@article {pmid42400155,
year = {2026},
author = {Harriman, T and Harraz, OF},
title = {Tau protein differentially affects Piezo1 and Kir2.1 channels in brain capillary endothelial cells.},
journal = {Biophysical journal},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.bpj.2026.07.003},
pmid = {42400155},
issn = {1542-0086},
abstract = {Accumulation of amyloid-β (Aβ) peptides and Tau proteins in the brain is a hallmark of neurodegeneration. Such build-up forms Aβ plaques and Tau neurofibrillary tangles, both of which are associated with synaptic loss, cognitive decline, and reduced cerebral blood flow in Alzheimer's disease (AD). Two ion channels in brain capillary endothelial cells (ECs)-the inwardly rectifying potassium channel Kir2.1 and the mechanosensitive channel Piezo1-are critical regulators of cerebral blood flow, and both display impaired activity in AD. Whether Aβ and Tau affect these channels remains incompletely understood. Using patch-clamp electrophysiology and freshly isolated mouse brain capillary ECs, we examined whether Aβ1-40 or Tau-441 directly modulate Kir2.1 or Piezo1 function. Exogenously applied Aβ1-40 (10-100 nM) and Tau-441 (10-50 nM) had minimal effect on Kir2.1 current density, indicating that the Kir2.1 deficits observed in AD are less likely caused by direct interactions with Aβ or Tau. In contrast, we previously demonstrated that nanomolar Aβ1-40 enhanced Piezo1 function. We further show here that 50 nM Tau-441 significantly increased Piezo1 open probability, and this enhancement was abolished by the superoxide dismutase and catalase mimetic EUK-134. These data collectively suggest that altered Piezo1 function in neurodegenerative disease could involve a direct effect of Aβ peptides or Tau proteins and further suggest that acute exposure to these proteins minimally impacts Kir2.1 activity. These novel findings present a new pathway through which Tau proteins could impair neurovascular function during neurodegeneration.},
}

@article {pmid42400308,
year = {2026},
author = {Sousa, RAL and Costa, JMM and Pereira, RRS and Vieira, LCDR and Magalhães, CODE and Dias-Peixoto, MF},
title = {Exercise Snacking in Alzheimer's Disease: A Mechanistic Rationale Based on Repeated Exerkine Signaling.},
journal = {Journal of neurochemistry},
volume = {170},
number = {7},
pages = {e70517},
pmid = {42400308},
issn = {1471-4159},
support = {304455/2026-1//Conselho Nacional de Desenvolvimento Científico e Tecnológico/ ; APQ-01160-26//FAPEMIG/ ; //Coordenação de Aperfeiçoamento de Pessoal de Nível Superior/ ; },
abstract = {[Image: see text]},
}

@article {pmid42400646,
year = {2026},
author = {Jabli, MA and Mourad, M},
title = {Beyond complex architectures: a streamlined CNN pipeline for robust Alzheimer's disease classification from brain MRI.},
journal = {Neuroradiology},
volume = {},
number = {},
pages = {},
pmid = {42400646},
issn = {1432-1920},
abstract = {BACKGROUND AND PURPOSE: Alzheimer's disease, a common type of dementia, gradually steals memories and impacts daily life as brain cells deteriorate. We explored how Artificial Intelligence (AI) could help spot early signs of Alzheimer's using MRI brain scans.

MATERIALS AND METHODS: Our study focused on a deep learning approach, specifically a convolutional neural network (CNN), to distinguish between Alzheimer's, Mild Cognitive Impairment (MCI), and healthy individuals. We used two well-known datasets, OASIS and ADNI, for this work. After carefully preparing the ADNI data (which included 21,324 MRI images: 7,572 from MCI patients, 5,904 from healthy controls, and 7,848 from Alzheimer's patients) and the OASIS data (6,400 MRI images), our model performed exceptionally well.

RESULTS: The CNN Model achieved an accuracy of 99.67% with the ADNI images and 99.06% with the OASIS images. These encouraging results, which stand up well against other studies, show that our method can effectively analyze large amounts of data and accurately classify Alzheimer's.

CONCLUSIONS: Our main hope is that this kind of technology can give doctors and caregivers better tools to predict and detect the disease, ultimately saving time, reducing costs, and helping those affected by Alzheimer's.},
}

@article {pmid42400765,
year = {2026},
author = {Josephs, O and Dymerska, B and Graedel, NN and Balbastre, Y and Corbin, N and Callaghan, MF},
title = {Online image reconstruction via Multiple Orthogonal Reference Sensitivity Encoding (MORSE).},
journal = {Magma (New York, N.Y.)},
volume = {},
number = {},
pages = {},
pmid = {42400765},
issn = {1352-8661},
support = {203147/Z/16/Z/WT_/Wellcome Trust/United Kingdom ; 226793/Z/22/Z/WT_/Wellcome Trust/United Kingdom ; },
abstract = {OBJECTIVE: Parallel imaging is ubiquitous in MRI, enabling higher spatial and/or temporal resolution. However, successful unfolding is contingent on robust and accurate estimation of relative coil sensitivities, which often involves computation times that preclude online deployment. We present a computationally efficient method of robustly estimating coil sensitivities, and reconstructing under-sampled images using a data-driven regularised SENSE formalism that is commensurate with online deployment for Cartesian k-space acquisitions.

MATERIALS AND METHODS: The proposed image reconstruction method via Multiple Orthogonal Reference Sensitivity Encoding (MORSE) estimates multiple sensitivities per voxel to address issues, such as rapidly varying sensitivities, chemical shift artefact, or insufficient fields of view. It simultaneously provides a data-driven regularisation term for noise control providing inherent adaptability to diverse imaging contexts.

RESULTS: MORSE has been successfully deployed in multiple neuroimaging studies at both 3T and 7T, including functional studies of autobiographical memory processing, visual and auditory perception, and quantitative MRI studies of neurodegenerative diseases including Huntington's, Alzheimer's and Parkinson's. Exemplar image reconstructions are presented and compared with GRAPPA, ENLIVE, ESPIRiT and LORAKS. We also showcase application of MORSE outside of the brain via application in liver and knee imaging. MORSE consistently produced high-quality, artefact-free images with reconstruction times feasible for online deployment.

DISCUSSION: The proposed method of sensitivity estimation and unfolding regularisation is flexible and robust. It is made available to the community in open-source as a library of functions within the vendor-agnostic Gadgetron image reconstruction framework.},
}

@article {pmid42400785,
year = {2026},
author = {D'Souza, D and Sumbatian, D and Sever, B and Altman, I and Leykind, Y and Frenkel-Morgenstern, M},
title = {Detection of Chimeric RNAs from RNA-Seq Data with ChiTaRS 8.0: Insights for Liquid Biopsy and Drug Target Identification.},
journal = {Methods in molecular biology (Clifton, N.J.)},
volume = {3024},
number = {},
pages = {23-42},
pmid = {42400785},
issn = {1940-6029},
mesh = {Humans ; Liquid Biopsy/methods ; *RNA-Seq/methods ; Computational Biology/methods ; Software ; *Drug Discovery/methods ; Biomarkers, Tumor/genetics ; Leukocytes, Mononuclear/metabolism ; *RNA/genetics ; Neoplasms/genetics ; },
abstract = {Chimeric RNAs (chiRNAs), generated via genomic rearrangements or splicing events, are increasingly recognized as biomarkers and therapeutic targets in cancer and neurodegenerative disorders. This chapter introduces an integrative framework for high-confidence chiRNA identification leveraging the ChiTaRS 8.0 database and the ChiTaH pipeline. ChiTaRS 8.0 encompasses 47,445 human chiRNAs, 1,055 Hi-C breakpoints, and 1,598 drug targets, while ChiTaH facilitates disease-specific analysis of RNA-seq data from 250 peripheral blood mononuclear cell (PBMC) samples-including glioblastoma and oral squamous cell carcinoma-and 199 healthy controls. Our approach combines reference-based fusion detection, BLAT validation against GRCh38, gene-pair compatibility checks, and protein domain conservation analysis. Functional annotation and protein-protein interaction modeling uncovered oncogenic chiRNAs absent from existing databases, exhibiting tissue-specific patterns. In Alzheimer's disease, liquid biopsy analyses identified unique chimeras-such as ENO1-MCUR1 and APOE-APOE-in cerebrospinal fluid, linked to neurotransmitter pathways and amyloid processing, and absent in healthy samples, highlighting their potential as early biomarkers. We describe a scalable digital hospital framework integrating AI-driven fusion detection, relational databases, and clinical metadata for real-time diagnostics and patient monitoring. This system supports fusion-targeted drug discovery and patient stratification, bridging translational gaps in oncology and neurodegeneration. By coupling computational pipelines with multiomics data, our approach advances personalized medicine while addressing challenges in artifact filtering and functional validation. Ultimately, the ChiTaRS-ChiTaH platform offers a versatile tool for chiRNA discovery and annotation across diverse disease contexts, providing insights into molecular mechanisms and clinical applications.},
}

Humans
Liquid Biopsy/methods
*RNA-Seq/methods
Computational Biology/methods
Software
*Drug Discovery/methods
Biomarkers, Tumor/genetics
Leukocytes, Mononuclear/metabolism
*RNA/genetics
Neoplasms/genetics

@article {pmid42401072,
year = {2026},
author = {Ma, L and Chen, S and Jia, Q and Tian, R and Zeng, Y and Luo, K and Meng, X and Yang, L},
title = {Therapeutic potential of scutellarin in central nervous system: A comprehensive review.},
journal = {Phytomedicine : international journal of phytotherapy and phytopharmacology},
volume = {159},
number = {},
pages = {158506},
doi = {10.1016/j.phymed.2026.158506},
pmid = {42401072},
issn = {1618-095X},
abstract = {BACKGROUND: Scutellarin (SCU) is a flavone glycoside mainly isolated from Erigeron breviscapus (Vant.) Hand. -Mazza, which is a type of medicinal herb broadly utilized in central nervous system (CNS) disorders. Although Scu possesses remarkable therapeutic actions on CNS disorders, the underlying mechanisms, pharmacokinetics, and safety issues are elusive. Meanwhile, the clinical trial and pharmaceutical study of SCU remain to be systematically delineated.

PURPOSE: The main purpose is to comprehensively summarize the updated information regarding the pharmacological actions, clinical studies, safety issues, pharmacokinetics and novel formulations of SCU used for CNS, to point out species of interest for further studies.

METHODS: The systematic search for SCU treatments for CNS disorders was performed considering all the articles published until November 2025 through multiple authoritative databases, including Web of Science, PubMed, Google Scholar, Chinese National Knowledge Infrastructure, and so on. The keywords included "scutellarin", "breviscapine", "central nervous system disorders", "ischemic stroke", "Alzheimer's disease", "pharmacokinetic", "clinical studies", and "novel preparation technology". All articles reporting the use of SCU to treat CNS disorders were retained for further analysis.

RESULTS: A total of 223 articles published between 2003 and 2026 were included, covering ten CNS diseases such as ischemic stroke, Alzheimer's disease, and Parkinson's disease. Regarding pharmacological mechanisms of SCU, 33 studies focused on oxidative stress, 48 on inflammatory responses, and 16 on mitochondrial function. Evidence from 23 clinical trials indicated that SCU has therapeutic potential for CNS diseases. Toxicity studies demonstrated good safety profile at therapeutic doses of SCU. Pharmacokinetic data revealed its rapid absorption, low bioavailability, and efficient systemic clearance (16 studies). Additionally, 22 studies indicated that novel formulations significantly improved the biological half-life and enhanced the bioavailability of SCU.

CONCLUSIONS: SCU is expected to become a pivotal phytochemical agent for the CNS protection. Extensive and intensive explorations on SCU are imperative to accelerate the utilization of SCU in the CNS disorders.},
}

@article {pmid42401161,
year = {2026},
author = {Prévot, V and Schwaninger, M and Nogueiras, R and Rasika, S},
title = {Tau-ing and fro-ing: the tanycytic shuttle in neurodegeneration.},
journal = {The journal of prevention of Alzheimer's disease},
volume = {13},
number = {8},
pages = {100643},
doi = {10.1016/j.tjpad.2026.100643},
pmid = {42401161},
issn = {2426-0266},
abstract = {After more than a century since Alzheimer's disease (AD) was described and decades of research into β-amyloid and Tau proteins, mechanisms underlying pathogenic protein clearance from brain remain poorly understood. Recent research identifies tanycytes-specialized hypothalamic cells lining the third ventricle-as a previously unrecognized clearance system for brain Tau. These cells actively transport Tau from cerebrospinal fluid to blood via pituitary portal circulation but are dramatically fragmented in AD brains. Single-nucleus RNA sequencing reveals altered stress and transport gene expression in AD tanycytes, while functional studies show disrupted tanycytic transport reduces Tau efflux and exacerbates pathology. Beyond protein clearance, tanycytes maintain critical metabolic and neuroendocrine pathways influencing cognition. Their unique blood-brain interface position makes them attractive therapeutic targets. As transcriptomic evidence suggests tanycytes are hotspots for age-related changes, their dysfunction may herald "tanycytopathies" underlying multiple neurodegenerative disorders.},
}

@article {pmid42401529,
year = {2026},
author = {Song, J and Pelekanos, M and Richter-Stretton, G and Leinenga, G and Chicoteau, A and Lee, W and Odabaee, M and Nestor, PJ and Saifzadeh, S and Simon, C and de Las Heras, R and Götz, J},
title = {Multidimensional Safety Assessment of a Low-Intensity Scanning Ultrasound (SUS) Protocol in Sheep.},
journal = {Ultrasound in medicine & biology},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.ultrasmedbio.2026.06.011},
pmid = {42401529},
issn = {1879-291X},
abstract = {OBJECTIVE: Preclinical studies in mouse models of Alzheimer's disease present low-intensity ultrasound in a scanning mode (SUS) as a promising neuromodulatory modality. However, given the significant differences in brain scale and complexity between mice and humans, we employed sheep as a large animal model to test a novel investigational device and assess safety as a necessary step before deploying SUS in clinical trials.

METHODS: Informed by functional assessments in mice, we used image-guided neuro-navigation to deliver a peak negative pressure of 2.6 MPa to four sheep using a scanning approach. Three sheep (#N1-3) underwent a non-recovery procedure followed by histological assessment, and one (#R1) received five repeated treatments spaced out 2-4 weeks over 12 weeks to assess long-term safety via magnetic resonance imaging (MRI) and behavioral observations.

RESULTS: In total, 631 sonications were performed, treating up to 50 individual spots per sheep. Evans blue extravasation, and hematoxylin and eosin and vanadium acid fuchsin-toluidine blue staining revealed no evidence of tissue damage or unintended blood-brain barrier (BBB) opening (given no microbubbles were used). Throughout the repeat treatments of sheep #R1, post-operative behavioral observations confirmed normal movement and no signs of pain or distress. MRI revealed no SUS-induced anatomical abnormalities, evidence of BBB opening, microhemorrhages and oedema, in agreement with the histological observations. Mild heating was observed at the inner skull surface following sonication, but no damage to skull or scalp tissue was detected.

CONCLUSION: Collectively, the acute and long-term safety assessment of the brain after SUS advocates translation to human studies.},
}

@article {pmid42401549,
year = {2026},
author = {Liu, C and Zhang, T and E, ED and Xu, TY and Yang, FR and Li, JW and Shang, Q and Zhang, ZY and Shen, HW and Zhang, XQ},
title = {Maraviroc attenuates inflammation-exacerbated cognitive and amyloid pathology in an early-stage Alzheimer's disease mouse model.},
journal = {Translational psychiatry},
volume = {},
number = {},
pages = {},
doi = {10.1038/s41398-026-04215-y},
pmid = {42401549},
issn = {2158-3188},
support = {32201322//National Natural Science Foundation of China (National Science Foundation of China)/ ; LY24H090001//Natural Science Foundation of Zhejiang Province (Zhejiang Provincial Natural Science Foundation)/ ; },
abstract = {Alzheimer's disease (AD) is an age-related neurodegenerative disorder characterized by progressive cognitive decline, and increasing evidence indicates that systemic inflammation can accelerate disease progression. Maraviroc, a CCR5 antagonist approved for the treatment of human immunodeficiency virus (HIV) infection, has shown neuroprotective effects in several neurological contexts, but its role in AD-related pathology remains unclear. In this study, cognitive performance was assessed in 5 × FAD mice using the Y-maze, novel object recognition, novel location recognition, and social discrimination tests. Amyloid-related changes were evaluated by hippocampal APP/Aβ immunoblotting and plaque staining using 6E10 and Thioflavin S. Glial responses were examined by IBA1 and GFAP immunostaining, and inflammatory cytokines were quantified by ELISA. We found that 5 × FAD mice exhibited age-dependent cognitive impairments, with detectable deficits emerging at 3 months of age. Systemic administration of lipopolysaccharide (LPS) further exacerbated cognitive dysfunction, amyloid-related alterations, and neuroinflammatory responses in young 5 × FAD mice. Maraviroc treatment attenuated LPS-associated cognitive impairments, reduced amyloid-related measures, and dampened pro-inflammatory cytokine responses, with a trend toward reduced microglial cell density. Collectively, these findings demonstrate that systemic inflammation accelerates Alzheimer's-like pathology and cognitive decline, and suggest that pharmacological modulation of neuroinflammatory signaling by maraviroc may mitigate inflammation-driven disease exacerbation at early stages.Schematic diagram illustrating the effects of maraviroc on LPS-induced cognitive deficits in 3-month-old 5 × FAD mice. In this model, maraviroc is associated with modulation of glial inflammatory responses, reduced pro-inflammatory cytokine levels, and alleviation of amyloid pathology in the hippocampus, which together coincide with improved cognitive performance. Figure created with BioRender.com.},
}

@article {pmid42401584,
year = {2026},
author = {Menze, I and Bernal, J and Kievit, RA and Tripathi, KP and Kaleck, T and Yakupov, R and Altenstein, S and Bartels, C and Buerger, K and Butryn, M and Dechent, P and Ewers, M and Fliessbach, K and Frommann, I and Gemenetzi, M and Glanz, W and Gref, D and Hellmann-Regen, J and Hetzer, S and Incesoy, EI and Janowitz, D and Kiliman, I and Kleineidam, L and Kronmüller, MT and Laske, C and van Lent, DM and Lüsebrink, F and Perneczky, R and Peters, O and Preis, L and Priller, J and Rauchmann, BS and Rostamzadeh, A and Roeske, S and Scheffler, K and Schott, BH and Schneider, A and Sodenkamp, S and Spottke, A and Spruth, EJ and Stark, M and Teipel, S and Wagner, M and Wiltfang, J and Jessen, F and Ramirez, A and Schreiber, S and Düzel, E and Ziegler, G},
title = {Joint trajectories of brain atrophy, white matter hyperintensities and cognition quantify brain maintenance.},
journal = {Nature communications},
volume = {17},
number = {1},
pages = {},
pmid = {42401584},
issn = {2041-1723},
mesh = {Humans ; *White Matter/pathology/diagnostic imaging ; Atrophy/pathology ; *Cognition/physiology ; *Brain/pathology/diagnostic imaging ; *Aging/pathology/physiology ; Magnetic Resonance Imaging ; Female ; Male ; Aged ; Aged, 80 and over ; Cognitive Dysfunction/pathology ; },
abstract = {Brain maintenance - the preservation of brain structure or function relevant to cognitive performance - remains challenging to quantify. Here, we propose a domain-general brain maintenance index derived by jointly modelling the longitudinal co-evolution of ageing-related atrophy (via medial temporal lobe to ventricle ratio, MTLV-ratio), white matter hyperintensities (WMH), and global cognition assessed by the preclinical Alzheimer's cognitive composite (PACC5) using latent growth curve modelling. We demonstrate its utility in 543 cognitively unimpaired older adults from the DELCODE cohort, followed annually over four years. We show that changes in MTLV-ratio and WMH additively predict cognitive change. We further show that higher neuroticism, depressive symptoms, lower openness, and faster biological ageing are related to unfavourable domain-specific trajectories and poorer brain maintenance. Our findings highlight the combined relevance of WMH and ageing-related atrophy dynamics for brain maintenance. Maintaining cerebrovascular and mental health alongside cognitive engagement could promote brain maintenance, delay cognitive decline and dementia.},
}

Humans
*White Matter/pathology/diagnostic imaging
Atrophy/pathology
*Cognition/physiology
*Brain/pathology/diagnostic imaging
*Aging/pathology/physiology
Magnetic Resonance Imaging
Female
Male
Aged
Aged, 80 and over
Cognitive Dysfunction/pathology

@article {pmid42401601,
year = {2026},
author = {Lam, J and Rodriguez-Cruces, R and Arafat, T and Royer, J and Chen, J and Dascal, A and Sahlas, E and Pana, R and Hopewell, R and Hsiao, CH and Massarweh, G and Soucy, JP and Rosa-Neto, P and Villeneuve, S and Caciagli, L and Koepp, M and Bernasconi, A and Bernasconi, N and Bernhardt, B},
title = {An open dataset of cerebral tau deposition in young healthy adults based on [[18]F]MK6240 positron emission tomography.},
journal = {Scientific data},
volume = {},
number = {},
pages = {},
doi = {10.1038/s41597-026-07656-8},
pmid = {42401601},
issn = {2052-4463},
support = {FDN-154298, PJT-174995, PJT-191853//Gouvernement du Canada | Canadian Institutes of Health Research (Instituts de Recherche en Santé du Canada)/ ; 14181//Brain Research Trust (BRT)/ ; NI17-039//Sick Kids Foundation/ ; RGPIN-2025-05932//Gouvernement du Canada | Natural Sciences and Engineering Research Council of Canada (Conseil de Recherches en Sciences Naturelles et en Génie du Canada)/ ; },
abstract = {Tauopathies are pathologies wherein phosphorylated insoluble tau aggregates in neurons, leading to dysfunction and degeneration. Positron emission tomography (PET) enables measurement of in vivo tau, with second-generation radiotracers such as [[18]F]MK6240 showing high tau affinity with minimal off-target binding. While tauopathies are commonly linked to age-related neurodegenerative diseases, notably Alzheimer's disease (AD), evidence suggests pathophysiological cascades may begin long before clinical onset. Increasingly, tau is recognized in pathologies affecting younger individuals, including autosomal dominant AD, Niemann-Pick disease type C, chronic traumatic encephalopathy, and epilepsy, thus highlighting the importance of normative data in non-geriatric populations. Here, we present a dataset of 33 young to middle-age healthy adults (mean age 34.0 ± 10.4 years, 12 female) with [[18]F]MK6240 PET data and T1w magnetic resonance imaging. Longitudinal data are also available in a subset of 9 participants with a minimum follow-up time of 1 year. Our dataset aims to support imaging biomarker studies on younger individuals potentially at risk for AD and to advance work in tauopathies affecting non-geriatric populations generally excluded from neurodegeneration studies.},
}

@article {pmid42401929,
year = {2026},
author = {Baghel, MS and Burns, GD and Tsapatsis, M and Peethambaran Mallika, A and Cruz, ALF and Cao, T and Chen, XK and De La Rosa, I and Marx, SR and Ye, Y and Sun, S and Li, T and Ling, JP and Wong, PC},
title = {TDP-43 dysfunction facilitates the pathological conversion of tau.},
journal = {Molecular neurodegeneration},
volume = {},
number = {},
pages = {},
doi = {10.1186/s13024-026-00968-8},
pmid = {42401929},
issn = {1750-1326},
abstract = {TDP-43 proteinopathy coexists with tauopathy in a variety of neurodegenerative disorders, including Alzheimer's Disease (AD) and AD related dementia (ADRD). While such co-pathology of TDP-43 is strongly associated with worsened neurodegeneration, the pathogenic mechanism underlying the exacerbated neuron loss remains elusive. Loss of TDP-43 splicing repression occurring during the early stage of neurodegenerative disease suggests that such loss could facilitate the pathological conversion of tau. Here, we report that TDP-43 loss-of-function (LOF) in forebrain neurons (Tau4R; CaMKII-CreER; Tardbp[f/f] mice) exacerbates tauopathy-dependent brain atrophy is associated with vulnerable neurons sensitive to caspase 3-dependent cleavage of endogenous tau. We demonstrate that TDP-43 LOF in human iPSC-derived cortical neurons promotes TDP-43 dependent cryptic splicing which precedes caspase 3-mediated endoproteolysis of tau. Using a genetic approach to seed tauopathy in CaMKII-CreER; Tardbp[f/f] mice by expressing a four-repeat microtubule binding domain of human tau, we show that the amount of tau seed correlates with caspase 3-dependent tau cleavage, accelerated tauopathy and the loss of vulnerable neurons deficient in TDP-43. Together, these results strongly support the view that TDP-43 dysfunction exacerbates tauopathy-dependent brain atrophy by promoting caspase 3-dependent endoproteolysis of tau, disclosing novel mechanistic insights and therapeutic targets for human tauopathies harboring the co-pathology of TDP-43.},
}

@article {pmid42401978,
year = {2026},
author = {Alsina, R and Riba, M and Sartorio, M and Romera, C and Riu, J and Vilaplana, G and Aldecoa, I and Compta, Y and Sánchez-Valle, R and Del Valle, J and Pelegrí, C and Molina-Porcel, L and Vilaplana, J},
title = {Regional wasteosome accumulation across neurodegenerative diseases points to a shared underlying mechanism potentially related to glymphatic insufficiency.},
journal = {Acta neuropathologica communications},
volume = {},
number = {},
pages = {},
doi = {10.1186/s40478-026-02362-3},
pmid = {42401978},
issn = {2051-5960},
support = {FPU//Ministerio de Ciencia, Innovación y Universidades/ ; Margarita Salas//Ministerio de Ciencia, Innovación y Universidades/ ; FPI//Ministerio de Ciencia, Innovación y Universidades/ ; PID2020-115475GB-I00//Ministerio de Ciencia, Innovación y Universidades/ ; 2021 SGR 00288 625//Generalitat de Catalunya/ ; },
abstract = {The glymphatic system plays a key role in clearing waste products from the brain and is essential for maintaining brain homeostasis. When dysfunctional, it appears to contribute to pathological changes that exacerbate brain disorders, including neurodegenerative diseases. Additionally, wasteosomes, also known as corpora amylacea, are structures that function as waste containers and are thought to increase in response to chronic glymphatic insufficiency. Hence, in this study, we evaluated whether the accumulation and distribution of wasteosomes are compatible with both the potential role of wasteosomes as a hallmark of the chronic glymphatic insufficiency and the presence of this insufficiency in certain neurodegenerative diseases. Accordingly, brain tissue from 185 donors was analysed, including cases of Alzheimer's disease, amyotrophic lateral sclerosis with TDP-43 proteinopathy, frontotemporal lobar degeneration with TDP-43 or tau proteinopathy, and non-diseased controls. Wasteosomes were examined across 28 brain regions comprised within 5 major brain areas, using region-specific scoring systems. Analysis was conducted through variance and covariance analyses, along with decision tree procedures. The findings reveal that wasteosomes are consistently found in specific critical regions, with a higher burden in donors with neurodegenerative diseases compared with controls. These regions are independent of the regional distribution of the underlying proteinopathy, and are potentially associated with glymphatic drainage pathways. From an integrated perspective, although further studies are required, the increased presence of wasteosomes in these critical regions across all diseased groups is consistent with the potential presence of chronic glymphatic insufficiency in these diseases.},
}

