultural expectations shaped the caregiving experiences and outcomes. The search revealed a scarcity of interventions tailored to this group to enhance overall well-being. Secondary caregivers play a vital role in dementia care. Future interventions that clarify caregiving roles, enhance communication, and provide culturally responsive, family-centered support can strengthen caregiver well-being and promote sustainable caregiving networks.},
}

@article {pmid42059452,
year = {2026},
author = {Jesudason, CD and Rangel-Barajas, C and Beach, CJ and Beck, DE and Caballero-Floran, IH and Clayton, WB and Da Silva, L and David, JC and Doolen, S and Faulkner, AN and Hamdani, AK and Huhe, H and Huynh, K and Imhoff, RD and Javens-Wolfe, J and Mason, ER and Moussaif, M and Singhal, K and Soni, DM and van Buuren-Milne, M and Williams, SP and Angus, SP and Chu, S and Dage, JL and Hipskind, PA and Johnson, TS and Kaddurah-Daouk, R and Lamb, BT and Meikle, PJ and Mesecar, AD and Palkowitz, AD and Quinney, SK and Sukoff Rizzo, SJ and Oblak, AL and Richardson, TI},
title = {Optimization and Characterization of SHIP1 Ligands for Cellular Target Engagement and Activity in Alzheimer's Disease Models.},
journal = {Journal of medicinal chemistry},
volume = {},
number = {},
pages = {},
doi = {10.1021/acs.jmedchem.6c00010},
pmid = {42059452},
issn = {1520-4804},
abstract = {SHIP1 is a lipid phosphatase that negatively regulates immune receptor signaling in hematopoietic cells and microglia. SAR studies guided by biochemical and cellular assays using multiple human and murine protein constructs and cells identified 3-((2-chlorobenzyl)oxy)-5-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)pyridine (32), which demonstrates SHIP1 target engagement, brain exposure, and evidence of a central pharmacodynamic response in vivo. In a protein-lipid overlay assay, compound 32 induced changes in the relative association of SHIP1 with phosphatidylinositols on a membrane surface. A thermal shift assay demonstrated cellular target engagement. Lipidomics revealed changes in the overall phosphoinositide pool consistent with target engagement and changes in phospho-AKT levels in THP-1 cells. Compound 32 enhanced uptake of myelin/membrane debris and amyloid by murine microglia, phenocopying reduced SHIP1 expression. Oral administration of 32 resulted in brain exposure sufficient to alter gene expression and reduce IL-1β levels as pharmacodynamic markers of microglial activation and neuroinflammation in an amyloidosis mouse model of Alzheimer's disease.},
}

@article {pmid42059651,
year = {2026},
author = {Vo-Eckerle, TT and Gillespie, NA and Christensen, K and Finkel, D and Kremen, WS and Nygaard, M and Sachdev, PS and Thalamuthu, A and Reynolds, CA},
title = {Subjective Sleep Traits and Cognition Across Mid- to Late-Adulthood: A Cross-Sectional Study of Gene-Environment Interplay.},
journal = {Sleep},
volume = {},
number = {},
pages = {},
doi = {10.1093/sleep/zsag119},
pmid = {42059651},
issn = {1550-9109},
abstract = {Genetic susceptibility to Alzheimer's disease (ad) may influence the extent to which environmental factors shape cognition, with individuals at higher genetic risk potentially exhibiting greater sensitivity to environmental exposures. Sleep, an important factor for both cognitive function and ad risk, may further moderate genetic influences (A), including both measured (AP) and latent (AL) components, as well as shared (C) and non-shared environmental (E) contributions to cognition. This study leveraged data from the Interplay of Genes and Environment across Multiple Studies (IGEMS) consortium (N = 3894; 1947 complete twin pairs, 842 monozygotic (MZ) pairs and 1105 dizygotic (DZ); Average age = 62.36 years, 38.75% female). Across six cognitive abilities, we examined whether an ad polygenic score (ad-PGS) moderated environmental influences on cognitive performance. We also examined whether sleep moderated genetic and environmental contributions on cognitive performance. Although the ad-PGS accounted for a negligible proportion of genetic variance as a main effect (B's = -0.004 to 0.02), we observed environment-by-PGS interactions. Increasing genetic risk for ad was associated with lower contributions from environmental experiences unique to each individual, on episodic memory, working memory, and verbal ability (B's = -0.03 to -0.05). These interaction effects, albeit small, were primarily observed with the ad-PGS including the APOE region. Hence, the role of person-specific environments on cognitive functioning was boosted for those at lower genetic risk for ad but reduced at greater genetic risk for ad. Although sleep moderation was minimal, results suggest that poorer sleep influences genetic influences on cognitive functioning.},
}

@article {pmid42059992,
year = {2026},
author = {Ghiyamihoor, F and Asemi Rad, A and Hassanifar, P and Kaur, R and Patel, JH and Kim, I and Marzban, A and Mehdizadeh, M and Levin, DB and Ghavami, S and Toncheva, A and Benali, S and Dubois, P and Balci, F and Habibi, HR and Manto, M and Marzban, H},
title = {Micro- and Nanoplastics in the Human Brain: Mechanistic Plausibility, Translational Challenges, and Links to Neurological Disease Trends.},
journal = {Molecular neurobiology},
volume = {63},
number = {1},
pages = {},
pmid = {42059992},
issn = {1559-1182},
mesh = {Humans ; *Brain/pathology/metabolism/drug effects ; *Nervous System Diseases/metabolism/pathology ; *Translational Research, Biomedical/trends ; *Microplastics/adverse effects/toxicity ; Animals ; Blood-Brain Barrier/metabolism ; },
abstract = {The exponential growth in plastic production since the mid-twentieth century has led to the pervasive presence of micro- and nanoplastics (MNPs) across ecosystems and human exposure pathways, coinciding with a rising global burden of neurological disorders. Increasing evidence demonstrates that MNPs are not confined to peripheral tissues but can accumulate even in the human brain, raising concerns about their potential contribution to neurological disease. This structured review synthesizes global trends in plastic production, environmental MNP burden, and human exposure, together with emerging data on brain accumulation, entry pathways, neurotoxic mechanisms, and key translational challenges. We present evidence showing that MNPs may cross brain barriers via multiple routes, including the blood-brain barrier, blood-cerebrospinal fluid barrier, olfactory, and circumventricular pathways, particularly under conditions of barrier vulnerability. Experimental studies reveal that once in neural tissue, MNPs may disrupt synaptic function, mitochondrial homeostasis, autophagy, and redox balance, while activating neuroinflammatory and gut-brain axis-mediated pathways. These mechanisms intersect with disease-relevant processes implicated in multiple neurological disorders whose global prevalence and societal burden have sharply increased over recent decades, including stroke, Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, mood disorders, and neurodevelopmental conditions. Despite growing mechanistic plausibility, translational and human epidemiological evidence remains limited by methodological heterogeneity, a lack of standardized detection methods, and the absence of longitudinal clinical data/studies. We highlight critical analytical and translational gaps, public health implications, and priorities for longitudinal, biomarker‑driven studies needed to rigorously test whether MNPs may contribute to population‑level risk of neurological disease.},
}

Humans
*Brain/pathology/metabolism/drug effects
*Nervous System Diseases/metabolism/pathology
*Translational Research, Biomedical/trends
*Microplastics/adverse effects/toxicity
Animals
Blood-Brain Barrier/metabolism

@article {pmid42060014,
year = {2026},
author = {de Carvalho, A and Mamede, I and Sanches, L and Juvenal, G and Viero, FT and Franco, GR and Tang, Y and Reis, EM and Ulrich, H},
title = {Uncovering Spatiotemporal and Functional Dynamics of Long Non-coding RNAs During Alzheimer's Progression in the Human Brain at Single-Cell Resolution.},
journal = {Molecular neurobiology},
volume = {63},
number = {1},
pages = {},
pmid = {42060014},
issn = {1559-1182},
support = {2024-2972//Conselho Nacional de Desenvolvimento Científico e Tecnológico, Brazil/ ; Finance Code 001//Coordenação de Aperfeiçoamento de Pessoal de Nível Superior/ ; 308012/2021-6//Conselho Nacional de Desenvolvimento Científico e Tecnológico/ ; 2018/07366-4//Fundação de Amparo à Pesquisa do Estado de São Paulo/ ; },
mesh = {Humans ; *Alzheimer Disease/genetics/pathology ; *RNA, Long Noncoding/genetics/metabolism ; *Brain/pathology/metabolism ; *Single-Cell Analysis/methods ; *Disease Progression ; Spatio-Temporal Analysis ; Transcriptome/genetics ; },
abstract = {Increasing prevalence of Alzheimer's disease, driven by population aging, highlights the need to investigate its underlying molecular mechanisms. Within this context, long non-coding RNAs (lncRNAs) have emerged as a key regulatory layer. To advance the understanding of lncRNA dysregulation and function during Alzheimer's disease progression, we reanalyzed publicly available single-nucleus RNA sequencing (snRNA-seq) datasets. The selected transcriptomic datasets were integrated and subjected to differential expression and genomic co-localization correlation analyses to infer putative cis-regulatory mechanisms. Our results reveal conserved cell-type composition and a shared transcriptional trajectory across brain regions during Alzheimer's disease progression. In contrast, lncRNAs displayed marked cell-type and context specificity and formed coordinated expression patterns with neighboring genes within defined chromatin contexts. These associations suggest potential cis-regulatory roles and implicate lncRNAs in processes such as synaptic plasticity and maladaptive oligodendrocyte differentiation linked to myelin dysfunction. While these findings are primarily hypothesis-generating, they provide a cross-regional framework and a prioritized set of candidate lncRNAs for future functional investigation in Alzheimer's disease.},
}

Humans
*Alzheimer Disease/genetics/pathology
*RNA, Long Noncoding/genetics/metabolism
*Brain/pathology/metabolism
*Single-Cell Analysis/methods
*Disease Progression
Spatio-Temporal Analysis
Transcriptome/genetics

@article {pmid42060036,
year = {2026},
author = {Haji, B and Tahami Monfared, AA and , },
title = {A Multimodal Latent Severity Axis for Alzheimer's Disease: Probabilistic PCA, Bayesian Trajectories, and Stage-Aware Timing Effects.},
journal = {Neurology and therapy},
volume = {},
number = {},
pages = {},
pmid = {42060036},
issn = {2193-8253},
abstract = {INTRODUCTION: Multimodal Alzheimer's disease (AD) cohorts capture cognition, function, neuroimaging, and fluid biomarkers, yet overall disease severity remains difficult to summarize on a single clinically meaningful scale. The apolipoprotein E ε4 (APOE ε4) allele is the strongest common genetic risk factor for late-onset AD, but its association with "progression" has been inconsistent because earlier placement along the disease continuum is often conflated with faster within-stage decline.

METHODS: Using data from the Alzheimer's Disease Neuroimaging Initiative (ADNI), we analyzed an amyloid-positive baseline cohort (N = 1058) and a longitudinal subset (N = 932; ≥ 2 visits and ≥ 4 of 13 measures per visit). Measures included standardized cognitive and functional assessments, structural and functional neuroimaging, cerebrospinal fluid biomarkers of amyloid‑beta and tau pathology, and plasma neurofilament light protein as a marker of neuroaxonal injury. Magnetic resonance imaging (MRI) volumes were adjusted using amyloid-negative cognitively normal controls with quadratic age and intracranial volume terms. Probabilistic principal component analysis (PPCA) was used to derive a latent severity coordinate, defined as the first principal component (PC1). Hierarchical Bayesian random-intercept and random-slope models were used to estimate individual trajectories, partition APOE ε4 effects into baseline severity and within-stage rate, and generate genotype-stratified ages at prespecified severity landmarks. Axis stability was assessed with 100 bootstrap refits, and predictive performance was assessed with participant-level fivefold cross-validation.

RESULTS: The PC1 explained 38.7% of baseline variance and produced a clinically interpretable multimodal severity axis. Stability was high across bootstrap refits, and residual association with age was minimal after MRI volume adjustment. Higher APOE ε4 dose was associated with greater baseline latent severity, whereas within-stage rate differences were smaller than the baseline severity-position effect. A latent symptomatic landmark was reached approximately 3.0-3.3 years earlier per ε4 allele. Adding APOE improved out-of-sample prediction by about 10% without loss of calibration.

CONCLUSIONS: Probabilistic principal component analysis provides a stable, multimodal, biologically informed severity axis for longitudinal modeling in amyloid-positive ADNI. Within this framework, APOE ε4 was associated primarily with latent severity position and model-implied timing along the continuum, whereas within-stage rate differences were smaller. These findings support stage-aware longitudinal inference and methodological applications within this cohort, while external clinical calibration and validation remain necessary.},
}

@article {pmid42060081,
year = {2026},
author = {Marei, HE and Cenciarelli, C},
title = {Neural Stem Cell-Derived Extracellular Vesicles: The Next Frontier in Neurological and Neurodegenerative Diseases.},
journal = {Stem cell reviews and reports},
volume = {},
number = {},
pages = {},
pmid = {42060081},
issn = {2629-3277},
abstract = {The present manuscript provides a comprehensive overview of neural stem cell (NSC)-derived extracellular vesicles (NSC-EVs(as a cell-free approach to treating central nervous system (CNS) disorders. The study noted that NSCs are regenerative and neuroprotective, but direct transplantation is limited by short survival, immunological rejection, and tumorigenic risk. However, NSC-EVs-nano-sized vesicles loaded with proteins, lipids, and RNAs-can replicate many of their parent cells' benefits without safety or ethical issues. NSC-EVs are the source of numerous biologically active molecular cargoes. Encompassing (BDNF, GDNF, VEGF), signaling lipids, and microRNAs (miR-124, miR-21, miR-146a, miR-219) that are essential in modulating and regulating key processes involved in the induction of neurogenesis, promoting angiogenesis, reducing inflammatory milieu, and improving neuronal survival. In preclinical models of Alzheimer's disease (AD), Parkinson's disease (PD), multiple sclerosis (MS), ischemic stroke, spinal cord injury (SCI), and traumatic brain injury (TBI), these vesicles reduce oxidative stress, suppress apoptosis, modulate microglia activation, enhance synaptic plasticity, and promote remyelination. Numerous translational obstacles remain, including heterogeneous EV isolation techniques, limited scalability of clinical-grade manufacturing, and inconsistent elucidation of long-term safety and biodistribution. This review discusses the therapeutic potential of NSC-EVs for neurological and neurodegenerative diseases. Additionally, leveraging the powerful, precise analytical capabilities of Artificial Intelligence (AI) with recent multi-omics data from NSC-EVs will improve the characterization and predictability of therapeutic efficacy. Combining the therapeutic potential of stem cells with the non-invasive, practical, and safe cell-free biologic is expected to transform regenerative neuroscience. A promising aim that requires establishing a multidisciplinary approach among neuroscientists, bioengineers, and clinicians to standardize the isolation process, validate the underlying mechanistic information, and test their therapeutic potential at the clinical level. The present review concludes that NSC-EVs are a promising research topic in regenerative neurotherapy, offering a potential therapeutic strategy for incurable neurological and neurodegenerative diseases.},
}

@article {pmid42060129,
year = {2026},
author = {Briel, N and Borsi, M and Schreiner, SJ and Schneider, T and Loosli, SV and Togni, C and Carta, MC and Loosli, J and Köpp, A and Ziegler, M and Nicoletti, T and Weller, M and Felbecker, A and Weiss, T and Jung, HH},
title = {Outcome associations of CSF total tau in suspected non-Alzheimer pathophysiology.},
journal = {Journal of neurology},
volume = {273},
number = {5},
pages = {},
pmid = {42060129},
issn = {1432-1459},
mesh = {Humans ; *tau Proteins/cerebrospinal fluid ; Male ; Female ; Aged ; Retrospective Studies ; Amyloid beta-Peptides/cerebrospinal fluid ; Biomarkers/cerebrospinal fluid ; Middle Aged ; Peptide Fragments/cerebrospinal fluid ; Aged, 80 and over ; *Neurodegenerative Diseases/cerebrospinal fluid/mortality/physiopathology ; Alzheimer Disease/cerebrospinal fluid ; *Cognitive Dysfunction/cerebrospinal fluid/mortality/physiopathology ; },
abstract = {INTRODUCTION: Cognitively impaired patients with negative biomarkers of amyloidosis but with neurochemical evidence of Tau pathophysiology or neurodegeneration or both are classified as "suspected non-Alzheimer pathophysiology" (SNAP), according to the 2018 research framework for a biological definition of Alzheimer's disease (AD). The SNAP concept remains incompletely characterized, and associations of amyloid and tau biomarkers with survival outcomes in the SNAP context remain unclear.

METHODS: We conducted a retrospective study in patients with a SNAP biomarker constellation, recruited from two tertiary centers between 2019 and 2024. We extracted clinical demographic variables, biomarker results, and survival times to all-cause-mortality or last seen from electronic health records. SNAP patients were defined based on normal cerebrospinal fluid (CSF) levels of amyloid-β1-42 (Aβ42) and a normal Aβ42/Aβ40 ratio, and abnormal levels of phospho-Tau-181 (pTau) and/or total Tau (tTau), as measured with the Lumipulse G chemiluminescence assay. We computed the Youden index to dichotomize SNAP subgroups by CSF biomarkers and demographic variables in a data-driven approach and assessed survival using Kaplan-Meier curves and multivariable Cox hazard models. Patients were categorized as having either idiopathic or secondary neurodegenerative diseases, while those with prion disease were excluded from the final analyses.

RESULTS: Compared across amyloid-tau-neurodegeneration-defined categories, patients with SNAP had a shorter median survival than those with AD (31 vs. 42 months), while the Alzheimer's pathological change with concurrent neurodegeneration (APC + N) category exhibited the shortest median survival at 16 months. Patients with SNAP (n = 99) had a median age of 72 (inter-quartile range, IQR: 64; 77) years and a median follow-up time of 12 (IQR 1;27, max. 60) months. Among selected variables, tTau performed best in predicting survival during the follow-up period (area under the curve, AUC = 0.83) in non-prion SNAP, followed by the pTau/tTau ratio (AUC = 0.82). The optimal prognostic tTau cutpoint of ≥ 600 pg/mL was higher than the age-adjusted diagnostic reference (300-500 pg/mL). Patients with SNAP exhibiting higher tTau levels or a reduced pTau-181/tTau ratio had significantly shorter median survival times. Multivariable Cox hazard modeling confirmed tTau to be independently associated with survival with a hazard ratio of 6.1-6.8 (p < 0.001).