@article {pmid42402181,
year = {2026},
author = {Osmanovic Barilar, J and Vlahov, L and Krsnik, A and Mihalic, L and Babic Perhoc, A and Virag, D and Homolak, J and Salkovic-Petrisic, M and Knezovic, A},
title = {Time- and Region-Specific Effects of Intranasal Insulin on Oxidative Stress Parameters in the Rat Brain.},
journal = {FASEB journal : official publication of the Federation of American Societies for Experimental Biology},
volume = {40},
number = {13},
pages = {e72119},
doi = {10.1096/fj.202601712R},
pmid = {42402181},
issn = {1530-6860},
support = {HRZZ-2022-10-1895//Hrvatska Zaklada za Znanost (HRZZ)/ ; DOK-NPOO-2023-10-3354//Hrvatska Zaklada za Znanost (HRZZ)/ ; DOK-2025-02-5472//Hrvatska Zaklada za Znanost (HRZZ)/ ; 10106-24-1453//Medicinski Fakultet, Sveučilište u Zagrebu (University of Zagreb Medical School)/ ; },
mesh = {Animals ; *Oxidative Stress/drug effects ; *Insulin/administration & dosage/pharmacology ; Male ; Rats, Wistar ; Administration, Intranasal ; *Brain/metabolism/drug effects ; Rats ; Oxidation-Reduction/drug effects ; Lipid Peroxidation/drug effects ; Sulfhydryl Compounds/metabolism ; Nasal Mucosa/metabolism/drug effects ; Superoxide Dismutase/metabolism ; },
abstract = {Understanding how intranasal insulin affects brain signaling and metabolism is essential for elucidating its therapeutic potential in neurodegenerative disorders with underlying metabolic dysfunction, such as Alzheimer's disease (AD). Oxidative stress, which increases with aging, has been observed in both AD and Type 2 diabetes, indicating a potential link between oxidative stress, brain insulin resistance and cognitive impairment. This study examined how intranasal insulin affects redox homeostasis across different brain regions and time points. Male Wistar rats received 2 IU of insulin intranasally and were sacrificed 3, 7.5, 15, 30, 60, and 120 min post-administration. Six animals served as intact controls. Redox homeostasis was assessed by measuring lipid peroxidation, total reductive capacity, thiol concentrations, and superoxide dismutase activity in plasma, nasal epithelia, and brain regions. The results were correlated with insulin signaling markers. Intranasal insulin induced rapid but regionally diverse redox responses. The most pronounced alterations occurred in nasal epithelia, where respiratory and olfactory regions exhibited distinct and opposing patterns. In the brain, significant alterations, particularly in thiol-related parameters, were observed across multiple regions including cortices, hippocampus, hypothalamus, olfactory bulb, and cerebellum. Plasma redox parameters remained largely unchanged, supporting the predominantly central action of intranasally delivered insulin. Correlation analyses revealed associations between oxidative stress markers and insulin signaling parameters, suggesting complex interactions between metabolic signaling pathways and redox regulation. These findings demonstrate that intranasal insulin modulates redox homeostasis in a rapid, region-specific, and time-dependent manner, highlighting the importance of spatial and temporal factors in insulin-mediated regulation of brain oxidative balance.},
}

Animals
*Oxidative Stress/drug effects
*Insulin/administration & dosage/pharmacology
Male
Rats, Wistar
Administration, Intranasal
*Brain/metabolism/drug effects
Rats
Oxidation-Reduction/drug effects
Lipid Peroxidation/drug effects
Sulfhydryl Compounds/metabolism
Nasal Mucosa/metabolism/drug effects
Superoxide Dismutase/metabolism

@article {pmid42402306,
year = {2026},
author = {Chen, ML and Hao, LY and Zhang, ZH and Xu, HF and Li, HF and Wen, L and Zheng, GQ},
title = {Preclinical Evidence for Icariin in Alzheimer's Disease: Methodological Quality, Efficacy, and Mechanisms.},
journal = {Ageing research reviews},
volume = {},
number = {},
pages = {103228},
doi = {10.1016/j.arr.2026.103228},
pmid = {42402306},
issn = {1872-9649},
abstract = {Alzheimer's disease (AD) currently lacks effective curative treatments. Icariin (ICA), a flavonoid from Epimedium, has been widely investigated in AD animal models with emerging neuroprotective potential. However, the methodological quality, reporting rigor, and translational reliability of this preclinical evidence have not yet been systematically evaluated. Studies investigating ICA in AD were retrieved from eight databases up to May 12, 2026. The reporting quality, risk of bias, and study quality were assessed using the ARRIVE 2.0 guidelines, the SYRCLE risk-of-bias tool, and the CAMARADES checklist, respectively. Meta-analyses were conducted to assess the therapeutic efficacy of ICA, and potential mechanisms were summarized. A total of 59 studies were included. The average reporting rate for ARRIVE 2.0 items was 56.12%, with major deficiencies in sample size calculation (0%), inclusion/exclusion criteria (0%), protocol registration (0%), randomization (5.08%), and blinding (11.86%). The SYRCLE assessment revealed that only a few domains were rated as low risk of bias. CAMARADES scores ranged from 2 to 5 (out of 10). Meta-analyses showed that ICA significantly improved cognitive performance in behavioral tests. In the Morris water maze, escape latency was reduced (SMD = -2.51, 95% CI -3.02 to -2.01), with similar improvements observed in the novel object recognition and Y-maze tests. ICA also significantly attenuated amyloid pathology, reducing hippocampal amyloid plaque number (SMD = -2.43, 95% CI -3.80 to -1.05), plaque area, and soluble Aβ1-42 levels. Preclinical evidence from AD animal models suggests that ICA improves cognitive performance and reduces amyloid burden through mechanisms involving neuroinflammation, amyloid and tau regulation, synaptic plasticity, mitochondrial and redox homeostasis. However, substantial methodological shortcomings-particularly in sample size calculation, randomization, blinding, and outcome pre-specification-limit confidence in the robustness and translational reliability of these findings. Strengthening methodological rigor and reporting transparency will be essential to support future clinical development.},
}

@article {pmid42402307,
year = {2026},
author = {Chen, Z and Yang, K and Lin, F and Tang, W and Shi, Y and Zhou, S and Liu, J and You, Y},
title = {White matter abnormalities in Alzheimer's disease: Implications for pathophysiology, diagnosis, and treatment.},
journal = {Ageing research reviews},
volume = {},
number = {},
pages = {103229},
doi = {10.1016/j.arr.2026.103229},
pmid = {42402307},
issn = {1872-9649},
abstract = {White matter (WM) abnormalities have emerged as a critical element in Alzheimer's disease (AD) pathogenesis, shifting from their former status as a passive consequence to an active contributor to disease progression. Notably, microstructural WM alterations, detectable early via advanced neuroimaging techniques such as diffusion tensor imaging, frequently precede overt gray matter atrophy and cognitive decline, highlighting their potential as early contributors to AD pathogenesis. The origins of WM pathology are multifactorial, involving a complex interplay among β-amyloid (Aβ) and tau aggregation, energy dysmetabolism, neuroinflammation, vascular dysfunction, and cellular senescence. Importantly, we emphasize a paradigm-shifting perspective: WM degeneration acts not merely as a downstream outcome but as a key driver of AD pathogenesis, capable of accelerating protein aggregation, amplifying neuroinflammation, and compromising neural plasticity. Given its early manifestation and close association with symptom onset, WM integrity has emerged as a sensitive and reliable biomarker for early AD detection and progression monitoring. Moving beyond diagnostics, the growing understanding of WM pathophysiology has unveiled a new frontier of therapeutic interventions aimed at myelin regeneration and WM protection. Despite persisting translational challenges, targeting WM integrity represents a pivotal avenue for developing disease-modifying therapies capable of slowing disease progression and improving clinical outcomes in patients with AD.},
}

@article {pmid42402621,
year = {2026},
author = {Calcagno, G and Mansuroglu, Z and Segrt, H and Conquet, L and Marin-Obando, JP and Bortolin, V and de Chaumont, F and Buée, L and Niedergang, F and Manet, C and Galas, MC and Montagutelli, X and Bonnefoy, E},
title = {Zika virus infection induces a persistent accumulation of Alzheimer's disease-like Tau phosphorylation in adult immunocompetent mice in association with memory and social behavior impairments.},
journal = {Acta neuropathologica communications},
volume = {},
number = {},
pages = {},
doi = {10.1186/s40478-026-02368-x},
pmid = {42402621},
issn = {2051-5960},
support = {ANR-20-CE16-0017//Agence Nationale de la Recherche/ ; ANR-20-CE16-0017//Agence Nationale de la Recherche/ ; ANR-20-CE16-0017//Agence Nationale de la Recherche/ ; ANR-20-CE16-0017//Agence Nationale de la Recherche/ ; ANR-20-CE16-0017//Agence Nationale de la Recherche/ ; ANR-20-CE16-0017//Agence Nationale de la Recherche/ ; ANR-20-CE16-0017//Agence Nationale de la Recherche/ ; ANR-10-LABX-62-IBEID//French Government's Investissement d'Avenir program, Laboratoire d'Excellence/ ; ANR-10-LABX-62-IBEID//French Government's Investissement d'Avenir program, Laboratoire d'Excellence/ ; },
abstract = {Clinical and epidemiological data support the link between viral encephalitis and neurodegeneration but its causal mechanism remains mostly unknown. Zika virus (ZIKV) is an emerging, neurotropic flavivirus susceptible to induce cognitive impairments in infected adults. In this work we have analyzed the capacity of ZIKV to induce the accumulation of pathological phosphorylated Tau protein (pTau), a major driver of neurodegenerative disorders such as Alzheimer's disease, throughout the infection of adult immunocompetent mice. The capacity of ZIKV to induce pTau in vivo, was analyzed in the long term in three Collaborative Cross mouse strains displaying different responses to ZIKV. The establishment and propagation of pTau was quantified up to 60 days post-infection (dpi) in correlation with the level and localization of neuronal viral infection and of microglia activation using immunofluorescence, immunohistochemistry, wide field and confocal microscopy and gene expression analysis. Strength, coordination, memory and social behavior were evaluated before and following the establishment and progression of pTau. The role of microglia on ZIKV-induced pTau was investigated by partially depleting microglial cells using PLX3397 (PLX). ZIKV infection induced a significant accumulation of pTau starting at 15 that persisted at least until 60 dpi. At 15 dpi, pTau was observed in ZIKV-infected neurons in the CA2 and CA1 regions of the hippocampus and in non-infected cortical neurons in association with neuroinflammation and social behavior alterations. At 30 dpi, pTau progressed independently of infection and inflammation, positively correlated to PLX-susceptible Apoe gene expression in association with short-term memory defects. These results shed light on how brain viral infections, which are a major concern for public health, drive pTau accumulation and propagation in link with memory impairment and social behavior alterations laying the groundwork for potential new therapeutic treatments.},
}

@article {pmid42402880,
year = {2026},
author = {, },
title = {[Standard operating procedure for pre-analytical blood biomarker processing in Alzheimer's disease (2026 edition)].},
journal = {Zhonghua yi xue za zhi},
volume = {106},
number = {25},
pages = {2568-2578},
doi = {10.3760/cma.j.cn112137-20260202-00363},
pmid = {42402880},
issn = {0376-2491},
support = {2023YFC3605400//National Key Research and Development Program of China/ ; 82588301//Natural Science Foundation of China/ ; 2024GGXM003//Joint Project of the Chongqing Science and Technology Bureau and the Health Commission/ ; },
mesh = {*Alzheimer Disease/blood/diagnosis ; Humans ; *Biomarkers/blood ; Amyloid beta-Peptides/blood ; tau Proteins/blood ; },
abstract = {Alzheimer's disease (AD) is a major health threat to the elderly. With the clinical application of disease-modifying therapeutic drugs, early and accurate diagnosis of AD has become increasingly essential. Given the ease of collection, blood biomarker detection has emerged as a crucial method for early screening, clinical diagnosis, and disease monitoring of AD. In recent years, substantial progress has been achieved in the research of AD blood biomarkers, and some indicators have been introduced into clinical practice. However, the detection of AD blood biomarkers, such as β-amyloid protein and phosphorylated tau protein, are highly susceptible to pre-analysis factors, which reduces the reliability of their clinical application and restricts the comparability among different blood biomarker studies. Currently, in China, there is a growing trend in the scientific research, testing product development, and clinical application of AD blood biomarkers. Therefore, it is necessary to standardize the AD blood biomarker detection in China. Based on this background, Cognitive Impairment Working Group of the National Medical Quality Control Center for Neurological Diseases established the "Standard operating procedure for pre-analytical blood biomarker processing in Alzheimer's disease (2026 edition)". This standard is developed in line with international recommendations, incorporating the practical experience of blood biomarker research in China and taking into consideration both clinical and research needs. It formulates a standardized operating procedure for the pre-treatment of blood samples, providing a quality control reference for the research and clinical application of AD blood biomarkers in China.},
}

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

@article {pmid42402882,
year = {2026},
author = {Tian, C and Wang, ZY and Liu, SY and Kang, XX and Yu, ZW and Pan, DH and Guo, Z and Qiao, HW and Peng, GP and Zhang, W and Chen, B and Zhang, ZX and Zhang, J},
title = {[Consistency evaluation of the domestic Lifotronic platform and foreign luminescence platforms in detecting core cerebrospinal fluid biomarkers in Chinese Alzheimer disease patients].},
journal = {Zhonghua yi xue za zhi},
volume = {106},
number = {25},
pages = {2589-2600},
doi = {10.3760/cma.j.cn112137-20260414-01014},
pmid = {42402882},
issn = {0376-2491},
mesh = {Aged ; Female ; Humans ; Male ; Middle Aged ; *Alzheimer Disease/cerebrospinal fluid ; Amyloid beta-Peptides/cerebrospinal fluid ; *Biomarkers/cerebrospinal fluid ; Luminescent Measurements ; Retrospective Studies ; tau Proteins/cerebrospinal fluid ; East Asian People ; },
abstract = {Objective: To evaluate the consistency of measurement results and diagnostic agreement of core cerebrospinal fluid (CSF) biomarkers for Alzheimer disease (AD) in a Chinese population, which were measured across a domestically developed electrochemiluminescence platform (Lifotronic eCL8000), a Japanese chemiluminescence immunoassay platform (LUMIPULSE), and an American electrochemiluminescence platform (Meso Scale Discovery, MSD). Methods: CSF samples were retrospectively collected from 253 subjects recruited at Peking Union Medical College Hospital, Xuanwu Hospital Capital Medical University, and Beijing Tiantan Hospital between July 2013 and September 2019. The cohort was comprised of 132 males and 121 females, with the age of (62.4±13.3) years. All CSF samples were collected via standardized protocols and cryopreserved at -80 ℃. Inter-assay repeatability (coefficient of variation, CV) of the Lifotronic platform on different days was validated. Spearman's rank correlation analysis was used to evaluate the degree of correlation between the results of the Pumen platform and those of the LUMIPULSE and MSD platforms, with the correlation coefficient expressed as ρ. Subsequently, 4 core CSF biomarkers [β-amyloid 40 (Aβ40), β-amyloid 42 (Aβ42), phosphorylated tau (p-tau), and total tau (t-tau)] were quantitatively measured across the three platforms. The consistency of test results between platforms was evaluated using the Passing-Bablok regression model and Bland-Altman analysis. The 95% limits of agreement (LoA) were calculated by Bland-Altman analysis, with good agreement indicated when <5% of points fell outside the limits. Proportional and constant errors between the measurement systems were quantified by the Passing-Bablok regression model, utilizing a robust non-parametric method. [18]F-florbetapir positron emission tomography/positron emission tomography/computed tomography (PET/CT) imaging has been performed on 40 of the 253 subjects. With the PET/CT diagnostic results utilized as the gold standard, the diagnostic agreement between the CSF results from the 3 platforms and the PET/CT findings was compared by calculating Cohen's Kappa coefficient. Furthermore, AD diagnostic reference cut-off values for each platform were determined by employing receiver operating characteristic (ROC) curves. Results: The Lifotronic platform demonstrated good repeatability in CSF testing (CV<10%). Spearman's rank correlation analysis was used to evaluate the correlation between the Lifotronic platform and the LUMIPULSE and MSD platforms, with correlation coefficients denoted by ρ. In comparison with the LUMIPULSE platform, all correlation coefficients (ρ) were>0.85. The correlation coefficient (ρ) between the MSD and Lifotronic platforms was>0.80, with a Kappa value of 0.698 (P<0.05). Bland-Altman analysis and Passing-Bablok regression models showed that for t-tau, the mean bias between Lifotronic and LUMIPULSE was 214.95 (95%LoA:-1 490.59-1 920.50), with 99.60% (252/253) of the data points falling within the 95%LoA. In the detection of t-tau, the regression slope between the Lifotronic and LUMIPULSE platforms was 2.041 (Equation: Y=2.041X-75.184), and the regression slope with the MSD platform was 2.360 (Equation: Y=2.360X-87.503). Based on PET/CT imaging validation, the CSF diagnostic results of the Lifotronic platform were consistent with the PET/CT results (Kappa=0.885, P<0.05), as were those of the MSD platform (Kappa=0.714, P<0.05). The Lifotronic platform established AD diagnostic reference thresholds based on the t-tau/Aβ42 and p-tau-181/Aβ42 ratios (the cut-off value for t-tau/Aβ42 was 0.32, and for p-tau-181/Aβ42 was 0.035). The Kappa value between the Lifotronic and LUMIPULSE platforms was 0.928 (P<0.05), and the Kappa value between the Lifotronic and MSD platforms was 0.698 (P<0.05). Conclusion: This study systematically validated the reliability of domestically developed Lifotronic electrochemiluminescence platform and its corresponding assay kits in detecting AD CSF biomarkers, as well as their comparability with international platforms, demonstrating comparable capabilities in terms of accuracy, consistency, and cost control.},
}

Aged
Female
Humans
Male
Middle Aged
*Alzheimer Disease/cerebrospinal fluid
Amyloid beta-Peptides/cerebrospinal fluid
*Biomarkers/cerebrospinal fluid
Luminescent Measurements
Retrospective Studies
tau Proteins/cerebrospinal fluid
East Asian People

@article {pmid42403010,
year = {2026},
author = {Erol Gunal, S and Teke Tuncel, S and Demir, İ and Baysal, İ and Telli, G and Sag Erdem, S and Ucar, G and Hanzlova, M and Musilek, K and Dogan, İ and Gokhan Kelekci, N},
title = {Design, Synthesis, and Biological Evaluation of Chiral Urea and Thiourea Derivatives as Multitarget-Directed Anti-Alzheimer Agents.},
journal = {Drug development research},
volume = {87},
number = {5},
pages = {e70341},
doi = {10.1002/ddr.70341},
pmid = {42403010},
issn = {1098-2299},
support = {219Z128//Scientific and Technological Research Council of Turkey (TÜBİTAK)/ ; 18082//Bogazici University Research Fund (BAP)/ ; 2206-2025//University of Hradec Kralove/ ; },
mesh = {*Thiourea/pharmacology/chemistry/chemical synthesis/analogs & derivatives ; *Alzheimer Disease/drug therapy ; Drug Design ; Humans ; *Urea/pharmacology/chemistry/analogs & derivatives/chemical synthesis ; Stereoisomerism ; *Cholinesterase Inhibitors/pharmacology/chemistry/chemical synthesis ; Molecular Docking Simulation ; Structure-Activity Relationship ; Monoamine Oxidase/metabolism ; Acetylcholinesterase/metabolism ; Animals ; Amyloid beta-Peptides/metabolism ; },
abstract = {A series of novel chiral urea and thiourea compounds were designed as multitarget-directed ligands for Alzheimer's disease and evaluated against hAChE, hBChE, and hMAO-B, with exploratory assessment of HSD10. These chiral compounds were synthesized and fully characterized, and their enantiopurity was confirmed via HPLC. Biological screening revealed that several of the 38 single-enantiomer derivatives exhibited potent triple inhibition of hAChE, hBChE, and hMAO-B. Biological screening revealed that a significant number of the 38 synthesized single-enantiomer urea and thiourea derivatives potent inhibition across the primary target panel. Among them, compounds 14S (hAChE: 0.08 μM, hBChE: 0.93 μM, hMAO-B: 0.02 μM), 23R (hAChE: 0.06 μM, hBChE: 0.74 μM, hMAO-B: 0.08 μM), 6S (hAChE: 0.08 μM, hBChE: 0.65 μM, hMAO-B: 0.08 μM), and 30S (hAChE: 0.04 μM, hBChE: 0.74 μM, hMAO-B: 0.19 μM) showed the most promising multitarget profiles. Compounds 6S and 23R also displayed anti-Aβ aggregation activity, whereas 12S combined dual hMAO-B/hAChE inhibition with antioxidant activity. Compounds 3R and 11R were found to be highly active against hMAO-B (0.03 μM and 0.06 μM, respectively) and hBChE (0.68 and 0.72 μM). HSD10 inhibition was limited overall, with only compound 26S showing moderate activity (52.2%) at higher micromolar concentration. Molecular docking and molecular dynamics simulations supported the proposed ligand-target interactions for the most active compounds. In addition, selected derivatives showed no acute cytotoxicity under the tested conditions in HepG2 cells and high permeability potential in the PAMPA-BBB assay. Based on their in vitro profiles, seven compounds (3R, 6S, 11R, 12S, 14S, 23R, and 30S) were advanced to in vivo evaluation, and compounds 6S, 12S, and 23R, 30S produced significant improvements in the Morris Water Maze model. Collectively, these findings identify chiral urea and thiourea derivatives as promising lead structures for further anti-Alzheimer drug discovery.},
}

*Thiourea/pharmacology/chemistry/chemical synthesis/analogs & derivatives
*Alzheimer Disease/drug therapy
Drug Design
Humans
*Urea/pharmacology/chemistry/analogs & derivatives/chemical synthesis
Stereoisomerism
*Cholinesterase Inhibitors/pharmacology/chemistry/chemical synthesis
Molecular Docking Simulation
Structure-Activity Relationship
Monoamine Oxidase/metabolism
Acetylcholinesterase/metabolism
Animals
Amyloid beta-Peptides/metabolism

@article {pmid42403013,
year = {2026},
author = {Tung, TH and Babu, S and Tang, X and Sciutto, AL and Romer, M and Racha, P and Xu, R and Fiesler, V and Saha, A and Thai, T and Saito, T and Saido, TC and Zhao, Y and Grinspan, JB and Mathys, H and Kozai, TDY and Cambi, F},
title = {Fus-depleted oligodendrocytes reduce neuronal damage and Alzheimer's disease progression in the AppNL-G-F mouse.},
journal = {Brain : a journal of neurology},
volume = {},
number = {},
pages = {},
doi = {10.1093/brain/awag234},
pmid = {42403013},
issn = {1460-2156},
abstract = {Alzheimer's Disease (AD) is an age-dependent neurodegenerative disorder and represents the most common type of dementia, increasing in incidence at an alarming rate in the aging population. The hallmarks of the disease are amyloid plaque accumulation, microglia and astrocyte activation, and loss of presynaptic structure leading to cognitive decline. Recently, oligodendrocyte (OL) and myelin abnormalities have emerged as important contributors to the pathogenesis of AD. In normal brain homeostatic conditions, OL maintain neuronal health through myelin axon interactions and by supplying neurotrophic and metabolic support. How strengthening OL function may support neuronal health in AD neurodegeneration remains to be fully characterized and represents a gap in knowledge and a missed therapeutic opportunity. This study sought to examine how myelin and OL may improve neuronal deficits associated with AD. We have generated a novel mouse model (AD/cKO) by crossing the AppNL-G-F mouse, an established AD model, which carries three human AD mutations in the mouse App gene, with the FusOLcKO whose OL depleted of Fus (Fused in Sarcoma) produce thicker myelin associated with greater cholesterol biosynthesis. We evaluated spatial memory function with standardized cognitive testing. We evaluated microglia density and state, astrocytic activation and toxic phenotype, myelin density, cholesterol content, amyloid plaque burden, presynaptic structures, and neuronal hypoxic and oxidative damage in the hippocampus and cortex. We characterized the transcriptome of AD/cKO hippocampal OL compared to AD by using single-cell transcriptomic studies. Spatial working memory was fully preserved in the aged AD/cKO mouse relative to the AD mouse. This outcome was associated with reduced neuronal oxidative damage, preserved presynaptic structures at the amyloid plaque niches, and a shift in microglia state at the niches in both hippocampus and cortex. In contrast, amyloid plaque burden and microglia density were decreased in the hippocampus but not in cortex, uncoupling the neuronal and microglia effects from the amyloid burden. Fus dependent myelin increase was present in both hippocampus and cortex. Single-cell transcriptomics of AD/cKO hippocampal OL revealed upregulation of energy metabolism and antioxidant genes, suggesting a role of OL enhanced energy metabolism in mediating protection of neurons and affecting microglia state in AD pathology. This work provides new insight into how oligodendrocytes may protect neurons in AD, communicate with other glial cellular players, and point to potential targets for disease intervention aimed at slowing AD progression.},
}

@article {pmid42403484,
year = {2026},
author = {Yüksel Dal, D and Kilic, BA and Gamgam, G},
title = {Local brain connectome parameters across the spectrum of clinical cognitive decline.},
journal = {Frontiers in neuroscience},
volume = {20},
number = {},
pages = {1840382},
pmid = {42403484},
issn = {1662-4548},
abstract = {Neurological disorders such as Alzheimer's disease, Parkinson's disease, and autism disrupt the brain's structural and functional organization, particularly in specific regions, and ultimately lead to cognitive impairments. In Alzheimer's disease-related dementia, neuronal degeneration impairs structural connectivity between brain regions, which in turn leads to functional breakdowns. This phenomenon, referred to as disconnection syndrome, manifests as connectivity breakdowns in affected regions, with these localized changes indirectly influencing the entire brain network. As the disease progresses, patterns consistent with compensatory-type reorganization have been described in the literature, accompanied by structural and functional changes that have been hypothesized to transiently mitigate cognitive decline during early stages. This study examines the structural and functional reorganization of the brain across the clinical spectrum of Alzheimer's disease by analyzing local nodal changes using measures such as degree, strength, clustering coefficient, and betweenness centrality. Our findings show that early-stage nodal patterns are consistent with this hypothesized reorganization, whereas later-stage changes are dominated by progressive structural decline alongside persistent functional reorganization. Because the present study is cross-sectional and group-level, the compensatory interpretation should be regarded as a working hypothesis rather than a confirmed mechanism, and these exploratory patterns require validation in independent and longitudinal cohorts before clinical translation.},
}

@article {pmid42403668,
year = {2026},
author = {Alshanberi, AM and Nukaly, HY and Mousa, AH and Alhartani, MM and Nassar, JY and Ahmed, RA and Talmesany, TA and Shaikhomer, M and Imam, AA and Abo-Ali, EA and Hassan, FE and Ansari, SA},
title = {Assessment of Dementia Patients Caregivers' Home Safety Knowledge in the Outpatient Setting of Jeddah, Saudi Arabia.},
journal = {Risk management and healthcare policy},
volume = {19},
number = {},
pages = {604540},
pmid = {42403668},
issn = {1179-1594},
abstract = {BACKGROUND: Home safety is a major issue for individuals involved in caring for dementia patients due to a lack of practice and awareness, as it accounts for more than 90% of the needs of patients with dementia. Such caregivers face constant challenges in preventing accidents while trying to maintain the dementia patients' independence and quality of life.