CONCLUSION: We have identified CSF tTau as a novel predictor of survival in patients with SNAP. Although this descriptive diagnosis encompasses primarily various idiopathic neurodegenerative causes, we also demonstrate tTau's prognostic value in the context of secondary neurodegenerative processes. This finding can enhance prognostication in clinical settings.},
}

Humans
*tau Proteins/cerebrospinal fluid
Male
Female
Aged
Retrospective Studies
Amyloid beta-Peptides/cerebrospinal fluid
Biomarkers/cerebrospinal fluid
Middle Aged
Peptide Fragments/cerebrospinal fluid
Aged, 80 and over
*Neurodegenerative Diseases/cerebrospinal fluid/mortality/physiopathology
Alzheimer Disease/cerebrospinal fluid
*Cognitive Dysfunction/cerebrospinal fluid/mortality/physiopathology

@article {pmid42060226,
year = {2024},
author = {Choi, JK and Kwon, OY and Lee, SH},
title = {Oral Administration of Bifidobacterium lactis Ameliorates Cognitive Deficits in Mice Intracerebroventricularly Administered Amyloid Beta via Regulation the Activation of Mitogen-activated Protein Kinases.},
journal = {Food science of animal resources},
volume = {44},
number = {3},
pages = {607-619},
doi = {10.5851/kosfa.2024.e5},
pmid = {42060226},
issn = {2636-0780},
abstract = {Probiotics are functional microorganisms that exhibit various biological activities, such as allergic reactions, inflammation, and aging. The aim of this study is to evaluate the effects of Bifidobacterium lactis CBT BL3 (BL) on the amyloid beta (Aβ)-mediated cognitive impairments. Oral administration of live BL to intracerebroventricularly Aβ-injected mice significantly attenuated short- and long-term memory loss estimated using the Y-maze and Morris water maze tests. We found that expression of apoptosis-related proteins such as caspase-9, caspase-3, and cleaved poly (ADP-ribose) polymerase was significantly elevated in the brain tissues of Aβ-injected mouse brains when compared to that of the control mouse group. Interestingly, these expression levels were significantly decreased in the brain tissue of mice fed BL for 6 wk. In addition, the abnormal over-phosphorylation of mitogen-activated protein kinases (MAPKs) such as ERK1/2, p38 MAPK, and JNK in the brain tissue of intracerebroventricularly Aβ-injected mice was significantly attenuated by oral administration of BL. Taken together, the results indicate that Aβ-induced cognitive impairment may be ameliorated by the oral administration of BL by controlling the activation of MAPKs/apoptosis in the brain. This study strongly suggests that BL can be developed as a functional probiotic to attenuate Aβ-mediated cognitive deficits.},
}

@article {pmid42060418,
year = {2026},
author = {Raev, G and Baev, D and Gerasimov, E and Chukanov, V and Pchitskaya, E},
title = {NEuRT: A Transformer-Based Model for Explainable Neuronal Activity Analysis.},
journal = {IEEE transactions on neural systems and rehabilitation engineering : a publication of the IEEE Engineering in Medicine and Biology Society},
volume = {PP},
number = {},
pages = {},
doi = {10.1109/TNSRE.2026.3689342},
pmid = {42060418},
issn = {1558-0210},
abstract = {The study of neuronal activity is essential for understanding brain function and its alterations in neurode-generative diseases. Advances in in vivo imaging have enabled real-time observation of neuronal dynamics, but classical statistical methods struggle to capture the complex, time-dependent interactions within neuronal networks. Machine learning offers promising solutions for analyzing high-dimensional neuronal data, yet their application in neuroscience remains limited. Here, we introduce NEuRT, a Bidirectional Encoder Representations from Transformers (BERT)-based model adapted for neuronal activity analysis. NEuRT leverages self-attention mechanisms to interpret complex neuronal interactions, providing insights into patterns that traditional methods may overlook. Pre-trained on the recently introduced large annotated dataset MICrONS for signal reconstruction, NeuRT demonstrates strong generalization, effectively reconstructing activity from both visual cortex two-photon and hippocampal miniature fluorescence microscopy. Built on the BERT architecture, the NEuRT model can be efficiently fine-tuned for a wide range of downstream tasks. We showcase its application in classifying wild-type and transgenic Alzheimer's disease model mice, based on hippocampal activity, revealing group-specific features through attention map analysis. By reducing reliance on extensive labeled data, addressing a critical challenge in neuroscience, NEuRT bridges fundamental neuroscience and disease research, offering a robust framework for AI-driven and explainable neuronal activity analysis.},
}

@article {pmid42060436,
year = {2026},
author = {Liu, C and Que, Y and Wong, WK and Liu, Y and Luo, X},
title = {Multi-view Hilbert Curve-based Hierarchical Information Aggregation for Incomplete Multimodal Alzheimer's Disease Diagnosis.},
journal = {IEEE transactions on medical imaging},
volume = {PP},
number = {},
pages = {},
doi = {10.1109/TMI.2026.3689332},
pmid = {42060436},
issn = {1558-254X},
abstract = {Timely identification of Alzheimer's disease (AD) benefits from combining neuroimaging, fluid biomarkers, and cognitive assessments, yet in practice one or more modalities are often unavailable due to various factors such as cost, patient compliance, and procedural risks. Furthermore, conventional convolutional neural network (CNN) architectures and even Transformer-based models struggle to efficiently capture both local and global dependencies, especially when dealing with high-dimensional and highly heterogeneous medical data. In this study, we introduce a novel hierarchical information aggregation and dynamic fusion (HI-AD) framework for incomplete multi-modal AD diagnosis. Our method couples a multi-view Hilbert curve-guided Mamba block with hierarchical spatial feature extraction to retain spatial continuity, model long-range dependencies, and integrate local context in neuroimaging data. To balance semantic alignment and modality-specific information, we propose a unified mutual information-driven learning objective with an active confidence evaluation mechanism, thereby preventing modality collapse and promoting robust representation learning. Extensive experiments on real-world datasets validate that our HI-AD framework consistently outperforms existing state-of-the-art methods across a diverse range of modality-missing scenarios, establishing an effective and generalizable solution for early-stage AD screening in heterogeneous clinical data environments.},
}

@article {pmid42060649,
year = {2026},
author = {Rosales-Gurmendi, DS and Fumagal-González, GA and Orozco, J and Farber, J and Treviño, V and Martinez-Ledesma, E and Martinez-Torteya, A and Rosales-Gurmendi, F and Tamez-Peña, J and , },
title = {Interpretable multivariate survival models: Improving predictions for conversion from mild cognitive impairment to Alzheimer's disease via data fusion and machine learning.},
journal = {PloS one},
volume = {21},
number = {4},
pages = {e0321671},
doi = {10.1371/journal.pone.0321671},
pmid = {42060649},
issn = {1932-6203},
mesh = {Humans ; *Alzheimer Disease/diagnosis/cerebrospinal fluid/pathology/diagnostic imaging ; *Cognitive Dysfunction/diagnosis/cerebrospinal fluid/diagnostic imaging/pathology ; *Machine Learning ; Male ; Female ; Aged ; Disease Progression ; Magnetic Resonance Imaging ; Biomarkers/cerebrospinal fluid ; Proportional Hazards Models ; Aged, 80 and over ; },
abstract = {Accurately predicting which individuals with mild cognitive impairment (MCI) will progress to Alzheimer's disease (AD) can improve patient care. This study examines the role of quantitative MRI (qMRI), cognitive evaluations, apolipoprotein [Formula: see text]4 (APOE [Formula: see text]4), and cerebrospinal fluid (CSF) biomarkers in Cox survival models to predict progression from MCI to AD. Data from 564 participants in the ADNI study, who transitioned from MCI to AD, were analyzed. The data set included 330 features encompassing qMRI, cognitive assessments, CSF biomarkers, and APOE [Formula: see text]4 status. Advanced machine learning (ML) methods were applied to evaluate the importance of these data sources, select relevant features, and develop interpretable Cox survival models within a cross-validation framework. The top optimized model achieved a sensitivity of 0.69, 95% CI [0.63, 0.76], and a specificity of 0.87, 95% CI [0.83, 0.90], and used all data sources. The results demonstrated that combining qMRI features with cognitive assessments, CSF biomarkers, and APOE [Formula: see text]4 status, analyzed using the BSWiMS model, resulted in a substantial improvement in the ability to predict progression from MCI to AD, achieving 81% precision and 87% specificity. These results exceed those obtained with other models evaluated. Finally, biomarker analysis showed that cognitive scores are the most relevant features to predict conversion, followed by CSF and qMRI biomarkers. These findings highlight the value of integrating multiple data sources in highly interpretable Cox survival models for the early identification of individuals at risk for AD.},
}

Humans
*Alzheimer Disease/diagnosis/cerebrospinal fluid/pathology/diagnostic imaging
*Cognitive Dysfunction/diagnosis/cerebrospinal fluid/diagnostic imaging/pathology
*Machine Learning
Male
Female
Aged
Disease Progression
Magnetic Resonance Imaging
Biomarkers/cerebrospinal fluid
Proportional Hazards Models
Aged, 80 and over

@article {pmid42060745,
year = {2026},
author = {De Strooper, B and Zetterberg, H},
title = {Tracking the turning point in Alzheimer's disease.},
journal = {Science (New York, N.Y.)},
volume = {392},
number = {6797},
pages = {468-469},
doi = {10.1126/science.aeb6987},
pmid = {42060745},
issn = {1095-9203},
mesh = {*Alzheimer Disease/blood/pathology/metabolism ; Humans ; *tau Proteins/blood/metabolism ; Biomarkers/blood ; *Amyloid beta-Peptides/blood/metabolism ; },
abstract = {A blood biomarker reveals the mechanistic shift from amyloid to tau pathology.},
}

*Alzheimer Disease/blood/pathology/metabolism
Humans
*tau Proteins/blood/metabolism
Biomarkers/blood
*Amyloid beta-Peptides/blood/metabolism

@article {pmid42060826,
year = {2026},
author = {Bawne, G and Coenen, L and Nutma, E and Middeldorp, J and Lorenowicz, MJ},
title = {When Viruses Talk through Extracellular Vesicles: a New Perspective on Sars-Cov-2-Induced Neurodegeneration.},
journal = {Journal of extracellular vesicles},
volume = {15},
number = {5},
pages = {e70272},
doi = {10.1002/jev2.70272},
pmid = {42060826},
issn = {2001-3078},
mesh = {*Extracellular Vesicles/metabolism/virology ; Humans ; *COVID-19/complications/virology/metabolism ; *SARS-CoV-2 ; MicroRNAs/metabolism ; *Neurodegenerative Diseases/virology/metabolism ; Alzheimer Disease/virology/metabolism ; Animals ; Parkinson Disease/virology/metabolism ; },
abstract = {SARS-CoV-2 infection is linked to persistent neurological symptoms Post-Acute Sequelae SARS-CoV-2 (neuro-PASC) and elevated risk of neurodegenerative disease, but molecular events connecting acute viral injury to long-term CNS dysfunction remain unclear. Here, we advance a perspective that Extracellular Vesicles (EVs) act as active mediators bridging SARS-CoV-2 infection and neurodegenerative processes. As nanoscale messengers capable of crossing the blood-brain barrier, EVs can transmit post-viral signals and orchestrate multi-target gene regulation in recipient cells through their microRNA (EV-miRNA) cargo. Our integrative analysis suggests that EV-miRNAs dysregulated in acute COVID-19, Alzheimer's Disease (AD), and Parkinson's Disease (PD) converge on pathways governing neurovascular integrity, redox and metabolic homeostasis, and neuronal proteostasis. We propose that sustained dysregulation of these interconnected modules-driven by EV-mediated signalling-may underlie the perpetuation of neuro-PASC and accelerate neurodegeneration in susceptible individuals. Viewing EVs as mechanistic agents that both transmit and amplify pathogenic cues reframes them as actionable targets for intervention and risk stratification. This perspective calls for translational frameworks that leverage EVs to illuminate, predict, and modify the trajectory of post-viral neurodegeneration.},
}

*Extracellular Vesicles/metabolism/virology
Humans
*COVID-19/complications/virology/metabolism
*SARS-CoV-2
MicroRNAs/metabolism
*Neurodegenerative Diseases/virology/metabolism
Alzheimer Disease/virology/metabolism
Animals
Parkinson Disease/virology/metabolism

@article {pmid42060857,
year = {2026},
author = {Mitchell, B and Harkess-Murphy, E and Douglas-Smith, N and Cheyne, J},
title = {Touch-Based Therapies in Dementia Care: A Systematic Review and Narrative Synthesis.},
journal = {Dementia (London, England)},
volume = {},
number = {},
pages = {14713012261445473},
doi = {10.1177/14713012261445473},
pmid = {42060857},
issn = {1741-2684},
abstract = {Touch-based therapies (massage, acupressure, reflexology/shiatsu, and therapeutic/healing touch) are used in dementia care, but effectiveness remains uncertain. The authors evaluated their impact on behavioural and psychological symptoms of dementia (BPSD) and pain, and extracted pragmatic "dose" and delivery parameters to inform a research blueprint. The authors searched major databases (MEDLINE, CINAHL, PsycINFO, Embase, CENTRAL) for studies from January 2005 to February 2023 involving people with any dementia aetiology/severity in community, residential, or inpatient settings. Eligible designs included randomised, quasi-experimental, and pre-post studies with a comparator (usual care, attention/quiet presence, or sham/light-touch). Data were extracted to a prespecified template; study quality was appraised using CASP tools. Owing to substantial clinical and methodological heterogeneity, the authors conducted a structured narrative synthesis as opposed to meta-analysis. Thirty-three studies met inclusion: 21 massage, 8 acupressure, 3 therapeutic/healing touch, and 2 reflexology/shiatsu. Most were in long-term care or inpatient settings. Interventions typically used brief, repeated sessions (5-20 minutes, several times per week for 2-6 weeks). The most consistent finding was short-term calming, particularly reductions in agitation immediately post-session or over brief treatment courses, with the clearest pattern for massage and acupressure. Effects on broader neuropsychiatric symptoms (e.g., NPI/NPI-NH domains) and pain were mixed. Where monitored, no serious adverse events were reported; minor transient issues (e.g., brief restlessness, skin sensitivity with aromatherapy oils) were infrequent and acceptability generally high. Risk of bias was mixed (≈49% low, 42% moderate, 9% high), and durability beyond 4-8 weeks was rarely assessed. Current evidence provides preliminary indications that brief, touch-based therapies may offer short-term calming effects when used alongside person-centred care, although certainty remains low and findings should be interpreted cautiously. The authors propose a pragmatic research blueprint that predefines session length, frequency, and course duration; uses attention/sham controls; adopts core outcomes (e.g., Cohen Mansfield Agitation Inventory (CMAI), Neuropsychiatric Inventory/Neuropsychiatric Inventory adapted for Nursing Homes (NPI/NPI-NH); Pain Assessment in Advanced Dementia (PAINAD) where relevant); ensures blinded assessment; and extends follow-up. The authors recommend that future work should prioritise feasibility/pilot studies, followed by adequately powered trials to determine effectiveness, durability, and scalability for practice.},
}

@article {pmid42060966,
year = {2026},
author = {Salerno, S and Fabbri, G and Di Paolo, ML and Piazzola, F and Piccarducci, R and Costa, B and Castellano, S and Dalla Via, L and Taliani, S and Da Settimo, F},
title = {Recent advances in the development of selective hMAO-B inhibitors for neurodegenerative diseases: An update from 2020 to present.},
journal = {European journal of medicinal chemistry},
volume = {313},
number = {},
pages = {118893},
doi = {10.1016/j.ejmech.2026.118893},
pmid = {42060966},
issn = {1768-3254},
abstract = {Neurodegenerative diseases (NDs) comprise a complex group of disorders characterized by the progressive loss of neurons in the CNS, resulting in cognitive and motor dysfunctions. Elucidating the molecular mechanisms underlying these diseases is essential to identify effective therapeutic strategies. The hallmarks of NDs include oxidative stress, mitochondrial dysfunction, neuroinflammation, and protein misfolding. Among the implicated molecular targets, monoamine oxidase B (MAO-B) plays a crucial role since it catalyzes the oxidative deamination of biogenic amines, such as amine neurotransmitters, and therefore plays an important role in the physiopathology of the brain and nervous system generating reactive oxygen species, so contributing to oxidative stress and inflammation. Elevated hMAO-B activity has been observed in Alzheimer's and Parkinson's disease, underscoring its potential as a therapeutic target for neuroprotection. Given the role of MAO-B activity in various molecular pathways related to neuroinflammatory and neurodegenerative processes that underlie the onset and progression of NDs, the development of more active and selective hMAO-B inhibitors could represent a promising avenue leading to safer and more effective therapies for Alzheimer's and Parkinson's disease. In this view, MAO-B inhibitors have long been investigated for their therapeutic potential in NDs. Building upon previous reviews, this updated overview focuses on the most recent advances from 2020 to today in the field of new small molecules hMAO-B inhibitors, highlighting results from preclinical studies. Attention is paid to the various classes of synthetic compounds that have emerged in recent years and, where available, the main structure-activity relationships (SARs) are discussed to provide insights into the molecular features responsible for hMAO-B inhibitory activity and selectivity. The aim is to provide researchers with a current perspective on the evolving landscape of hMAO-B inhibitor-based therapies for NDs.},
}

@article {pmid42060983,
year = {2026},
author = {Al Mamun, A and Konecny, J and Hrabinova, M and Sorf, A and Muckova, L and Fibigar, J and Kucera, T and Pulkrabkova, L and Jun, D and Prchal, L and Panek, D and Finger, V and Soukup, O and Cailly, T and Collot, V and Novakova, L and Cahlikova, L and Korabecny, J},
title = {Carltonine B derivatives: Synthesis and structure-activity relationship insights for selective butyrylcholinesterase inhibition.},
journal = {Bioorganic chemistry},
volume = {177},
number = {},
pages = {109894},
doi = {10.1016/j.bioorg.2026.109894},
pmid = {42060983},
issn = {1090-2120},
abstract = {Butyrylcholinesterase (BChE) is recognized as a promising therapeutic target for the late stages of Alzheimer's disease (AD) due to its role in the hydrolysis of acetylcholine (ACh), while acetylcholinesterase (AChE) activity declines during disease progression. Here, we have reported an efficient chemistry procedure for the naturally occurring Amaryllidaceae alkaloid carltonine B, along with the design and synthesis of 36 novel carltonine-based analogues to determine structure-activity relationship (SAR). Most of the synthesized compounds exhibited potent and selective human BChE (hBChE) inhibition, with IC50 values ranging from low micromolar to nanomolar concentrations. The drug-like properties of the molecules were assessed by in silico tools, using the blood-brain barrier (BBB) score algorithm, and subsequently validated by in vitro permeability assessment via parallel artificial membrane permeability assay (PAMPA). The derivatives exhibited potent hBChE inhibition in the low micromolar to submicromolar range, while their cytotoxicity against human neuroblastoma (SH-SY5Y) cells was observed only at higher micromolar concentrations, indicating a favorable safety profile. The synthesized alkaloid carltonine B (37) and its N-ethyl derivative (38) emerged as the most potent and selective hBChE inhibitors, with IC50 values of 0.014 ± 0.002 μM and 0.013 ± 0.001 μM, respectively. Enzyme kinetic studies were conducted to elucidate the inhibition mechanism toward hBChE enzyme. Compound 37 demonstrated competitive inhibition with Ki value of 0.055 μM. In contrast, compound 38 showed a noncompetitive inhibition profile, with a Ki value of 0.067 μM. Molecular modeling suggested that the superior potency of compounds 37 and 38 arises from their more optimal engagement of the BChE active-site gorge compared to compound 33. For the additional safety assessment, CYP inhibition assay revealed that compounds 37 and 38 may pose a risk of CYP3A4-mediated drug-drug interactions during chronic administration.},
}

@article {pmid42060990,
year = {2026},
author = {Hsu, YH and Liang, CK and Chou, MY and Davidson, J and Wang, YC and Nalls, MA and Ferrucci, L and Cookson, M and Iwaki, H},
title = {Amyloid pathology and modifiable risk factors in cognitive decline among cognitively unimpaired older adults.},
journal = {The journal of prevention of Alzheimer's disease},
volume = {13},
number = {6},
pages = {100574},
doi = {10.1016/j.tjpad.2026.100574},
pmid = {42060990},
issn = {2426-0266},
abstract = {BACKGROUND: Alzheimer's disease (AD) pathology, particularly amyloid-β (Aβ) deposition, occurs years before clinical symptoms. Modifiable risk factors may influence cognitive trajectories during this preclinical stage, but whether amyloid status alters their effects remains unclear.