OBJECTIVE: The objective of this unicentric study was to assess the correlates of dementia patients' caregivers' home safety practices.

METHODS: A cross-sectional study was conducted in an outpatient setting of a private hospital in Jeddah (Saudi Arabia) from November 2022 until January 2023 by assessing the possible correlation between the caregivers' demographics among 128 dementia patients' caregivers. It also evaluates their service experience including the type of care, assistance duration, duration of caregiving, average time spent with persons living with dementia, dementia care training experience and their home safety practice quality. A questionnaire utilizing selected items from the validated "Alzheimer's Association Home Safety Checklist" was employed to assess the caregivers' home safety practices. Besides, the caregivers' psychological well-being and depression were assessed through a validated "Patient Health Questionnaire-2.

RESULTS: Although 66% of caregivers showed good home safety practices, 29% of caregivers reported depressive symptoms. Caregivers with extended caregiving duration (more than 5 years) demonstrated significantly better home safety practices as compared to those with shorter duration (AOR: 5.68, 95% CI: 1.76-18.33, p = 0.004). Further, depressed caregivers provided poor service as compared to non-depressed caregivers (AOR: 2.94, 95% CI: 1.19-7.24, p = 0.019).

CONCLUSION: Short-term and long-term dementia training aligning with cultural values and traditions of Saudi Arabia are required to ensure the care of such persons living with dementia is achieved in an effective and respectful way. Moreover, trained caregivers can improve quality of life, delay institutionalization and reduce healthcare costs.},
}

@article {pmid42403700,
year = {2026},
author = {Coury, SM and Lopez, SD and Savoca, PW and Gaines, EM and Parenti, B and Razon, A and Dosanjh, KK and Labus, JS and Jacobs, JP and Eich, TS and Wong, MD and Callaghan, BL and Silvers, JA},
title = {Does sex moderate health and Alzheimer's disease risk tied to early educational experiences? The reducing inequities through social and educational change follow-up in early adulthood extension study protocol.},
journal = {Brain, behavior, & immunity - health},
volume = {55},
number = {},
pages = {101294},
pmid = {42403700},
issn = {2666-3546},
abstract = {Alzheimer's disease (AD) -a progressive neurodegenerative disorder that is characterized by insidious cognitive decline and distinct neuropathological features- significantly impacts daily life functioning and behavior and is disproportionally prevalent in women compared to men. The reasons and risk factors for sex-based disparities in AD prevalence are still largely unclear, however early life exposures (e.g., education and stress) may be important contributing factors. Therefore, it is increasingly important to disentangle the complex interactions between known early environmental protective and risk factors and genetic susceptibility and uncover how these factors might impact and shape neurobiological processes. Moreover, it is critical to assess how these processes, in turn, influence later cognitive and brain health outcomes that may confer sex-specific pathways of risk for developing AD. In this paper we describe the rationale and study protocol for The Reducing Inequities through Social and Educational Change Follow-Up in Early Adulthood Extension (RISE-Up EA+; R01AG089426) study, a follow-up study of 300 participants aged 24-26 years old that leverages a natural quasi-experimental cohort to investigate how health outcomes tied to socioeconomic mobility opportunity may contribute to sex-specific vulnerability for developing AD later in life. To examine how sex-specific vulnerabilities related to early educational experiences may set the stage for later AD risk, we will assess self-report, cognitive, biological (e.g., inflammation and microbiome), and brain health measures. Results from this work provide the opportunity to better understand how adolescent mobility opportunities might contribute to later life health outcomes and influence sex-specific developmental pathways important for later AD risk.},
}

@article {pmid42403709,
year = {2026},
author = {Fontán-Baselga, T and Cañeque-Rufo, H and Rivera-Illades, E and Gramage, E and Zapico, JM and de Pascual-Teresa, B and Ramos-Álvarez, MDP and Vicente-Rodríguez, M and Herradón, G},
title = {Chronic inhibition of receptor protein tyrosine phosphatase β/ζ reduces amyloid plaque load and modulates pleiotrophin-expressing glial cells, glial-plaque interactions and genes related to amyloid beta clearance.},
journal = {Frontiers in pharmacology},
volume = {17},
number = {},
pages = {1839516},
pmid = {42403709},
issn = {1663-9812},
abstract = {Alzheimer's disease (AD) is the most common cause of dementia. Pleiotrophin (PTN) is a neurotrophic factor relevant for central nervous system repair, neuron differentiation and survival. It is upregulated in different neuroinflammatory conditions. PTN is an endogenous inhibitor of Receptor Protein Tyrosine Phosphatase (RPTP) β/ζ. In a previous study, we showed that a short treatment with the RPTPβ/ζ inhibitor MY10 reduced amyloid beta (Aβ) plaque formation and glial activation in old APP/PS1 mice. Nevertheless, these preliminary data required new studies to prove the disease-modifying potential of RPTPβ/ζ inhibition by using younger animals and a longer treatment with MY10. Thus, we have now treated for 3 months five- to seven-month-old wild type (WT) and APP/PS1 mice with MY10. This treatment decreased Aβ plaque formation and increased the number of microglial cells in the dorsal subiculum of APP/PS1 mice. In addition, MY10 reduced the number of GFAP+, not Iba1+, cells surrounding Aβ plaques. As expected, PTN expression was upregulated in the brain of APP/PS1 compared to WT mice and it was mainly found in Iba1+ and GFAP+ cells. Interestingly, treatment with MY10 significantly decreased the expression of PTN and the number of PTN-expressing Iba1+ and GFAP+ cells. MY10 induced a significant decrease of Mmp9 expression in the hippocampus of APP/PS1 mice, a key enzyme in AD progression. In summary, chronic inhibition of RPTPβ/ζ in APP/PS1 mice reduces Aβ plaque deposition, modulating glial-plaque interactions and the expression of specific genes including Ptn and its receptor.},
}

@article {pmid42403869,
year = {2026},
author = {Tuleubayeva, A},
title = {Cardiovascular Biomarkers as a Primary Care Gateway to Early Alzheimer's Disease Detection: The Case for an Integrated Screening Approach.},
journal = {Cureus},
volume = {18},
number = {6},
pages = {e110287},
pmid = {42403869},
issn = {2168-8184},
abstract = {Alzheimer's disease (AD) affects millions of Americans and represents one of the leading causes of disability and healthcare expenditure in the United States. The vast majority of patients are diagnosed at the symptomatic stage, when substantial neuronal loss has already occurred and the therapeutic window for disease-modifying treatment has closed. Recently approved disease-modifying therapies have created an urgent clinical need for pre-symptomatic patient identification. The cardiovascular risk factors most commonly managed in primary care -- hypertension, dyslipidemia, type 2 diabetes, atrial fibrillation, and chronic heart failure -- are among the most powerful modifiable antecedents of AD pathology, operating through systemic inflammation, cerebral small vessel disease, impaired glymphatic clearance, and tau hyperphosphorylation. The biomarkers used to monitor these conditions -- C-reactive protein, cardiac troponin, NT-proBNP, and homocysteine -- reflect active neurodegeneration risk processes already measured routinely in primary care. This clinical perspective proposes a three-stage integrated neuro-cardiological screening protocol linking cardiovascular biomarker assessment to plasma P-tau217 blood testing for AD confirmation. This framework addresses the implementation gap identified in recent United States primary care literature and represents a practical step toward closing the AD diagnostic gap.},
}

@article {pmid42403942,
year = {2026},
author = {Wang, W and He, Y and Xing, H and Zhang, H},
title = {Toward clinical translation of TMS-EEG: an integrative review of multidimensional neurophysiological measures.},
journal = {Frontiers in human neuroscience},
volume = {20},
number = {},
pages = {1804482},
pmid = {42403942},
issn = {1662-5161},
abstract = {Transcranial magnetic stimulation combined with electroencephalography (TMS-EEG) has emerged as a promising noninvasive approach for probing cortical reactivity and network dynamics with millisecond temporal resolution, with growing relevance for mechanistic and clinical neuroscience. However, despite rapid expansion of the field, TMS-EEG findings remain difficult to interpret because of substantial inter-individual variability and fragmentation across distinct analytical domains, including time-domain, spatially integrated, and time-frequency measures. These issues limit cross-study comparability and hinder clinical translation. In this review, we summarize the conceptual basis of TEPs, the physiological interpretation of canonical components (e.g., N15, P30), and commonly adopted analytical considerations. We further synthesize spatially integrated measures, including global and local mean field power (GMFP and LMFP), which quantify distributed cortical responses across multiple electrodes. Time-frequency indices, such as time-related spectral perturbation (TRSP) and inter-trial phase coherence (ITPC), are also reviewed to characterize TMS-induced oscillatory modulations. Drawing on the existing TMS-EEG literature in humans, we outline representative applications of these multidimensional metrics in neuropsychiatric and neurological conditions, including Alzheimer's disease, depression, epilepsy, and stroke. Finally, we discuss key methodological and translational challenges, such as stimulation-related artifacts, inter-individual variability, state-dependency of baseline oscillatory activity, and limited standardization, and highlight how these issues complicate the interpretation of TMS-EEG findings across studies and individuals. Together, this review aims to provide a structured reference framework for integrating and interpreting multidimensional TMS-EEG measures, thereby supporting more consistent understanding of the literature and informing future efforts toward harmonization and clinical translation.},
}

@article {pmid42403969,
year = {2026},
author = {Baquerizo-Burgos, J and Baquerizo-Burgos, E and Puga-Tejada, M and Baquerizo Y Flores, J},
title = {Normative Values for Prosaccade and Antisaccade Eye Movements in Adolescents Using a New Saccadometry Test.},
journal = {Journal of the American Academy of Audiology},
volume = {37},
number = {3},
pages = {197-208},
pmid = {42403969},
issn = {2157-3107},
mesh = {Humans ; *Saccades/physiology ; Adolescent ; Female ; Male ; Child ; Cross-Sectional Studies ; Reference Values ; },
abstract = {BACKGROUND: Saccadic eye movements (SEMs) are rapid, precise movements that reorient the visual fovea toward an object of interest. In clinical practice, assessing SEMs can help in differentiating and monitoring various neurologic, otoneurologic, and psychiatric conditions. Deviations from adequate saccadic patterns offer critical diagnostic information, enabling clinicians to more accurately identify related conditions such as schizophrenia, attention deficit hyperactivity disorder, Alzheimer's disease, and cognitive impairment in vestibular migraine, among others.

PURPOSE: Establish normative data for prosaccades (PSs) and antisaccades (ASs) in healthy adolescents aged 12-17 years.

RESEARCH DESIGN: A cross-sectional, single-center study conducted between June and December 2023.

STUDY SAMPLE: Data were reported on 138 healthy participants aged 12 to 17 years with no history of head trauma, neurologic, vestibular, behavioral, or psychiatric disorders, and use of medications affecting SEMs.

RESULTS: This study included 138 participants (mean age, 14.5 years; 44.2 percent female). A mean accuracy, latency, velocity, and directional error (DE) of 91.5 percent, 211 milliseconds (ms), 249.5 degrees per second (°/s), and 0.8 percent in PSs and 117.0 percent, 304.7 ms, 249.8°/s, and 11.8 percent for ASs were obtained, respectively. Significant reductions were found in horizontal random saccade velocity (p = 0.027), PS velocity (p = 0.001), AS latency (p < 0.001), and DE (p < 0.001) from younger to older adolescents. With age maturation, ASs' latency and DE showed a significant reduction. Compared with females, male participants have lower AS latencies (p < 0.041). Younger males (<15 years) have higher PS velocities (p = 0.02). Young females and males have higher latencies (p = 0.031 and p < 0.01, respectively) and DE (p < 0.01 and p < 0.01, respectively) than the older participants (≥15 years) in ASs.

CONCLUSIONS: This study established normative data for PSs and ASs for individuals aged 12-17 years using commercially available equipment. The findings indicate age-related variations, particularly in AS latency and DE.

CLINICAL RELEVANCE STATEMENT: The normative values obtained in this study could assist clinicians in the detection of cognitive control impairment or oculomotor dysfunction, and support complementary diagnostic tools in differentiating neurologic, vestibular, behavioral, or psychiatric disorders affecting adolescents.},
}

Humans
*Saccades/physiology
Adolescent
Female
Male
Child
Cross-Sectional Studies
Reference Values

@article {pmid42404124,
year = {2026},
author = {Hu, G and Feng, L and He, L and Liu, N and Wang, H},
title = {Sequential [18]F-AV45/[18]F-AV1451 dual-tracer brain PET imaging in Alzheimer's disease: amyloid-tau deposition, diagnostic performance, cognitive associations, and modulation by APOE ε4.},
journal = {Frontiers in neurology},
volume = {17},
number = {},
pages = {1877217},
pmid = {42404124},
issn = {1664-2295},
abstract = {OBJECTIVE: Alzheimer's disease (AD) is neuropathologically defined by amyloid-β (Aβ) plaques and tau neurofibrillary tangles. The AT(N) framework underscores the importance of in vivo dual-pathology imaging, yet large-scale clinical data on sequential [18]F-AV45 (Aβ) and [18]F-AV1451 (tau) PET remain limited. This study aimed to characterize Aβ-tau deposition, evaluate the pathological discriminatory performance of dual-tracer PET for typical amnestic AD, investigate cognitive correlations, and examine the modulatory role of APOE ε4 in a large clinical cohort.

METHODS: We conducted a retrospective cross-sectional study of 438 participants, including 325 AD patients, 68 mild cognitive impairment (MCI) patients, and 45 healthy controls (HC). All underwent sequential [18]F-AV45 and [18]F-AV1451 PET/CT. SUVRs were calculated in whole brain and 10 predefined regional ROIs, with the inferior cerebellar cortex as reference. Z-score normalization and binary logistic regression models were adopted to combine dual-tracer SUVR data for diagnostic performance assessment. Cognitive assessments included MMSE, MoCA, and ADAS-Cog. Statistical analyses comprised ANOVA, ROC (DeLong's test), Pearson correlation, and multivariable linear regression.

RESULTS: Whole-brain and regional SUVRs for both tracers were significantly higher in AD than in MCI and HC (all p < 0.001), with peak uptake in the temporoparietal lobe. The dual-tracer strategy with standardized combination methods yielded superior pathological discriminatory efficacy for typical amnestic AD compared with single tracers, with an AUC of 0.97 for AD versus HC and 0.93 for AD versus MCI. Tau deposition showed stronger cognitive correlations than Aβ. Tau burden and APOE ε4 were independent predictors of cognitive impairment. Aβ and tau SUVRs were strongly correlated (r = 0.65-0.81), most prominently in the precuneus and inferior temporal gyrus. APOE ε4 carriers exhibited significantly higher Aβ and tau deposition.

CONCLUSION: Sequential [18]F-AV45/[18]F-AV1451 dual-tracer PET enables accurate in vivo characterization of AD-related Aβ-tau pathology, and standardized combined analysis further improves its ability to distinguish typical sporadic amnestic AD from other groups. Tau is an independent driver of cognitive decline, while Aβ remains relevant for amyloid-targeted therapies. APOE ε4 modulates Aβ-tau interactions. Dual-tracer PET is a robust tool for clinical AD evaluation, pathological staging, and therapeutic monitoring of typical amnestic AD.},
}

@article {pmid42404237,
year = {2026},
author = {Dobrushina, M and Krohn, F and Chandni, S and Dietrich, L and Glanz, W and Butryn, M and Hämmerer, D and Penalba-Sánchez, L},
title = {Behind the scenes of a 7T MRI clinical study in Alzheimer's disease: challenges and recommendations for future research.},
journal = {Frontiers in aging neuroscience},
volume = {18},
number = {},
pages = {1731961},
pmid = {42404237},
issn = {1663-4365},
abstract = {Combining pharmacological interventions with neuroimaging in Alzheimer's disease (AD) research presents logistical and methodological challengesparticularly during early study phases, such as recruitment and study visits. Yet, these challenges are rarely reported in detail. This perspective article shares early-phase experiences from a 7-tesla (7T) fMRI clinical study involving individuals with mild cognitive impairment due to AD (MCI-AD) and mild Alzheimer's disease dementia (mild ADD), highlighting recruitment hurdles and offering practical recommendations. From a pool of 1,001 patients, 476 had a clinical diagnosis of MCI-AD or mild ADD; after pre-selection and screening, only 48 participants (10%) met all inclusion criteria. Major exclusion factors included metal or tattoos (8%), missing surgical documentation (2%), beta-blocker use (27.5%), recent cancer/chemotherapy or brain radiation (1%), and lack of interest (20%). Effective communication, often requiring caregiver assistance, was essential for obtaining accurate medical histories and improving adherence. Internally, clear team coordination supported scheduling and protocol compliance. While strict eligibility criteria improve data quality, they can substantially limit recruitment and feasibility in pharmacological and high-field MRI drug studies. We propose strategies to optimize recruitment and screening, facilitate data collection, and balance scientific rigor with real-world clinical feasibility.},
}

@article {pmid42404238,
year = {2026},
author = {Li, N and Jiang, K and Peng, X and Yang, C and Xiong, W and Wang, W},
title = {Ershiwuwei Shanhu Pill ameliorates cognitive impairment in Alzheimer's disease mice by remodeling gut microbiota and host serum metabolites.},
journal = {Frontiers in aging neuroscience},
volume = {18},
number = {},
pages = {1820691},
pmid = {42404238},
issn = {1663-4365},
abstract = {Alzheimer's disease (AD), with the most prominent pathological feature of the accumulation of amyloid-beta (Aβ) plaques and neurofibrillary tangles of hyperphosphorylated tau proteins (P-tau), is the foremost cause of dementia. Ershiwuwei Shanhu Pill (ESP) is commonly used in clinical practice in Tibetan areas to treat AD, and has been shown to alleviate cognitive impairment. However, whether ESP exerts its therapeutic effects by modulating the gut microbiota and serum metabolites remains unclear. In this study, APPswe/PSEN1dE9 transgenic (APP/PS1) mice (n = 11 per group) were treated with ESP (200 mg/kg, oral gavage) daily for 2 months and evaluated using the Morris Water Maze (MWM), brain histopathology, immunofluorescence, 16S rRNA sequencing, and untargeted serum metabolomics. ESP improved cognitive performance, reduced Aβ deposition and P-tau levels, and attenuated neuroinflammation. Concurrently, ESP significantly reshaped the gut microbiota (e.g., increasing Dubosiella and decreasing Bacteroides) and altered serum metabolites involved in tryptophan metabolism and glycolysis pathways (e.g., elevating Fructose 1,6-bisphosphate and reducing N-Acetylserotonin). In conclusion, these neuroprotective effects of ESP are associated with a remodeling of the gut microbiota and metabolic profile, providing a pharmacological basis for its clinical application and novel insights into AD intervention via the gut microbiota-metabolite-brain axis.},
}

@article {pmid42404289,
year = {2026},
author = {Larson, ST and Susman, JL},
title = {Navigating Alzheimer's Disease in Primary Care: Practical Strategies for Diagnosis and Management.},
journal = {International journal of general medicine},
volume = {19},
number = {},
pages = {603347},
pmid = {42404289},
issn = {1178-7074},
abstract = {Alzheimer's disease (AD), the most common form of dementia, is a neurodegenerative disorder that primarily affects older adults. Because the number of Americans 65 years of age and older living with AD is expected to increase and the availability of specialty physicians, such as neurologists and geriatricians, is limited, the role of primary care in diagnosing and managing patients with AD is expected to grow. Several guidelines for primary care providers are available for the evaluation, diagnosis, and treatment of patients with AD. However, there is no single concise and convenient reference tool for use in the primary care setting. In the primary care setting, clinicians are responsible for identifying patients at risk or demonstrating signs of cognitive impairment, administering cognitive tests, identifying appropriate referrals, and, in some cases, ordering blood-based biomarker testing. Although definitive testing and treatment identification may occur in the specialty care setting, in addition to serving as the hub to coordinate the multidisciplinary care team, primary care clinicians remain responsible for guiding patients and caregivers through shared decision-making regarding treatment, as well as the myriad responsibilities related to comorbidities, patient and caregiver psychological well-being, social support, and safety. This review aims to provide practical recommendations to primary care clinicians for the diagnosis, management, and long-term care of patients with AD.},
}

@article {pmid42404296,
year = {2026},
author = {You, X and Guo, Z},
title = {Multimodal Neuroimaging Mechanisms of Apathy in Alzheimer's Disease: A Narrative Review of Structural, Functional, and Molecular Evidence.},
journal = {International journal of general medicine},
volume = {19},
number = {},
pages = {622802},
pmid = {42404296},
issn = {1178-7074},
abstract = {Apathy is the most common neuropsychiatric symptom in Alzheimer's disease (AD) and is conceptualized as a pathological reduction of goal-directed motivation and behavior. It is currently believed that apathy has an independent neurobiological basis rather than merely accompanying cognitive decline. This narrative review synthesizes evidence from structural, functional, and molecular neuroimaging studies published up to 2025, identified through targeted PubMed searches and reference tracking, without applying formal systematic inclusion/exclusion criteria. Existing imaging evidence indicates that the core mechanism of apathy lies in the specific impairment of the prefrontal-basal ganglia motivational circuit: gray matter atrophy and hypometabolism in the anterior cingulate cortex (ACC) and orbitofrontal cortex are closely associated with impaired motivation integration and reward evaluation, whereas structural damage to the dorsolateral prefrontal cortex contributes to executive planning deficits. Functional network analysis further reveals suppression of the default mode network and ineffective compensation of the central executive network. Molecular imaging studies confirm that structural degeneration of the locus coeruleus, dopaminergic presynaptic transmission dysfunction, and synergistic pathological accumulation of amyloid-beta and Tau proteins in the motivational circuit collectively constitute the neurobiological basis of apathy. Furthermore, computational modeling has already been employed as an analytical framework to dissect these mechanisms, revealing altered effort-based decision-making and abnormal frontoparietal connectivity. Given the frequent impairment in self-awareness (anosognosia) regarding their own apathy in AD, informant-based assessments are essential for accurate clinical evaluation. Ultimately, integrating these multimodal biomarkers may facilitate early identification and stratified interventions, including dopaminergic and noradrenergic pharmacotherapies as well as non-invasive brain stimulation techniques such as transcranial magnetic stimulation (TMS).},
}

@article {pmid42404383,
year = {2026},
author = {Ramirez-Perez, N and Solis, I and Martinez, L and Bonillas Felix, N and Medrano, R and Ribas, A and Silva, GE and Martinez, JE and Giudicessi, A and Munera, D and Alcina, J and Vila-Castelar, C and Gonzalez Catalan, M and Ramirez-Gomez, LA and Saldana, D and Quiroz, YT},
title = {The Latin American Spanish PACC5 (LAS-PACC5): Advancing Cognitive Assessment in Latinos.},
journal = {Alzheimer's & dementia (Amsterdam, Netherlands)},
volume = {18},
number = {1},
pages = {e70311},
pmid = {42404383},
issn = {2352-8729},
abstract = {INTRODUCTION: To address the need for validated Spanish-language cognitive assessments in Latino populations at risk for Alzheimer's disease (AD), we evaluated the psychometric performance of a Latin American Spanish adaptation of the Preclinical Alzheimer's Cognitive Composite-5 (LAS-PACC5).

METHODS: A total of 121 Spanish-speaking older adults from the Boston Latino Aging Study (BLAST; Mean age = 64.98 ± 6.98 years; 69% female) were included. The LAS-PACC5 replaced literacy-dependent tasks with culturally and linguistically appropriate measures. Convergent validity was examined using measures validated in diverse Spanish-speaking populations.

RESULTS: LAS-PACC5 showed moderate associations with naming ability, episodic memory, and global cognition (all p's < 0.001) and differentiated cognitively unimpaired (n = 98) from impaired participants (n = 23; p = 0.005). Results were consistent across alternative cognitive classification approaches.