OBJECTIVES: To investigate interactions between amyloid pathology and modifiable risk factors in predicting longitudinal cognitive decline among cognitively unimpaired older adults.

DESIGN AND SETTING: This study was a secondary analysis of data derived from two large multicenter longitudinal cohort studies, the Anti-Amyloid Treatment in Asymptomatic Alzheimer Disease (A4) Study and the Longitudinal Evaluation of Amyloid Risk and Neurodegeneration (LEARN) Study.

PARTICIPANTS: A total of 1707 cognitively unimpaired adults aged 65-85 years were included, comprising 1169 amyloid-positive participants from the A4 Study (Aβ+) and 538 amyloid-negative participants from the LEARN Study (Aβ-).

MEASUREMENTS: Cognitive function was assessed every six months using the Preclinical Alzheimer's Cognitive Composite (PACC) over a mean follow-up of 4.9 years. Eight established modifiable risk factors-low education, alcohol use, diabetes, high cholesterol, high blood pressure, obesity, depressive symptoms, and physical inactivity-were evaluated. Linear mixed-effects models were applied to examine associations between each risk factor and longitudinal PACC decline, and to test interactions with amyloid status, adjusting for demographic and genetic covariates.

RESULTS: Significant interactions between amyloid status and modifiable risk factors were observed for diabetes (adjusted β = -0.206, p = 0.032), high cholesterol (adjusted β = -0.155, p < 0.001), and physical inactivity (adjusted β = -0.161, p = 0.046), indicating combined effects rather than additive effects on cognitive decline among Aβ+ individuals. In the A4 study (Aβ+), low education, diabetes, high cholesterol, and physical inactivity were independently associated with accelerated cognitive decline, whereas obesity was linked to slower decline. In contrast, in the LEARN study (Aβ-), these associations were not statistically significant.

CONCLUSIONS: In conclusion, the significant interactions with amyloid status were observed for diabetes, high cholesterol, and physical inactivity, indicating that these risk factors were associated with faster cognitive decline specifically in Aβ+ individuals. The results suggest that consideration of amyloid status may be important when evaluating the potential role of metabolic and lifestyle risk factors in preclinical cognitive decline. In Aβ+ individuals, obesity was associated with slower cognitive decline, while low education was linked to lower baseline cognition or a reduced symptom threshold, without a significant interaction with amyloid status. Future studies should incorporate amyloid status and longitudinal biomarkers to assess whether modifying these factors can slow preclinical cognitive decline.},
}

@article {pmid42061026,
year = {2026},
author = {Doppler, CEJ and Sembowski, N and Plottka, D and Hommelsen, M and Röttgen, S and Schwabedal, JTC and Schreiner, SJ and Fink, GR and Borghammer, P and Bialonski, S and Sommerauer, M},
title = {Impaired sleep microarchitecture is associated with locus coeruleus degeneration in Parkinson's disease.},
journal = {Parkinsonism & related disorders},
volume = {147},
number = {},
pages = {108339},
doi = {10.1016/j.parkreldis.2026.108339},
pmid = {42061026},
issn = {1873-5126},
abstract = {STUDY OBJECTIVES: Sleep disorders are common non-motor symptoms of Parkinson's disease (PD) that significantly impact patients' quality of life. Specifically, alterations in sleep microstructure - such as reduced slow-wave activity and sleep spindles - are prevalent in PD. The locus coeruleus (LC), the brain's primary source of noradrenaline, plays a pivotal role in regulating sleep and wakefulness and is highly vulnerable to neurodegeneration in PD. This study explores whether disruptions in sleep microarchitecture in PD are linked to LC degeneration.

METHODS: We assessed polysomnography for sleep macroarchitecture, EEG spectral power, and spindle density in 32 PD patients and 24 age- and sex-matched controls. In a sample subset (n = 42), neuromelanin-sensitive MRI was performed, and LC neuromelanin contrast was correlated to sleep metrics.

RESULTS: PD patients exhibited reduced slow-wave activity (p < 0.01), slow-to-fast frequency ratio (p < 0.01), and spindle density (p < 0.05) compared to HC subjects. LC neuromelanin contrast was diminished in PD patients (p < 0.05). Even though group differences were detected for slow-wave activity, a positive correlation between LC contrast and spindle density but not slow-wave activity was observed in the entire sample.

CONCLUSIONS: The findings indicate that spindle density, but not slow-wave activity, is associated with LC degeneration. Further research is needed to determine whether, besides this association, noradrenergic dysfunction is causal for impaired sleep microarchitecture and whether this connection also contributes to cognitive decline in PD and other neurodegenerative diseases, such as Alzheimer's disease.},
}

@article {pmid42061654,
year = {2026},
author = {Yao, Z and Godje, ISG and Jiao, B and Shen, L and Luo, SL},
title = {Apolipoprotein E4 and Synaptic Dysfunction in Alzheimer's Disease: Mechanisms and Therapeutic Implications.},
journal = {Ageing research reviews},
volume = {},
number = {},
pages = {103153},
doi = {10.1016/j.arr.2026.103153},
pmid = {42061654},
issn = {1872-9649},
abstract = {Alzheimer's disease (AD) is characterized by progressive cognitive decline, with synaptic dysfunction as the strongest correlate of clinical symptoms. The apolipoprotein E ε4 (ApoE4) allele is the most potent genetic risk factor for late-onset AD. Beyond its roles in amyloid-β aggregation and tau hyperphosphorylation, ApoE4 disrupts synaptic integrity by perturbing lipid metabolism, neuroimmune regulation, mitochondrial dynamics, and activity-dependent plasticity. These ApoE4-driven mechanisms impair presynaptic vesicle trafficking, destabilize postsynaptic receptor and scaffolding networks (including PSD-95, SynGAP, and Shank3), and accelerate complement- and microglia-mediated synaptic pruning. Collectively, these processes converge to destabilize neuronal circuits and drive early cognitive decline. In this review, we synthesize current evidence on the molecular mechanisms by which ApoE4 compromises synaptic function, with particular emphasis on lipid microdomain instability, mitochondrial failure, and the collapse of postsynaptic density proteins. We also discuss therapeutic strategies to enhance synaptic resilience, including modulation of glutamatergic transmission, restoration of lipid homeostasis, augmentation of neurotrophic signaling, and regulation of microglial activity. Targeting synaptic preservation in APOE ε4 carriers holds promise as a disease-modifying approach to mitigate cognitive decline in AD.},
}

@article {pmid42061810,
year = {2026},
author = {Arasmou-Idrovo, MS and Marín-Rodríguez, B and Gironda-Martínez, A and García, AG and León, R and Pascual-Guerra, J and Torres-Rico, M},
title = {UNEXPECTED MECHANISMS OF REPURPOSED DRUGS IN THE PATHOGENIC PATHWAYS OF NEURODEGENERATIVE DISEASES. DISCOVERING NEW NEUROPROTECTIVE THERAPIES IN CELLULAR MODELS.},
journal = {Neuropharmacology},
volume = {},
number = {},
pages = {110994},
doi = {10.1016/j.neuropharm.2026.110994},
pmid = {42061810},
issn = {1873-7064},
abstract = {Advances in biomedicine have increased life expectancy, leading to a growing prevalence of age-related neurodegenerative diseases such as Alzheimer's and Parkinson's disease, alongside disorders of genetic or environmental origin including multiple sclerosis, Huntington's disease, and amyotrophic lateral sclerosis. Despite their diverse etiologies, these conditions share convergent pathogenic mechanisms-calcium overload, neuroinflammation, and oxidative stress-that drive neuronal apoptosis and progressive neurodegeneration. Developing therapies that effectively target these interconnected pathways remains a major challenge. Here, we applied a drug-repurposing pipeline integrating computational chemistry, calcium channel affinity prediction, and in vitro validation in SH-SY5Y and HEK293 cells. Eight clinically approved CNS drugs were screened for activity against Caᵥ1, Orai1, and P2X7 channels, and subsequently evaluated in neuroprotection assays. Several compounds demonstrated significant efficacy, with chlorpromazine showing broad-spectrum activity (neuroprotection, Caᵥ1.2 and P2X7 antagonism, anti-inflammatory effects), trimipramine emerging as a potent antioxidant, and vilazodone displaying synergistic neuroprotection in combination with procyclidine. These findings reveal multi-target pharmacological profiles in well-tolerated drugs not currently used for neurodegenerative indications. By highlighting both individual and combinatorial strategies, this work provides a foundation for translational studies aimed at repurposing approved agents for complex neurological disorders, with particular relevance to Parkinson's disease.},
}

@article {pmid42061814,
year = {2026},
author = {Meng, N and Li, C and Bai, F and Zhang, J and Li, X and Zhang, J and Zhang, C and Fu, J and Fu, J and An, L},
title = {Lipoprotein lipase facilitates Aβ transport across the blood-brain barrier via LRP1: Validation of the obesity paradox in Alzheimer's disease.},
journal = {Journal of advanced research},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.jare.2026.04.062},
pmid = {42061814},
issn = {2090-1224},
abstract = {INTRODUCTIONS: Being obese in mid-life is an increased risk of dementia and cognitive decline in late-life, while being obese in late-life is shown to be associated with a lower risk of these outcomes in some studies, which the above phenomenon is known as the "obesity paradox", however, the mechanisms underlying the phenomenon "obesity paradox" in Alzheimer's disease (AD) have not been clarified. Alterations in lipoprotein lipase (LPL) levels in adipose tissue and skeletal muscle are significant for individuals predisposed to obesity or those undergoing weight loss. LPL promotes the entry of low-density lipoprotein (LDL) into cells, which leads to the release of free cholesterol, influencing low-density lipoprotein receptor-related protein 1 (LRP1) levels. LRP1 located in brain microvascular endothelial cells plays a vital role in mediating intracerebral beta-amyloid protein (Aβ) trans-blood-brain barrier (BBB) transport. However, it is unknown whether LPL in peripheral tissues inhibits intracerebral Aβ trans-BBB transport via LRP1, and explains the observed "obesity paradox" in AD.

OBJECTIVES: This study aims to investigate whether LPL in peripheral tissues contributes to the "obesity paradox" by regulating LRP1 expressed on brain microvascular endothelial cells in AD.

METHODS: A population-based epidemiological case-control study, coupled with in vivo and in vitro experiments were adopted to elucidate the role of LPL in AD.

RESULTS: A population-based epidemiological case-control study was adopted to elucidate the interaction between LPL alleles (rs285 and rs328) and apolipoprotein E4 (APOE4, the main risk gene for sporadic AD) promotes the occurrence and development of AD. We have adopted in vivo and in vitro experiments to elucidate LPL in adipose tissue influences the occurrence and development of AD by regulating LRP1 located in brain microvascular endothelial cells.

CONCLUSION: These findings provide evidence that LPL plays a pivotal role in the pathogenesis of AD, and its variations in adipose tissue may explain the observed "obesity paradox" in AD.},
}

@article {pmid41794773,
year = {2026},
author = {Soliman, AR and Fahmy, E and Mahmoud Ahmed, R},
title = {The obesity-brain axis: a comprehensive review of neurological complications and therapeutic interventions in metabolic syndrome.},
journal = {Diabetology & metabolic syndrome},
volume = {18},
number = {1},
pages = {},
pmid = {41794773},
issn = {1758-5996},
abstract = {BACKGROUND: Obesity has emerged as a major global health issue, affecting multiple organ systems. Within the central nervous system obesity causes a series of disruptions that can significantly affect neurological function. Identifying obesity as a modifiable risk factor presents opportunities for preventive and therapeutic strategies that may significantly diminish neurological sequelae.

OBJECTIVE: This narrative review aims to summarize current evidence on how obesity contributes to different neurological diseases and focusing on biological mechanisms linking obesity to these conditions, outlines the characteristic clinical presentations of obesity-related neurological diseases across different age groups and potential therapeutic strategies.

METHODS: This narrative review integrates findings from comprehensive search of PubMed, EMBASE, and Cochrane Library to investigate how obesity and metabolic syndrome relate to a broad spectrum of neurological disorders. After screening 1,950 records, 48 studies were included supplemented by nine manually identified articles.

RESULTS: Obesity triggers a range of biological changes in the nervous system such as increased oxidative stress, persistent low‑grade inflammation, disruption of the blood–brain barrier, and impaired mitochondrial function. Together, these changes raise the risk of several neurological problems, including cognitive decline, Alzheimer’s disease, stroke, faster progression of multiple sclerosis, greater epilepsy‑related complications, transformation of episodic into chronic migraine, idiopathic intracranial hypertension, and various peripheral neuropathies. The impact of body mass index on neurological health differs across diseases and age groups with obesity in midlife representing a high risk. Lifestyle‑based strategies especially Mediterranean or ketogenic dietary patterns, regular physical activity and weight reduction show encouraging potential in reducing these neurological risks.

CONCLUSIONS: Obesity is a modifiable contributor to many neurological disorders. Identifying at‑risk individuals early and adopting healthier daily habits, following tailored diets and managing weight effectively may help lessen the neurological consequences of obesity. Continued research is essential to clarify underlying mechanisms and refine treatment strategies for different patient groups.},
}

@article {pmid41993417,
year = {2026},
author = {Pressman, PS and Basaran, C and Foltz, P and AuYeung, WT and Steele, J and Silbert, L and Hunter, LE},
title = {Dynamic thermodynamic-informational entropic relationship (TIER) models of selective vulnerability to neurodegeneration.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
pmid = {41993417},
issn = {2692-8205},
abstract = {BACKGROUND: Neurodegenerative diseases share selective vulnerability patterns suggesting common physical mechanisms. We apply unified mechanics theory to neural systems, predicting that brain regions accumulate structural damage proportional to computational workload.

METHODS: We simulated a hierarchical neural network implementing relationships between mechanical work (W = F × D), proportional thermodynamic entropy accumulation (Δs ∝ W), and structural failure thresholds. Neural architectures at three hierarchical levels employed Hebbian learning across 2000 simulation sets, tracking thermodynamic entropy generation and dynamic stability. A coupled "siphon" model simulated cortical and subcortical support populations under constant cognitive demand.

RESULTS: Heteromodal integration nodes consistently exhibited elevated work, accelerated entropy accumulation, and dynamic instability across architectures. Support systems reached 50% population loss before cortical systems despite lower absolute work, demonstrating accelerated compensatory failure.

DISCUSSION: These thermodynamic-informational entropic relationship (TIER) models depict mechanisms underlying selective vulnerability across neurodegeneration, reframing neurodegeneration as the physical consequence of evolutionary trade-offs optimizing cognitive performance over longevity.},
}

@article {pmid42050061,
year = {2026},
author = {Chang, SH and Lin, HL and Qian, H and Liu, ZT and Lu, J and Zhong, BL},
title = {Diagnostic accuracy of digital clock drawing test for Alzheimer disease and mild cognitive impairment.},
journal = {NPJ digital medicine},
volume = {},
number = {},
pages = {},
doi = {10.1038/s41746-026-02687-2},
pmid = {42050061},
issn = {2398-6352},
support = {WX23A99//Wuhan Medical Research Project 2023 (Healthy Development)/ ; WX23A99//Wuhan Medical Research Project 2023 (Healthy Development)/ ; 2024020801020405//the 2024 Wuhan Natural Science Foundation Exploration Plan Municipal Medical Institutions Clinical Research Key Project/ ; 2024020801020405//the 2024 Wuhan Natural Science Foundation Exploration Plan Municipal Medical Institutions Clinical Research Key Project/ ; 202305AF150180//Academician Song Weihong Workstation in Yunnan Province/ ; EWEITONG [2021]74//the Young Top Talent Programme in Public Health from the Health Commission of Hubei Province/ ; },
abstract = {Alzheimer's disease (AD) and mild cognitive impairment (MCI) are major public health concerns, requiring accurate and scalable diagnostic tools. The digital clock drawing test (dCDT) captures drawing data and enables extraction of process-related features that may improve diagnostic performance. However, existing evidence remains inconsistent, highlighting the need for a systematic synthesis to support its clinical translation. We searched Web of Science, Embase, PubMed, PsycINFO, IEEE Xplore, CNKI, and Wanfang from inception to January 8, 2026. A bivariate mixed-effects model was used to pool sensitivity and specificity. A total of 13 studies comprising 17 diagnostic tests were included, and risk of bias was notable across studies. For MCI, the standalone dCDT showed pooled sensitivity of 0.765 (95% CI: 0.683-0.832), specificity of 0.752 (95% CI: 0.673-0.817), and pooled area under the summary receiver operating characteristic curve (AUC) of 0.825 (95% CI: 0.790-0.856). When both standalone and augmented dCDT tests were considered for MCI, the pooled sensitivity and specificity were 0.760 and 0.800, respectively, and the pooled AUC increased to 0.845. For AD, the pooled sensitivity, specificity, and AUC of dCDT were 0.820 (95% CI: 0.721-0.889), 0.897 (95% CI: 0.860-0.923), and 0.928 (95% CI: 0.902-0.948), respectively. Exploratory subgroup analyses of standalone dCDT for MCI suggested diagnostic performance appeared higher in studies employing algorithm-based approaches than in those using traditional-scoring approaches. Overall, the available evidence supports dCDT as a promising digital screening tool for cognitive impairment. Further multicenter studies and standardized protocols are needed to enhance its role in early diagnostic and clinical practice.},
}

@article {pmid42050120,
year = {2026},
author = {Esteve, M and Martinez-Gracia, A and Rodríguez-Sala, JJ and Brotons-Mas, JR and Falcó, A},
title = {Retraction Note: A novel approach integrating topological deep learning from EEG Data in Alzheimer's disease.},
journal = {Scientific reports},
volume = {16},
number = {1},
pages = {},
doi = {10.1038/s41598-026-50185-y},
pmid = {42050120},
issn = {2045-2322},
}