DISCUSSION: The LAS-PACC5 demonstrated convergent and discriminative validity, supporting its utility for early cognitive assessment in Spanish-speaking older adults and for improving Latino representation in AD Research.},
}

@article {pmid42404415,
year = {2025},
author = {Kazemi, S and Hesni Langroudi, N and Hasani Abharian, P and Tavakol, K and Joghataei, MT and Tavakol, S and Arbabi Bidgoli, S},
title = {Short-term Efficacy of Commercial Curcumin Nanomicelle on Cognition, Oxidative Stress and Choline Esterase in Alzheimer's Disease.},
journal = {Basic and clinical neuroscience},
volume = {16},
number = {3},
pages = {595-608},
pmid = {42404415},
issn = {2008-126X},
abstract = {INTRODUCTION: Alzheimer's disease (AD) is a progressive neurodegenerative disease accompanied by cognitive dysfunction. Preclinical changes can precede the onset of clinical symptoms by decades, highlighting the need for preventative and therapeutic strategies to mitigate or delay disease progression. This pilot clinical trial aimed to investigate the effects of commercially available curcumin nanomicelles on oxidative stress pathways and serum cholinesterase levels in patients with AD.

METHODS: Fifteen volunteers with mild-to-severe AD and 15 age-matched healthy controls were enrolled. Participants with AD received 80 mg of thermodynamically stable 10 nm curcumin nanomicelles on alternate days for two months. Cognitive function, as assessed by the mini-mental state examination (MMSE), did not exhibit significant changes in patients with AD following curcumin nanomicelle administration (19.8 versus 20.6). Serum levels of oxidative stress biomarkers, including catalase (CAT), superoxide dismutase (SOD) inhibition, malondialdehyde (MDA) concentration, and cholinesterase activity, were evaluated before and after intervention.

RESULTS: The results showed no significant differences in cognition improvement, CAT activity, SOD inhibition, MOD concentration, or cholinesterase activity between patients with AD and healthy controls or before and after curcumin nanomicelle administration.

CONCLUSION: Although curcumin nanocarriers did not enhance antioxidant biomolecule levels, they did not provoke lipid peroxidation. Therefore, this study suggests that optimizing nanocarrier parameters, including concentration, particle size larger than 10 nm, and blood-brain barrier (BBB)targeting, warrants further investigation in a long-term study to explore their potential as supplemental therapies for AD.},
}

@article {pmid42404420,
year = {2025},
author = {Zhang, P and Xiao, H},
title = {Vitis Vinifera L. Flavones Preserve Mitophagy in the Amyloid-beta 1-42-induced Model of Alzheimer's Disease Neurodegeneration.},
journal = {Basic and clinical neuroscience},
volume = {16},
number = {3},
pages = {641-656},
pmid = {42404420},
issn = {2008-126X},
abstract = {INTRODUCTION: Alzheimer's disease (AD) is a prevalent neurodegenerative disorder characterized by amyloid-beta (Aβ) accumulation, leading to inflammation, oxidative stress, and impaired synaptic function. This study aimed to investigate the neuroprotective mechanisms of Vitis vinifera L. flavones (VTF) against Aβ-induced neurodegeneration and their potential as AD therapeutics.

METHODS: In an in vitro analysis, Aβ1-42 oligomers were used to induce mitophagy in SHSY5Y neuroblastoma cells. Cells were treated with VTF alone and in combination with chloroquine (CQ), a lysosomal inhibitor, to assess Aβ1-42-induced mitophagy. Transmission electron microscopy (TEM) and immunofluorescence (IFC) were used to investigate the effects of Aβ1-42 on autophagosomes and deposition. Cellular protection against Aβ-induced damage was assessed using the Cell Counting Kit-8 (CCK-8) assay. Western blotting (WB) was used to determine the expression of autophagy-lysosomal pathway proteins (Beclin-1, Atg7, p62, and BACE1) and the LC3-II/LC3-I ratio, which serves as a marker of autophagy.

RESULTS: CQ and VTF demonstrated significant neuroprotection against Aβ1-42-induced neurodegeneration (P<0.05). VTF, alone or with CQ, increased viable cell count (~1.2-fold; P<0.05), indicating reparative capabilities. TEM and IFC showed robust protection by VTF and CQ against Aβ protein deposition, as well as preservation of mitochondrial and autophagosomal structures. VTF and CQ treatments reduced Beclin-1, Atg7, and BACE1 levels, indicating the modulation of mitophagy and autophagy-lysosomal suppression. VTF+CQ maintained LC3-II/LC3-I balance, confirming VTF's role in preserving autophagy (P<0.01).

CONCLUSION: This study reveals the novel neuroprotective role of VTF, emphasizing its potential as an AD therapeutic. Future research should extend investigations to in vivo models and clinical settings to enhance our understanding of VTF's neuroprotective efficacy.},
}

@article {pmid42404421,
year = {2025},
author = {Mansouri, Z and Motamedi, F and Khodagholi, F and Zahmatkesh, M},
title = {Histone Deacetylase Class IIb Inhibition Improves Amyloid-β-induced Learning and Memory Deficits in Male Rats.},
journal = {Basic and clinical neuroscience},
volume = {16},
number = {3},
pages = {583-594},
pmid = {42404421},
issn = {2008-126X},
abstract = {INTRODUCTION: Alzheimer's disease (AD) is a neurodegenerative disease associated with progressive impairment of cognitive function. The primary pathological features of AD include aggregation of amyloid-β (Aβ) and hyperphosphorylation of the tau protein. Histone deacetylases (HDACs) play a crucial role in the pathophysiology of neurodegenerative diseases. This study aimed to investigate the potential neuroprotective effects of HDAC6 and HDAC10 inhibition in a rodent model of AD.

METHODS: Learning and memory deficits were induced by bilateral intra-hippocampal Aβ injections in male Wistar rats. Tubacin (HDAC6 inhibitor) and bufexamac (HDAC6 and 10 inhibitors) were microinjected 30 minutes after Aβ injection. The possible molecular changes in the hippocampus following Aβ injection were also assessed by western blotting analysis of pCREB/CREB and Pp70/P70 ratios.

RESULTS: Our results revealed that bufexamac significantly recovered learning and memory impairments induced by Aβ in the Morris water maze (MWM) task. Tubacin improved memory decline without affecting learning. Bilateral intra-hippocampal injection of each of the HDAC inhibitors significantly increased the pCREB/CREB and Pp70/p70 ratios compared to the Aβ group, which was concurrent with behavioral alterations.

CONCLUSION: HDAC IIb treatment may be a promising strategy for improving learning and memory impairments in an animal model of AD, suggesting that HDAC targeting is a valuable strategy for further investigation.},
}

@article {pmid42404434,
year = {2026},
author = {Lao, PJ and Lee, S and Talmasov, D and Dass, D and Chikwem, N and Johnson, A and Smith, A and Guzman, D and Okafor, A and Houlihan, H and Heuer, L and Sanchez, T and Maldonado, A and Palacios, C and Rossano, S and Andrews, H and Reitz, C and Kreisl, WC and Noble, JM and Qureshi, YH and Small, SA},
title = {Inflammatory alterations mediate tau-associated neurodegeneration.},
journal = {Brain communications},
volume = {8},
number = {4},
pages = {fcag242},
pmid = {42404434},
issn = {2632-1297},
abstract = {Microglia monitor and respond to the brain's microenvironment to maintain homeostasis. However, in Alzheimer's disease and related dementias, chronically pro-inflammatory microglia may contribute to pathology. We hypothesized that inflammatory alterations, measured as microglia density via 18 kDa translocator PET, would be elevated with a topography similar to tau, be most strongly associated with tau compared to amyloid and neurodegeneration, and mediate pathways among amyloid, tau and neurodegeneration. Participants (21 cognitively unimpaired, 25 cognitively impaired) from the Longitudinal Imaging of Microglial Activation in Different Clinical Variants of Alzheimer's Disease study underwent baseline amyloid PET (Florbetaben standard uptake value ratio), tau PET (MK6240 standard uptake value ratio), 18 kDa translocator PET (ER176 standard uptake value ratio) and structural MRI (grey matter volume). Biomarkers were quantified in 13 a priori regions of interest. Cognitive assessments and consensus diagnoses were performed at the Columbia Alzheimer's Disease Research Center with biomarker information when available to define cognitive impairment. We evaluated cross-sectional regional colocalization of microglia density and amyloid, tau and neurodegeneration biomarker elevations in cognitively impaired individuals compared to amyloid-negative cognitively unimpaired individuals, microglia density associations with amyloid, tau and neurodegeneration biomarkers and microglia density mediation pathways among amyloid, tau and neurodegeneration. Exploratory analyses were stratified by amyloid positivity. Across all cognitively impaired individuals with different underlying brain microenvironments to which microglia are sensitive, higher microglia density colocalized with greater tau (10 regions) more often than with amyloid (8 regions) and neurodegeneration (4 regions), was associated with greater tau (β = 0.29-0.67 in cingulate, lingual and parietal regions) and neurodegeneration (β = -3.6 to -0.14 in limbic and medial temporal regions), and mediated tau-associated neurodegeneration (β = -0.44 to -0.26 in limbic, temporal and parietal regions). In the context of amyloid-positivity, microglia may also mediate amyloid-associated tau (β = 0.24-0.25 in parietal regions) and tau spreading (β = 0.09-0.12 across progressive Braak stage regions), whereas amyloid may not be necessary for tau-associated neurodegeneration, particularly in limbic regions (β = -0.46 to -0.37 in amyloid-negative individuals with cognitive impairment alone). Glia may represent a promising target for intervening on tau-associated neurodegeneration across individuals with cognitive impairment.},
}

@article {pmid42404763,
year = {2026},
author = {Wang, X and Piao, Y and Xia, B and Chu, W and Yao, X and Li, W},
title = {Diet, gut microbiota, and the gut-brain axis: mechanistic interactions and therapeutic implications in neuropsychiatric disorders.},
journal = {Frontiers in cellular and infection microbiology},
volume = {16},
number = {},
pages = {1834069},
pmid = {42404763},
issn = {2235-2988},
mesh = {Humans ; *Diet ; *Gastrointestinal Microbiome/physiology ; *Mental Disorders/therapy/microbiology ; *Brain ; Animals ; Dysbiosis ; *Brain-Gut Axis/physiology ; Probiotics/therapeutic use ; Fecal Microbiota Transplantation ; },
abstract = {The gut microbiota is a dynamic trans-kingdom ecosystem that contributes to host immunological, metabolic, and neuroendocrine homeostasis through the microbiota-gut-brain axis (MGBA). Diet is one of the major environmental factors shaping this axis, as it influences microbial composition, microbial production of neuroactive metabolites, and intestinal barrier integrity. Dysbiosis has been increasingly associated with neurological, psychiatric, and neurodevelopmental disorders, including Alzheimer's disease, Parkinson's disease, depression, autism spectrum disorder, and attention-deficit/hyperactivity disorder. Experimental studies have identified several potential mechanisms linking gut microbiota to brain function, including immune modulation, vagus nerve signaling, microbial metabolite production, and blood-brain barrier regulation. However, translating these findings into clinical practice remains challenging because human studies are affected by genetic heterogeneity, dietary variation, medication use, lifestyle factors, and disease-specific confounders. In this review, we summarize current evidence on the interactions among diet, gut microbiota, and brain function, with particular emphasis on microbial metabolites, immune mediators, and barrier-related mechanisms. We also critically discuss microbiota-targeted interventions, including precision nutrition, probiotics, and fecal microbiota transplantation, highlighting both their therapeutic potential and their current limitations. A more cautious and mechanistically integrated understanding of the MGBA may support the development of personalized strategies for neuropsychiatric disease prevention and management.},
}

Humans
*Diet
*Gastrointestinal Microbiome/physiology
*Mental Disorders/therapy/microbiology
*Brain
Animals
Dysbiosis
*Brain-Gut Axis/physiology
Probiotics/therapeutic use
Fecal Microbiota Transplantation

@article {pmid42404899,
year = {2026},
author = {Oh, SJ and Shin, OS and Hur, JY},
title = {From infection to dysfunction: viral triggers and antiviral immune factors in Alzheimer's disease pathology.},
journal = {Frontiers in immunology},
volume = {17},
number = {},
pages = {1839357},
pmid = {42404899},
issn = {1664-3224},
mesh = {Humans ; *Alzheimer Disease/immunology/pathology/virology ; Animals ; *Virus Diseases/immunology ; Brain/immunology/virology/pathology ; Host-Pathogen Interactions/immunology ; SARS-CoV-2/immunology ; },
abstract = {Neurodegenerative diseases and neurocognitive disorders increasingly appear to share a common and underappreciated contributor: the viral-immune axis in the brain. This review presents current evidence linking neurotropic viruses and host antiviral immunity to the onset and progression of neurodegeneration and neurocognitive dysfunction. We explore how viral infections, particularly by Herpesviruses, Severe Acute Respiratory Syndrome Coronavirus 2, and Human Immunodeficiency Virus, disrupt neural homeostasis through neuroinflammation, amyloidosis, tauopathy, and autophagy dysregulation in neurodegeneration including Alzheimer's disease (AD). Simultaneously, host antiviral mechanisms, including type I interferons and interferon regulatory factors, often amplify neuronal damage when dysregulated. By examining viral and immune interactions within the neurodegenerative diseases, this review aims to broaden our understanding of the viral-immune axis in the brain and inspire novel approaches to prevention and treatment.},
}

Humans
*Alzheimer Disease/immunology/pathology/virology
Animals
*Virus Diseases/immunology
Brain/immunology/virology/pathology
Host-Pathogen Interactions/immunology
SARS-CoV-2/immunology

@article {pmid42404903,
year = {2026},
author = {Guo, H and Yang, Z and Cheng, L},
title = {Cholinergic regulation of neuroinflammation: linking microglia, immunometabolism, and neuromodulation.},
journal = {Frontiers in immunology},
volume = {17},
number = {},
pages = {1837643},
pmid = {42404903},
issn = {1664-3224},
mesh = {Humans ; *Microglia/metabolism/immunology ; Animals ; *Neuroinflammatory Diseases/metabolism/immunology ; *Neuroimmunomodulation ; Signal Transduction ; Receptors, Cholinergic/metabolism ; },
abstract = {Neuroinflammation is increasingly recognized as a core pathological process in various neurological diseases, including neurodegenerative disorders, stroke, autoimmune demyelinating diseases, and acute brain dysfunction associated with systemic inflammation. Among its regulatory mechanisms, the cholinergic anti-inflammatory pathway links neural activity with immune regulation. However, its neurological relevance extends beyond the classical peripheral vagus nerve-mediated inflammatory reflex. Within the central nervous system, cholinergic signaling interacts with resident immune cells, particularly microglia, and influences inflammatory tone, neuronal vulnerability, and tissue repair. Recent advances in immunometabolism further suggest that metabolic reprogramming may bridge cholinergic signaling and microglial inflammatory phenotypes. In this review, we discuss the role of cholinergic regulation of neuroinflammation from three interrelated perspectives: microglia as the hub of core cells, immune metabolism as the basis of mechanism, and neural regulation as the frontier of transformation. We first reviewed the cholinergic system and its role in neuroimmune communication, then discussed how cholinergic signals shape microglial state and metabolic process, and finally evaluated its disease-specific evidence in Alzheimer's disease, Parkinson's disease, stroke, multiple sclerosis and acute inflammatory brain dysfunction. We will also discuss pharmacological and bioelectronic methods, including targeting cholinergic receptors and vagus nerve stimulation, as emerging therapeutic strategies. By integrating cholinergic biology, microglial heterogeneity, and metabolic reprogramming, this review proposes an updated framework for understanding neuroinflammation in neurology, and highlights the future opportunities for precise neuroimmune intervention.},
}

Humans
*Microglia/metabolism/immunology
Animals
*Neuroinflammatory Diseases/metabolism/immunology
*Neuroimmunomodulation
Signal Transduction
Receptors, Cholinergic/metabolism

@article {pmid42404994,
year = {2026},
author = {Gunasekaran, TI and Meena, D and Lee, AJ and Wu, S and Dumitrescu, L and Sperling, R and Hohman, TJ and Huang, J and , and , and Dehghan, A and Tzoulaki, I and Mayeux, R and Vardarajan, B},
title = {Common and rare variant analyses implicate JARID2 in cerebral tau deposition.},
journal = {NPJ dementia},
volume = {2},
number = {1},
pages = {52},
pmid = {42404994},
issn = {3005-1940},
abstract = {Genetic research on Alzheimer's disease (AD) has primarily focused on amyloid-β (Aβ), with fewer studies exploring tau pathology. We performed common variant GWAS on tau-PET SUVRs from A4 (n = 311 preclinical AD) and ADNI (n = 375 across diagnostic groups) cohorts. We complemented this with locus-specific rare variant analyses in 1561 individuals across five cohorts. Genetic findings were evaluated using circulating plasma proteins from the UK Biobank Pharma Proteomics Project (n = 54,129). Polygenic risk scores (PRS) for tau and amyloid-SUVR were tested for association with AD. GWAS identified two loci: rs78636169 (P = 5.76 × 10[-10]) in JARID2 and rs7292124 (P = 2.20 × 10[-8]) near ISX. Rare-variant analysis in JARID2 revealed chr6:15257832:A:G (P = 7.08 × 10[-05]) in harmonized analysis and chr6:15492808:C:T (P = 1.65 × 10[-09]) in rare-variant meta-analysis. Pleiotropy analyses suggested limited overlap between tau- and amyloid-related genetic signals. Gene-based analysis highlighted JARID2, a component of the PRC2 multi-protein complex. Mendelian randomization analysis identified LRRFIP1, a protein that binds with PRC2, as potentially causally linked to tau pathology. Amyloid-PRS, but not tau-PRS, was associated with AD clinical status, with age-dependent effects in APOE-ε4 carriers. Leveraging both GWAS and a large rare-variant cohort, we identified JARID2 as a candidate gene associated with tau pathology and observed patterns consistent with partially distinct roles of Aβ and tau in AD progression.},
}

@article {pmid42405563,
year = {2026},
author = {Riccioppo Rodrigues, G},
title = {Diluting the signal: Class-level pooling and the ecological fallacy in meta-analyses of anti-amyloid monoclonal antibodies.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877261467048},
doi = {10.1177/13872877261467048},
pmid = {42405563},
issn = {1875-8908},
abstract = {The recent Cochrane review of amyloid-β-targeting monoclonal antibodies concludes that future research on disease-modifying treatments for Alzheimer's disease should focus on alternative mechanisms. This conclusion rests on class-level pooling of nine pharmacologically heterogeneous agents, only three of which received FDA approval. This analytical decision commits an ecological fallacy at the drug level, diluting the signal of the agents that have modified clinical practice. This commentary situates the review within the broader literature, discusses the methodological origins of the error, and argues for stratified approaches that preserve clinical and regulatory relevance in syntheses of heterogeneous drug classes.},
}

@article {pmid42405963,
year = {2026},
author = {Williams, J},
title = {Correction: Are we fully exploiting genetic discoveries to understand and treat Alzheimer's disease?.},
journal = {Mammalian genome : official journal of the International Mammalian Genome Society},
volume = {37},
number = {1},
pages = {},
doi = {10.1007/s00335-026-10247-y},
pmid = {42405963},
issn = {1432-1777},
}

@article {pmid42406171,
year = {2026},
author = {Wu, H and Xia, J and Shi, Z and Zhang, C and Chen, S and Dai, L and He, L},
title = {Vorinostat Rescues Cognitive Deficits in a Neuroinflammatory Mouse Model: A Study of Sex Differences and the Underlying TLR4/NF-κB Mechanism.},
journal = {Neurochemical research},
volume = {51},
number = {4},
pages = {},
pmid = {42406171},
issn = {1573-6903},
mesh = {Animals ; *Toll-Like Receptor 4/metabolism ; Male ; *Vorinostat/therapeutic use/pharmacology ; Female ; *NF-kappa B/metabolism ; Mice, Inbred C57BL ; Mice ; *Neuroinflammatory Diseases/drug therapy/metabolism/chemically induced ; Lipopolysaccharides ; *Sex Characteristics ; *Cognitive Dysfunction/drug therapy/metabolism/chemically induced ; Signal Transduction/drug effects ; Microglia/drug effects/metabolism ; Neuroprotective Agents/therapeutic use/pharmacology ; Disease Models, Animal ; Hippocampus/drug effects/metabolism ; Histone Deacetylase Inhibitors/therapeutic use/pharmacology ; },
abstract = {With the acceleration of global aging, Alzheimer's disease (AD) poses a significant public health challenge, and effective treatments are still lacking. Neuroinflammation, particularly microglia-mediated inflammation, plays a central role in AD pathogenesis, with the Toll-like receptor 4 (TLR4)/nuclear factor-κB (NF-κB) signaling pathway being a key regulator. The histone deacetylase inhibitor (HDACi) Vorinostat (SAHA) has shown anti-inflammatory and neuroprotective potential in preclinical studies. Given the significant sex differences in AD incidence, pathology, and treatment response, this study aimed to systematically investigate the effects of SAHA on lipopolysaccharide (LPS)-induced neuroinflammation and cognitive dysfunction, analyzing its sex-specific effects and underlying mechanisms. An LPS-induced neuroinflammation model was established in male and female C57BL/6 mice via intraperitoneal injection (1 mg/kg) for 7 consecutive days, followed by SAHA (50 mg/kg) gavage intervention for 23 days. Cognitive function was assessed using Y-maze, novel object recognition, and passive avoidance tests. Hippocampal pathology was analyzed via hematoxylin-eosin (HE) staining and Nissl staining. Western blot and quantitative PCR (qPCR) were used to detect hippocampal expression of the TLR4/TRAF6/IKKα/NF-κB pathway, inflammatory factors (IL-6, IL-1β, TNF-α, iNOS), and neuroplasticity-related proteins (BDNF, p-CREB). In vitro experiments using LPS-stimulated BV2 microglia validated SAHA's anti-inflammatory mechanisms via CCK-8, Griess assay, qPCR, and Western blot. Results showed that LPS treatment significantly activated the TLR4/TRAF6/IKKα/NF-κB pathway, upregulated hippocampal pro-inflammatory factors, caused neuronal damage, and impaired learning and memory; these effects appeared more pronounced in female mice, though this observation is exploratory and requires cautious interpretation. SAHA treatment markedly alleviated LPS-induced inflammation, neuropathology, and cognitive deficits. Notably, SAHA appeared to produce differential effects across sexes: female mice showed potentially stronger and more comprehensive improvements in cognitive recovery, downregulation of inflammatory factors, and upregulation of BDNF and p-CREB compared to males, suggesting a possible sexually dimorphic response. In vitro experiments further confirmed that SAHA significantly reduced inflammation in LPS-stimulated BV2 microglia by inhibiting the TLR4/TRAF6/IKKα/NF-κB pathway. In conclusion, this study demonstrates that SAHA exerts neuroprotective effects by inhibiting the TLR4/NF-κB pathway, thereby improving cognitive impairment, and may have a more pronounced protective effect in females. These findings suggest SAHA is a promising drug for treating neuroinflammation-induced cognitive dysfunction and highlight the importance of considering sex as a biological variable in epigenetic therapy for precision medicine.},
}

Animals
*Toll-Like Receptor 4/metabolism
Male
*Vorinostat/therapeutic use/pharmacology
Female
*NF-kappa B/metabolism
Mice, Inbred C57BL
Mice
*Neuroinflammatory Diseases/drug therapy/metabolism/chemically induced
Lipopolysaccharides
*Sex Characteristics
*Cognitive Dysfunction/drug therapy/metabolism/chemically induced
Signal Transduction/drug effects
Microglia/drug effects/metabolism
Neuroprotective Agents/therapeutic use/pharmacology
Disease Models, Animal
Hippocampus/drug effects/metabolism
Histone Deacetylase Inhibitors/therapeutic use/pharmacology

@article {pmid42406197,
year = {2026},
author = {Saikat, SN and Siam, NH},
title = {Translational potential of medicinal plants for Alzheimer's disease: integrated evidence from molecular mechanisms to preclinical and clinical findings.},
journal = {Natural products and bioprospecting},
volume = {16},
number = {1},
pages = {},
pmid = {42406197},
issn = {2192-2195},
abstract = {Alzheimer's disease (AD) is a progressive neurodegenerative disorder driven by amyloid-β accumulation, tau hyperphosphorylation, oxidative stress, neuroinflammation, mitochondrial dysfunction, and cholinergic deficits. Despite extensive research, current FDA-approved therapies provide only modest symptomatic relief, underscoring the urgent need for safe and multi-targeted alternatives. This comprehensive review synthesizes evidence from in vitro, in vivo, and clinical studies on 15 medicinal plants and their 21 active compounds with therapeutic relevance to AD. Studies were included based on defined screening criteria: reported neuroprotective activity in at least one AD-related pathway, mechanistic evidence from preclinical or clinical investigations, and publication between 2015 and 2025. Analysis demonstrates that numerous plant extracts and isolated compounds including those from Allium sativum, Bacopa monnieri, Centella asiatica, Crocus sativus, Curcuma longa, Ginkgo biloba, Hericium erinaceus, Melissa officinalis, Nigella sativa, Salvia miltiorrhiza, Vitis vinifera, and others exert neuroprotective actions through convergent mechanisms. These include attenuation of oxidative and inflammatory pathways, inhibition of acetylcholinesterase and BACE-1, suppression of amyloid and tau pathology, enhancement of synaptic plasticity, mitochondrial support, and activation of neurotrophic signaling such as BDNF, TrkB and NRF2. Several compounds, including crocin, crocetin, curcumin, bilobalide, tanshinone IIA, bacosides, thymoquinone, and salvianolic acid B, demonstrate strong mechanistic activity across multiple AD-related pathways. Clinical trials further validate translational potential, with improvements reported in cognitive performance, behavioral symptoms, biomarker regulation, and daily functioning in individuals with mild cognitive impairment, AD, or age-related cognitive decline. Together, the evidence highlights medicinal plants as promising complementary or alternative strategies for modifying disease-relevant mechanisms and supporting cognitive health. Continued high-quality clinical investigations and optimized formulations are essential to advance these candidates toward therapeutic application.},
}