@article {pmid42050212,
year = {2026},
author = {Li, XY and Zhang, Y and Ran, Z and Luo, JX and Yu, XQ and Lu, MH},
title = {CD33 Isoform Splicing Dysregulation: A Molecular Determinant of Microglial Dysfunction in Alzheimer's Disease Pathology.},
journal = {Molecular neurobiology},
volume = {63},
number = {1},
pages = {},
pmid = {42050212},
issn = {1559-1182},
support = {Grant No. 2025ZNSFSC1799//Sichuan Science and Technology Program/ ; Grant No. 25MSZX550//Sichuan Provincial Administration of Traditional Chinese Medicine/ ; },
mesh = {*Alzheimer Disease/genetics/pathology/metabolism ; Humans ; *Sialic Acid Binding Ig-like Lectin 3/genetics/metabolism ; *Microglia/metabolism/pathology ; Protein Isoforms/genetics/metabolism ; Animals ; *Alternative Splicing ; *RNA Splicing ; },
abstract = {Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by amyloid-β (Aβ) plaques, neurofibrillary tangles, and chronic neuroinflammation. Genome-wide association studies (GWAS) have identified microglial dysfunction as central to AD pathogenesis, with CD33 emerging as a critical genetic risk factor. This review explores the dual roles of CD33 isoforms, CD33M (pro-pathogenic) and CD33m (protective), in modulating microglial activity, Aβ clearance, and neuroinflammatory responses. We dissect the molecular mechanisms underlying isoform formation, including genetic polymorphisms (e.g., rs3865444, rs12459419) and splicing regulation by hnRNPA/B, PTBP1, and SRSF1. Additionally, we highlight the antagonistic interplay between CD33 and TREM2, emphasizing their convergence on DAP12 signaling and downstream pathways. Emerging therapeutic strategies targeting CD33, such as isoform-specific immunotherapies, small-molecule splicing modulators, and Siglec-glycan interactions, are critically evaluated for their potential to mitigate AD pathology. By integrating recent preclinical and clinical advancements, this review underscores the necessity of precision approaches to harness CD33's therapeutic potential while addressing challenges like blood-brain barrier penetration and species-specific discrepancies.},
}

*Alzheimer Disease/genetics/pathology/metabolism
Humans
*Sialic Acid Binding Ig-like Lectin 3/genetics/metabolism
*Microglia/metabolism/pathology
Protein Isoforms/genetics/metabolism
Animals
*Alternative Splicing
*RNA Splicing

@article {pmid42050268,
year = {2026},
author = {Kern, LM and Fowler, NR and Nothelle, SK},
title = {Family Caregivers and the Need to Navigate Healthcare for People with Alzheimer's Disease and Related Dementias.},
journal = {Journal of general internal medicine},
volume = {},
number = {},
pages = {},
doi = {10.1007/s11606-026-10460-0},
pmid = {42050268},
issn = {1525-1497},
support = {R01AG087243/AG/NIA NIH HHS/United States ; K23AG072037/AG/NIA NIH HHS/United States ; },
}

@article {pmid42050365,
year = {2026},
author = {Dos Reis, S and Tran, P and Mohanty, K and Amill-Rosario, A and Johnson, A and Ryan, K and Alsdurf, H and Oraichi, D and Yun, H},
title = {Reduced risk of dementia with recombinant zoster vaccine in US adults age 65 or older.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {22},
number = {5},
pages = {e71407},
doi = {10.1002/alz.71407},
pmid = {42050365},
issn = {1552-5279},
support = {//GSK/ ; },
mesh = {Humans ; Aged ; Female ; Male ; *Herpes Zoster Vaccine/therapeutic use ; United States/epidemiology ; *Dementia/epidemiology/prevention & control ; Medicare/statistics & numerical data ; Aged, 80 and over ; Incidence ; Alzheimer Disease/epidemiology/prevention & control ; Vaccines, Synthetic ; Herpes Zoster/prevention & control ; Proportional Hazards Models ; Risk Factors ; Vaccination ; },
abstract = {INTRODUCTION: Herpes zoster vaccines may lower the risk of dementia onset. We evaluated new-onset dementia among US Medicare beneficiaries ≥65 years old following recombinant zoster vaccination (RZV).

METHODS: We matched one RZV-exposed to two RZV-unvaccinated on age, sex, and race/ethnicity. Individuals were ≥65 years old on the RZV dose 2 date (RZV-exposed) or preventive care visit date (RZV-unvaccinated), enrolled in Medicare ≥11 months before this date, and had no pre-existing dementia of any type. Weighted Cox proportional hazards models generated hazard ratios (HR) of new-onset dementia, Alzheimer's disease (AD), and vascular dementia (VD).

RESULTS: The incidence per 1000 person-years of new-onset dementia for 15,061/502,845 RZV-exposed and 36,526/1,005,690 RZV-unvaccinated was 10.45 and 15.73, respectively. Time-dependent HRs (95% confidence interval) for ≤3 and >3 years' follow-up were as follows: 0.67 (0.65, 0.68); 0.74 (0.69, 0.79) for dementia; 0.72 (0.69, 0.74); 0.83 (0.74, 0.94) for AD; 0.67 (0.64, 0.70); 0.66 (0.57, 0.78) for VD.

DISCUSSION: Two-dose RZV may lower new-onset dementia, AD, and VD risk.},
}

Humans
Aged
Female
Male
*Herpes Zoster Vaccine/therapeutic use
United States/epidemiology
*Dementia/epidemiology/prevention & control
Medicare/statistics & numerical data
Aged, 80 and over
Incidence
Alzheimer Disease/epidemiology/prevention & control
Vaccines, Synthetic
Herpes Zoster/prevention & control
Proportional Hazards Models
Risk Factors
Vaccination

@article {pmid42050369,
year = {2026},
author = {Tao, Q and Han, J and Ang, TFA and Hou, L and Liu, C and Murabito, JM and Lunetta, KL and Mez, J and Alosco, ML and Stein, TD and Zhang, X and Au, R and Farrer, L and Palmisano, JN and Hamburg, NM and Qiu, WQ},
title = {Peripheral vascular function, including endothelium-dependent measures, and dementia risk: The Framingham Heart Study.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {22},
number = {5},
pages = {e71396},
doi = {10.1002/alz.71396},
pmid = {42050369},
issn = {1552-5279},
support = {N01-HC-25195//National Heart, Lung, and Blood Institute (NHLBI), National Institutes of Health/ ; 75N92025D00012/HL/NHLBI NIH HHS/United States ; NS-17950//National Institute of Neurological Disorders and Stroke (NINDS), National Institutes of Health/ ; AG-008122//National Institute on Aging (NIA), National Institutes of Health/ ; AG-16495//National Institute on Aging (NIA), National Institutes of Health/ ; AG-022476//National Institute on Aging (NIA), National Institutes of Health/ ; //U.S. Department of Veterans Affairs (VA) Merit Award/ ; },
mesh = {Humans ; Female ; Male ; Middle Aged ; Magnetic Resonance Imaging ; Aged ; Biomarkers/blood ; *Brachial Artery/physiopathology/diagnostic imaging ; Brain/pathology/diagnostic imaging ; *Endothelium, Vascular/physiopathology ; *Alzheimer Disease/epidemiology/physiopathology ; Risk Factors ; Hyperemia/physiopathology ; },
abstract = {INTRODUCTION: The relationship between peripheral vascular health, including endothelia, cognitive decline, and Alzheimer's disease (AD) dementia risk is unclear.

METHODS: In this study, 2844 dementia-free Framingham Offspring participants (mean age 60.6 years, 53.2% women) had baseline brachial artery flow-mediated dilation (FMD%) and reactive hyperemia (RH). Participants were then followed for a median of 17 years for incident AD and underwent plasma biomarker testing and brain magnetic resonance imaging.

RESULTS: FMD% (hazard ratio [HR] = 0.83, 95% confidence interval [CI] 0.76 to 0.91, p < 0.001) and RH (HR = 0.89, 95% CI 0.79 to 0.99, p = 0.049) were negatively associated with incident AD dementia after adjusting for confounders. Associations were stronger in individuals with elevated C-reactive protein. Poor vascular function correlated with higher plasma AD biomarkers, smaller brain volumes, greater white matter injury, and increased cerebral microbleeds.

DISCUSSION: Poor FMD% and RH may serve as a prognostic biomarker for cerebrovascular pathology, including endothelial dysfunction in the AD brain.},
}

Humans
Female
Male
Middle Aged
Magnetic Resonance Imaging
Aged
Biomarkers/blood
*Brachial Artery/physiopathology/diagnostic imaging
Brain/pathology/diagnostic imaging
*Endothelium, Vascular/physiopathology
*Alzheimer Disease/epidemiology/physiopathology
Risk Factors
Hyperemia/physiopathology

@article {pmid42050370,
year = {2026},
author = {Aravena, JM and Castro, H and Poblete, R and Saavedra, G and Briceño, R and Torres, W and Vecchi, M and Budinich, M and Fuentes, P and Albala, C and Levy, BR},
title = {Designing a communication strategy to promote Alzheimer's disease prevention: The CULTIVAMENTE campaign.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {22},
number = {5},
pages = {e71448},
doi = {10.1002/alz.71448},
pmid = {42050370},
issn = {1552-5279},
support = {//National Research and Development Agency of Chile/ ; //Yale Social and Behavioral Sciences Research Fund/ ; //Yale University Council on Latin American and Iberian Studies/ ; //Yale MacMillan Center for International and Area Studies/ ; //Yale Center for the Study of Race, Indigeneity, and Transnational Migration/ ; R01AG067533/AG/NIA NIH HHS/United States ; U01AG032284/AG/NIA NIH HHS/United States ; },
mesh = {Humans ; *Alzheimer Disease/prevention & control ; Male ; Female ; Aged ; *Health Promotion/methods ; *Communication ; Health Personnel ; *Health Knowledge, Attitudes, Practice ; Qualitative Research ; Middle Aged ; },
abstract = {INTRODUCTION: Awareness of Alzheimer's disease (AD) prevention remains limited in community settings, contributing to low adoption of evidence-based recommendations. This study aimed to design a context-tailored communication strategy for older adults and health-care providers.

METHODS: A three-phase, multi-method study using a design-thinking framework was conducted in senior centers, including qualitative research, contextual observations, and participatory codesign.

RESULTS: A total of 101 older adults and 54 health-care providers contributed to the development phase. The resulting strategy, CULTIVAMENTE, uses positive aging imagery and nudge-based cues to deliver evidence-based AD prevention messages through posters, brochures, and websites. After implementation, older adults in intervention centers reported increased knowledge of prevention strategies (32.7%-61.4%) and more frequent discussions with health-care providers (9.9%-21.8%). Health-care providers reported high acceptability and use of campaign materials.

DISCUSSION: CULTIVAMENTE is a low-intensity and context-tailored approach that was feasible to implement and supported improvements in AD prevention awareness.},
}

Humans
*Alzheimer Disease/prevention & control
Male
Female
Aged
*Health Promotion/methods
*Communication
Health Personnel
*Health Knowledge, Attitudes, Practice
Qualitative Research
Middle Aged

@article {pmid42050390,
year = {2026},
author = {Xu, Y and Denkinger, MN and Liu, M and Gong, K and Chen, Y and Western, D and Timsina, J and Cheng, Y and Xie, Y and Mu, R and Budde, J and Beach, TG and Serrano, GE and Reiman, EM and Singh, A and Alfradique-Dunham, I and Benzinger, TLS and Schindler, SE and Morris, JC and Holtzman, DM and Perlumtter, JS and Snider, BJ and Campbell, MC and Kotzbauer, PT and Ashton, NJ and Cruchaga, C},
title = {GPND-AI NULISA: A 15-Protein AI classifier for diagnosis and co-pathology profiling across neurodegenerative diseases.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {22},
number = {5},
pages = {e71420},
doi = {10.1002/alz.71420},
pmid = {42050390},
issn = {1552-5279},
support = {R01-AG064614//the National Institutes of Health/ ; U01-AG084514//the National Institutes of Health/ ; P01-NS131131//the National Institutes of Health/ ; R01-AG078964//the National Institutes of Health/ ; R01-AG058501//the National Institutes of Health/ ; R01-AG071706//the National Institutes of Health/ ; P30-AG066444//the National Institutes of Health/ ; R01-AG064877//the National Institutes of Health/ ; P30AG066444//the National Institutes of Health/ ; P01AG03991//the National Institutes of Health/ ; P01AG026276//the National Institutes of Health/ ; },
mesh = {Humans ; *Neurodegenerative Diseases/diagnosis/pathology/classification ; Male ; Female ; Aged ; *Artificial Intelligence ; Proteomics/methods ; Parkinson Disease/diagnosis/pathology ; Alzheimer Disease/diagnosis/pathology ; Lewy Body Disease/diagnosis/pathology ; Biomarkers ; Frontotemporal Dementia/diagnosis/pathology ; Middle Aged ; Aged, 80 and over ; },
abstract = {INTRODUCTION: Accurate clinical diagnosis of neurodegenerative diseases remains challenging, particularly when individuals have mixed pathologies. We implemented the generalizable protein-based neurodegenerative disease artificial intelligence (GPND-AI) classifier using the NUcleic acid-Linked Immuno-Sandwich Assay (NULISA) central nervous system (CNS) panel to classify Alzheimer's disease, Parkinson's disease, frontotemporal dementia, dementia with Lewy bodies, and healthy controls, while disentangling mixed pathologies.

METHODS: Proteomic and clinical information from the Charles F. and Joanne Knight Alzheimer's Disease Research Center (Knight-ADRC) and Movement Disorder Clinic were used to train and test the GPND-AI classifier. External validation was performed in a Banner Sun Health Research Institute cohort and additional Knight-ADRC samples with neuropathologically confirmed diagnoses.

RESULTS: GPND-AI identified 15 proteins that achieve an area under the curve (AUC) of 0.955 and 92.3% accuracy across five diagnostic categories. In validation cohort, predicted co-pathologies significantly correlated with clinical characteristics.

DISCUSSION: GPND-AI identified a 15-protein panel that accurately classifies individuals across the four major neurodegenerative diseases. Validation against neuropathology-confirmed diagnoses supports the utility of proteomics-based approaches for mapping disease-specific and co-existing neurodegenerative processes.},
}

Humans
*Neurodegenerative Diseases/diagnosis/pathology/classification
Male
Female
Aged
*Artificial Intelligence
Proteomics/methods
Parkinson Disease/diagnosis/pathology
Alzheimer Disease/diagnosis/pathology
Lewy Body Disease/diagnosis/pathology
Biomarkers
Frontotemporal Dementia/diagnosis/pathology
Middle Aged
Aged, 80 and over

@article {pmid42050423,
year = {2026},
author = {Hornbecker, M and Suchsland, MZ and MacLeod, T and Koppenhofer, MJ and Selzler, KJ and Ferrell, P and Deckert, A},
title = {The Davos Alzheimer's Collaborative Healthcare System Preparedness US Early Detection of Cognitive Impairment Program in primary care: Methodology.},
journal = {BMC primary care},
volume = {},
number = {},
pages = {},
doi = {10.1186/s12875-026-03312-7},
pmid = {42050423},
issn = {2731-4553},
}

@article {pmid42050540,
year = {2026},
author = {Zhang, H and Xie, L and Meng, F and Cui, J and Ma, B and Wang, Y and Zhang, K and Miao, X},
title = {Shared genetic architecture between Alzheimer's disease and psychiatric disorders revealed by multi-trait genome-wide analyses.},
journal = {BMC medical genomics},
volume = {},
number = {},
pages = {},
doi = {10.1186/s12920-026-02354-1},
pmid = {42050540},
issn = {1755-8794},
}

@article {pmid42050739,
year = {2026},
author = {Chung, SJ and Kang, M and Park, YJ and Oh, K and Koh, SB and Kang, SH},
title = {Impact of appendicular skeletal muscle mass on Alzheimer's disease in relation to age and comorbidities: an 8-year longitudinal follow-up study of a nationwide cohort.},
journal = {Alzheimer's research & therapy},
volume = {},
number = {},
pages = {},
doi = {10.1186/s13195-026-02063-y},
pmid = {42050739},
issn = {1758-9193},
support = {20240088//the 2024 Inje University Research Grant/ ; },
}

@article {pmid42050742,
year = {2026},
author = {Zhang, Y and Tan, Q and Wu, S and Xu, X},
title = {Women's reproductive life patterns, intrinsic capacity, and the risk of all-cause and cause-specific dementia: a prospective cohort study.},
journal = {Alzheimer's research & therapy},
volume = {},
number = {},
pages = {},
doi = {10.1186/s13195-026-02066-9},
pmid = {42050742},
issn = {1758-9193},
support = {21-416//China Medical Board/ ; 72474197//the Natural Science Foundation of China/ ; },
abstract = {BACKGROUND: Few studies comprehensively examined women's life-course reproductive patterns and the risk of dementia. This study aims to examine the association between women's reproductive life sequence and dementia, and to explore the potential role of intrinsic capacity (IC) on such association.

METHODS: This study used data of 153,909 women who were post-menopause and free of dementia at baseline from the UK Biobank. We conducted sequence analysis and cluster analysis to identify women's life-course reproductive sequence and its potential patterns based on self-reported single reproductive factors. Women's IC at baseline comprised four functional domains: psychology, sensory, vitality, and locomotion. Participants were followed from baseline to the onset of dementia, death, or the end of follow-up (September 1, 2023). Fine and Gray's subdistribution hazard models were used to examine the associations between reproductive life sequences, IC, and dementia.

RESULTS: During a median follow-up of 14.5 years, 2,940 dementia (including 1,509 Alzheimer's disease and 577 vascular dementia) cases were documented. Patterns of reproductive life sequences identified were: standard sequence (46.4%), early childbearing and oophorectomy menopause (6.5%), short reproductive span with natural menopause (17.7%), early childbearing and hysterectomy menopause (11.4%), and high parity with long birth span (18.1%). Compared to the standard sequence, short reproductive span with natural menopause (hazard ratio [HR] = 1.30, 95% confidence interval [CI] = 1.18-1.44), early childbearing and hysterectomy menopause (HR = 1.17, 95% CI = 1.04-1.32), and high parity with long birth span (HR = 1.13, 95% CI = 1.03-1.25) were associated with a higher risk of dementia. These associations would be strengthened when combining with IC impairment. For example, women with the combined sequence of short reproductive span with natural menopause and IC impairment had 2.40-fold (1.77-3.24) increased risk of dementia, compared to those with the standard sequence and no IC impairment. The associations between reproductive life patterns and dementia risk were stronger among women with more impairment items of IC.