@article {pmid42406259,
year = {2026},
author = {Nguyen, TH and Nguyen, HNT and Pham, MQ and Phung, HTT},
title = {Tetrapeptide inhibitors of BACE-1 revealed by combined data-driven screening and physics-based free-energy refinement.},
journal = {Molecular diversity},
volume = {},
number = {},
pages = {},
pmid = {42406259},
issn = {1573-501X},
abstract = {Alzheimer's disease remains a major global health challenge, and β-site amyloid precursor protein cleaving enzyme 1 (BACE-1) represents a critical therapeutic target as it catalyzes the rate-limiting step in amyloid-β production. While computational studies have extensively explored small-molecule BACE-1 inhibitors, large-scale screening combined with physics-based refinement has rarely been applied to peptide scaffolds. Here, we report an integrated machine learning (ML)-to- free energy perturbation (FEP) pipeline, combining XGBoost-based screening, molecular docking, replicate explicit-solvent molecular dynamics (MD), and absolute FEP calculations, as a multi-stage alternative to single-scoring approaches for tetrapeptide lead discovery against BACE-1. Screening a library of 16,000 tetrapeptides with an XGBoost model prioritized four candidates (HWRE, HWER, WHRR, and HWRQ) for structure-based evaluation. Molecular docking confirmed favorable positioning within the catalytic cleft, while replicate MD simulations revealed multivalent binding through hydrogen bonds, salt bridges to the catalytic dyad (Asp32/Asp228), and hydrophobic contacts with conserved pocket residues; interaction-fingerprint and hotspot analyses provided residue-level guidance for optimization. FEP calculations delivered quantitative thermodynamic ranking, separating three strong predicted binders (HWRE, WHRR, HWRQ; ΔGFEP = - 29.45 to - 32.00 kcal mol[-1]) from the weaker candidate HWER (ΔGFEP = - 14.78 kcal mol[-1]). The three high-affinity peptides share a conserved H/W/R motif with persistent dyad anchoring and dense hydrogen-bond networks, a compact scaffold amenable to peptidomimetic optimization, with HWRE as the top lead across all computational stages. This study delivers experimentally testable tetrapeptide candidate inhibitors and establishes a scalable framework for peptide-based ligand discovery against BACE-1 and related aspartyl proteases.},
}

@article {pmid42406414,
year = {2026},
author = {Zhang, S and Qin, RZ and Ajisafe, MP and Qin, HL},
title = {Sulfonamides: a decade of development in synthetic methods and biological activity studies.},
journal = {Organic & biomolecular chemistry},
volume = {},
number = {},
pages = {},
doi = {10.1039/d6ob00639f},
pmid = {42406414},
issn = {1477-0539},
abstract = {Sulfonamides are privileged structural motifs widely found in bioactive molecules and pharmaceuticals, and their derivatives exhibit excellent structural diversity, a feature proven useful for discovering novel therapeutic agents. The development of novel sulfonamide-containing compounds with reduced toxicity, low production costs, and high potency constitutes a research focus in medicinal chemistry. Recent advances in sulfur dioxide insertion, reactions of sulfinate salts, transformation of thiols/disulfides, and sulfonyl precursor coupling have enabled efficient, green, and functional-group-tolerant synthesis of diverse sulfonamides. Moreover, the biological applications and structure-activity relationships of sulfonamides are comprehensively reviewed, including anti-diabetic, antimicrobial, anti-inflammatory, carbonic anhydrase inhibitory, anticancer, and anti-Alzheimer's disease activities, highlighting their critical roles in medicinal chemistry and drug development. In addition, FDA-approved drugs bearing the sulfonamide moiety over the past 50 years are also summarized. It is anticipated that this review will provide medicinal chemists with clear insights for the structural design and development of low-toxicity, high-potency sulfonamide-based drugs targeting numerous life-threatening diseases.},
}

@article {pmid42406507,
year = {2026},
author = {Rachmian-Cooper, N and Shmulevich, R and Akiva, H and Pokorna, S and Dassa, B and Cherqui, U and Malitsky, S and Itkin, M and Kliger, BA and Goliand, I and Salame, TM and Krizhanovsky, V},
title = {Senescent cells accumulate lipid droplets.},
journal = {Aging},
volume = {18},
number = {1},
pages = {768-786},
doi = {10.18632/aging.206390},
pmid = {42406507},
issn = {1945-4589},
mesh = {*Lipid Droplets/metabolism ; Animals ; Humans ; Microglia/metabolism ; *Cellular Senescence/physiology ; *Alzheimer Disease/metabolism/pathology ; Mice ; Fibroblasts/metabolism ; Lipid Metabolism ; Brain/metabolism/pathology ; Senescence-Associated Secretory Phenotype ; Disease Models, Animal ; },
abstract = {Senescent cells (SnCs) are growth-arrested yet remain metabolically active and undergo extensive reprogramming to support their survival and the Senescence-Associated Secretory Phenotype (SASP). SnCs undergo key metabolic changes, including increased glycolysis, altered mitochondrial function and dysregulated lipid metabolism. While these metabolic changes are increasingly recognized, a comprehensive understanding of how they contribute to the pathophysiological effects of SnCs is still lacking. Here, through metabolic profiling, we identified elevated levels of glycolytic metabolites in SnCs, which coincided with an increased presence of lipid metabolites, specifically triacylglycerol derivatives, the precursors of lipid droplets (LDs). We show that SnCs accumulate LDs in a classical primary human fibroblast model, and that senescent microglia upregulate LDs markers in a mouse model of Alzheimer's disease (AD), where they play a pathological role. Single-nucleus analysis of brains from AD patients further revealed an elevated levels of LDs markers in senescent brain cells, including microglia. Previous studies implicated both lipid droplet-containing microglia and senescent microglia in AD pathology. Our findings provide evidence that these may represent the same cell population, in which the co-occurrence of LDs accumulation and the senescent state jointly contribute to their disease-promoting properties.},
}

*Lipid Droplets/metabolism
Animals
Humans
Microglia/metabolism
*Cellular Senescence/physiology
*Alzheimer Disease/metabolism/pathology
Mice
Fibroblasts/metabolism
Lipid Metabolism
Brain/metabolism/pathology
Senescence-Associated Secretory Phenotype
Disease Models, Animal

@article {pmid42406553,
year = {2026},
author = {Wen, S and Gao, J and Wang, Z and Ma, Q and Xu, XL and Chen, J},
title = {EphB1-Mediated Transient Blood-Brain Barrier Opening Facilitates a Ferritin-Based Nanotherapeutic for Alzheimer's Disease.},
journal = {Advanced science (Weinheim, Baden-Wurttemberg, Germany)},
volume = {},
number = {},
pages = {e76480},
doi = {10.1002/advs.76480},
pmid = {42406553},
issn = {2198-3844},
support = {ZKJC2203//Zhejiang Rehabilitation Medical Center/ ; ZKXK02//Zhejiang Rehabilitation Medical Center/ ; 2021C03050//Development Program of Zhejiang Province/ ; 82372109//National Natural Science Foundation of China/ ; },
abstract = {The treatment of Alzheimer's disease (AD) is severely hampered by the blood-brain barrier (BBB), which limits the delivery of therapeutic agents like donepezil (DPZ), an acetylcholinesterase inhibitor. While DPZ has multi-faceted benefits, its clinical efficacy is constrained by poor BBB penetration, requiring high doses that lead to significant side effects. To overcome this, we developed a brain-targeted nanotherapeutic utilizing apoferritin (AFn) nanoparticles loaded with DPZ (AFn-DPZ). We demonstrate that this platform, by binding to the EphB1 receptor on the blood-brain barrier, enables transient and reversible opening of the blood-brain barrier, thereby facilitating efficient and targeted drug delivery. Following intravenous administration in an AD mouse model, AFn-DPZ exhibited enhanced brain accumulation and sustained release of DPZ. This targeted delivery inhibited acetylcholinesterase activity, reduced amyloid plaque burden, alleviated neuroinflammation, attenuated oxidative damage, restored mitochondrial function, and upregulated the expression of brain-derived neurotrophic factor (BDNF). Consequently, AFn-DPZ treatment significantly improved cognitive performance compared to free DPZ. Our findings establish EphB1-mediated facilitation of BBB traversal as a promising strategy for enhancing nanotherapeutic delivery to the brain, offering a potent approach to address the complex pathology of AD.},
}

@article {pmid42406649,
year = {2026},
author = {Zawadzki, S and Okła, E and Michlewska, S and Bednarek, R and Ortega López, P and de la Mata, FJ and Jansons, J and Skrastina, D and Kreišmane, M and Piļipenko, V and Jansone, B and Ionov, M and Bryszewska, M and Miłowska, K},
title = {Tiered Evaluation of Carbosilane Dendrimer-siRNA Nanoplatform from Single-Cell Biocompatibility to Blood-Brain Barrier Model Dynamics and Murine Alzheimer Model Behavior Assessment.},
journal = {ACS applied materials & interfaces},
volume = {},
number = {},
pages = {},
doi = {10.1021/acsami.6c06099},
pmid = {42406649},
issn = {1944-8252},
abstract = {Blood-brain barrier (BBB) transport remains a primary constraint on achieving predictable central nervous system exposure for Alzheimer's disease (AD) therapeutics, motivating the evaluation of delivery platforms with barrier-resolved and functionally relevant end points. We assessed a carbosilane dendrimer (G3Si PEG6000) and its siRNA dendriplex using a tiered, upstream strategy spanning cell internalization, DNA damage screening, BBB model integrity and permeability, and in vivo AD-relevant murine model learning. At the cellular level, the dendrimer enhanced intracellular siRNA-associated signal with predominantly cytoplasmic localization, and siRNA complexation attenuated genotoxicity relative to the noncomplexed carrier. In a BBB triculture model, barrier function was preserved without sustained transendothelial electrical resistance (TEER) loss, and complementary tracer flux readouts showed time- and formulation-dependent, nonmonotonic changes, including TEER-permeability decoupling consistent with nonuniform perturbation and time-dependent changes in barrier-associated paracellular responses. In APOE4 knock-in mice, dendriplex treatment increased platform-zone crossings in the Morris Water Maze probe trial, whereas target-quadrant time showed only a modest, nonsignificant trend. Collectively, these integrated results indicate that siRNA complexation improves the BBB-relevant safety-performance balance of G3Si PEG6000 and supports further studies that directly link brain exposure and target engagement to cognitive outcomes.},
}

@article {pmid42399965,
year = {2026},
author = {Bell, TR and Franz, CE and Fennema-Notestine, C and Sundermann, EE and Hughes, SB and Panizzon, MS and Lerman, I and Elman, JA and Kremen, WS},
title = {Chronic pain as a risk factor for Alzheimer's disease pathology: a longitudinal ADNI study.},
journal = {Alzheimer's research & therapy},
volume = {},
number = {},
pages = {},
doi = {10.1186/s13195-026-02137-x},
pmid = {42399965},
issn = {1758-9193},
support = {K01AG081559/AG/NIA NIH HHS/United States ; K01AG063805/AG/NIA NIH HHS/United States ; R01AG050595/AG/NIA NIH HHS/United States ; },
abstract = {BACKGROUND: Growing evidence supports chronic pain (CP) as a risk factor for Alzheimer's disease and Alzheimer's disease-related dementias (AD/ADRD). We examined whether CP is associated with longitudinal worsening of AD-related biomarkers, brain structure, and cognition, and whether effects differ by APOE-ε4 status.

METHODS: Data were drawn from 1,493 participants in the Alzheimer's Disease Neuroimaging Initiative (ADNI) without baseline dementia (mean age = 72.4 ± 7.19 years; 48% female). Linear mixed-effects models tested longitudinal change in cerebrospinal fluid (CSF) and positron emission tomography (PET) amyloid-β (Aβ) and phosphorylated tau (p-tau181), structural MRI indices (AD-related cortical signature, hippocampal and entorhinal volumes, precuneus thickness), and cognitive outcomes (episodic memory, executive function, Mini-Mental State Examination [MMSE]). Models included fixed effects of CP status, APOE-ε4 status, time (years since baseline), and their two-way and three-way interactions, adjusting for age, sex, education, baseline Aβ positivity status, and time-varying depressive symptoms.

RESULTS: At baseline, 30% of participants (n = 452) reported CP and 45% (n = 666) were APOE-ε4 carriers. CP and APOE-ε4 status did not independently predict baseline CSF Aβ42/Aβ40, PET Aβ burden, or CSF p-tau181. Longitudinally, the CP+/ε4 + group showed greater AD-like changes in CSF Aβ42/Aβ40 and CSF p-tau181, thinning of the precuneus (β=-0.09, p<.001) and faster decline in episodic memory (β=-0.08, p<.001), compared to all other groups. Many of these associations remained when excluding participants with MCI or restricting to Aβ-negative participants.

CONCLUSIONS: The combination of CP and APOE-ε4 carriership was associated with greater longitudinal worsening of brain structure and cognitive function, even among individuals who were Aβ-negative at baseline. These findings provide in vivo evidence that CP is associated with greater AD-related worsening over time in the context of genetic susceptibility. As evidence accumulates, CP may warrant recognition as a risk factor in dementia prevention frameworks, though causal inferences require further study.},
}

@article {pmid42399983,
year = {2026},
author = {Bavarsad, MS and Pereira, FL and Reinhardt, MM and Satpati, A and Spina, S and Seeley, WW and Jagust, W and Rabinovici, GD and Green, A and Grinberg, LT},
title = {Regional mapping of CSF1R-positive microglia in neurodegenerative diseases and progressive MS, with exploratory presynaptic marker analyses.},
journal = {Journal of neuroinflammation},
volume = {},
number = {},
pages = {},
doi = {10.1186/s12974-026-03945-6},
pmid = {42399983},
issn = {1742-2094},
abstract = {BACKGROUND: Microglial colony-stimulating factor-1 receptor (CSF1R) is a therapeutic and imaging target, yet the regional, disease-specific distribution of CSF1R-positive microglia in the human brain remains incompletely defined, limiting interpretation of emerging CSF1R-PET signals. We sought to build a cross-disease, multi-region, quantitative map of CSF1R-positive microglia in neurodegenerative conditions and progressive multiple sclerosis (MS) lesions, with an exploratory comparison to presynaptic marker burden.

METHODS: CSF1R mRNA‑positive microglia were quantified by RNAscope across six cortical regions (MFG, IFG, ITG, AG, CA1, EC) in early‑onset Alzheimer's disease (EOAD), late‑onset AD (LOAD), progressive supranuclear palsy (PSP), and frontotemporal lobar degeneration with TDP-43 inclusions due to progranulin mutation (FTLD‑GRN), and in primary and secondary progressive MS (PPMS, SPMS) within cortical gray‑matter plaques, plaque-adjacent gray matter and white matter. Positivity was defined a priori as ≥ 3 puncta with housekeeping‑probe pass and negative‑control verification, counting blinded, and densities were cortical‑thickness corrected. Iba-1 immunolabeling verified microglial identity. Western blot provided protein‑level verification. We explored ROI‑level associations of CSF1R with SV2A and synaptophysin previously measured in the same regions/cases.

RESULTS: In neurodegeneration, increases were smaller and region‑specific (e.g., EOAD-ITG/CA1; LOAD-AG; PSP-AG; FTLD‑GRN-IFG/ITG/AG/EC), with minimal white‑matter change. In progressive MS, gray-matter CSF1R-positive microglia densities did not differ from controls, whereas SPMS white matter was increased. Exploratory analysis showed that CSF1R and SV2A were positively associated across ROIs in neurodegenerative diseases (e.g., PSP approximately ρ = 0.66), and weakest in LOAD; synaptophysin showed similar patterns, suggesting that regions with higher CSF1R-positive microglia density can coincide with relative preservation of presynaptic markers.

CONCLUSIONS: A cross‑disease, region‑resolved map reveals region‑specific changes in CSF1R + cell density in neurodegeneration, but only white matter in MS. These findings provide the histological context needed to interpret future CSF1R‑PET. Prospective studies pairing CSF1R‑PET with SV2A‑PET and multiplex tissue profiling are warranted to define microglial states and synaptic outcomes in vivo.},
}

@article {pmid42400072,
year = {2026},
author = {Keller-Norrell, PR and Casali, BT and Yost, LN and Reed, EG},
title = {Neonatal estradiol influences regional gene expression for early sex-specific inflammatory responses in the 5xFAD mouse model.},
journal = {Biology of sex differences},
volume = {},
number = {},
pages = {},
doi = {10.1186/s13293-026-00948-z},
pmid = {42400072},
issn = {2042-6410},
support = {R01AG075897/AG/NIA NIH HHS/United States ; A2021036S//BrightFocus Foundation/ ; Institutional Funding//Northeast Ohio Medical University/ ; },
abstract = {BACKGROUND: Alzheimer's disease (AD), the most prevalent form of dementia, exhibits a strong sex bias, with women comprising two-thirds of all patients, for reasons that remain unclear. Microglia, as the brain's resident immune cell, are key players in AD pathogenesis and are increasingly understood as being sex-specific. However, the mechanisms underlying these differences, and how they may in turn contribute to distinct pathogenesis has not been well examined. Therefore, this study aimed to investigate the organizational role of neonatal estradiol (E2) in early-life sex-patterning of microglia for disease onset and progression.

METHODS: We assessed the effect of neonatal estradiol exposure on microglial and neuronal density, microgliosis, and gene expression related to microglial identity and responses using immunohistochemistry, qPCR, and ProteinSimple Jess on-capillary immunoblotting.

RESULTS: We find neonatal estradiol administration influences the expression of genes and proteins involved in inflammation and X chromosome inactivation, without affecting cellular composition of the cortex and hippocampus. Additionally, we observed genotype-dependent changes to the female reproductive cycle in E2 treated 5xFAD females.

CONCLUSIONS: Overall, the results of the present study provide novel insight into the role of steroid sex hormones in neonatal microglial programing, and how this programming may set the stage for further sex- and disease-linked alterations later in life.},
}

@article {pmid42400119,
year = {2026},
author = {Choudhary, HH and Yoshida, J and Islam, R and Wang, Z and Hanafy, KA},
title = {EXPRESS: Toll Like Receptor 4 (TLR4) in Neuroinflammation: From Acute Hemorrhagic Stroke to Chronic Neurodegeneration.},
journal = {Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism},
volume = {},
number = {},
pages = {271678X261468877},
doi = {10.1177/0271678X261468877},
pmid = {42400119},
issn = {1559-7016},
abstract = {Subarachnoid Hemorrhage (SAH) remains a leading cause of morbidity and mortality worldwide. While the primary injury is defined by mechanical tissue disruption, the progression of secondary brain injury is largely driven by robust neuroinflammatory cascades initiated by blood derived damage-associated molecular patterns (DAMPs). Among the key mediators of this response, Toll-like receptor 4 (TLR4) has emerged as a central regulator. TLR4 activation in microglia triggers downstream signaling through both MyD88 dependent and TRIF dependent pathways, driving the production of pro inflammatory cytokines and type I interferons. Additionally, non-canonical regulation of TLR4 by Lyn kinase introduces a critical modulatory mechanism that can shift microglial responses between inflammatory and phagocytic phenotypes in a sex dependent manner. Beyond hemorrhagic stroke, TLR4 mediated neuroinflammation also plays a significant role in the progression of Alzheimer's disease, where it influences amyloid-β recognition, clearance, and chronic glial activation. Emerging therapeutic strategies targeting TLR4 and its downstream signaling components including small molecules, natural compounds, aptamers, and TLR4-Lyn interaction modulators demonstrate promising potential in attenuating neuroinflammation and improving neurological outcomes. This review highlights the molecular mechanisms of TLR4 signaling in neuroinflammation and underscores its translational relevance as a therapeutic target in both acute and chronic neurodegenerative conditions.},
}

@article {pmid42398643,
year = {2026},
author = {Başoğlu, H and Göçmen, AY and Yiğit, E and Aydin-Abidin, S and Uydu, HA and Öztürk, H and Keser, H and Abidin, İ},
title = {Cortical Cholesterol Deficit and Reduced Network Excitability in ApoE-Deficient Mice.},
journal = {Archives of biochemistry and biophysics},
volume = {},
number = {},
pages = {110921},
doi = {10.1016/j.abb.2026.110921},
pmid = {42398643},
issn = {1096-0384},
abstract = {Apolipoprotein E (ApoE) is a key regulator of cholesterol transport in both the periphery and the central nervous system and is the major genetic risk factor for late-onset Alzheimer's disease. Although ApoE deficiency is known to elevate circulating cholesterol levels, its consequences for brain cholesterol homeostasis, synaptic integrity, and cortical network excitability remain incompletely understood. In the present study, ApoE knockout (ApoE[-]/[-]) and wild-type (WT) mice were used to evaluate systemic and brain cholesterol levels, synaptic protein expression, and cortical electrophysiological activity. ApoE deficiency resulted in significantly elevated serum cholesterol levels compared with wild-type mice. In contrast, cortical cholesterol levels were significantly reduced in ApoE[-]/[-] mice, whereas hippocampal cholesterol levels remained unchanged. Consistent with altered cortical lipid homeostasis, synaptophysin (SYP) and postsynaptic density protein-95 (PSD-95) levels were significantly decreased in ApoE-deficient animals. At the functional level, ApoE deficiency was associated with reduced basal cortical network activity, reflected by lower electrocorticographic (ECoG) power. Moreover, pharmacological excitation with 4-aminopyridine (4-AP) produced a markedly attenuated increase in cortical excitability in ApoE-deficient mice. Inflammatory markers, tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6), showed no differences between WT and ApoE[-]/[-] mice. Similarly, oxidative stress markers measured in cortex and hippocampus did not indicate a consistent increase in oxidative damage. These findings demonstrate that ApoE deficiency is associated with a multilevel disruption characterized by elevated peripheral cholesterol, reduced cortical cholesterol availability, synaptic protein loss, and diminished cortical network excitability under both basal and hyperexcitable conditions. The results highlight a potential link between impaired brain cholesterol homeostasis and altered synaptic network function in the cortex of ApoE-deficient mice.},
}

@article {pmid42398685,
year = {2026},
author = {Tang, Y and Huang, L and Li, W and Gao, T and Shi, N and Zhu, Y and Wang, Y and Nan, J and Zhu, Y and Li, J and Ma, Y},
title = {Efficacy of Non-Invasive Brain Stimulation in Alzheimer's Disease: An Umbrella Review of Meta-Analyses.},
journal = {Neuroscience and biobehavioral reviews},
volume = {},
number = {},
pages = {106844},
doi = {10.1016/j.neubiorev.2026.106844},
pmid = {42398685},
issn = {1873-7528},
abstract = {This umbrella review integrates systematic reviews and meta-analyses to evaluate the efficacy of non-invasive brain stimulation (NIBS) in Alzheimer's disease (AD). We searched seven databases from inception to 20 June 2025 for relevant literature. Effect sizes and 95% confidence intervals were extracted using a structured approach and visualized through effect size heatmaps and evidence mapping. Methodological quality and evidence certainty were assessed using AMSTAR 2 and GRADE, respectively. A total of 42 publications, encompassing 130 primary studies and 5,771 patients, were included. NIBS yielded significant immediate improvements in global cognition, daily living, neuropsychiatric symptoms, memory, language, executive function, global impression, visuospatial function, and cholinergic transmission. Among 119 outcome associations, 57.1% were statistically significant (p < 0.05). Long-term benefits were sustained only in global cognition. Moreover, these techniques exhibited modality-specific effects on cognitive and clinical outcomes. Subgroup analysis identified repetitive transcranial magnetic stimulation (rTMS) as the most effective technique, supported by 16 moderate- to high-quality associations. Transcranial direct current stimulation (tDCS) showed inconsistent results with only three moderate-quality associations, while transcranial alternating current stimulation (tACS) demonstrated potential but limited evidence. Intermittent theta burst stimulation (iTBS) showed no significant cognitive benefits in the limited available evidence. Available safety evidence, though limited, suggests generally mild and transient adverse effects. NIBS, particularly rTMS, shows therapeutic potential for AD, though this is based on preliminary evidence. Future multicenter long-term studies and standardized protocols are needed to facilitate the precise application of NIBS in AD treatment.},
}

@article {pmid42398763,
year = {2026},
author = {Busse, PJ and Brown, ES and Wisnivesky, J and Federman, A and Busse, WW},
title = {Impact of cognitive impairment and depression on asthma in older patients.},
journal = {The journal of allergy and clinical immunology. In practice},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.jaip.2026.06.037},
pmid = {42398763},
issn = {2213-2201},
abstract = {Depression and cognitive decline in older adults with asthma are associated with poorer disease control, increased risks for exacerbations, higher healthcare utilization, and greater mortality risk. In this age group, depression and cognitive impairment also negatively impact self-management behaviors and alter perception of asthma symptoms. Conversely, data suggest that in some individuals, asthma can induce depression and cognitive deficits, increasing the risk of dementia, including Alzheimer's disease. Because there is a bidirectional communication between the lungs and brain, asthma, particularly in the aged, may result in functional and structural changes of the central nervous system. Identifying and addressing depression and cognitive decline in older patients is often insufficiently integrated into clinical practice. Asthma in the aged is a distinctive phenotype and is complicated by increased risks for depression and loss of cognition, which collectively compromise management.},
}

@article {pmid42398801,
year = {2026},
author = {Zhang, W and Wang, Y and Tocci, D and Wang, C and Zhang, C},
title = {HDAC11 as a potential therapeutic target for Alzheimer's disease.},
journal = {Drug discovery today},
volume = {},
number = {},
pages = {104730},
doi = {10.1016/j.drudis.2026.104730},
pmid = {42398801},
issn = {1878-5832},
abstract = {Alzheimer's disease (AD) is the leading cause of dementia. It is characterized by amyloid and tau pathological hallmarks, accompanied by synaptic dysfunction, neuroinflammation, and progressive neuronal loss. Although amyloid-reducing antibodies have recently expanded the disease-modifying therapeutic options, no disease-modifying small-molecule therapeutics are currently available for AD. Epigenetic regulators, particularly histone deacetylases (HDACs), have attracted increasing attention as potential therapeutic targets. Among them, HDAC2, 3 and 6 are supported by broad AD-related evidence, whereas HDAC11 has emerged as a mechanistically distinct potential target. As the sole class IV HDAC and a relatively brain-enriched but not brain-specific lysine defatty-acylase, HDAC11 connects lipid metabolism, innate immunity, microglial function, neuroinflammation, and AD-associated pathology. We discuss advances in HDAC11 biology and AD-related pathology, position HDAC11 among other established AD-relevant HDAC isoforms, and discuss progress relating to HDAC11-selective inhibitors. We pay particular attention to target druggability, chemical probe development, blood-brain barrier penetration, pharmacokinetics, safety and off-target liabilities, and translational promise. In summary, HDAC11 is an emerging therapeutic target in AD, but future studies are needed for chemical optimization, for pathological validation using other disease models, and to show safety and efficacy in the AD context.},
}