CONCLUSION: Our study showed cumulative associations of women's life-course reproductive factors with the risk of dementia in later life, and IC impairment could strengthen such associations. These results suggest the need to prioritize women with high-risk reproductive sequences, with special focus on their IC, in the prevention strategies for dementia.},
}

@article {pmid42050895,
year = {2026},
author = {Tunç, T and Kılınç, N and Demirel, N and Alım, Z},
title = {Design, Synthesis, and Enantioselective Cholinesterase Inhibition of Novel Chiral Anthranilic Diamide Derivatives: In Vitro and In Silico Studies.},
journal = {Chirality},
volume = {38},
number = {5},
pages = {e70104},
doi = {10.1002/chir.70104},
pmid = {42050895},
issn = {1520-636X},
mesh = {*Cholinesterase Inhibitors/chemistry/chemical synthesis/pharmacology ; Stereoisomerism ; Acetylcholinesterase/metabolism/chemistry ; Butyrylcholinesterase/metabolism/chemistry ; *Drug Design ; Molecular Docking Simulation ; *ortho-Aminobenzoates/chemistry/chemical synthesis/pharmacology ; *Diamide/chemistry/pharmacology/chemical synthesis ; Humans ; Animals ; },
abstract = {Acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) enzymes are responsible for the hydrolysis of acetylcholine and play a vital role in Alzheimer's disease (AD) pathology. The observation of decreased AChE activity and a significant increase in BChE activity in the advanced stages of AD makes the identification of novel inhibitors targeting both AChE and BChE enzymes crucial. In this study, novel chiral anthranilic acid-based diamide derivatives (5a-5d, 7a, and 7b) with pure enantiomer structures were synthesized, and their inhibitory potential on AChE and BChE was comprehensively investigated. The structures of the synthesized compounds were confirmed by [1]H NMR, [13]C NMR, IR, and LC-MS analyses. In vitro cholinesterase inhibition studies showed that all compounds exhibited significant inhibitory activity against both enzymes. Specifically, compounds 7a and 7b, containing 2,6-pyridine dicarbonyl, exhibited higher AChE and BChE inhibition compared with the reference drug tacrine, displaying IC50 values at the nanomolar level. Enantioselective analyses showed that S-enantiomers were significantly more effective in AChE inhibition, while enzyme-specific inverse stereoselective preferences emerged in BChE inhibition. Experimental findings were supported by induced coherent molecular docking (IFD), MM-GBSA binding free energy calculations, and 250-ns molecular dynamics simulations. In silico analyses confirmed that 7b exhibited high stability and strong interactions in the AChE active site and 7a in the BChE active pocket. Furthermore, ADME analyses revealed that the compounds possessed favorable pharmacokinetic and drug-like properties. In conclusion, this study demonstrates that chiral anthranilic diamide derivatives are promising novel AChE/BChE inhibitor candidates that act as potent and selective cholinesterase inhibitors.},
}

*Cholinesterase Inhibitors/chemistry/chemical synthesis/pharmacology
Stereoisomerism
Acetylcholinesterase/metabolism/chemistry
Butyrylcholinesterase/metabolism/chemistry
*Drug Design
Molecular Docking Simulation
*ortho-Aminobenzoates/chemistry/chemical synthesis/pharmacology
*Diamide/chemistry/pharmacology/chemical synthesis
Humans
Animals

@article {pmid42051019,
year = {2026},
author = {Hacımüftüoğlu, A and Saraçoğlu, N and Saffour, S and Abad, N and Kesgun, Y and Zegheb, N and Gundeger, E and Yeşilyurt, F and Ateş, MN and Bati-Ayaz, G and Altunlu, Ö and Çınar, B and Yörük, MA and Okkay, U and Özkaraca, M and Ateş, O and Taghizadehghalehjoughi, A and Lafzi, F and Türkez, H},
title = {Multi-Target Neuroprotective Compound Exhibits EAAT2-Modulating and Alzheimer's Pathology-Attenuating Effects in In Vitro and In Vivo Models.},
journal = {ACS chemical neuroscience},
volume = {},
number = {},
pages = {},
doi = {10.1021/acschemneuro.5c00873},
pmid = {42051019},
issn = {1948-7193},
abstract = {Alzheimer's disease (AD) is a debilitating neurodegenerative disorder characterized by cognitive decline and memory loss. Current treatments offer limited efficacy, necessitating the development of innovative multitarget therapeutic strategies. Here, we present N[3],N[5]-bis(2-(5-methoxy-1H-indol-3-yl)ethyl)-2,6-dimethyl-4-(2-nitrophenyl)pyridine-3,5-dicarboxamide (HCM-01), a novel compound developed to target multiple neurodegenerative pathways implicated in AD. In vitro assays included MTT-based cell viability analyses performed in two complementary experimental settings: primary neuronal cultures and astrocyte-based in vitro cell culture models exposed to glutamate. In primary hippocampal neuronal cultures, glutamate exposure induced a statistically significant reduction in cell viability compared with vehicle-treated controls, consistent with glutamate-induced excitotoxicity. Under these conditions, HCM-01 treatment resulted in a statistically significant improvement in neuronal viability, showing a greater protective effect compared with donepezil and memantine. In contrast, in astrocyte-based in vitro cultures, the applied glutamate concentration did not induce overt cytotoxicity, in line with the intrinsic neuroprotective and glutamate-buffering role of astrocytes. Accordingly, astrocytic experiments were designed to assess functional modulation of glutamate-handling mechanisms rather than cell survival. Western blot analysis in C8-D1A astrocytic cells demonstrated increased expression of excitatory amino acid transporter 2 (EAAT2) following HCM-01 treatment compared with control and reference drug-treated groups, suggesting modulation of astrocyte-mediated glutamate homeostasis. In parallel, redox analyses revealed that HCM-01 improved oxidative/antioxidative balance, as evidenced by increased total antioxidant capacity (TAC) and reduced total oxidant status (TOS), supporting an indirect antioxidant contribution to its functional effects. In vivo behavioral assessment of HCM-01 in a streptozotocin (STZ)-induced Alzheimer's model in female Sprague-Dawley rats demonstrated that administration of HCM-01 at doses of 50 mg/kg orally (oral, P.O. and intraperitoneal, I.P.) and 100 mg/kg (P.O.), significantly improved cognitive and memory functions in the passive avoidance (PA), Morris water maze (MWM), and locomotor activity tests. Moreover, histopathological and immunohistochemical analyses of different hippocampal regions revealed reduced neuronal damage, attenuation of tau pathology, antiamyloidogenic effect, and restoration of cholinergic function. Complementary in silico studies, including molecular docking, molecular dynamics simulations (MDS), and free energy calculations, suggested potential interactions of HCM-01 with the allosteric site of EAAT2. Taken together, these findings suggest that HCM-01 exerts neuroprotective effects against glutamate-induced excitotoxicity in primary hippocampal neurons while additionally modulating glutamatergic homeostasis and redox balance through functional mechanisms in astrocyte-based models, supporting its relevance as a multitarget preclinical candidate for early stage AD mechanisms.},
}

@article {pmid42051092,
year = {2026},
author = {Sun, Y and Chan, TW and Liao, W and Li, M and Mao, X and Feng, Y and Rong, J and Zhao, J},
title = {In Silico Design and Evaluation of Diosmin Analogs for Targeting Peroxisome Proliferator-activated Receptor γ (PPAR-γ) Against Alzheimer's Disease.},
journal = {Current neuropharmacology},
volume = {},
number = {},
pages = {},
doi = {10.2174/011570159X453424260218065734},
pmid = {42051092},
issn = {1875-6190},
abstract = {Alzheimer's disease (AD) is a neurodegenerative disorder characterized by progressively declining cognitive abilities and memory impairment. This disease increasingly challenges the quality of life and health of the elderly population, underscoring the need for effective therapeutic strategies. The existing anti-AD medications are designed to improve symptoms but not to cure the disease. Novel drugs are urgently needed to target the specific mechanisms that mediate disease progression. Peroxisome proliferator-activated receptor gamma (PPAR-γ) is a potential target for the development of anti-AD therapies. Through virtual screening of natural PPAR-γ ligands, the flavonoid diosmin was found to bind to PPAR-γ with high potency. This study exploited diosmin as a lead compound to design a panel of diosmin analogs via chemical modifications for better biological efficacy in targeting PPAR-γ. These diosmin analogs were evaluated using in silico approaches, including molecular docking, absorption, distribution, metabolism, and excretion (ADME) predictions, and molecular dynamics (MD) simulations. As a result, molecular docking identified 12 di-osmin analogs with better binding affinity to PPAR-γ compared with diosmin. ADME and MD analyses demonstrated that S1DhP1 exhibited lower binding free energy, better water solubility, and stability than diosmin. Thus, this study provides important information via in silico approaches and hypotheses, suggesting S1DhP1 as a promising PPAR-γ agonist for the treatment of AD that warrants further experimental validation.},
}

@article {pmid42051097,
year = {2026},
author = {Kasthuri, S and Padmavathi, S and Jeevitha, M and Rajangam, J},
title = {Therapeutic Innovations in Parkinson's and Alzheimer's Disease: Molecular Mechanisms and Emerging Strategies.},
journal = {CNS & neurological disorders drug targets},
volume = {},
number = {},
pages = {},
doi = {10.2174/0118715273445849260403045802},
pmid = {42051097},
issn = {1996-3181},
abstract = {Parkinson's Disease (PD) and Alzheimer's Disease (AD) are still significant neurodegenerative disorders that have few disease-modifying therapies. In this review, recent advances are assessed based on the strength of evidence for major molecular targets and the therapeutic approaches that have been developed around those targets. Alpha-synuclein is a key target in PD, as indicated by genetic correlations, pathological distribution, and experimental evidence supporting its involvement in neuronal injury. Initial trials of alpha-synuclein antibodies and vaccines show evidence of target engagement, with yet-to-be-determined clinical outcomes. Interventions targeting gene-based dopamine synthesis restoration using AADC or multi-enzyme vectors have shown consistent biological effects, with clinical variability, and determining optimized delivery and patient selection is necessary. In AD, amyloid-beta- and tau-directed interventions have produced measurable changes in biomarkers, and some agents have demonstrated a slight deceleration of deterioration at an early stage of the disease. The experience with previous BACE inhibitors also demonstrates that excellent mechanistic rationale does not always translate into clinical efficacy in the case of interference with critical physiological processes by target modulation. Regenerative methods, such as stem-cell-based neuronal grafts in PD and neurotrophic factor gene delivery in AD, show potential to repair network function, but still pose issues regarding long-term stability, integration, and the complexity of the procedures. Lifestyle-driven interventions, control of the gut microbiome, and neuromodulation methods also remain of interest and can be included in the list of supportive strategies offered to complement molecular therapies. AI-based analytics and digital tools are helpful in the earlier detection, monitoring, and trial stratification. Taken together, existing evidence suggests that authenticated protein targets, neurotransmitter-targeted remedial strategies, and technology-enabled accuracy methods are the most promising approaches for the development of disease-modifying therapies in PD and AD.},
}

@article {pmid42051098,
year = {2026},
author = {Khan, N and Doshi, G},
title = {Zebrafish (Danio rerio) as a Model for Neurodegenerative Disease Research: Mechanisms, Biomarkers, and Translational Promise.},
journal = {CNS & neurological disorders drug targets},
volume = {},
number = {},
pages = {},
doi = {10.2174/0118715273442688260330060220},
pmid = {42051098},
issn = {1996-3181},
abstract = {Zebrafish (Danio rerio) have gained prominence as a versatile vertebrate model for studying neurodegenerative disorders due to their genetic similarity to humans, rapid development, transparency, and suitability for high-throughput drug screening. The usefulness of zebrafish in modelling human neurological disorders is supported by the similarity of their brains' anatomical and neurochemical characteristics, including comparable divisions of the forebrain, midbrain, and hindbrain, as well as dopaminergic, serotonergic, glutamatergic, and GABAergic pathways. Zebrafish have been used to successfully model several neurodegenerative diseases, including Alzheimer's disease (via tau phosphorylation and amyloid-beta aggregation), Parkinson's disease (via dopaminergic neuronal loss and alpha-synuclein pathology), Huntington's disease (via polyglutamine-expanded huntingtin), and amyotrophic lateral sclerosis (via mutant SOD1 and TDP- 43 transgenes). They have also been used to study multiple sclerosis, spinocerebellar ataxias, and Rett syndrome, enabling mechanistic exploration and preclinical drug discovery. This review crucially depicts how zebrafish models provide an affordable, morally acceptable, and scalable platform for early-stage neurodegeneration research. These models complement, rather than replace, rodent- and human-derived systems. Additionally, we will review how to bridge the gap between therapeutic screening and basic mechanistic findings, highlighting their increasing significance in the neuroscience research continuum.},
}

@article {pmid42051176,
year = {2026},
author = {Blundo, C and Ricci, M},
title = {The caregiver's inventory neuropsychological diagnosis dementia (CINDD) as useful tool in differential diagnosis of dementias.},
journal = {The Clinical neuropsychologist},
volume = {},
number = {},
pages = {1-15},
doi = {10.1080/13854046.2026.2664025},
pmid = {42051176},
issn = {1744-4144},
abstract = {Objective: This study confirms the validity and diagnostic utility of the CINDD (Cargiver's Inventory Neuropsychological Diagnostic Dementia) in assessing cognitive status and behavioral-personality changes through informant-based questions grounded in real-life contexts. We explored the discriminative capacity of the CINDD across various dementia types. Method: We enrolled caregivers of 111 patients at their first diagnostic evaluation. The Clinical population included patients with Alzheimer's Disease (AD), behavioral Fronto-Tempoal Dementia (bvFTD), Dementia with Lewy Body (LBD), non-fluent Primary Progressive Aphasia (nfvPPA), and AD-like Mild Cognitive Impairment (MCI-AD). Patients also underwent a comprehensive neuropsychological assessment including memory, language, visuospatial, and executive function tests. Results: Each CINDD's domain demonstrated meaningful correlations with standard cognitive measures, supporting its construct validity. Notably, the Memory cluster showed strong associations with verbal memory but not with executive or language tasks, while the Language and Perception clusters aligned well with respective cognitive domains. Conversely, Executive and Personality/Behavior clusters did not show significant correlations with any of the neuropsychological measures. The Illusion/Delusion cluster, though targeting neuropsychiatric symptoms, also captured elements of cognitive disorganization seen in conditions like LBD and bvFTD. Diagnostic analyses provided robust cluster-specific cutoffs with acceptable sensitivity and specificity. Particularly, the Memory cluster effectively distinguished memory-dominant dementias (e.g. AD, MCI-AD) from language-predominant variants (e.g. nfvPPA). Conclusion: Finally, given its informant-based structure, the CINDD is especially valuable for assessing individuals with low education, illiteracy, or migrant backgrounds. We recommend its integration with traditional neuropsychological tools to enhance diagnostic accuracy in diverse clinical populations.},
}

@article {pmid42051279,
year = {2026},
author = {Hadinezhad, P and Noroozian, M},
title = {Montreal Cognitive Assessment (MoCA) Scale: Strengths, Limitations, and Implication for Clinical Practice.},
journal = {Iranian journal of psychiatry},
volume = {21},
number = {1},
pages = {140-150},
pmid = {42051279},
issn = {1735-4587},
abstract = {Objective: Mild Cognitive Impairment (MCI) is a transitional state between normal aging and dementia, with high risk of progression. Early detection is essential, and so the Montreal Cognitive Assessment (MoCA) has become a widely used screening tool. Despite its popularity, concerns remain about its psychometric limitations and cultural applicability. This review aims to critically analyze the MoCA, focusing on the validity and limitations of its subtests, and to propose directions for refinement and clinical adaptation. Method : We conducted a structured narrative review (2005-2024) using PubMed, Scopus, and Web of Science databases. Search terms included "Montreal Cognitive Assessment", "MoCA", "validity", "psychometrics", and "cultural adaptation". Studies evaluating psychometric performance, cultural adaptations, and clinical applications of the MoCA were included. Case reports and studies lacking psychometric evaluation were excluded. An item-by-item critical appraisal was performed. Results: The MoCA shows superior sensitivity for MCI detection compared to the Mini-Mental State Examination (MMSE), with strengths in brevity, multidomain coverage, and accessibility. However, limitations include: superficial executive function (EF) assessment, cultural and educational bias, lack of recognition/cueing in memory testing, simplistic binary scoring, and risk of floor/ceiling effects. These may affect diagnostic accuracy across populations. Conclusion: The MoCA remains a valuable tool but should not be used in isolation. Clinicians must consider the cultural/educational context when interpreting results. Refinements such as weighted scoring, cued recall, and culturally adapted items, alongside digital versions, could improve accuracy and fairness. Further empirical validation of these modifications is needed.},
}

@article {pmid42051295,
year = {2026},
author = {Jerez, PA and Rhie, A and Kim, J and Hebbar, P and Nag, S and Antipov, D and Koren, S and Lara, E and Beilina, A and Hansen, NF and Arber, C and Zulueta, J and Crea, PW and Patel, D and Hickey, G and Waltz, B and Malik, L and Skarnes, WC and Reed, X and Genner, R and Daida, K and Pantazis, CB and Grenn, F and Nalls, MA and Billingsley, K and Fossati, V and Wray, S and Ward, M and Ryten, M and Singleton, AB and Cookson, MR and Jain, M and Paten, B and Phillippy, AM and Blauwendraat, C},
title = {The complete genome of the KOLF2.1J reference iPSC line.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.03.06.710144},
pmid = {42051295},
issn = {2692-8205},
abstract = {While induced pluripotent stem cells (iPSCs) have gained popularity in studying neurodegenerative diseases, the heterogeneity of stem cells used across studies impacts cross-study comparison. The iPSC Neurodegenerative Disease Initiative (iNDI) selected the KOLF2.1J cell line and prioritized its use as a reference standard for studying the effects of pathogenic variants on cell biology due to its stability and neutral neurodegenerative disease genetic risk. This cell line, and its derivatives expressing over 100 variants related to Alzheimer's disease, Parkinson's disease, and other neurological diseases, are available for academic and industry access. Current genomic data analyses are limited by the use of a human reference genome that does not capture the complete genetic background of a given iPSC line. While in the future this issue may be partially mitigated by the creation of a comprehensive human pangenome, previous work has shown that generating custom genomes is of value both to characterize the variation present and to serve as a more appropriate genomic reference. Here, we generated and characterized a custom complete genome assembly from KOLF2.1J. Mapping of sequencing reads to a personalized diploid assembly results in more comprehensive mapping compared to traditional linear references (i.e GRCh38). In addition, we provide a comprehensive custom gene annotation along with isoform expression and differential methylation analyses across multiple cell types. The assembly and all additional data is browsable and publicly available. This resource will enable more accurate investigation of the KOLF2.1J cell line and any genomics data generated compared to using traditional generalized references, while also serving as a foundational approach for establishing custom reference assemblies for other high-value iPSC lines.},
}

@article {pmid42051535,
year = {2026},
author = {Lv, S and Kuang, JY and Wang, TW and Zhang, LP and Liu, J and Wang, WD and Yang, MF and Ni, QB and Sun, BL and Sun, JY},
title = {Deciphering the peripheral immune landscape of Alzheimer's disease through integrated multi-omics research and cohort validation.},
journal = {Frontiers in immunology},
volume = {17},
number = {},
pages = {1648591},
pmid = {42051535},
issn = {1664-3224},
mesh = {Humans ; *Alzheimer Disease/immunology/genetics ; Genome-Wide Association Study ; Mendelian Randomization Analysis ; Transcriptome ; Cohort Studies ; Male ; Female ; Aged ; Biomarkers ; Multiomics ; },
abstract = {OBJECTIVE: This study investigated molecular drivers of AD-associated peripheral immune dysregulation to identify pathogenic genes and therapeutic targets for precision diagnosis and intervention.

METHODS: A large-scale GWAS meta-analysis (n = 894,710) was performed, followed by two-sample Mendelian randomization (MR) using multi-tissue cis-eQTL data to identify putative causal genes. Immune response differential genes (IRDGs) were defined from AD peripheral blood transcriptomes and the MSigDB database. A three-step summary-data-based MR framework integrating blood cis-eQTLs and cis-mQTLs was applied to prioritize causal genes and epigenetic regulatory elements. Findings were validated through colocalization analysis, PBMC scRNA-seq and blood-tissue TWAS. Multi-dimensional clinical validation was performed in the ADNI cohort encompassing gene expression, CSF biomarkers, cognitive measures, immune cell profiles, survival analysis, and plasma proteomics, with cross-cohort transcriptomic replication in AddNeuroMed.

RESULTS: Two-sample MR identified eight putative AD pathogenic genes. The three-step SMR and colocalization analysis prioritized five candidate causal genes, whose differential expression in immunocytes was confirmed by scRNA-seq and independently replicated. In the ADNI cohort, PTK2B expression was elevated in AD (ANOVA P = 0.0023), inversely correlated with MMSE (r = -0.164, P = 0.017), and predictive of MCI-to-AD conversion (Cox HR = 1.741, P = 0.050), with independent replication in AddNeuroMed (FDR P = 3.56 × 10[-4]). PLEKHA1 and PTK2B expression were strongly associated with peripheral neutrophil and lymphocyte proportions (P < 10[-7]), and PLEKHA1 correlated with CSF total tau (partial r = 0.102, P = 0.036). The prioritized probe cg19863426 at the PLEKHA1 promoter showed progressive hypermethylation across the CN-MCI-AD continuum (F = 3.45, P = 0.032) and was inversely correlated with PLEKHA1 mRNA (r = -0.33, P = 2.68 × 10[-]¹²).

CONCLUSION: Integrating GWAS, multi-omics Mendelian randomization, single-cell transcriptomics, transcriptome-wide association study, and clinical cohort validation, this study identified peripheral immune causal genes for AD whose blood transcriptomic and epigenetic signatures track with CSF pathology, cognitive decline, and disease progression, supporting their translational potential for early diagnosis and therapeutic development.},
}

Humans
*Alzheimer Disease/immunology/genetics
Genome-Wide Association Study
Mendelian Randomization Analysis
Transcriptome
Cohort Studies
Male
Female
Aged
Biomarkers
Multiomics

@article {pmid42051542,
year = {2026},
author = {Ailani, T and Jauhari, R and Rani, A and Singh, R},
title = {Comment on "AlzStack: Forecasting early-onset Alzheimer's with an explainable AI system using multiple data balancing techniques".},
journal = {Global epidemiology},
volume = {11},
number = {},
pages = {100260},
pmid = {42051542},
issn = {2590-1133},
}

@article {pmid42051551,
year = {2026},
author = {Palmer, JA and Billinger, SA},
title = {APOE4 carriers resistant to cognitive decline show unique relationships between cerebrovascular response to exercise and dual-task cognitive-balance performance.},
journal = {Frontiers in neuroscience},
volume = {20},
number = {},
pages = {1716713},
pmid = {42051551},
issn = {1662-4548},
abstract = {BACKGROUND: Cognitive-motor dual-tasking is an early marker for cognitive impairment, with particular implications for Apolipoprotein E4 (APOE4) carriers who are at higher genetic risk for Alzheimer's disease. While APOE4 carriers typically show accelerated cognitive decline and impaired cerebrovascular function with aging, exceptions to this norm exist and may provide insights into resilience mechanisms. The relationship between cerebrovascular response and cognitive-motor dual-task performance in cognitively-normal APOE4 carriers who maintain preserved function remains unclear.

METHODS: Thirty cognitively-normal older adults (76 ± 4 years, 8 APOE4 carriers, 22 non-carriers) completed clinical balance and cognitive testing under single-task and dual-task conditions. Balance performance was assessed as distance traversed during challenging beam walking. Cognitive performance was assessed as response time during an auditory Stroop test. Transcranial Doppler ultrasound measured cerebrovascular response to moderate-intensity aerobic exercise. We tested group differences in cognitive-balance dual task performance and relationships between cerebrovascular response and dual-task interference (DTI) in balance and cognitive domains, and effects of APOE4 genotype on these relationships.

RESULTS: No differences in cerebrovascular response or dual-task performance were observed between APOE4 carriers and non-carriers. However, APOE4 carriers displayed unique cerebrovascular-behavioral relationships. In APOE4 carriers, higher cerebrovascular response to exercise was associated with less balance DTI (r = 0.839, p = 0.009) and less cognitive DTI (r = 0.832, p = 0.020), while no relationships were observed in non-carriers (p > 0.187).

CONCLUSIONS: Cognitively-normal APOE4 carriers with preserved cognitive-balance dual-task function represent exceptions that may model aging resilience mechanisms. The unique cerebrovascular-behavioral relationships suggest that maintaining cerebrovascular function supports neuromotor and neurocognitive resilience to dual-task challenges in genetically vulnerable populations.},
}

@article {pmid42051575,
year = {2026},
author = {Spencer, C and , and Prashant, NM and Hong, A and Casey, C and Shao, Z and Alvia, M and Argyriou, S and Katsel, P and Auluck, PK and Barnes, LL and Marenco, S and Bennett, DA and Girdhar, K and Voloudakis, G and Haroutunian, V and Bendl, J and Hoffman, GE and Fullard, JF and Lee, D and Roussos, P},
title = {Decoding Pathogenic and Resilient Gene Regulatory Interactions in Alzheimer's Disease.},
journal = {medRxiv : the preprint server for health sciences},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.02.19.26346666},
pmid = {42051575},
abstract = {The molecular basis of cognitive resilience in Alzheimer's disease (AD), wherein individuals harbor substantial neuropathology yet maintain cognition, remains poorly understood. To systematically decode the regulatory logic underlying divergent cognitive outcomes, we constructed the largest cell-type-resolved gene regulatory network (GRN) atlas of AD to date, profiling 1.7 million nuclei from 687 individuals classified as Controls, cognitively Resilient, or AD dementia across 27 cell types in the human dorsolateral prefrontal cortex. From 223 high-confidence transcription factor regulons, we identify a three-state framework of transcriptional dysregulation: homeostatic erosion of IRF8/STAT1 interferon programs in microglia (State I), compensatory NF-κB suppression via BCL6 in glial populations that distinguishes resilient from demented individuals despite equivalent neuropathological burden (State II), and pathogenic escalation through FLI1/IKZF1 network expansion driving vascular-immune remodeling in AD (State III). NF-κB emerges as the central regulatory hub, with BCL6-mediated repression and FLI1/RELA-driven activation constituting opposing molecular switches that determine cognitive trajectory. These findings, replicated across independent cohorts, reframe resilience as an active regulatory state rather than attenuated disease, and nominate BCL6, IRF8, and FLI1 as priority targets for interventions aimed at extending the compensatory window before dementia onset.},
}

@article {pmid42051629,
year = {2026},
author = {Cullins, MJ and Converse, AK and Rowe, LM and Hoerst, AG and Hibbard, WK and Russell, JA and Connor, NP and Ciucci, MR},
title = {Oropharyngeal dysphagia and amyloid beta pathology in the TgF344-AD rat model of Alzheimer's disease.},
journal = {Frontiers in behavioral neuroscience},
volume = {20},
number = {},
pages = {1812480},
pmid = {42051629},
issn = {1662-5153},
abstract = {INTRODUCTION: Dysphagia is a major consequence of Alzheimer's disease (AD) that is understudied and undertreated. Neuropathology in AD occurs early in the disease progression, but little is known about pathologies underlying functional swallowing changes; this knowledge gap is a barrier to developing effective treatment. We hypothesized that an established AD rat model (TgF344-AD) would demonstrate significant deficits in oromotor/swallowing function versus Wild Type (WT) with corresponding amyloid beta pathology in brain structures critical to swallowing.

METHODS: Nine male TgF344-AD and 6 Wildtype Fisher 344 rats underwent deglutition assessments and PET imaging using the radiotracer [[11]C]PiB to assess brain and brainstem amyloid beta (Aβ) pathology at 11 months of age-a time point corresponding to early-middle stage AD progression. A priori brain regions of interest (ROIs) included those commonly associated with Aβ pathology and more specific swallowing associated structures such as brainstem nuclei and cortical motor areas. Deglutition was assessed using a videofluoroscopic swallow study and a pasta biting task.

RESULTS: Significantly increased levels of Aβ in the AD group were found in regions critical to swallowing motor control including the secondary motor area, thalamus, nucleus ambiguus, and hypoglossal nuclei. The AD group demonstrated significant changes in aerodigestive coordination, including delayed swallow onset, increased apnea duration, and increased frequency of aberrant post-swallow inhale pattern that was correlated with nucleus ambiguus Aβ levels. The AD group also exhibited altered oral processing including reduced bolus size and mastication rate.

CONCLUSION: The TgF344-AD rat model of Alzheimer's exhibits robust changes in oral processing and respiratory-swallow coordination that parallel clinical AD dysphagia. At this early-middle stage timepoint, Aβ pathology is primarily impacting cerebral swallowing networks as well as the nucleus ambiguus and hypoglossal nuclei in the brainstem. Our finding of increased Aβ in the nucleus ambiguus warrants further study as this motor nucleus plays a role in swallowing, respiration, and vocalization-all factors that are known to be impacted by AD in the clinical population.},
}

@article {pmid42051919,
year = {2026},
author = {Pavithra, P and Bradshaw Bernacchi, JK and Ahmed, S and McDermott, G and McCarron, M and McCallion, P and McGlinchey, E and Lopez Valdes, A},
title = {EEG hyperscanning in intellectual disability: a scoping review with implications for cognitive stimulation therapy.},
journal = {Frontiers in neuroergonomics},
volume = {7},
number = {},
pages = {1757738},
pmid = {42051919},
issn = {2673-6195},
abstract = {Electroencephalography (EEG) hyperscanning has emerged as a valuable method for examining social dynamics during group-based activities and may serve as a promising outcome measure in group interventions. Cognitive stimulation therapy (CST) is one such interventions shown to improve cognition and quality of life in people with dementia and has recently been adapted for individuals with intellectual disability (ID). However, the potential for obtaining objective neural markers of CST benefit via EEG and hyperscanning is yet to be explored. This scoping review aims to identify existing evidence and gaps related to the use of EEG within CST research for adults with ID by examining three relevant areas: (1) the use of individual EEG and hyperscanning to evaluate cognitive and social outcomes in CST; (2) the evidence base for individual and group-based CST in people with ID; and (3) the use of EEG to evaluate cognitive and social outcomes for people with ID. Following the PRISMA-ScR guidelines, studies were searched in CINAHL, MEDLINE, PsychInfo, and EMBASE. Our search focused on adult participants with ID and studies that used EEG for the purpose of evaluating cognitive or social outcomes. Currently, there are no studies that use EEG to evaluate CST in adults with ID. Following screening and eligibility assessment, no studies met the inclusion criteria for EEG and CST. Five studies were included for CST and ID, and 14 articles met criteria for EEG and ID. In total, 19 articles were included in the final review. The evidence base suggests that EEG has been successfully used to investigate neural mechanism in ID and Down Syndrome related Alzheimer's disease. Existing CST research in ID remains largely feasibility-focused but some preliminary findings show cognitive benefits, enhanced enjoyment, and social connectedness. Our review shows that there is a large gap when it comes to any objective metrics for CST in general. Given that there is evidence of EEG studies including populations with ID, we propose that this gap can be filled by EEG hyperscanning which offers a non-invasive, objective approach to evaluate cognitive and social outcomes in people with ID in future CST research.},
}

@article {pmid42052139,
year = {2026},
author = {Liu, W and Wang, Y and Shi, Y and Huang, L and Tan, C and Tan, L and Xu, W and , },
title = {Dynamic trajectories of neuropsychiatric symptoms predict Alzheimer's disease risk and clinical phenotypes.},
journal = {General psychiatry},
volume = {39},
number = {},
pages = {e70018},
pmid = {42052139},
issn = {2517-729X},
abstract = {BACKGROUND: Neuropsychiatric symptoms (NPS) may serve as early predictors of Alzheimer's disease (AD). However, NPS evolve over time, and most existing studies have relied on single or sparse assessments that do not capture clinically meaningful longitudinal patterns.

AIMS: To examine whether distinct trajectories of NPS are associated with the risk of incident AD, neurodegeneration and cognitive decline.

METHODS: NPS were assessed using the neuropsychiatric inventory questionnaire. We first characterised and compared the retrospective trajectories of NPS between 290 incident AD dementia cases and 74 healthy controls who remained free of dementia during 8 years of follow-up. Latent class growth modelling was then applied to identify NPS trajectories over the first 3 years among 982 people without dementia at baseline. Cox regression and linear mixed-effects models were used to investigate the associations between NPS trajectories and incident AD risk, cognitive decline, brain atrophy and changes in brain metabolism during early (baseline to year 3) and later (years 3-8) follow-up periods. Interaction between NPS trajectories and APOE ε4 was examined. Causal mediation analyses were conducted to assess whether neurodegeneration mediated the associations between NPS trajectories and cognitive function.

RESULTS: Compared to individuals who remained free of dementia, people who developed AD showed progressively increasing NPS levels prior to AD diagnosis (p < 0.005). Three NPS trajectories were identified: consistently no symptoms (71.8%, as reference), increasing trajectory (18.6%) and remitting trajectory (9.6%). The increasing trajectory was significantly associated with a higher risk of AD during both the early (hazard ratio [HR] = 1.720, p < 0.001) and late (HR = 2.130, p = 0.026) follow-up periods. The remitting trajectory was associated with an elevated risk of AD only in the early follow-up (HR = 1.980, p < 0.001). The increasing trajectory was also linked to faster brain atrophy (β = -139.662, p < 0.001 for the hippocampus, β = -108.642, p = 0.007 for the entorhinal cortex and β = -305.059, p = 0.003 for the middle temporal regions), greater declines in brain metabolism (β = -0.013, p = 0.007) and accelerated cognitive deterioration (β = -0.162 for the memory, β = -0.154 for the executive function, all p < 0.001) during the late follow-up period. These associations were stronger among APOE ε4 carriers. Brain volume loss and metabolism decline partially mediated the relationships of increasing NPS and cognitive impairment.

CONCLUSIONS: NPS trajectories can predict AD risk, neurodegeneration and cognitive decline, especially among APOE ε4 carriers. Progressive neurodegenerative changes may underlie these associations.},
}

@article {pmid42052145,
year = {2026},
author = {Tariot, PN and Chumki, SR and Wang, D and Such, P and Palma, AM and Zhang, Z and Montano, CB},
title = {Brexpiprazole for Agitation in Patients with Alzheimer's Dementia with and without Co-Occurring Psychosis: Post Hoc Analysis of Short- and Long-Term Trials.},
journal = {Neuropsychiatric disease and treatment},
volume = {22},
number = {},
pages = {586701},
pmid = {42052145},
issn = {1176-6328},
abstract = {PURPOSE: Patients with Alzheimer's dementia may experience co-occurring agitation and psychosis symptoms. This exploratory post hoc analysis aimed to analyze the efficacy and safety of brexpiprazole for agitation in patients with Alzheimer's dementia with and without co-occurring psychosis.

PARTICIPANTS AND METHODS: Data were pooled from two Phase 3, 12-week, randomized, double-blind, placebo-controlled, fixed-dose trials of brexpiprazole versus placebo in participants with Alzheimer's dementia and agitation, conducted in Europe, Russia, and the US (ClinicalTrials.gov identifiers: NCT01862640, NCT03548584). Post hoc, participants were stratified into subgroups with or without co-occurring psychosis at baseline, defined as a score ≥4 on the Neuropsychiatric Inventory Delusions domain, Hallucinations domain, or both. Efficacy was assessed by the Cohen-Mansfield Agitation Inventory Total score. Safety was assessed by treatment-emergent adverse events (TEAEs).

RESULTS: 142/607 participants (23.4%) had co-occurring psychosis at baseline. Brexpiprazole 2 or 3 mg/day was associated with greater improvement in agitation compared with placebo in participants with co-occurring psychosis (least squares mean difference at Week 12, -9.18 [95% confidence interval -15.2 to -3.12]; P=0.004; Cohen's d=0.52) and in participants without co-occurring psychosis (-4.22 [-6.91 to -1.54]; P=0.002; Cohen's d=0.29). In participants with co-occurring psychosis, for brexpiprazole and placebo respectively, 52.9% and 40.0% had TEAEs, and 3.4% and 9.1% discontinued due to TEAEs. No deaths occurred among participants with co-occurring psychosis. In participants without co-occurring psychosis, for brexpiprazole and placebo respectively, 49.3% and 38.2% had TEAEs, and 5.5% and 2.6% discontinued due to TEAEs. Two participants without co-occurring psychosis died; neither death was considered related to brexpiprazole treatment.

CONCLUSION: In this post hoc analysis, brexpiprazole improved agitation and was generally well tolerated in patients with Alzheimer's dementia with and without co-occurring psychosis. These exploratory data suggest that brexpiprazole may be of value to patients with Alzheimer's dementia who present with agitation and psychosis in clinical practice.},
}

@article {pmid42052379,
year = {2026},
author = {Yan, X and Liang, C and Zhou, Y and Hong, G and Li, C and Wang, K and Huang, Y and Xiao, X},
title = {Plasma chaperone-mediated autophagy associated protein HSPA8 combined with white matter hyperintensities serves as the predictive marker of early-stage Alzheimer's disease.},
journal = {Frontiers in aging neuroscience},
volume = {18},
number = {},
pages = {1753692},
pmid = {42052379},
issn = {1663-4365},
abstract = {BACKGROUND: The relationship between plasma chaperone-related autophagy proteins and white matter hyperintensity (WMH) in Alzheimer's disease (AD) remains unclear.

METHODS: We employed 4D-DIA proteomics to identify plasma protein changes, and evaluated the clinical relevance of the chaperone-mediated autophagy (CMA)-related protein HSPA8. Additionally, using ITK-SNAP software to assess WMH volume's role in AD. We analyzed the ROC curves for both HSPA8 and WMH in the AD spectrum. Among which, using One-Anova, Kruskal-Wallis, and multivariable logistic analyses to detect the population data. Moreover, the impact of age on WMH volume changes between the AD group and the CN group will be assessed using sensitivity analysis and testing the age-diagnosis interaction.

RESULTS: Significant factors in the AD population included age, MMSE score, MoCA score, and WMH volumes. The OR for age in MCI and for WMH volume in AD patients were significant. The expression of HSPA8 was decline in the AD disease spectrum, but it had no statistical difference. Importantly, HSPA8 protein had the highest AUC value for distinguishing between cognitively normal (CN)/mild cognitive impairment (MCI) and MCI/AD groups. Meanwhile, WMH was significant in the AD disease spectrum. And the influence of age on WMH is comparable in cognitively normal elderly individuals and those with AD. Combining HSPA8 with WMH improved the AUC value, which was further enhanced by including age and gender.

CONCLUSION: We found that the level of CMA-related protein HSPA8 is decline in the AD disease continuum, and WMH volume may help differentiate the AD spectrum. Moreover, Age is the primary factor influencing WMH changes in both CN and AD groups, with AD status having no significant effect on WMH levels or their progression. Thus, age should be carefully considered when evaluating elevated WMH in AD patients. It is noteworthy that the integration of HSPA8 and WMH may function as a potential early biomarker for AD, thereby enhancing the accuracy of its early diagnosis. Including age and gender increases the diagnostic model's AUC value, indicating HSPA8 and WMH are crucial for early AD diagnosis.},
}

@article {pmid42052380,
year = {2026},
author = {Yuan, J and Liu, Y and Jin, J and Li, S and Zhang, Y},
title = {Early detection of Alzheimer's disease via multimodal MRI and machine learning.},
journal = {Frontiers in aging neuroscience},
volume = {18},
number = {},
pages = {1794982},
pmid = {42052380},
issn = {1663-4365},
abstract = {OBJECTIVE: This study aimed to identify effective biomarkers associated with early-stage Alzheimer's disease (AD) by integrating multimodal neuroimaging features with machine learning (ML), addressing clinical challenges posed by global population aging.