@article {pmid42398843,
year = {2026},
author = {Guan, L and Lin, M and Zhang, R and Shao, X and Chen, B and Yang, J and Zhao, Z and Huang, P},
title = {Segmentation of the parasagittal dura mater on multi-center 3D-FLAIR MRI.},
journal = {NeuroImage},
volume = {},
number = {},
pages = {122099},
doi = {10.1016/j.neuroimage.2026.122099},
pmid = {42398843},
issn = {1095-9572},
abstract = {The parasagittal dura (PSD), located bilaterally alongside the superior sagittal sinus (SSS), has been increasingly implicated in cerebrospinal fluid-meningeal lymphatic communication, contributing to CSF waste clearance and immune surveillance. We assembled a training set of 55 3D-Fluid-Attenuated Inversion Recovery (3D-FLAIR) scans from Alzheimer's Disease Neuroimaging Initiative(ADNI) and local datasets to train an nnU-Net-based model for automated PSD segmentation (mcPSD-Net). Segmentation performance was assessed against manual ground truth in an independent test set (N=25) containing images acquired from various scanners. Three voxel overlap metrics (DICE, Precision and Recall) and three surface distance metrics (HD, HD95, ASSD) were used to evaluate the accuracy of the mcPSD-Net. Multiple linear regression models were performed to evaluate the associations of PSD volume (normalized by intracranial volume) with age, and sex in the whole ADNI3 dataset and a local community dataset. In the testing dataset, mcPSD-Net achieved good performance (Dice coefficient=0.76; precision=0.84; recall=0.73; HD=21.42mm; HD95=4.00mm; ASSD=0.53mm). Regression analyses demonstrated that PSD volume increased significantly with age in both the ADNI3 (standardized β = 0. 390, p<0.001) and local community dataset (standardized β = 0. 307, p<0.001). Compared to females, males had a significantly larger PSD volume in both datasets (p<0.001 for all). Furthermore, including scanner vendor as a covariate did not improve model fitting in the ADNI3 dataset. In summary, we developed a deep learning model that segments PSD from 3D-FLAIR images acquired using different vendors and imaging protocols, providing a tool for related clinical imaging studies.},
}

@article {pmid42398884,
year = {2026},
author = {Turkelson, A and Ng, YT and Garabedian, R and Gonzalez, R and Benson, L and Birditt, KS},
title = {Your Heart Beats Next To Mine: Daily Physiological Synchrony Among Black And White ADRD Caregiver-Care Recipient Dyads.},
journal = {Biological psychology},
volume = {},
number = {},
pages = {109341},
doi = {10.1016/j.biopsycho.2026.109341},
pmid = {42398884},
issn = {1873-6246},
abstract = {Close relationships are often physiologically synchronous, showing correlated changes in cardiovascular reactivity that vary by relationship quality and predict well-being. Little is known about physiological synchrony among dementia caregiver-care recipient dyads, which may be impacted by the chronic strain of caregiving and functional declines due to dementia. The present study examined physiological synchrony among caregivers and care recipients in daily life using heart rate data and whether synchrony varied by interpersonal tensions, relationship type, and race. A total of 148 Alzheimer's disease and related dementia (ADRD) caregivers (ages 22 to 86; 27% Black; 79% female; 63% spousal caregivers) and their care recipients participated in a 5-day ecological momentary assessment study in which caregivers completed mobile phone surveys every three hours, six times per day, and both caregivers and care recipients wore mobile heart rate monitors 24hours per day. Stability and influence models revealed that caregivers and care recipients were physiologically synchronous in daily life (i.e., past moment heart rate of one dyad member was associated with current moment heart rate of the other dyad member). Physiological synchrony was stronger for spousal and White caregiver dyads, particularly during periods of higher interpersonal tension, whereas Black caregiver dyads exhibited physiological synchrony during periods of lower interpersonal tension. This study adds to the growing literature on physiological synchrony by examining an understudied interpersonal context of dementia caregiving in a diverse sample. Implications of these findings for interventions among ADRD caregiving dyads are discussed.},
}

@article {pmid42398889,
year = {2026},
author = {Musaeus, CS and Waldemar, G and Kjær, TW and Andersen, BB and Høgh, P and Kidmose, P and Fabricius, M and Hribljan, MC and Hemmsen, MC and Rank, ML and Frederiksen, KS},
title = {Epileptiform discharges are associated with increased theta activity over time in patients with Lewy body dementia.},
journal = {Neuroscience},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.neuroscience.2026.06.040},
pmid = {42398889},
issn = {1873-7544},
abstract = {Electroencephalography (EEG) slowing and reduced functional connectivity are markers of Alzheimer's disease (AD) and Lewy body dementia (DLB), but the significance of epileptiform discharges to these changes remains unknown. To investigate whether epileptiform discharges are associated with EEG slowing or decreased functional connectivity over time. In this longitudinal observational exploratory study, we included a total of 15 healthy controls, 25 patients with AD, and 10 patients with DLB. The patients underwent conventional resting-state EEG up to three times over 6 months. A baseline ear-EEG recording was used to quantify the number of epileptiform discharges per 24 h. We found that compared to healthy controls, DLB and AD patient groups showed a pattern of slowing and decreased alpha coherence. Epileptiform discharges were not associated with slowing or coherence at baseline. In longitudinal analyses, patients with DLB and epileptiform discharges demonstrated an increase in relative theta power over six months compared with patients with DLB without epileptiform discharges. No significant longitudinal theta-power changes were observed in patients with AD. These findings suggest that while EEG slowing is a characteristic feature of neurodegenerative diseases, epileptiform discharges are not directly associated with baseline EEG theta activity but may be linked to a distinct longitudinal trajectory of theta activity in DLB. Given the small group sizes and unbalanced subgroups analysis, these observations should be considered exploratory and require confirmation in larger longitudinal studies.},
}

@article {pmid42399261,
year = {2026},
author = {Bergendorf, A and Park, JH and Ball, BK and Brubaker, DK},
title = {Modeling single nucleus microglia across species identifies immune pathways and therapeutic candidates in Alzheimer's disease.},
journal = {NPJ systems biology and applications},
volume = {},
number = {},
pages = {},
doi = {10.1038/s41540-026-00775-3},
pmid = {42399261},
issn = {2056-7189},
support = {DGE-1842166//National Science Foundation Graduate Research Fellowship Program/ ; NIH T32 predoctoral fellowship T32DK101001/DK/NIDDK NIH HHS/United States ; },
abstract = {Alzheimer's disease (AD) is a progressive neurodegenerative disease characterized by memory loss and behavioral changes. A pivotal influence on AD pathology is the dysregulation of microglia in the brain. Despite promising findings in mouse models, there are limitations to the translatable biological information across species due to differences in the physiology, timeline of disease, and human heterogeneity. To address these interspecies discrepancies, we developed a novel implementation of the Translatable Components Regression (TransComp-R) framework, which integrated microglial single-nucleus transcriptomic data to identify biological pathways in mice AD models predictive of human AD. We compared model variations with sparse and traditional principal component analysis (PCA), finding that standard PCA encoded more interpretable mouse PCs compared to sPCA despite limited differences in technical performance. Mouse PCs significantly differentiated human AD from control microglial cells in the BA41/42, BA6/8, hippocampus and entorhinal cortex brain regions. However, these PCs had limited separation of human AD from control microglia in the prefrontal cortex. Additionally, we identified gene signatures from FDA-approved drugs that correlated with significant mouse component loadings, including valproic-acid and calcifediol. This computational framework may support the discovery of cross-species disease similarities, including the identification of candidate pharmacological solutions that may translate across species.},
}

@article {pmid42399299,
year = {2026},
author = {Kang, EH and Choi, SR and Shin, A and Han, M and Lee, EB},
title = {Anemia and risk of dementia in the general population: a propensity-score based cohort study.},
journal = {Scientific reports},
volume = {},
number = {},
pages = {},
doi = {10.1038/s41598-026-57471-9},
pmid = {42399299},
issn = {2045-2322},
support = {#18-2022-0005//Seoul National University Graduate School of Convergence Science and Technology/ ; RS-2025-02215880//Korea Health Industry Development Institute/Republic of Korea ; },
abstract = {An elevated risk of dementia among anemic population has been reported in previous studies. However, measurement on the risk of individual subtypes of dementia has been limited. We aimed to quantify risk of dementia and its subtypes in the general population with anemia, using Korean National Health Insurance Service data linked to biennial national health check-ups. We conducted a cohort study on propensity-score fine-stratification (PSS)-weighted 50,008 anemic and 992,497 non-anemic participants aged ≥ 60 years who underwent three consecutive check-ups during 2006-2011. Anemia was defined as hemoglobin levels (Hb) <12 g/dL (females) or < 13 g/dL (males) and non-anemia as levels above the cut-offs at all three check-ups, requiring chronicity of low Hb. The primary outcome was incident dementia. Secondary outcomes included Alzheimer's disease (AD) and vascular dementia (VD). We estimated PSS-weighted hazard ratios (HRs) and 95% confidence intervals (CIs) using Cox models. Dose-responsive (Hb ≥ 10 g/dL as mild, < 10 g/dL as moderate-to-severe) and subgroup (age, sex, income, diabetes, and cardiovascular disease at baseline) analyses were done. Over 11.8 years on average, 430,161 dementia cases developed with a HR (95% CI) of 1.09 (1.08-1.11) for dementia, 1.10 (1.08-1.11) for AD, and 1.04 (1.01-1.07) for VD. The risk of dementia was higher for moderate-to-severe anemia (HR 1.20, 95% CI 1.15-1.26) than mild anemia (HR 1.09, 95% CI 1.08 - 1.10) versus non-anemia. The association was consistent across subgroups, being greater in males than females (p for interaction < 0.05, HR 1.14, 95% CI 1.12-1.17 in males, HR 1.07, 95% CI 1.05-1.09 in females). This large population-based cohort study shows that the risk of dementia associated with persistent anemia was greater for AD than VD, of which association was dose-responsive and affected by sex.},
}

@article {pmid42399403,
year = {2026},
author = {Endrizzi, W and Ragni, F and Bovo, S and Chandra, A and Moroni, M and Jurman, G and Osmani, V},
title = {The landscape of artificial intelligence in neurodegenerative diseases: a systematic review.},
journal = {Communications medicine},
volume = {},
number = {},
pages = {},
doi = {10.1038/s43856-026-01669-5},
pmid = {42399403},
issn = {2730-664X},
abstract = {BACKGROUND: The rising global burden of neurodegenerative diseases underscores an urgent need for advanced research in diagnosis, prognosis, and treatment. Artificial Intelligence (AI) methods, particularly when applied to multimodal data, offer a powerful tool to address these challenges. However, a comprehensive overview and critique of the current landscape of AI methods is lacking.

METHODS: 4,685 records of peer-reviewed, primary research articles were screened and 1,956 articles reviewed in full text, yielding 1,186 included studies. For each included study, clinical objectives, disease focus, data modalities, modelling approach, evaluation strategy, and reporting practices were extracted.

RESULTS: Fewer than 5% of studies integrated pharmacological treatments into their predictive models, limiting the extent to which models can directly inform clinical decision-making. Neuroimaging was the predominant input modality, while integration of other clinically relevant data types was relatively rare. Reproducibility rates remain critically low at 35%, and external validation practices fail to use geographically and demographically diverse datasets.

CONCLUSIONS: Overall, AI research in neurodegenerative diseases suffers from significant limitations in reproducibility, data inclusivity, and clinical translatability. We provide a set of recommendations that can be adopted to address these issues and improve reliability and downstream clinical utility.},
}

@article {pmid42399414,
year = {2026},
author = {Du, JN and Tio, ES and Bennett, DA and Schneider, JA and Sevim Bayrak, C and Alexander-Bloch, A and Zhang, B and Felsky, D},
title = {Copy number variant scores are associated with cerebrovascular pathology in aging.},
journal = {Molecular psychiatry},
volume = {},
number = {},
pages = {},
pmid = {42399414},
issn = {1476-5578},
support = {P30AG10161//U.S. Department of Health & Human Services | NIH | National Institute on Aging (U.S. National Institute on Aging)/ ; P30AG72975//U.S. Department of Health & Human Services | NIH | National Institute on Aging (U.S. National Institute on Aging)/ ; R01AG15819//U.S. Department of Health & Human Services | NIH | National Institute on Aging (U.S. National Institute on Aging)/ ; R01AG17917//U.S. Department of Health & Human Services | NIH | National Institute on Aging (U.S. National Institute on Aging)/ ; U01AG46152//U.S. Department of Health & Human Services | NIH | National Institute on Aging (U.S. National Institute on Aging)/ ; U01AG61356//U.S. Department of Health & Human Services | NIH | National Institute on Aging (U.S. National Institute on Aging)/ ; R01MH133843//U.S. Department of Health & Human Services | NIH | National Institute of Mental Health (NIMH)/ ; R01MH132934//U.S. Department of Health & Human Services | NIH | National Institute of Mental Health (NIMH)/ ; R01MH134896//U.S. Department of Health & Human Services | NIH | National Institute of Mental Health (NIMH)/ ; },
abstract = {Late-onset Alzheimer's disease (LOAD) is the most common cause of dementia in older adults, with specific genomic copy number variants (CNVs) implicated in its pathology. However, the aggregate burden of genome-wide CNVs in dementia and age-related neuropathologies is uncharacterized. This study investigated the association between genome-wide CNV scores (CNV-S) and dementia, as well as LOAD-related neuropathologies, in 1011 elderly participants (mean age 88.06) from two ongoing US-based longitudinal clinical-pathological cohort studies who were initially dementia-free and consented to brain donation upon death. Participants exhibited varying cognitive statuses at death (429 dementia, 258 mild cognitive impairment, 324 cognitively normal). We evaluated effects of (1) eight individual-level CNV-S based on gene loss intolerance and dosage sensitivity; (2) a single nucleotide polymorphism (SNP)-based LOAD polygenic score (PGS-LOAD) calculated using Bayesian continuous shrinkage; and (3) covariates (age, sex, and education). Outcomes included cognitive scores across 19 tests, clinical diagnoses of Alzheimer's disease or mild cognitive impairment, and four LOAD-related neuropathologies assessed postmortem. Analyses identified 4867 CNVs (3918 deletions, 949 duplications) mapped to 3211 genes. Higher deletion CNV-S were significantly associated with increased cerebrovascular pathologies (pLI: β = 0.14, 95% CI [0.08, 0.21]; LOEUF: β = 0.14, 95% CI [0.08, 0.20]; pHI: β = 0.15, 95% CI [0.08, 0.21]; binarized pHI: β = 0.14, 95% CI [0.08, 0.21]). Models predicting cerebral atherosclerosis that included deletion CNV-S significantly outperformed models based on only PGS-LOAD (R[2] increase: 0.02). These findings suggest that genome-wide CNV burden, particularly deletions in dosage-sensitive genes, contributes to cerebrovascular pathology in aging. CNV-S may augment existing LOAD genetic risk models by capturing vascular pathways distinct from traditional SNP-based risk.},
}

@article {pmid42399591,
year = {2026},
author = {Song, Y and Guo, Y and Wang, Y and Zhou, J},
title = {Rethinking Alzheimer's Origins: Antimicrobial Amyloid and Tau Point to Potential Upstream Immune Triggers.},
journal = {Neuroscience bulletin},
volume = {},
number = {},
pages = {},
pmid = {42399591},
issn = {1995-8218},
}

@article {pmid42399717,
year = {2026},
author = {Chédotal, H and Povlsen, K and Narayanan, D and Gotfredsen, CH and Gajhede, M and Bach, A and Clausen, MH},
title = {Discovery of Ligands for the TNFR1 Extracellular Domain Using Fragment-Based Drug Discovery.},
journal = {ChemMedChem},
volume = {21},
number = {13},
pages = {e70365},
doi = {10.1002/cmdc.70365},
pmid = {42399717},
issn = {1860-7187},
support = {1032-00084B//Danmarks Frie Forskningsfond/ ; //Villum Fonden/ ; NNF19OC0055818//Novo Nordisk Fonden/ ; CF19-0072//Carlsbergfondet/ ; 2018-07152//Vetenskapsrådet/ ; 2018-04969//VINNOVA/ ; 2019-02496//Svenska Forskningsrådet Formas/ ; },
mesh = {*Receptors, Tumor Necrosis Factor, Type I/antagonists & inhibitors/metabolism/chemistry ; Ligands ; Humans ; Crystallography, X-Ray ; *Drug Discovery ; Surface Plasmon Resonance ; *Small Molecule Libraries/chemistry/pharmacology/chemical synthesis ; Structure-Activity Relationship ; Protein Domains ; Molecular Structure ; Models, Molecular ; Dose-Response Relationship, Drug ; },
abstract = {Tumor necrosis factor receptor 1 (TNFR1) plays a major role in immunoregulation. It is involved in inflammatory and autoimmune diseases like rheumatoid arthritis, psoriasis, Alzheimer's disease, and multiple sclerosis. However, few small-molecule inhibitors of TNFR1 have been reported, even though they constitute a good alternative to already existing antibody therapies targeting the TNF pathway. Here, we report the discovery of a new class of molecules for the extracellular domain of TNFR1 using a fragment-based approach through primary screening by NMR spectroscopy, followed by orthogonal validation by surface plasmon resonance (SPR) and X-ray crystallography. Guided by these results, we have synthesized 46 analogs with micromolar potency showing up to ∼10-fold improved affinity toward TNFR1 compared to the fragment hits. These results can provide a structural basis for the discovery of novel TNFR1 inhibitors in the future.},
}

*Receptors, Tumor Necrosis Factor, Type I/antagonists & inhibitors/metabolism/chemistry
Ligands
Humans
Crystallography, X-Ray
*Drug Discovery
Surface Plasmon Resonance
*Small Molecule Libraries/chemistry/pharmacology/chemical synthesis
Structure-Activity Relationship
Protein Domains
Molecular Structure
Models, Molecular
Dose-Response Relationship, Drug

@article {pmid42399802,
year = {2026},
author = {Kong, L and Zhu, F and Zhang, L and Yang, Q},
title = {Scoping review on orofacial pain management in older adults with dementia.},
journal = {BMC geriatrics},
volume = {},
number = {},
pages = {},
doi = {10.1186/s12877-026-07953-2},
pmid = {42399802},
issn = {1471-2318},
abstract = {BACKGROUND/OBJECTIVES: Orofacial pain in older adults with dementia is often overlooked due to cognitive decline and impaired communication, impairing patients' quality of life and exacerbating neuropsychiatric behavioural symptoms. This scoping review aimed to map available evidence regarding prevalence, assessment tools, clinical management strategies and research gaps, with the aim of informing clinical practice and guiding future research.

METHODS: Systematic literature searches were performed in PubMed, Web of Science, Embase and Cochrane Library from database inception to December 2025. Two independent reviewers performed literature screening and data extraction, and any disagreements were resolved via consensus discussion. Narrative synthesis was adopted to summarise findings, and the review strictly followed PRISMA-ScR guidelines. This review was retrospectively registered on the Open Science Framework on 5 March 2026 (OSF: https://osf.io/qmg64). The literature search was completed prior to registration.

RESULTS: Twenty one studies were included. Orofacial pain prevalence varied: 7.4%-21.7% in community-dwelling older adults; 11.9% (rest) and 21.9% (mastication) in hospitalised patients; up to 48.8% in nursing home residents with severe dementia. A meta-analysis (n = 6115) reported a pooled prevalence of 19.0%. Nearly half (50.3%) of patients without self-reported pain had underlying oral pathological lesions. Based on limited validation studies, the OPS-NVI demonstrates relatively stronger psychometric properties compared to other available tools, though evidence remains preliminary and head-to-head comparisons are lacking, while the OHAT-NL may be suitable for community screening by caregivers. Paracetamol is frequently recommended as a first-line option for mild to moderate pain based on general geriatric pain guidelines, but direct evidence for orofacial pain in dementia is limited. Multidimensional non-pharmacological strategies, including staged oral care, caregiver training and multidisciplinary collaboration, are generally suggested. Major systemic barriers include limited dental service access, insufficient caregiver training, and information fragmentation.

CONCLUSIONS: Orofacial pain represents a substantial underrecognised burden among older adults with dementia. Immediate priorities include integrating oral health assessment into routine care, promoting scenario-specific use of validated tools, and strengthening caregiver education. Future research should prioritise subtype-specific investigations and translate existing evidence into implementable clinical protocols.},
}

@article {pmid42399884,
year = {2026},
author = {Noppert, GA and Stebbins, RC and Zhang, KP and Kobayashi, L and Langa, KM and Levin, B and Li, C and Aiello, AE},
title = {Associations between immunosenescence and domain-specific cognition in the Health and Retirement Study Harmonized Cognitive Assessment Protocol.},
journal = {BMC biology},
volume = {},
number = {},
pages = {},
doi = {10.1186/s12915-026-02679-4},
pmid = {42399884},
issn = {1741-7007},
support = {R01AG075719/NH/NIH HHS/United States ; R01 AG070953/NH/NIH HHS/United States ; },
abstract = {BACKGROUND: Alzheimer's disease and related dementias (ADRD) pose a critical challenge for the aging U.S. population, yet many biological pathways remain unclear. Recent work has focused on whether peripheral immunosenescence contributes to cognitive aging. Using the Health and Retirement Study (HRS), we examined associations between peripheral immunosenescence and domain-specific cognitive function.

RESULTS: Immune function was associated with general and domain-specific cognition, with variation by sex and immune marker. The CD4 + EMRA:Naïve T Cell Ratio, CD4 + Naïve:CD8 + EMRA Ratio, and CMV IgG showed the most consistent associations, particularly with general and executive function. A one-SD increase in CMV IgG was associated with 0.06 SD lower executive function (95% CI: -0.07, -0.05), persisting after adjustment for confounders.

CONCLUSIONS: Associations with peripheral immune markers suggest a potential role for peripheral immunosenescence in cognitive aging. The immune system may be an early contributor to cognitive vulnerability, underscoring the need to integrate immune aging into ADRD research.},
}

@article {pmid42343639,
year = {2026},
author = {Watzlawik, JO and Bustillos, BA and Rodriguez Martinez, C and Dickson, DW and Wszolek, ZK and Ross, OA and Springer, W and Fiesel, FC},
title = {Robust and sensitive ELISA detection of total and activated PRKN.},
journal = {Autophagy},
volume = {},
number = {},
pages = {1-16},
doi = {10.1080/15548627.2026.2694658},
pmid = {42343639},
issn = {1554-8635},
abstract = {Parkinson disease (PD) is closely linked to disruptions in mitochondrial quality control, a process regulated by the ubiquitin kinase PINK1 and the E3 ubiquitin ligase PRKN/parkin. Upon mitochondrial damage, PINK1 phosphorylates ubiquitin, which in turn recruits and activates PRKN. Full activation of PRKN is mediated by PINK1-dependent phosphorylation of PRKN at serine 65, which leads to widespread ubiquitination of mitochondrial substrates and amplifies the mitophagy response. Disruption of this pathway results in mitochondrial accumulation, oxidative stress, and neuronal death, all key mechanisms of PD pathogenesis. Genetic studies have shown biallelic loss-of-function mutations in PRKN are the most common cause of early-onset PD. Although the role of haploinsufficiency remains under investigation, PRKN protein becomes insoluble and inactive with aging or post-translational modifications, indicating that functional protein levels are a key determinant of disease risk. Reliable quantification of total and activated PRKN in samples has not been feasible, limiting research and clinical assessment. To address this, we developed and validated knockout (KO)-verified sandwich ELISA assays that quantify both total PRKN and PINK1-phosphorylated p-S65-PRKN. These assays provide absolute quantification of PRKN, improving functional diagnosis, and patient stratification in PD. Application of these methods established the concentration of PRKN in cells and in brain and revealed significant effects of a common genetic PRKN variant, further highlighting the importance of determining functional PRKN protein levels. The developed immunoassays complement previously established PINK1 and p-S65-Ub measurements, enhancing mechanistic insight into mitophagy and enabling effective monitoring of PD therapies and other neurodegenerative diseases.Abbreviations: AD: Alzheimer disease; CCCP: carbonyl cyanide 3-chlorophenylhydrazone; ECL: electrochemiluminescence; ELISA: enzyme-linked immunosorbent assay; IBR: In-between-RING; iPSC: induced pluripotent stem cell; KO: knockout; LoB: limit of blank; LoD: limit of detection; LoQ: limit of quantification; MSD: Meso Scale Discovery; PD: Parkinson disease; p-S65-PRKN: serine 65 phosphorylated PRKN; p-S65-Ub: serine 65 phosphorylated ubiquitin; REP: repressor element of PRKN; RING: really interesting new gene; Ub: ubiquitin; UBL: ubiquitin-like domain; VCL: vinculin; WT: wild-type.},
}

@article {pmid42392247,
year = {2026},
author = {Kumar, R and Sinha, S and Babu, MA},
title = {Interactions-Guided Blueprint of Acetylcholinesterase Binding: A Review on Structural and Molecular Determinants.},
journal = {Chemico-biological interactions},
volume = {},
number = {},
pages = {112224},
doi = {10.1016/j.cbi.2026.112224},
pmid = {42392247},
issn = {1872-7786},
abstract = {Acetylcholinesterase (AChE) remains one of the most extensively studied enzymatic targets in neuropharmacology due to its central role in cholinergic neurotransmission and its relevance in symptomatic cognitive disorders, toxicology, and neuromodulation. AChE terminates cholinergic neurotransmission by hydrolysing acetylcholine, and its inhibition provides clinically established symptomatic relief in cholinergic dysfunction-associated pathological conditions. For any newly discovered ligand, the precise target binding mode often remains challenging, and unfortunately, the binding patterns of most reported compounds have not been experimentally resolved. However, with recent advances in structural biology, particularly biomolecular crystallographic structures deposited in the Protein Data Bank, have significantly enriched our understanding of the active site of AChE and its interactions with diverse chemical classes of ligands. To this end, this article presents a comprehensive systematic analysis of 202 AChE-ligand complexes (1993-2025) since the first breakthrough, categorizing ligands by their core scaffolds or functional groups, including decamethonium, huprine, galanthamine, quinoline, huperzine, tacrine, pyridinium, sulphonamide, and quaternary amine derivatives. Crucial interactions with core residues of the binding pocket, such as hydrogen bonding, cation-π, carbon-π, π-π stacking, and van der Waals forces, primarily associated with the stabilization of AChE-ligand complexes, are discussed involving organisms like Tetronarce californica, Homo sapiens, and Mus musculus, emphasizing their role in inhibitory potency. All ligands are further evaluated using Lipinski's Rule of Five filters to assess drug-likeness and identify optimization strategies for improved bioavailability and pharmacokinetics. By integrating structural insights with ligand features, this article provides a comprehensive framework for the rational design and optimization of next-generation AChE modulators across neurological and toxicological conditions.},
}

@article {pmid42392306,
year = {2026},
author = {Zhang, Y and Pu, J and Shen, Z and Ye, Z and Liu, J and Zhang, D and Deng, K and Yao, Y},
title = {Global Trends and Evolving Frontiers in Intranasal Delivery for CNS Diseases (2000-2025): A Bibliometric Analysis and Systematic Review.},
journal = {World neurosurgery},
volume = {},
number = {},
pages = {125172},
doi = {10.1016/j.wneu.2026.125172},
pmid = {42392306},
issn = {1878-8769},
abstract = {BACKGROUND: Intranasal administration (nose-to-brain delivery) has emerged as a pivotal non-invasive strategy to bypass the blood-brain barrier (BBB) for treating central nervous system (CNS) disorders. However, the exponential growth of literature in this domain presents challenges in grasping the holistic research trajectory and identifying emerging hotspots.