MATERIALS AND METHODS: Multimodal neuroimaging-including resting-state functional MRI (rs-fMRI), structural MRI (sMRI), and diffusion tensor imaging (DTI)-was combined with ML techniques. A total of 234 subjects [cognitively normal (CN), mild cognitive impairment (MCI), and AD] were selected from the AD Neuroimaging Initiative (ADNI) database. Brain functional, structural, and microstructural features were extracted, and nine ML models, including support vector machine (SVM), random forest (RF), and Naive Bayes, were trained and evaluated across three binary classification tasks: AD-CN, MCI-CN, and AD-MCI.

RESULTS: The SVM model achieved the highest performance for AD-CN (AUC = 0.901) and MCI-CN (AUC = 0.839), while RF performed best for AD-MCI classification (AUC = 0.809). Functional analyses revealed significant abnormalities in key regions, including the anterior cingulate cortex, hippocampus, and middle frontal gyrus in AD patients. Structural analyses confirmed that hippocampal subfield atrophy was strongly associated with cognitive decline. Diffusion metrics, particularly the DTI-ALPS index, reflected microstructural white matter damage effectively.

CONCLUSION: Integrating multimodal neuroimaging with ML enhances diagnostic accuracy for AD and MCI and identifies potential neuroimaging biomarkers, providing objective evidence to support early clinical intervention.},
}

@article {pmid42052506,
year = {2026},
author = {Butters, E and Collins-Jones, L and Mesquita, RC and Acharya, D and McKiernan, E and Laurell, AAS and Low, A and Srinivasan, S and O'Brien, JT and Su, L and Bale, G},
title = {Brain network analysis in Alzheimer's disease and mild cognitive impairment using high-density diffuse optical tomography.},
journal = {Imaging neuroscience (Cambridge, Mass.)},
volume = {4},
number = {},
pages = {},
pmid = {42052506},
issn = {2837-6056},
abstract = {Dementia is associated with altered resting-state connectivity, measures of which could aid in its early detection and monitoring. High-density diffuse optical tomography (HD-DOT) is well suited to detect these alterations at scale due to its numerous practical advantages, but it has not yet been applied to dementia. In this study, we investigated resting-state functional connectivity across the prefrontal cortex in individuals with mild cognitive impairment (MCI, n = 22), Alzheimer's disease (AD, n = 21), and in healthy controls (n = 22). A graph theoretical approach was taken to characterise both global and local patterns of prefrontal connectivity over a 5-minute resting period. We found that individuals with MCI exhibited denser and stronger networks with shorter path lengths, which normalised in AD, accompanied by a redistribution of network hubs that were less stable. These results perhaps reflect the recruitment of additional connections in the early stages of pathology to maintain short-term network stability, which is ultimately associated with less efficient and more fragmented network organisation in later stages. Following the demonstration of HD-DOT's capacity to detect differences between healthy ageing and AD-type cognitive impairment, this work opens up new possibilities for the use of optical imaging in the study of this clinical population and HD-DOT's potential for scalable clinical use.},
}

@article {pmid42052655,
year = {2026},
author = {Zhao, R and Guo, M and Yang, F and Yan, Y and Tian, D and Deng, L and Wang, Q and Xie, M},
title = {A microglia membrane biomimetic platinum-based MOF-loaded quercetin nanodrug delivery system for the treatment of Alzheimer's disease.},
journal = {Journal of materials chemistry. B},
volume = {},
number = {},
pages = {},
doi = {10.1039/d6tb00201c},
pmid = {42052655},
issn = {2050-7518},
abstract = {The aberrant deposition of β-amyloid (Aβ) is a central pathological hallmark of Alzheimer's disease (AD), triggering oxidative stress, metal ion dyshomeostasis, and excessive microglial activation in a self-perpetuating pathological cascade. To address these interconnected processes, a platinum-based metal-organic framework (Pt-MOF) with intrinsic antioxidant enzyme-mimetic activity was constructed and loaded with quercetin (Qu) to regulate microglial dysfunction. To enhance blood-brain barrier (BBB) penetration and inflammation-targeting capability, Pt-MOF/Qu was further camouflaged with microglial cell membranes (BV2), yielding Pt-MOF/Qu/BV2 nanoparticles. In vitro studies demonstrated that Pt-MOF/Qu/BV2 efficiently scavenged reactive oxygen species and effectively chelated Cu[2+] ions via surface functional groups, thereby inhibiting Aβ aggregation and promoting the disassembly of preformed Aβ aggregates. In addition, the Pt-MOF enabled efficient loading and controlled release of Qu, which significantly restored mitochondrial membrane potential and alleviated microglial over-activation. The BV2 membrane coating markedly improved the biocompatibility and BBB translocation efficiency of the nanoplatform. Furthermore, Pt-MOF/Qu/BV2 significantly reduced reactive oxygen species (ROS) in vivo and Aβ brain plaque accumulation in the head region, alleviated neurotoxicity and improved the behavioral phenotype in the C. elegans AD model. Overall, this biomimetic multifunctional MOF-based nanoplatform represents a promising multi-target therapeutic strategy for AD.},
}

@article {pmid42052757,
year = {2026},
author = {Svobodova, I and Bendova, Z and Novotny, J},
title = {Astrocytes and Their Role in the Development and Progression of Alzheimer's Disease: Gatekeepers of Neurodegeneration.},
journal = {Journal of integrative neuroscience},
volume = {25},
number = {4},
pages = {49765},
doi = {10.31083/JIN49765},
pmid = {42052757},
issn = {0219-6352},
support = {23-07184S//Czech Grant Foundation/ ; },
mesh = {*Alzheimer Disease/metabolism/pathology ; Humans ; *Astrocytes/metabolism ; Animals ; Disease Progression ; },
abstract = {Astrocytes are increasingly recognized as central players in the pathogenesis of Alzheimer's disease (AD), exhibiting both neuroprotective and neurotoxic functions, which complicates their role in disease progression. Under physiological conditions, astrocytes support neuronal homeostasis, facilitate synaptic function, and promote the clearance of Amyloid-β (Aβ), thereby contributing to neuroprotection. In the context of AD, however, reactive astrocytes can adopt detrimental phenotypes, releasing pro-inflammatory cytokines, generating oxidative stress, and disrupting neuronal networks, thereby exacerbating neurodegeneration. Consequently, the shift from a protective to a neurotoxic phenotype may not only drive neuronal loss but also accelerate AD progression. The dual roles of astrocytes and the dynamic changes in their functions-protecting neurons under normal conditions while promoting pathology when dysregulated-underscore their complex contribution to AD pathophysiology. Elucidating the mechanisms underlying astrocyte-mediated neuroprotection and neurotoxicity is essential for developing targeted therapeutic strategies aimed at modulating astrocyte activity to slow or prevent disease progression. This review aims to present and critically discuss recent advances and ongoing controversies concerning the involvement of astrocytes in AD.},
}

*Alzheimer Disease/metabolism/pathology
Humans
*Astrocytes/metabolism
Animals
Disease Progression

@article {pmid42052761,
year = {2026},
author = {Guo, Y and Zhang, Z and Chen, B and Liu, H and Wei, F and Liu, X and Guo, Z},
title = {Functional Connectivity Alterations in the Cholinergic Neural Circuits of Patients With Alzheimer's Disease: A Donepezil Intervention Study Using Resting-State Functional Magnetic Resonance Imaging.},
journal = {Journal of integrative neuroscience},
volume = {25},
number = {4},
pages = {50039},
doi = {10.31083/JIN50039},
pmid = {42052761},
issn = {0219-6352},
support = {2017KY109//General Project of the Department of Science and Technology of Zhejiang Province/ ; 2020358406//General Project of the Department of Science and Technology of Zhejiang Province/ ; 2018KY031//General Project of the Department of Science and Technology of Zhejiang Province/ ; 2024KY873//General Project of the Department of Science and Technology of Zhejiang Province/ ; [2024]90662//National Leading Medical Specialty Development Project-Department of Geriatrics, Tongde Hospital of Zhejiang Province/ ; [2024]10//Zhejiang Provincial Alliance of Traditional Chinese Medicine Advantage Specialty for Geriatric Diseases/ ; },
mesh = {Humans ; *Donepezil/pharmacology/administration & dosage ; *Alzheimer Disease/drug therapy/diagnostic imaging/physiopathology ; Male ; Female ; Magnetic Resonance Imaging ; Aged ; *Cholinesterase Inhibitors/pharmacology/administration & dosage ; *Nerve Net/diagnostic imaging/drug effects/physiopathology ; Middle Aged ; *Connectome ; *Basal Forebrain/diagnostic imaging/drug effects/physiopathology ; Longitudinal Studies ; *Nootropic Agents/pharmacology/administration & dosage ; Cerebellum/diagnostic imaging/physiopathology/drug effects ; Aged, 80 and over ; },
abstract = {BACKGROUND: Although donepezil alleviates Alzheimer's disease (AD) symptoms by raising acetylcholine levels, its impact on cholinergic pathways remains unclear. In this longitudinal, resting-state functional magnetic resonance imaging (rs-fMRI) study, we investigated donepezil-induced changes in cholinergic pathway networks in AD.

METHODS: AD patients and healthy controls (HCs) were enrolled. AD patients received 24 weeks of donepezil treatment. Cognitive and emotional symptoms were assessed using the Mini-Mental State Examination (MMSE), Cornell Scale for Depression in Dementia (CSDD), and Neuropsychiatric Inventory (NPI) pre- and post-treatment. rs-fMRI was used to examine basal forebrain (BF) functional connectivity.

RESULTS: Sixteen AD patients and 16 HCs completed the study. Post-treatment MMSE scores improved, and NPI and CSDD scores decreased. Reduced BF functional connectivity in the left cerebellar lobule VI, post-treatment, was revealed by rs-fMRI. Compared with HCs, post-treatment AD patients showed lower BF functional connectivity in the right postcentral gyrus (PoG); pre-treatment patients exhibited higher BF functional connectivity in the left cerebellar lobule VI. Right PoG functional connectivity was negatively correlated with disease duration pre-treatment and positively correlated with MMSE post-treatment.

CONCLUSIONS: Donepezil improved clinical symptoms in AD by modulating the BF-PoG cholinergic pathway.},
}

Humans
*Donepezil/pharmacology/administration & dosage
*Alzheimer Disease/drug therapy/diagnostic imaging/physiopathology
Male
Female
Magnetic Resonance Imaging
Aged
*Cholinesterase Inhibitors/pharmacology/administration & dosage
*Nerve Net/diagnostic imaging/drug effects/physiopathology
Middle Aged
*Connectome
*Basal Forebrain/diagnostic imaging/drug effects/physiopathology
Longitudinal Studies
*Nootropic Agents/pharmacology/administration & dosage
Cerebellum/diagnostic imaging/physiopathology/drug effects
Aged, 80 and over

@article {pmid42052762,
year = {2026},
author = {Balakrishnan, J and Kannan, S and Shanmugam, K and Sugasini, D},
title = {Targeting Lipid Metabolism in Alzheimer's Disease: Emerging Insights and Future Directions.},
journal = {Journal of integrative neuroscience},
volume = {25},
number = {4},
pages = {48436},
doi = {10.31083/JIN48436},
pmid = {42052762},
issn = {0219-6352},
mesh = {Humans ; *Alzheimer Disease/metabolism/genetics/drug therapy ; *Lipid Metabolism/physiology ; Animals ; Lipidomics ; },
abstract = {Alzheimer's disease (AD) is a multifactorial neurodegenerative disease that is conventionally characterized by amyloid-β and tau pathology. There is growing evidence, however, that lipid metabolic disturbances are part of the biology of the disease, and not a secondary phenomenon. Lipid signaling controls membrane organization, amyloid precursor protein, tau phosphorylation, mitochondrial energetics, neuroinflammatory signaling, and synaptic stability. The accumulating genetic evidence, including risk variants in the APOE (apolipoprotein E), ABCA1 (ATP-binding cassette subfamily A member 1), ABCA7 (ATP-binding cassette subfamily A member 7), and TREM2 (Triggering receptor expressed on myeloid cells 2) genes, further makes lipid transport and lipid-sensing pathways central to late-onset AD vulnerability. Recent developments in lipidomics based on mass spectrometry have revealed concerted changes in phospholipids, sphingolipids, sterols, and oxidized lipid derivatives in brain tissue and peripheral biofluids. Instead of single abnormalities, directional metabolic imbalance is indicated by pathway changes, including decreased sphingomyelin-to-ceramide ratios and decreased polyunsaturated phospholipids. Co-analysis of lipidomic, genomic, and proteomic data has shown the existence of metabolically different subgroups, which aids genotype stratified risk evaluation and the lipid responder phenotype concept. Protein-centered therapies are complemented by therapeutic strategies that focus on lipid homeostasis, such as the regulation of cholesterol efflux, sphingolipid metabolism, pro-resolving lipid mediators, and metabolic reprogramming. There is also emerging evidence that implicates peroxisomal dysfunction and compromised glymphatic clearance in interfering with lipid balance. Although this field of research has come a long way, the issues of proving causality, standardizing lipidomic techniques, and converting pathway signatures into clinically useful resources persist. Restructuring AD as a lipid network instability disorder offers a systems level model of earlier diagnosis and targeted treatment.},
}

Humans
*Alzheimer Disease/metabolism/genetics/drug therapy
*Lipid Metabolism/physiology
Animals
Lipidomics

@article {pmid42052769,
year = {2026},
author = {Wang, Z and Pan, Y and Shu, M and Zou, L},
title = {The Lysosomal-Associated Protein Transmembrane Family and Neurological Disorders: Therapeutic Potential and Future Research Directions.},
journal = {Journal of integrative neuroscience},
volume = {25},
number = {4},
pages = {47903},
doi = {10.31083/JIN47903},
pmid = {42052769},
issn = {0219-6352},
support = {82201590//National Natural Science Foundation of China/ ; 2022CFB721//Natural Science Foundation of Hubei Province/ ; ZNJC202536//The Translational Medicine, the Interdisciplinary Research Joint Fund of Zhongnan Hospital of Wuhan University/ ; CXPY202535//Science and Technology Innovation Cultivation Fund of Zhongnan Hospital of Wuhan University/ ; },
mesh = {Humans ; *Nervous System Diseases/metabolism/therapy ; Animals ; *Membrane Proteins/metabolism ; Lysosomes/metabolism ; *Oncogene Proteins/metabolism ; },
abstract = {Lysosomal-associated protein transmembrane (LAPTM) family members-including LAPTM4A, LAPTM4B, and LAPTM5-are key regulators of lysosomal integrity, autophagy-lysosome flux, lipid metabolism, and immune responses. Dysregulation of LAPTM proteins contributes to neurological disorders such as Alzheimer's disease, Parkinson's disease, ischemic stroke, and gliomas, affecting neuronal survival, glial homeostasis, neuroinflammation, and tumor progression. In this review, we summarize recent insights into the structural features and molecular mechanisms of LAPTM proteins in the nervous system and highlight their therapeutic potential in promoting protein aggregate clearance, mitigating oxidative stress, regulating microglial polarization, and enhancing tumor immunotherapy. Future research integrating gene therapy, small-molecule modulators, multi-omics profiling, and advanced delivery platforms may enable translation of LAPTM-targeted interventions into clinical practice, offering new avenues for diagnosis, prognosis, and treatment of neurological diseases.},
}

Humans
*Nervous System Diseases/metabolism/therapy
Animals
*Membrane Proteins/metabolism
Lysosomes/metabolism
*Oncogene Proteins/metabolism

@article {pmid42052844,
year = {2026},
author = {Chen, W and Wang, J and Li, Q and Zhang, L and Wu, X and Luo, S and Xie, Y and Guo, P},
title = {Keap1-Nrf2 Signaling Pathway-Mediated Antioxidant Defense in Neurodegenerative Diseases: Mechanisms and Traditional Chinese Medicine Therapeutic Strategies.},
journal = {Frontiers in bioscience (Landmark edition)},
volume = {31},
number = {4},
pages = {45233},
doi = {10.31083/FBL45233},
pmid = {42052844},
issn = {2768-6698},
support = {81660671//National Natural Science Foundation of China/ ; 202101AZ070001-172//Yunnan Provincial Science and Technology Department-Applied Basic Research Joint Special Funds of Chinese Medicine/ ; 202105AG070014//Yunnan Provincial Key Laboratory of Formula Granules/ ; zyzdxk-2023192//High-level Discipline Construction Project of Dai Medicine, National Administration of Traditional Chinese Medicine/ ; 2024SS24045//Yunnan Key Laboratory for Dai and Yi Medicines/ ; },
mesh = {Humans ; *NF-E2-Related Factor 2/metabolism ; *Signal Transduction/drug effects ; *Kelch-Like ECH-Associated Protein 1/metabolism ; *Neurodegenerative Diseases/metabolism/drug therapy ; *Medicine, Chinese Traditional/methods ; *Antioxidants/metabolism/therapeutic use ; Oxidative Stress/drug effects ; Animals ; Drugs, Chinese Herbal/therapeutic use ; },
abstract = {Neurodegenerative diseases (NDs) are incurable, progressively disabling disorders marked by sustained neuronal degeneration and loss. Their molecular basis involves intricate regulatory networks, while current therapeutic strategies remain inadequate. Oxidative stress (OS) constitutes a major driver in the initiation and progression of age-related pathologies. Kelch-like enoyl-CoA hydratase-associated protein-1 (Keap1)-Nuclear factor Erythroid 2-related factor 2 (Nrf2) signaling pathway, an essential antioxidant system, exerts protective effects by limiting OS-mediated cellular injury. Extensive evidence demonstrates a close association between Nrf2 signaling and the pathological processes of NDs, including Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), and amyotrophic lateral sclerosis (ALS). Traditional Chinese medicine, characterized by multi-target and multi-pathway regulatory actions of its bioactive constituents, offers distinctive therapeutic potential for NDs. This review provides an integrated analysis of current advances of Nrf2 involvement in NDs and evaluates therapeutic strategies based on traditional Chinese medicine and its active components, with the aim of guiding future clinical translation.},
}

Humans
*NF-E2-Related Factor 2/metabolism
*Signal Transduction/drug effects
*Kelch-Like ECH-Associated Protein 1/metabolism
*Neurodegenerative Diseases/metabolism/drug therapy
*Medicine, Chinese Traditional/methods
*Antioxidants/metabolism/therapeutic use
Oxidative Stress/drug effects
Animals
Drugs, Chinese Herbal/therapeutic use

@article {pmid42052872,
year = {2026},
author = {Tosun, D},
title = {APOE shifts the tipping point: addressing pathological heterogeneity in Alzheimer's disease trials.},
journal = {Brain : a journal of neurology},
volume = {},
number = {},
pages = {},
doi = {10.1093/brain/awag151},
pmid = {42052872},
issn = {1460-2156},
}