METHODS: This study conducted a comprehensive bibliometric analysis of 4,009 publications retrieved from the Web of Science Core Collection (WoSCC) spanning from 2000 to 2025. Tools including VOSviewer, CiteSpace, and R-bibliometrix were employed to map spatiotemporal trends, collaborative networks, and keyword evolution.

RESULTS: The analysis reveals a robust upward trend in global research output, predominantly driven by China and the United States. Keyword clustering identified five major research sub-domains: Alzheimer's disease, Oxytocin (behavioral/psychiatric applications), Stroke and Neuroinflammation, Brain Tumors, and Nanoparticles. Burst detection analysis elucidates a distinct paradigm shift in scientific focus: early investigations prioritized mucosal absorption mechanisms and tolerance; the focus subsequently transitioned to specific therapeutic agents (e.g., insulin, oxytocin); and most recently, the field has been dominated by the optimization of delivery vectors, specifically lipid-based nanoparticles and exosomes.

CONCLUSION: While nanotechnology has become the current technological frontier for enhancing brain targeting, a critical gap remains between promising preclinical results and clinical translation. Future research must prioritize the development of biomimetic delivery systems and highly predictive translational models to bridge the divide between bench and bedside. This review provides a strategic roadmap for researchers to navigate current trends and address the barriers hindering clinical application.},
}

@article {pmid42392339,
year = {2026},
author = {Salman, Y and Denning, AE and Schaeverbeke, JM and Tomé, SO and Joudiou, N and Khandelwal, P and Yushkevich, PA and Vandenberghe, R and Gallez, B and Wisse, LE and Hanseeuw, BJ},
title = {Volumetric postmortem MRI of the medial temporal lobe in Alzheimer's disease and related disorders: methodological advances and implications for in vivo biomarker development.},
journal = {NeuroImage},
volume = {},
number = {},
pages = {122098},
doi = {10.1016/j.neuroimage.2026.122098},
pmid = {42392339},
issn = {1095-9572},
abstract = {Magnetic resonance imaging (MRI) is central to the study and diagnosis of neurodegenerative diseases. Yet, no MRI biomarker is currently specific to a given neurodegenerative disease. This may result from the limited resolution of conventional MRI, which restricts detailed investigation of medial temporal lobe (MTL) subregions, a crucial hub for many neuropathologies. Moreover, in vivo MRI cannot be directly compared with neuropathological data, the gold standard for disease definition. Even when antemortem MRI and postmortem analyses are combined, the time gap between imaging and neuropathological examination allows pathogenic processes to progress, reducing the accuracy of these correlations. Over the past two decades, postmortem MRI has gained increasing interest because it enables long, motion-free acquisitions and the use of specialized coils and preclinical scanners, providing ultra-high spatial resolution. Additionally, it allows direct correspondence between imaging and neuropathological measures. Consequently, volumetric postmortem MRI, particularly investigations of the MTL, has become an increasingly common approach in Alzheimer's disease and related disorders (ADRD). This narrative review specifically focuses on volumetric postmortem MRI of the MTL and summarizes the main methodologies for anatomical postmortem MTL imaging in ADRD and recent advances in the characterization of neurodegenerative changes, from brain preparation to MRI acquisition. It also highlights the translational potential of volumetric postmortem MRI for developing in vivo biomarkers, optimizing imaging protocols and segmentation methods, and assessing the impact of proteinopathies. Finally, it outlines current limitations, technical challenges, and perspectives for future research.},
}

@article {pmid42392383,
year = {2026},
author = {Dhar, I and Gupta, S and Mishra, R and Dadhich, A},
title = {Gingipains as macromolecular mediators at the periodontal-brain interface: Mechanistic, diagnostic, and therapeutic evidence in Alzheimer's and Parkinson's diseases.},
journal = {International journal of biological macromolecules},
volume = {},
number = {},
pages = {153320},
doi = {10.1016/j.ijbiomac.2026.153320},
pmid = {42392383},
issn = {1879-0003},
abstract = {Chronic periodontitis, driven by Porphyromonas gingivalis, has emerged as a modifiable risk factor for Alzheimer's disease (AD) and Parkinson's disease (PD) the two most prevalent and socioeconomically burdensome neurodegenerative disorders through systemic dissemination of its signature cysteine proteases, gingipains (RgpA, RgpB, Kgp). This narrative critical review is explicitly scoped to AD and PD, the only neurodegenerative conditions for which postmortem detection of gingipains in affected brain regions, mechanistic evidence from cellular and animal models, and clinical epidemiological data currently exist in sufficient depth to support an integrated synthesis. Robust meta-analyses confirm that periodontitis is associated with elevated AD/PD risk (OR/HR 1.2-3.5), while gingipains have been detected in a high proportion (>85-90%) of postmortem AD/PD brains, correlating with tau/α-synuclein pathology, neuroinflammation, and neuronal loss. Mechanistic studies in cellular and animal models demonstrate that gingipains can disrupt blood-brain barrier integrity via tight-junction cleavage, trigger NF-κB/NLRP3-driven glial activation, catalyse amyloid-β/α-synuclein seeding, induce tau truncation/hyperphosphorylation, and precipitate mitochondrial oxidative damage, thereby generating self-amplifying neurotoxic cascades. Salivary gingipain activity offers a non-invasive, high-sensitivity biomarker candidate for early risk stratification that may outperform conventional fluid markers in prodromal cohorts. Therapeutically, small-molecule gingipain inhibitors have shown neuroprotective effects in preclinical models (e.g., atuzaginstat/COR388 failed primary endpoints in the Phase 2/3 GAIN trial but demonstrated subgroup benefits in P. gingivalis-positive participants; the next-generation inhibitor LHP588 is advancing in the Phase 2 SPRING trial). Emerging approaches including nanotechnology, CRISPR-based virulence gene disruption, and targeted delivery platforms aim to improve brain exposure and specificity. This review provides an integrated, isoform-resolved framework linking gingipain structure-function to neurodegeneration. While associative and mechanistic evidence is compelling, definitive causation in humans and disease-modifying efficacy require further validation through biomarker-guided clinical trials. Precision inhibition of gingipains represents a promising upstream strategy for addressing a potentially modifiable microbial contributor at the oral-brain interface.},
}

@article {pmid42392515,
year = {2026},
author = {Pandey, JK and Verma, SK and Kumar, J and Perwej, Y and Jha, DSK and Panchal, BY and Ferdouse, R and V, S and Banerjee, S and Tiwari, M and Badal, R and Mandal, P and Baghel, JS},
title = {Transformative Role of Advanced Neural Computation in Clinical Image Diagnostics: A Review of Key Concepts and Applications.},
journal = {Seminars in ultrasound, CT, and MR},
volume = {},
number = {},
pages = {},
doi = {10.1053/j.sult.2026.06.010},
pmid = {42392515},
issn = {1558-5034},
abstract = {Medical imaging plays a crucial role in modern diagnostic practices, but traditional techniques often face limitations in accuracy, efficiency, and scalability. The emergence of deep learning (DL) has led to significant improvements that are transforming this field. This review discusses how DL algorithms are enhancing diagnostic imaging by improving accuracy, enabling automated analysis, and supporting personalized treatment plans. It focuses on key deep learning (DL) frameworks, including convolutional neural networks (CNNs), recurrent neural networks (RNNs), and generative adversarial networks (GANs). The review examines their applications in important medical imaging tasks such as image classification, segmentation, reconstruction, and disease prediction. It also considers how DL techniques are integrated with tools like radiomics, data augmentation strategies, and predictive analytics models. DL methods have shown superior performance in detecting and classifying diseases like pneumonia, tuberculosis, and Alzheimer's. They also improve the quality and speed of imaging modalities such as MRI, CT, and ultrasound. Despite these advances, challenges remain in data availability, model interpretability, clinical validation, and ethical issues related to bias and privacy. Addressing these challenges is essential for the successful clinical use of DL in medical imaging. This review ends with suggestions for future directions and best practices for ethically and practically integrating DL technologies into routine healthcare.},
}

@article {pmid42392701,
year = {2026},
author = {Li, JY and Wang, XX and Wan, SF and Feng, TT and Guo, AJ and Liu, JY and Feng, K},
title = {[Research progress on role of PINK1/Parkin-mediated mitophagy in Alzheimer's disease and TCM interventions].},
journal = {Zhongguo Zhong yao za zhi = Zhongguo zhongyao zazhi = China journal of Chinese materia medica},
volume = {51},
number = {8},
pages = {2143-2152},
doi = {10.19540/j.cnki.cjcmm.20260113.701},
pmid = {42392701},
issn = {1001-5302},
mesh = {Humans ; PTEN-Induced Putative Kinase ; *Protein Kinases/metabolism/genetics ; *Alzheimer Disease/drug therapy/metabolism/genetics/physiopathology ; *Ubiquitin-Protein Ligases/metabolism/genetics ; *Mitophagy/drug effects ; Animals ; *Drugs, Chinese Herbal/administration & dosage ; Mitochondria/metabolism/drug effects ; },
abstract = {Alzheimer's disease(AD) is a neurodegenerative disorder characterized by progressive cognitive decline. Current treatment strategies mainly focus on symptomatic regulation of the neurotransmitter system, but their intervention effects on key pathological processes such as amyloid β(Aβ) deposition and abnormal phosphorylation of Tau protein remain limited. Therefore, it is urgent to explore new intervention targets from the perspective of the key mechanisms underlying the disease's occurrence and development. In recent years, mitochondrial dysfunction and imbalanced mitophagy have been recognized as closely related to the onset and progression of AD. The PTEN-induced putative kinase 1(PINK1)/E3 ubiquitin-protein ligase parkin(Parkin) pathway is a classic mechanism for the recognition, ubiquitination marking, and autophagic clearance of damaged mitochondria. Multiple studies have shown that under AD pathological conditions, the expression of this pathway is blocked, or its activity is reduced, leading to restricted mitophagy flux and obstacle clearance, which in turn exacerbate oxidative stress, energy metabolism disorders, and synaptic function damage, accelerating neuronal degeneration. Based on this, intervention strategies targeting PINK1/Parkin-mediated mitophagy have gradually attracted attention. Existing research indicates that single components and formulas of TCM, as well as some bioactive molecules, can reduce Aβ deposition, inhibit abnormal phosphorylation of Tau protein, and enhance synaptic plasticity by regulating PINK1/Parkin-mediated mitophagy, thereby exerting neuroprotective effects and improving cognitive function. However, the current evidence mainly comes from experimental studies, and the blood-brain barrier permeability, long-term safety, and clinical reproducibility of these interventions still need further verification. This article systematically reviewed the molecular mechanisms and upstream regulatory networks of PINK1/Parkin-mediated mitophagy, elaborated on the research evidence of its role in the pathological process of AD, and focused on summarizing the research progress of TCM interventions targeting this pathway, aiming to provide references for subsequent mechanism verification, evidence-based research design, and exploration of comprehensive intervention strategies.},
}

Humans
PTEN-Induced Putative Kinase
*Protein Kinases/metabolism/genetics
*Alzheimer Disease/drug therapy/metabolism/genetics/physiopathology
*Ubiquitin-Protein Ligases/metabolism/genetics
*Mitophagy/drug effects
Animals
*Drugs, Chinese Herbal/administration & dosage
Mitochondria/metabolism/drug effects

@article {pmid42392719,
year = {2026},
author = {Yuan, CB and Ju, YT and Liu, YM and Wang, BS and Zhang, L and Yu, CY and Yang, YL and Chen, WY and Leng, YJ and Cheng, MJ and Min, DY},
title = {[Quercetin improves cognitive impairment in mice with Alzheimer's disease by inhibiting inflammatory response and activating cAMP/PKA/CREB signaling pathway].},
journal = {Zhongguo Zhong yao za zhi = Zhongguo zhongyao zazhi = China journal of Chinese materia medica},
volume = {51},
number = {8},
pages = {2323-2334},
doi = {10.19540/j.cnki.cjcmm.20251210.801},
pmid = {42392719},
issn = {1001-5302},
mesh = {Animals ; *Alzheimer Disease/drug therapy/genetics/immunology/psychology/metabolism ; Male ; *Quercetin/administration & dosage ; Signal Transduction/drug effects ; Mice ; *Cyclic AMP Response Element-Binding Protein/genetics/metabolism ; Humans ; *Cyclic AMP/metabolism/genetics/immunology ; *Cyclic AMP-Dependent Protein Kinases/genetics/metabolism ; Mice, Inbred C57BL ; *Cognitive Dysfunction/drug therapy/genetics ; Mice, Transgenic ; Disease Models, Animal ; Hippocampus/drug effects ; },
abstract = {This study aimed to investigate the effects of quercetin on cognitive dysfunction in a mouse model of Alzheimer's disease(AD) and to explore its potential mechanisms. Network pharmacology was used to construct a "drug-core component-key target-pathways-disease" network to identify potential targets and related pathways associated with drug efficacy. Thirty 3-month-old male APP/PS1 transgenic mice were randomly divided into a model group, a quercetin group(100 mg·kg~(-1)), and a donepezil hydrochloride group(0.5 mg·kg~(-1)), while age-matched C57BL/6J mice from the same litter served as the control group. Each group consisted of 10 mice, and the treatment groups received the corresponding drug interventions for 24 weeks. The Morris water maze(MWM) test was used to assess memory performance, and the nest-building test was applied to evaluate daily living ability. hematoxylin-eosin(HE) staining, Nissl staining, and immunohistochemistry were used to assess pathological changes in hippocampal neurons. Western blot analysis was used to detect the expression levels of tau, phosphorylated(p)-tau, interleukin-1β(IL-1β), tumor necrosis factor-α(TNF-α), brain-derived neurotrophic factor(BDNF), cyclic adenosine monophosphate(cAMP), protein kinase A(PKA), p-PKA, cAMP response element-binding protein(CREB), and p-CREB-related signaling proteins in hippocampal tissue. Network pharmacology analysis identified 165 quercetin-related active component targets and 4 324 learning-and memory-related targets. Intersection analysis yielded 71 AD-related core genes. Protein-protein interaction(PPI) network analysis identified protein kinase B(Akt1), estrogen receptor 1(ESR1), epidermal growth factor receptor(EGFR), and non-receptor tyrosine kinase(SRC) as core target genes. Kyoto Encyclopedia of Genes and Genomes(KEGG) pathway analysis indicated that quercetin may regulate AD progression through the PI3K/Akt signaling pathway, cAMP signaling pathway, TNF signaling pathway, and EGFR tyrosine kinase inhibitor resistance-related pathways. Animal experiments showed that, compared with the control group, the model group exhibited significantly reduced nesting scores, prolonged escape latency(P<0.05), and fewer platform crossings(P<0.05). The number of neurons in the cortex and hippocampus was significantly decreased, and extracellular amyloid β(Aβ) deposition was significantly increased(P<0.01). In addition, the expression levels of p-tau/tau, IL-1β, TNF-α, cAMP, p-PKA/PKA, and p-CREB/CREB in hippocampal tissue were significantly elevated(P<0.01), whereas BDNF protein expression was significantly reduced(P<0.01). Compared with the model group, the quercetin and donepezil hydrochloride groups showed significantly increased nesting scores, shortened escape latency(P<0.05), and increased numbers of platform crossings(P<0.05). The number of neurons in the hippocampal CA1 region was significantly increased(P<0.01), and the expression levels of p-tau/tau, IL-1β, TNF-α, cAMP, p-PKA/PKA, and p-CREB/CREB in hippocampal tissue were significantly decreased(P<0.05, P<0.01). These results indicate that quercetin can significantly improve cognitive impairment in APP/PS1 transgenic mice, and its mechanism may be associated with activation of the cAMP/PKA/CREB signaling pathway and reversal of the upregulation of pro-inflammatory cytokines, including TNF-α and IL-1β.},
}

Animals
*Alzheimer Disease/drug therapy/genetics/immunology/psychology/metabolism
Male
*Quercetin/administration & dosage
Signal Transduction/drug effects
Mice
*Cyclic AMP Response Element-Binding Protein/genetics/metabolism
Humans
*Cyclic AMP/metabolism/genetics/immunology
*Cyclic AMP-Dependent Protein Kinases/genetics/metabolism
Mice, Inbred C57BL
*Cognitive Dysfunction/drug therapy/genetics
Mice, Transgenic
Disease Models, Animal
Hippocampus/drug effects

@article {pmid42392731,
year = {2026},
author = {Lyu, SY and Wang, XZ and Chen, XY and Guo, R},
title = {[Exploring mechanism of "treating different diseases with the same method" for depression and Alzheimer's disease based on "liver-spleen-kidney" axis and advances in traditional Chinese medicine intervention].},
journal = {Zhongguo Zhong yao za zhi = Zhongguo zhongyao zazhi = China journal of Chinese materia medica},
volume = {51},
number = {10},
pages = {2726-2738},
doi = {10.19540/j.cnki.cjcmm.20260108.302},
pmid = {42392731},
issn = {1001-5302},
mesh = {Humans ; *Alzheimer Disease/drug therapy/physiopathology/metabolism ; *Drugs, Chinese Herbal/administration & dosage/therapeutic use ; *Spleen/drug effects/physiopathology ; *Kidney/drug effects/physiopathology ; *Liver/drug effects/physiopathology ; Animals ; *Medicine, Chinese Traditional ; *Depression/drug therapy/physiopathology ; },
abstract = {Depression(major depressive disorder, MDD) and Alzheimer's disease(AD) are two highly prevalent neuropsychiatric disorders. With the aging population, their comorbidity rate continues to rise. The pathogenesis of MDD and AD is complex, and modern medicine still lacks strategies that can simultaneously intervene in the core processes of both diseases. The theory of "treating different diseases with the same method" in traditional Chinese medicine(TCM) is an important therapeutic principle, which means that different diseases showing identical syndromes during their development can be treated with the same approach. This provides a TCM perspective for the diagnosis and treatment of their comorbidity. Based on the theory of the "liver-spleen-kidney" axis, this study identified that MDD and AD shared common pathogenesis: liver dysfunction in free coursing, spleen dysfunction in transportation, and kidney essence deficiency. It further connected this pathogenesis with the dysregulation of the neuroendocrine-immune(NEI) network in modern medicine, revealing common pathological mechanisms in neuroinflammation, dysfunction of the "hypothalamic-pituitary-adrenal"(HPA) axis, and gut microbiota dysbiosis. Meanwhile, it also reviewed specific mechanisms of TCM herbs such as Bupleuri Radix(Chaihu), Paeoniae Radix Alba(Baishao), and Astragali Radix(Huangqi), as well as their active components, in treating MDD and AD by regulating the NEI network through multiple targets and pathways. This may provide evidence for the application of the "treating different diseases with the same method" theory and broaden the perspective for the treatment of MDD and AD.},
}

Humans
*Alzheimer Disease/drug therapy/physiopathology/metabolism
*Drugs, Chinese Herbal/administration & dosage/therapeutic use
*Spleen/drug effects/physiopathology
*Kidney/drug effects/physiopathology
*Liver/drug effects/physiopathology
Animals
*Medicine, Chinese Traditional
*Depression/drug therapy/physiopathology

@article {pmid42392749,
year = {2026},
author = {Liu, MY and Zhong, XQ and Zhang, H and Huang, MT and Liang, YS and Ren, YK and Huang, LP and Deng, MZ},
title = {[Mechanism of Ding-Zhi-Xiao-Wan on sphingolipid metabolism disorders in Alzheimer's disease based on network pharmacology, molecular docking, and animal experiments].},
journal = {Zhongguo Zhong yao za zhi = Zhongguo zhongyao zazhi = China journal of Chinese materia medica},
volume = {51},
number = {10},
pages = {2906-2917},
doi = {10.19540/j.cnki.cjcmm.20260104.801},
pmid = {42392749},
issn = {1001-5302},
mesh = {Animals ; *Alzheimer Disease/metabolism/drug therapy/genetics ; Mice ; *Sphingolipids/metabolism ; Network Pharmacology ; Molecular Docking Simulation ; Humans ; *Drugs, Chinese Herbal/administration & dosage/chemistry ; Male ; Disease Models, Animal ; Signal Transduction/drug effects ; Oxidative Stress/drug effects ; Apoptosis/drug effects ; },
abstract = {Exploring the mechanism of Ding-Zhi-Xiao-Wan(DZXW) on disorders of sphingolipid metabolism in Alzheimer's disease(AD) through network pharmacology, molecular docking and animal experiments. The chemical constituents of DZXW were obtained via the TCMSP, with target prediction conducted using the SwissTargetPrediction database; the GeneCards database was consulted to identify targets associated with AD and sphingolipid metabolism disorders. The intersecting targets from these three databases underwent GO and KEGG enrichment analyses. Cytoscape was employed to construct networks and screen core components and targets for molecular docking validation. Animal experiments employed AD model mice, utilising the water maze, ELISA, qPCR, LC-MS, and Western blot to evaluate the effects of DZXW on behavioural, oxidative stress, inflammatory, apoptotic, and sphingolipid metabolism-related indicators. Network pharmacology identified 51 common targets, with enrichment analysis indicating their involvement in multiple pathways including signal transduction, apoptosis, and the phosphatidylinositol 3kinase/protein kinase B(PI3K/Akt) pathway. Molecular docking revealed that multiple components within DZXW(such as cerevisterol and isorhamnetin) interacted with targets including caspase 3(CASP3), mitogen-activated protein kinase 14(MAPK14), estrogen receptor 1(ESR1), and silent information regulator factor 2 related enzyme 1(SIRT1), with SIRT1 being particularly crucial. Animal studies indicate that DZXW enhances learning and memory capacity in AD mice, reduces ceramide levels, and inhibits oxidation factors [4-hydroxynonenal(4-HNE), 8-hydroxy-2'-deoxyguanosine(8-OHdG), nicotinamide adenine dinucleotide phosphate oxidase 4(NOX4)] and inflammatory factors [tumour necrosis factor-α(TNF-α), interleukin(IL)-1β], downregulates CASP3, MAPK14, sphingomyelin phosphodiesterase 1-3(SMPD1-3), B cell chronic lymphocytic leukaemia/lymphoma-2(Bcl-2)-associated X protein(Bax), and increases IL-10, ESR1, mammalian target of rapamycin(mTOR), SIRT1, PI3K phosphorylation, Akt phosphorylation, and Bcl-2. In conclusion, DZXW may improve sphingolipid metabolism disorders in AD by inhibiting neuronal apoptosis and mitigating oxidative and inflammatory responses through the SIRT1/PI3K/Akt pathway.},
}

Animals
*Alzheimer Disease/metabolism/drug therapy/genetics
Mice
*Sphingolipids/metabolism
Network Pharmacology
Molecular Docking Simulation
Humans
*Drugs, Chinese Herbal/administration & dosage/chemistry
Male
Disease Models, Animal
Signal Transduction/drug effects
Oxidative Stress/drug effects
Apoptosis/drug effects

@article {pmid42392863,
year = {2026},
author = {Jiménez-Huete, A and Rognoni, T and Montoya, G and Borda, MG and Riverol, M and , },
title = {Diagnostic accuracy of a two-cut-off approach using the FAQ/MMSE ratio and FAQ for clinical preselection of patients for anti-amyloid therapy.},
journal = {Journal of neurology, neurosurgery, and psychiatry},
volume = {},
number = {},
pages = {},
doi = {10.1136/jnnp-2026-338997},
pmid = {42392863},
issn = {1468-330X},
abstract = {BACKGROUND: Anti-amyloid therapies for Alzheimer's disease (AD) require efficient patient selection. The Clinical Dementia Rating (CDR) scale is the reference standard for staging, but it is time-consuming to administer. Simple tools to distinguish early-stage cognitive impairment (CDR 0.5-1) from more advanced stages (CDR 2-3) would therefore be of substantial clinical value.

METHODS: Participants from the Alzheimer's Disease Neuroimaging Initiative (ADNI) cohorts 1-3 with CDR ≥0.5 were analysed. Three logistic regression models using Mini-Mental State Examination (MMSE), Functional Assessment Questionnaire (FAQ) or the FAQ/MMSE ratio as predictors were developed. Two cut-offs per model were selected to ensure minimum sensitivity and specificity of 0.99, defining rule-out, rule-in and intermediate (uncertain) zones. Performance was assessed using discrimination, calibration and decision curve analysis.

RESULTS: Among 1533 ADNI participants with CDR ≥0.5, two-thirds (n=1022) were assigned to the training set and one-third (n=511) to the test set. FAQ/MMSE and FAQ showed excellent discrimination (area under the curve, AUC 0.97-0.98), outperforming MMSE (AUC 0.94-0.95). FAQ/MMSE demonstrated the best overall performance, although differences compared with FAQ were small and not statistically significant. Dual cut-offs for FAQ/MMSE (0.67 and 1.44) and FAQ (12 and 27) enabled clinically meaningful stratification, with 80% and 70% of participants classified into high-confidence zones, respectively. Results were consistent across the training and test sets.