@article {pmid42052893,
year = {2026},
author = {Geithus, S and Flønes, IH and Alves, G and Tysnes, OB and van de Berg, WDJ and Pihlstrøm, L and Nido, GS and Tzoulis, C},
title = {Comparative transcriptomics reveal molecular convergence and divergence in parkinsonian disorders.},
journal = {Brain : a journal of neurology},
volume = {},
number = {},
pages = {},
doi = {10.1093/brain/awag153},
pmid = {42052893},
issn = {1460-2156},
abstract = {Neurodegenerative parkinsonisms are phenotypically diverse disorders including Parkinson's disease, dementia with Lewy bodies, multiple system atrophy, progressive supranuclear palsy, and corticobasal degeneration. These currently incurable diseases are characterized by overlapping but also distinct clinicopathological and molecular features, and largely unknown pathogenesis. Transcriptomic studies have offered insights, but are limited by small sample sizes, technical variability, and limited reproducibility. Here, we present a large comparative bulk transcriptomic analysis of parkinsonian syndromes, comprising n = 977 post-mortem prefrontal cortex samples from pathologically-confirmed Parkinson's disease (n = 448), dementia with Lewy bodies (n = 80), multiple system atrophy (n = 35), progressive supranuclear palsy (n = 42), corticobasal degeneration (n = 17), Alzheimer's disease (n= 72), and neurologically healthy controls (n = 283). Accounting for key covariates including age, sex, RNA integrity (RIN), brain bank origin, and cell type composition, we identify convergent and divergent gene expression and pathway profiles across parkinsonisms and Alzheimer's disease. All diseases showed neuronal transcript loss and enrichment of glial signatures, consistent with neurodegeneration. Across the parkinsonian spectrum, we identified consistent downregulation of pathways related to protein homeostasis, mitochondrial energy metabolism, RNA processing, and DNA repair, highlighting core processes associated with neurodegeneration. Lewy body diseases (Parkinson's disease, dementia with Lewy bodies) and tauopathies (progressive supranuclear palsy and corticobasal degeneration) formed distinct similarity clusters, while multiple system atrophy occupied an intermediate position, possibly reflecting its glial pathology. To facilitate further research and discovery, we provide an open-access interactive web resource (https://parkdb.decode-pd.org) enabling researchers to query, visualize, and compare differential gene and pathway expression across disorders. This study establishes the most comprehensive comparative transcriptomic map of neurodegenerative parkinsonisms to date, identifies shared and distinct molecular mechanisms in α-synucleinopathies and tauopathies, and provides a resource for hypothesis generation and therapeutic target discovery.},
}

@article {pmid42053112,
year = {2026},
author = {Dharshan, SS and Madesh, S and Ramamurthy, K and Radhakrishnan, J and Salamuthu, K and Almutairi, MH and Almutairi, BO and Namasivayam, SKR and Kumaradoss, KM and Arockiaraj, J},
title = {Combating Cadmium-Induced Neurotoxicity, Oxidative Stress, and Inflammatory Pathways Using DOPA-31, a Dioxopiperidinamide Derivative in an In Vivo Zebrafish Model.},
journal = {Journal of biochemical and molecular toxicology},
volume = {40},
number = {5},
pages = {e70872},
doi = {10.1002/jbt.70872},
pmid = {42053112},
issn = {1099-0461},
mesh = {Animals ; Zebrafish ; *Oxidative Stress/drug effects ; *Cadmium/toxicity ; Disease Models, Animal ; *Neuroprotective Agents/pharmacology ; *Inflammation/chemically induced/metabolism/drug therapy ; *Neurotoxicity Syndromes/metabolism/drug therapy/pathology ; Antioxidants/pharmacology ; },
abstract = {Cadmium (Cd), a prevalent environmental toxin and pollutant capable of causing neurodegenerative diseases (NDs) like Alzheimer's and Parkinson's, primarily through oxidative stress, calcium imbalance, and neuroinflammation-induced mechanisms. Cd exposure increases the level of reactive oxygen species (ROS) and disrupts neurotransmitters by lowering antioxidants, leading to neuron death. Cd exposure in zebrafish results in neurodegeneration, with motor, mental, and behavioral impairments. The efficacy of the DOPA-31 intervention at varying concentrations was evaluated through the behavioral tests, biochemical assays for antioxidant enzyme activities (SOD, CAT, GSH, MDA), and histopathological analysis. Additionally, the alterations in expression levels of inflammation (tnf-α, il-1β) and neuroprotective (bdnf, syn2a) genes were also assessed. The Cd exposure exhibited the major deficits in the key behavioral parameters (motor, anxiety, and cognitive impairment). It disrupted antioxidant enzyme activity, increased lipid peroxidation, and elevated acetyl cholinesterase (AChE) activity, leading to cholinergic dysfunction. Histopathology showed extensive neuronal damage and amyloid-like protein aggregation. DOPA-31 at a 20 µM concentration, substantially exhibited antioxidant and AChE activity by reducing oxidative stress and improving motor and cognitive functions. Molecular analysis of DOPA-31 treatment showed significant downregulation of pro-inflammatory markers and upregulation of neuroprotective factors. In addition, DOPA-31 restored behavioral changes by potentially mitigating neuronal damage and protein aggregation caused by the Cd-induced neurotoxicity. This research investigation suggests the novel drug candidate DOPA-31 as a preliminary treatment for Neurodegenerative Disorder (NDD)-like features and warrants further exploration in higher animal models to assess clinical relevance.},
}

Animals
Zebrafish
*Oxidative Stress/drug effects
*Cadmium/toxicity
Disease Models, Animal
*Neuroprotective Agents/pharmacology
*Inflammation/chemically induced/metabolism/drug therapy
*Neurotoxicity Syndromes/metabolism/drug therapy/pathology
Antioxidants/pharmacology

@article {pmid42053135,
year = {2026},
author = {Arslan, B and Gobom, J and Simrén, J and Fahlén, H and Andreasson, U and Andrea Lessa Benedet, and Kvartsberg, H and Zetterberg, H},
title = {Real-world performance of Lumipulse G plasma p-tau217: a six-month experience of a specialized clinical neurochemistry laboratory.},
journal = {Clinical chemistry and laboratory medicine},
volume = {},
number = {},
pages = {},
pmid = {42053135},
issn = {1437-4331},
abstract = {OBJECTIVES: Plasma p-tau217 is a leading blood-based biomarker for Alzheimer's disease (AD), offering high diagnostic accuracy and potential utility for treatment eligibility and monitoring. However, real-world data on concordance between cerebrospinal fluid (CSF) Aβ42/40 and plasma p-tau217 in routine clinical laboratory settings remain limited.

METHODS: We retrospectively evaluated all plasma p-tau217 tests performed in the Clinical Neurochemistry Laboratory at Sahlgrenska University Hospital between August 2025 and March 2026. De-identified plasma p-tau217, additional blood biomarkers, and available CSF results were extracted from the laboratory information system. Concordance between plasma p-tau217 and CSF Aβ42/40 was evaluated by calculating positive and negative percent agreement, with CSF Aβ42/40 used as the reference standard. In addition, diagnostic accuracy for brain amyloid positivity was assessed using two predefined clinical cutoffs for plasma p-tau217 (<0.22 vs. >0.34 ng/L). Internal analytical performance was monitored over a six-month period using commercial quality control materials, with additional evaluation of lot-to-lot consistency for plasma p-tau217.

RESULTS: Among 1,352 plasma p-tau217 measurements, paired CSF Aβ42/40 data were available for 121 individuals. Based on plasma p-tau217 probability categories, 541 samples (40.0 %) were classified as low probability, 228 (16.9 %) as intermediate probability, and 583 (43.1 %) as high probability for amyloid pathology. Using CSF Aβ42/40 as the reference standard, plasma p-tau217 demonstrated a positive percent agreement of 84.5 % (95 % CI: 72.6-92.7 %) and a negative percent agreement of 87.5 % (95 % CI: 73.2-95.8 %). Internal quality control analyses showed good within-batch precision, with coefficients of variation below 7.3 %. Batch-dependent bias was observed in QC measurements, most notably for one batch (+14.4-18.4 %); however, subsequent QC investigations indicated that this deviation originated from the QC material rather than from assay-related performance. Lot-to-lot consistency assessment did not reveal systematic reagent lot-dependent effects during the study period.

CONCLUSIONS: Lumipulse plasma p-tau217 demonstrated stable analytical performance and consistent concordance with CSF Aβ42/40 in routine clinical practice. The observed agreement supports the feasibility of plasma p-tau217 as a supportive tool in the clinical evaluation of AD, while underscoring the need for continued quality control monitoring and prospective evaluation of assay performance.},
}

@article {pmid42053356,
year = {2026},
author = {Pandey, P and Kruger, M and Sharma, A and Swanepoel, W and Rodrigo, H and Beukes, E and Manchaiah, V},
title = {Effects of Hearing Devices for Adults With Mild-to-Severe Hearing Loss: A Systematic Review and Meta-Analysis of Randomized Controlled Trials.},
journal = {Journal of speech, language, and hearing research : JSLHR},
volume = {},
number = {},
pages = {1-24},
doi = {10.1044/2026_JSLHR-25-00737},
pmid = {42053356},
issn = {1558-9102},
abstract = {OBJECTIVES: The aim of this study was to evaluate the effect of hearing devices for adults with mild-to-severe hearing losses. Specifically, we assessed the magnitude of change across outcome domains, identified measurement tools used, and reported adverse effects associated with device use.

DESIGN: We conducted a systematic review and meta-analysis following Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. Searches were performed in PubMed, CINAHL, and Embase. Included studies were randomized controlled trials (RCTs) involving adults (≥ 18 years of age) with mild-to-severe hearing loss, comparing any air-conduction hearing device to passive or active controls. Effect sizes were calculated as Hedges's g, and random-effects models estimated pooled effects.

RESULTS: Thirty-three RCTs (N = 4,471 participants) met the inclusion criteria, although pooled estimates could be derived from only a subset of trials due to limited reporting. Hearing aids demonstrated moderate-to-large benefits on hearing-related self-report outcomes compared with no-intervention or waitlist controls; however, pooled meta-analytic estimates could not be generated for this comparison because of insufficient data across trials. Compared with placebo, hearing aids yielded a small pooled effect (g ≈ 0.37), driven largely by trials including participants with comorbid Alzheimer's disease. Personal sound amplification products (PSAPs) showed a pooled medium effect compared with no intervention (g ≈ 0.42), with benefits primarily observed for hearing-specific self-report outcomes and selected behavioral measures. In head-to-head comparisons, hearing aids showed a large pooled advantage over other hearing devices, including smartphone hearing aid applications (SHAAs) and extended-wear hearing aids (EWHAs; g ≈ 0.88), based on data from two trials. Across the included studies, most outcomes were self-reported (≈ 81%) and behavioral (≈ 45%), with very limited assessment of cognitive or neurophysiological domains. Nine studies reported adverse events, with only one device-related incident. Heterogeneity was high (I[2] > 80%), but no publication bias was detected.

CONCLUSIONS: Hearing aids provide substantial benefit for hearing-related self-reported outcomes in comparison to PSAPs, SHAAs, EWHAs, and placebo. However, high heterogeneity prevents reliable conclusions based on pooled estimates. There also remains limited evidence on cognitive, neurophysiological, and long-term behavioral outcomes, underscoring the need for more rigorous, domain-diverse RCTs in this field.

SUPPLEMENTAL MATERIAL: https://doi.org/10.23641/asha.32086299.},
}

@article {pmid42053514,
year = {2026},
author = {},
title = {RETRACTION: The 12-15-Lipoxygenase is a Modulator of Alzheimer's-Related Tau Pathology In Vivo.},
journal = {Aging cell},
volume = {25},
number = {5},
pages = {e70524},
doi = {10.1111/acel.70524},
pmid = {42053514},
issn = {1474-9726},
abstract = {P. F. Giannopoulos, Y. B. Joshi, J. Chu, and D. Praticò, "The 12-15-Lipoxygenase is a Modulator of Alzheimer's-Related Tau Pathology In Vivo," Aging Cell 12, no. 6 (2013): 1082-1090, https://doi.org/10.1111/acel.12136. The above article, published online on 17 July 2013 in Wiley Online Library (wileyonlinelibrary.com), has been retracted by agreement between the journal Editor-in-Chief, Monty Montano; The Anatomical Society; and John Wiley & Sons Ltd. The retraction has been agreed upon following an investigation into concerns raised by the corresponding author, D. Praticò. This identified image duplication of the tau1 bands in Figures 3A and 5A. As a result, the data and the conclusions are considered unreliable. D. Praticò and Y. B. Joshi agreed to the decision to retract. P. F. Giannopoulos and J. Chu were informed of the decision to retract but remained unresponsive.},
}

@article {pmid42053612,
year = {2026},
author = {Shen, X and Ding, L and Li, X and Gu, L and Yang, J},
title = {Diagnosis of Alzheimer's disease based on particle swarm optimization EEG signal channel selection and gated recurrent unit.},
journal = {Computer methods in biomechanics and biomedical engineering},
volume = {},
number = {},
pages = {1-16},
doi = {10.1080/10255842.2026.2661797},
pmid = {42053612},
issn = {1476-8259},
abstract = {Electroencephalogram (EEG) reflect changes in the electrophysiological activity of the brain and can be used in the diagnosis of Alzheimer's disease (AD). Each EEG channel provides real-time information about the brain, while different EEG channels contain different information about the brain. Using all EEG channel data for AD diagnosis contains redundancy data, leading to increased computation and reduced data analysis accuracy. In this paper, a diagnostic method for AD based on Particle Swarm Optimization (PSO) EEG channel selection and Gated Recurrent Unit (GRU) is proposed. Using EEG energy as the fitness function and PSO to select EEG channels, the redundant information in EEG data is reduced and the accuracy of EEG data analysis is improved. GRU is a special kind of recurrent neural network (RNN) structure. It uses EEG data extracted by the principal component analysis (PCA) feature based on singular value decomposition (SVD) as input to the model. And it has a good advantage in analyzing the time series of EEG. The results show that the classification accuracy of the method in this paper reaches 0.9487, which is higher than the performance of other proposed methods. Compared to the results of using all EEG channel data analysis, the classification accuracy of this method was improved by 0.0757. It shows that the method proposed in this paper can improve the classification accuracy of EEG in AD classification tasks and can be applied to related classification tasks.},
}

@article {pmid42053700,
year = {2026},
author = {Lin, C and Qi, L and Gao, X and Hu, L and Qian, B and Deng, Y and Zhou, C and Wang, C and Liu, G and Ding, Q and Lin, Z and Zhu, X and Zhang, M},
title = {Therapeutic Mechanisms of Stem Cell-Derived Exosomes for Neurological Disorders: An Overview.},
journal = {Molecular neurobiology},
volume = {63},
number = {1},
pages = {},
pmid = {42053700},
issn = {1559-1182},
support = {82271747//the National Natural Science Foundation of China/ ; 82505180//the National Natural Science Foundation of China/ ; ZY2023013//Wenzhou Major Scientific and Technological Innovation Project/ ; 2025C02081//he Zhejiang Provincial Key Research and Development Program/ ; 2025M783998//the China Postdoctoral Science Foundation/ ; },
mesh = {*Exosomes/metabolism/transplantation ; Humans ; Animals ; *Nervous System Diseases/therapy ; *Stem Cells/metabolism ; *Stem Cell Transplantation/methods ; },
abstract = {The current management of neurological disorders remains largely symptomatic. In recent years, stem cell-derived exosomes have emerged as a promising alternative therapeutic strategy. This narrative review synthesizes evidence from preclinical studies investigating the mechanisms and efficacy of exosome-based therapy for neurological conditions. The included studies encompass animal models and in vitro systems. Accumulating preclinical evidence consistently supports the therapeutic potential of stem cell-derived exosomes across several neurological disorders. In Alzheimer's disease models, stem cell-derived exosomes reduce β-amyloid plaque deposition and attenuate neuroinflammation. For Parkinson's disease, they exert neuroprotective effects on dopaminergic neurons. They also inhibit α-synuclein aggregation. In ischemic stroke and spinal cord injury, stem cell-derived exosomes promote functional recovery through multiple mechanisms. These include suppressing ferroptosis, promoting angiogenesis, and stimulating axonal regeneration. Improved delivery strategies, such as intranasal administration and hydrogel encapsulation, have further enhanced brain targeting and treatment durability. Despite these promising preclinical findings, several challenges remain. A primary issue is the lack of standardized preparation protocols. Significant uncertainties also exist regarding long-term safety. Furthermore, pathways for clinical translation are still unclear. Future research should prioritize elucidating the underlying mechanisms of exosome therapy. The refinement of targeted delivery systems is equally important. Finally, advancing rigorously designed clinical trials is crucial to facilitate the translation of these therapies into clinical practice.},
}

*Exosomes/metabolism/transplantation
Humans
Animals
*Nervous System Diseases/therapy
*Stem Cells/metabolism
*Stem Cell Transplantation/methods

@article {pmid42053826,
year = {2026},
author = {Pradhan, D and Upadhyay, RK},
title = {Unravelling the spatiotemporal dynamics of amyloid- β -induced astrocyte-neuron network model in Alzheimer's disease.},
journal = {Journal of mathematical biology},
volume = {92},
number = {5},
pages = {},
pmid = {42053826},
issn = {1432-1416},
support = {CRG/2023/000583//Science and Engineering Research Board, IN/ ; },
mesh = {*Alzheimer Disease/physiopathology/metabolism/etiology/pathology ; *Astrocytes/physiology/metabolism ; Humans ; *Neurons/physiology/metabolism ; *Models, Neurological ; *Amyloid beta-Peptides/metabolism/physiology ; Computer Simulation ; Calcium Signaling/physiology ; Mathematical Concepts ; Nerve Net/physiopathology ; Animals ; Synapses/physiology ; },
abstract = {Recent research highlights that calcium dysfunction, emerging from impaired neuron-astrocyte interactions plays a crucial role in the pathogenesis of Alzheimer's disease (AD). In our current study, we investigate this through a computational model of bidirectional coupling between a neuron and an astrocyte within a tripartite synapse framework. Individually, neuron is designed to exhibit neuronal firing dynamics, while the astrocyte captures amyloid- β -mediated calcium signaling. In particular, we consider the spatiotemporal version of the model across three scenarios: (i) no diffusion; (ii) diffusion in either neurons or astrocytes; and (iii) diffusion in both. Without diffusion, bifurcation analysis reveals that astrocytic feedback can trigger neuronal firing via a supercritical Andronov-Hopf bifurcation, emphasizing astrocytic regulation of excitability. With diffusion only in neurons, complex Ginzburg-Landau analysis (CGLE) reveals spiral and antispiral wave patterns. When only astrocytic diffusion is present, regular and distorted hexagonal patterns emerge. The third scenario yields Turing-like structures. We further extend the model to a spatial network to explore collective dynamics and synchronization behaviors, where stronger coupling leads to partially synchronized neuronal activity. These findings demonstrate how astrocyte-neuron crosstalk and diffusion-driven instabilities contribute to emergent wave-like activity, shedding light on spatial mechanisms in AD progression.},
}

*Alzheimer Disease/physiopathology/metabolism/etiology/pathology
*Astrocytes/physiology/metabolism
Humans
*Neurons/physiology/metabolism
*Models, Neurological
*Amyloid beta-Peptides/metabolism/physiology
Computer Simulation
Calcium Signaling/physiology
Mathematical Concepts
Nerve Net/physiopathology
Animals
Synapses/physiology