CONCLUSIONS: The FAQ/MMSE ratio and FAQ score show high accuracy in distinguishing early-stage (CDR 0.5-1) from more advanced cognitive impairment (CDR 2-3). These simple measures may support the clinical preselection of patients for further evaluation in the context of anti-amyloid therapy.},
}

@article {pmid42392958,
year = {2026},
author = {Zhao, H and King, KY and Wong, ST},
title = {Clonal hematopoiesis in Alzheimer's brain: Protective, pathogenic, and context-dependent?.},
journal = {Trends in molecular medicine},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.molmed.2026.06.009},
pmid = {42392958},
issn = {1471-499X},
abstract = {Clonal hematopoiesis is emerging as a surprising modifier of Alzheimer's disease. Recent findings suggest that mutant myeloid cells may enter or expand within the brain, adopting either inflammatory or reparative states. We propose that their effects depend on the mutation, timing, clone size, brain niche, and disease stage.},
}

@article {pmid42392996,
year = {2026},
author = {Zhang, Y and Zhu, F and Wu, X and Li, Z and Huang, P and Gao, Y and Zeng, L},
title = {[Epigenetic regulator DOT1L controls neuronal amyloid pre-cursor protein expression via the p38 mediated mitochondrial fission-fusion homeostasis axis].},
journal = {Zhejiang da xue xue bao. Yi xue ban = Journal of Zhejiang University. Medical sciences},
volume = {},
number = {},
pages = {1-13},
doi = {10.3724/zdxbyxb-2025-0706},
pmid = {42392996},
issn = {1008-9292},
abstract = {OBJECTIVES: To investigate the regulatory role of epigenetic regulator disruptor of telomeric silencing 1-like (DOT1L) and its mediated histone H3 lysine 79 (H3K79) methylation in modulating neuronal amyloid precursor protein (APP) expression, and to elucidate the underlying mechanisms involving mitochondrial homeostasis and the upstream p38 kinase.

METHODS: Alzheimer's disease (AD) models were established using APP/presenilin-1 (APP/PS1) double-transgenic mice and N2a cells overexpressing the human Swedish mutant APP (N2a-APPswe). Immunofluorescence staining was employed to assess DOT1L expression and localization in mouse brain tissues. N2a-APPswe cells were treated with the DOT1L-specific inhibitor EPZ5676 and divided into four groups: blank control, solvent control, DOT1L inhibitor, and DOT1L inhibitor plus p38 agonist (Gynostemma pentaphyllum extract). Western blotting was performed to measure the phosphorylation levels of DRP1 at Ser616 and Ser637 (key mitochondrial fission regulators), the levels of autophagy-related proteins p62 and the LC3-Ⅱ/LC3-Ⅰ ratio, the phosphorylation level of p38, as well as the expression of APP and APP-processing proteins BACE1 and PS1. Real-time quantitative polymerase chain reaction was used to detect mRNA levels of APP and genes involved in mitochondrial fission and fusion. Proteomics data were systematically analyzed through Gene Ontology analysis, WikiPathways enrichment analysis, and STRING protein-protein interaction network analysis to identify key signaling pathways. Mitochondrial morphology was evaluated by Mito-Tracker fluore-scence staining to measure average branch length.

RESULTS: DOT1L expression was signifi-cantly reduced in neurons of APP/PS1 mice compared to wild-type controls. DOT1L inhibition led to decreased H3K79me2 levels (P<0.01), accompanied by a marked increase in APP protein expression (P<0.01), although APP mRNA levels were reduced (P<0.01). Proteomics analysis revealed that differentially expressed proteins were highly enriched in the mitochondrial electron transport chain. Compared with the solvent control, the DOT1L inhibitor group showed inhibited mitochondrial fission, as evidenced by decreased p-DRP1 (Ser616), increased p-DRP1 (Ser637), downregulated MIEF1 mRNA, upregulated MFN1 mRNA (all P<0.05), and increased average mitochondrial branch length (P<0.05), along with reduced p-p38 levels (P<0.05). Co-administration of the p38 agonist significantly reversed these mitochondrial dynamics abnormalities (all P<0.05) and attenuated the abnormally elevated protein levels of APP, BACE1, and PS1 (P<0.05) compared to the DOT1L inhibitor group.

CONCLUSIONS: DOT1L maintains normal mito-chondrial fission and functional homeostasis through regulation of the p38 signaling pathway, thereby modulating APP expression.},
}

@article {pmid42393071,
year = {2026},
author = {Feng, LR},
title = {The cancer Alzheimer's disease paradox.},
journal = {npj aging},
volume = {12},
number = {1},
pages = {},
pmid = {42393071},
issn = {2731-6068},
}

@article {pmid42393277,
year = {2026},
author = {Weinberg, MS and Kodali, MC and Li, Z and Galler, JA and Tidball, AR and Reynolds, WC and Young, C and Devitte-McKee, K and Fatima, HA and Kivisäkk, P and Chatterjee, M and Kulkarni, A and Billingsly, JM and Bartlett, AL and Sui, SH and Kühtreiber, WM and Gerber, J and McManus, AJ and Tanzi, RE and Das, S and Faustman, DL and Arnold, SE},
title = {Bacillus Calmette-Guérin (BCG) immunotherapy reprograms CNS immunity and alters Alzheimer's biomarkers: results from two open-label clinical trials.},
journal = {Communications medicine},
volume = {6},
number = {1},
pages = {},
pmid = {42393277},
issn = {2730-664X},
support = {T32-MH112485//U.S. Department of Health & Human Services | NIH | Office of Extramural Research, National Institutes of Health (OER)/ ; UL3AG067696//U.S. Department of Health & Human Services | NIH | National Institute on Aging (U.S. National Institute on Aging)/ ; P30AG062421//U.S. Department of Health & Human Services | NIH | National Institute on Aging (U.S. National Institute on Aging)/ ; UL1TR002541//U.S. Department of Health & Human Services | NIH | National Center for Advancing Translational Sciences (NCATS)/ ; UM1TR004408//U.S. Department of Health & Human Services | NIH | National Center for Advancing Translational Sciences (NCATS)/ ; AACSF-22-970716/ALZ/Alzheimer's Association/United States ; PTC REG-20-653582/ALZ/Alzheimer's Association/United States ; },
abstract = {BACKGROUND: Immune aging may contribute to Alzheimer's disease. Bacillus Calmette-Guérin (BCG), a vaccine known to induce trained immunity, has been linked to reduced Alzheimer's risk in prior studies. However, whether trained immunity can be observed in the human central nervous system remains unclear. We assessed whether BCG induces trained immunity-like responses in adults with and without Alzheimer's-related changes.

METHODS: We conducted two related one-year, open-label clinical trials in adults aged 55 years or older (n = 12 without Alzheimer's-related pathology; n = 11 with Alzheimer's-related pathology) recruited at a single center. Participants received two intradermal BCG vaccinations one month apart. Protocol-defined objectives included safety, neurocognitive outcomes, and longitudinal immune and Alzheimer's biomarker changes in blood and cerebrospinal fluid. Immune responses were assessed using cytokine assays and single-cell profiling. All enrolled participants were included where data were available; longitudinal changes were analyzed using mixed-effects models.

RESULTS: Here we show that BCG induces persistent, trained immunity-like changes in immune cells in cerebrospinal fluid, including enhanced innate responsiveness and associated transcriptional programs. These responses differ from blood, suggesting compartment-specific immune imprinting. In participants without Alzheimer's-related changes, these immune shifts are accompanied by decreased amyloid-β levels in cerebrospinal fluid and increased levels in blood. BCG was well tolerated, with no unexpected safety signals observed.

CONCLUSIONS: These findings suggest trained immunity-like responses in the central nervous system that may influence Alzheimer's-relevant pathways. This approach may represent an early neurodegenerative intervention strategy, although larger controlled studies are needed to confirm these observations.

TRIAL REGISTRATION: ClinicalTrials.gov NCT04507126 (June 23, 2020) and NCT05004688 (August 6, 2021).},
}

@article {pmid42393306,
year = {2026},
author = {Benussi, A and Bozzali, M},
title = {Mixing apples and antibodies: when the Cochrane average obscures the evidence in Alzheimer's disease.},
journal = {Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology},
volume = {47},
number = {7},
pages = {},
pmid = {42393306},
issn = {1590-3478},
}

@article {pmid42393367,
year = {2026},
author = {Vostrý, M and Binter, J and Kovářová, K and Posel, Z and Kubová, N and Cmorej, PC and Kroufek, R},
title = {Feasibility and preliminary effects of outdoor versus indoor cognitive-motor therapy in women with Alzheimer's disease: A randomized single-blind pilot study.},
journal = {Scientific reports},
volume = {},
number = {},
pages = {},
doi = {10.1038/s41598-026-60446-5},
pmid = {42393367},
issn = {2045-2322},
support = {CZ.02.01.01/00/23_021/0010653//Programme Johannes Amos Comenius/ ; },
abstract = {Alzheimer's disease is associated with progressive cognitive, functional and social decline. Non-pharmacological interventions that combine cognitive and motor stimulation are increasingly used in long-term care, but less is known about the feasibility and preliminary effects of delivering such programmes in outdoor rather than indoor settings. This exploratory randomized single-blind pilot study compared outdoor and indoor cognitive-motor therapy in institutionalized older women with Alzheimer's disease, focusing on global cognitive performance, selected functional outcomes, attendance and practical implementation. Fifty women aged 66.1-70.2 years with late-onset Alzheimer's disease were randomized to a seven-month outdoor cognitive-motor programme (n = 25) or an indoor cognitive-motor programme (n = 25). Sessions were delivered five times weekly for 45 min. Outcome assessors and data analysts were blinded to group allocation; therapists and participants could not be blinded because of the intervention setting. Global cognition was assessed with the Mini-Mental State Examination (MMSE). Functional outcomes were assessed using modified FIM-based indicators for daily tasks, mobility and social adaptability. Attendance and adverse events were recorded as feasibility outcomes. All randomized participants completed the study. Mean attendance was 91% in the outdoor group and 89% in the indoor group, and no intervention-related adverse events were recorded. Both groups improved on the MMSE, with a median increase of approximately two points. The outdoor group showed statistically significant within-group improvements in all three FIM-based indicators (daily tasks, mobility and social adaptability), whereas the indoor group did not show statistically significant functional change. However, these broader gains were observed in the context of baseline functional imbalance, including lower outdoor-group mobility and social-adaptability scores, and the small female-only sample and partial non-equivalence of intervention content limit between-group causal interpretation. A seven-month cognitive-motor programme was feasible in participating long-term care facilities. The findings suggest that outdoor delivery may be associated with broader functional gains than indoor delivery, but the results should be interpreted as preliminary and in light of the baseline functional imbalance. A fully powered, prospectively registered trial with more equivalent intervention arms, repeated measurement points, standardized functional outcomes and detailed monitoring of comorbidities and medication changes is warranted.},
}

@article {pmid42393497,
year = {2026},
author = {Ramesh, A and Reddy, R and Patel, AB},
title = {Quantitative Assessment of Neurometabolism by Deuterium and Proton NMR Spectroscopy Using [6,6'-[2]H2]Glucose.},
journal = {ACS chemical neuroscience},
volume = {},
number = {},
pages = {},
doi = {10.1021/acschemneuro.6c00030},
pmid = {42393497},
issn = {1948-7193},
abstract = {Neurometabolic analysis is routinely performed using [13]C NMR/MRS in conjunction with the administration of [13]C-labeled tracers. Despite its widespread use, the low sensitivity of [13]C NMR necessitates long acquisition times. To address this limitation, the present study introduces an indirect approach that uses a single [1]H NMR acquisition to measure deuterium labeling by exploiting labeling at specific sites, thereby providing a novel and more efficient strategy for assessing neurometabolism. In this study, male SD rats were infused with [6,6'-[2]H2]glucose for 10-90 min, and the [2]H labeling of cortical metabolites was measured ex vivo using [2]H NMR spectroscopy. After 90 min of [6,6'-[2]H2]glucose infusion, resonances corresponding to [3-[2]H2]lactate, [4-[2]Hx]glutamate, [4-[2]Hx]glutamine, and [3-[2]H]aspartate (∼2.60 ppm) were detected. In contrast, signals corresponding to [2-[2]H]aspartate (∼3.90 ppm), [2-[2]H]glutamate (∼3.76 ppm), and [3-[2]H]glutamate (∼2.09 ppm) were not detected, even after prolonged infusion, suggesting complete loss of the [2]H label during the second turn of the tricarboxylic acid cycle. The cerebral metabolic rate of glucose oxidation, estimated by fitting an exponentially saturating curve to the pooled labeling of [4-[2]Hx]glutamate, [4-[2]Hx]glutamine, and [3-[2]H]aspartate, was 0.389 ± 0.031 μmol/g/min. The [4-[2]Hx]glutamate levels were also derived by subtracting the [4-[1]H2]glutamate resonance intensity from total [4-[1]H2]glutamate intensity estimated using the [3-[1]H2]glutamate intensity in unedited [1]H NMR spectra. The concentrations of [4-[2]Hx]glutamate determined from [1]H NMR spectra were comparable to those determined from [2]H NMR. Moreover, when applied to 5xFAD mice (2.53 ± 0.43 μmol/g, n = 7), a model of Alzheimer's disease, this indirect approach revealed significantly reduced (p = 0.028) [4-[2]Hx]glutamate levels compared with controls (2.99 ± 0.15 μmol/g, n = 7). This decrease was comparable to that observed with the direct [2]H NMR measurements and was consistent with findings from [13]C tracer-based studies.},
}

@article {pmid42393517,
year = {2026},
author = {Wen, Y and Dong, H},
title = {Generalizable Protein Folding Pathway Exploration with DA2-GRASP: Extending Beyond Miniproteins.},
journal = {Journal of chemical theory and computation},
volume = {},
number = {},
pages = {},
doi = {10.1021/acs.jctc.6c00480},
pmid = {42393517},
issn = {1549-9626},
abstract = {Elucidating protein dynamics is crucial for deciphering fundamental biological processes, from enzyme catalysis to cellular signaling, as its dysregulation directly causes protein misfolding diseases such as Alzheimer's and Parkinson's. While artificial intelligence has revolutionized static protein structure prediction, capturing the high-dimensional dynamics of protein folding remains a formidable challenge that limits our ability to fully understand these vital biological phenomena. Here we present DA2-GRASP, a computational framework that overcomes this barrier by integrating deep learning with advanced sampling techniques to map protein folding pathways with unprecedented efficiency and accuracy. DA2-GRASP learns low-dimensional latent representations of protein conformations via a variational autoencoder and combines multidirectional generative sampling guided by local potential energy gradients to efficiently steer conformational transitions along energetically favorable paths, enabling accurate and efficient reconstruction of folding pathways. Our method achieves sublinear computational scaling with sequence length, contrasting the quadratical scaling of molecular dynamics-based conventional approaches, enabling tractable simulations. It maintains high precision in quantifying mutation-induced perturbations to folding thermodynamics, crucial for understanding disease mutations. It also enables atomistic characterization of the folding process of medium-sized proteins such as ubiquitin and small ubiquitin-like modifier (SUMO, ∼80 residues) on standard workstations, a task typically requiring specialized supercomputing platforms such as Anton. Analysis of these proteins provides new mechanistic insights into how structurally similar folds with low sequence identity navigate divergent folding pathways. DA2-GRASP thus establishes a versatile and powerful framework for exploring protein-folding dynamics and their functional consequences.},
}

@article {pmid42393750,
year = {2026},
author = {Zhang, J and Yang, N and Zou, P and Zong, X},
title = {Microglial checkpoint collapse in Alzheimer's disease: a tri-axial framework for biomarker-informed neuroimmune therapy.},
journal = {Journal of neuroinflammation},
volume = {},
number = {},
pages = {},
doi = {10.1186/s12974-026-03924-x},
pmid = {42393750},
issn = {1742-2094},
support = {24CDA1269588//American Heart Association/ ; },
abstract = {BACKGROUND: Anti-amyloid antibodies have validated amyloid-β (Aβ) as a disease-relevant target in Alzheimer's disease (AD), but their modest clinical effect, efficacy largely restricted to early disease, and amyloid-related imaging abnormalities (ARIA) indicate that Aβ removal alone does not resolve the glial, lipid, and inflammatory programmes that sustain neurodegeneration. Microglia sit at the centre of this therapeutic gap. Single-nucleus and spatial profiling has resolved several AD-associated microglial states, yet state labels remain descriptive and do not explain why adaptive engagement becomes maladaptive.

MAIN BODY: We frame AD-relevant microglial dysfunction as checkpoint collapse: progressive failure of regulatory nodes that coordinate lipid sensing, lysosomal competence, neuronal restraint, and inflammatory threshold control. The central nodes are TREM2-mediated lipid and apolipoprotein sensing, progranulin-associated lysosomal regulation, CX3CR1-dependent neuron-microglia restraint, and CD33/Siglec-3 inhibitory tone. When these controls destabilise, downstream pathology can be organised around three coupled effector axes: a lipid axis centred on APOE-biased cholesterol trafficking, ACSL1/DGAT2-driven lipid-droplet accumulation, and impaired lysosomal flux; an iron/ferroptosis axis involving labile iron, phospholipid peroxidation, and insufficient GPX4/FSP1 defences; and an inflammation/complement axis linking NLRP3 activation, type-I interferon signalling, and C1q/C3-dependent synaptic engulfment to tau pathology and synapse loss. White-matter injury, astrocyte-microglia crosstalk, and cGAS-STING-linked senescence are integrated as cross-axis amplifiers.

CONCLUSIONS: This framework is proposed as a hypothesis-generating scaffold for biomarker-informed translational studies, rather than as a validated clinical stratification system. It may help organise stage-aware therapeutic hypotheses, including regulatory-node preservation in early disease, lipid-handling restoration and ferroptosis control at intermediate stages, and complement- or senescence-directed modulation in later disease. Current glial, iron, inflammatory, and imaging biomarkers remain insufficiently specific to assign individual patients reliably to discrete pathological axes in clinical practice.},
}

@article {pmid42393875,
year = {2026},
author = {Behera, A and Chandrasekaran, Y and Dhonthi Shekar, N and Saravanan, S and Manickam Dakshinamoorthi, B and Srinivasan, GP and Dharmalingam Jothinathan, MK},
title = {Genetic Approaches in Zebrafish Neurology: Genetic, Drug and Therapy Insights.},
journal = {Current drug research reviews},
volume = {},
number = {},
pages = {},
doi = {10.2174/0125899775470368260619041554},
pmid = {42393875},
issn = {2589-9783},
abstract = {Zebrafish (Danio rerio) has emerged as a valuable vertebrate model organism widely used in biological and biomedical research due to its rapid embryonic development, optical transparency, high fecundity, and genetic similarity to humans. These characteristics have made zebrafish an important experimental model in developmental biology, toxicology, cancer research, and particularly in the investigation of neurodegenerative diseases. A significant proportion of human genes have functional counterparts in zebrafish, allowing researchers to explore disease mechanisms and genetic pathways relevant to human neurological disorders. Advances in genetic technologies, including CRISPR-Cas9 genome editing, transgenic approaches, and mutagenesis screening, have further strengthened the use of zebrafish in neuroscience research. These tools enable precise manipulation of genes involved in neuronal development, degeneration, and disease progression. Zebrafish models have been successfully employed to study major neurodegenerative disorders such as Alzheimer's disease, Parkinson's disease, and Huntington's disease. In addition, the model provides an efficient platform for drug screening, neurotoxicity studies, and therapeutic evaluation. This review highlights the role of zebrafish in genetic approaches to neurological research, emphasizing its contributions to disease modeling, drug discovery, and the development of potential therapeutic strategies for complex neurodegenerative disorders.},
}

@article {pmid42393905,
year = {2026},
author = {Zelek, MC and Walker Ii, JQ and Crocker-Sabbagh, I},
title = {Real-World Cognitive Stabilization via CDSS-Guided Multidomain Interventions in MCI and Older Adults with Cognitive Concerns.},
journal = {Current aging science},
volume = {},
number = {},
pages = {},
doi = {10.2174/0118746098476197260627055743},
pmid = {42393905},
issn = {1874-6128},
abstract = {INTRODUCTION: Randomized multidomain trials have established that cognitive decline requires coordinated action across modifiable contributors, but routine care lacks delivery infrastructure. We evaluated real-world cognitive trajectories in older adults receiving uMETHOD Health clinical decision support system (CDSS)-guided care plans and assessed whether this multidomain approach could be operationalized in routine care.

METHODS: This retrospective, nonrandomized implementation-and-outcomes study analyzed the complete eligible paired cohort: individuals with CDSS-guided care plans and two valid sameinstrument cognitive assessments ≥6 months apart. No additional selection was made by outcome, adherence, or trajectory. The CDSS integrates EHR-derived diagnoses, medications, biomarkers, vital signs, genomics, and lifestyle factors through expert clinical rules with constrained AI support to generate individualized clinician-, patient-, and caregiver-facing plans.

RESULTS: Favorable cognitive trajectories were observed in 294 of 345 matched assessment pairs (85.2%) over a mean follow-up of 14.1 months. Assessments used seven validated instruments; mean age was 74.6 years, and baseline medication use was 11.7 medications/patient. Favorable trajectories included 83.5% stable, improved, or minor decline without diagnostic progression and 1.7% slower-than-expected decline on benchmarked instruments (MoCA, MMSE, or SAGE).

DISCUSSION: The CDSS served as an implementation layer, translating multidomain evidence into prioritized, patient-specific next-best actions within ordinary clinical workflows. This positions multidomain cognitive management as a scalable, routine-care activity rather than a researchonly protocol.

CONCLUSION: Multidomain cognitive management was made executable in routine practice, with favorable trajectories observed in 85.2% of paired assessments. The practical implication is immediate: evidence-based cognitive management can be operationalized now at the point of care.},
}

@article {pmid42394082,
year = {2026},
author = {Khan, A and Kabir, H},
title = {Evaluating the User Experience and Therapeutic Efficacy of Humanoid Socially Assistive Robots in Alzheimer's Disease and Related Dementias (ADRD) Care.},
journal = {Studies in health technology and informatics},
volume = {338},
number = {},
pages = {626-630},
doi = {10.3233/SHTI260920},
pmid = {42394082},
issn = {1879-8365},
mesh = {Humans ; *Alzheimer Disease/therapy/psychology ; Female ; *Robotics ; Male ; *Self-Help Devices ; Aged ; *Dementia/therapy/psychology ; Aged, 80 and over ; Intelligent Systems ; Treatment Outcome ; },
abstract = {BACKGROUND: Addressing neuropsychiatric symptoms in Alzheimer's Disease and Related Dementias (ADRD) requires scalable, non-pharmacological interventions. This study evaluated the user experience and clinical efficacy of a humanoid Socially Assistive Robot (SAR) in an ADRD care setting.

METHODS: A randomized, 8-week, baseline-controlled intervention was conducted (N=19), utilizing each participant's pre-intervention status as the control. Outcomes included acute mood change, sustained depressive symptoms via the Geriatric Depression Scale (GDS), and user acceptance via the User Experience Questionnaire (UEQ).

RESULTS: The SAR achieved "Excellent" UEQ ratings (x > 2.0) across all dimensions, indicating high accessibility and engagement. Analysis revealed a significant acute positive mood boost (p < 0.001) and a sustained reduction in GDS scores over 8 weeks compared to baseline. A strong correlation existed between robotic stimulation and clinical GDS improvement (p < 0.01).

CONCLUSION: Humanoid SARs are highly accepted and efficacious adjunctive tools for improving emotional health in ADRD populations, supporting their integration into formal dementia care protocols.},
}

Humans
*Alzheimer Disease/therapy/psychology
Female
*Robotics
Male
*Self-Help Devices
Aged
*Dementia/therapy/psychology
Aged, 80 and over
Intelligent Systems
Treatment Outcome

@article {pmid42394100,
year = {2026},
author = {Yoon, S and Patterson, M and Sun, F and Broadwell, P and Crupi, R and Kim, M and Davis, N},
title = {Leveraging the J48 Algorithm to Inform Community-Based AI Solutions for African American Dementia Caregiving.},
journal = {Studies in health technology and informatics},
volume = {338},
number = {},
pages = {713-717},
doi = {10.3233/SHTI260938},
pmid = {42394100},
issn = {1879-8365},
mesh = {Humans ; *Black or African American ; *Caregivers/psychology ; *Artificial Intelligence ; *Dementia/ethnology/nursing ; *Algorithms ; Adult ; Female ; Male ; Middle Aged ; United States ; Adolescent ; Young Adult ; Alzheimer Disease ; },
abstract = {We applied the J48 machine learning algorithm to build models that identify demographic and caregiving factors associated with perceived risks and benefits of community-based AI solutions for African American family caregiving. 572 diverse family members of a person with Alzheimer's disease and related dementias (ADRD) participated in this online survey in the U.S. The J48 algorithm (C4.5) identified race as the primary predictor for AI support, with African Americans favoring AI-enabled hospital-based diagnostic testing and faith-based apps regardless of their demographic or caregiving factors. Conversely, risk perceptions were heightened among highly educated White family members (aged 25-34) for clinical AI and among younger family members (ages 18-34) for community-based meal-related apps. Overall, model's F-measures (0.83) and PRC areas (0.74) confirm that community-based AI preference is driven more by cultural context and specific use cases than by general caregiving circumstances. While African Americans are willing to support the development of AI applications, enthusiasm does not extend uniformly across all community settings. While scientists should prioritize AI in clinical and faith-based settings, they must exercise caution in the nutritional domain where algorithms may perpetuate bias.},
}

Humans
*Black or African American
*Caregivers/psychology
*Artificial Intelligence
*Dementia/ethnology/nursing
*Algorithms
Adult
Female
Male
Middle Aged
United States
Adolescent
Young Adult
Alzheimer Disease

@article {pmid42394275,
year = {2026},
author = {Hernandez-Kapila, YL and Weisenberger, DJ},
title = {Of mice and men-The emerging oral-gut-brain axis of health and disease.},
journal = {Periodontology 2000},
volume = {},
number = {},
pages = {},
doi = {10.1111/prd.70064},
pmid = {42394275},
issn = {1600-0757},
support = {U54AG089335/NH/NIH HHS/United States ; },
abstract = {OBJECTIVES: Oral health's inextricable links to systemic health are highlighted by the emerging oral-gut-brain axis and other well-known axes. There is growing evidence of a complex oral-gut-brain axis linking mouth and gut microbiomes with the central nervous system. Axis disruptions, characterized as oral and gut dysbiosis or microbial imbalances, can trigger oral and systemic inflammation and neuroinflammation, contributing to diseases such as Alzheimer's disease and Parkinson's disease.

MATERIALS AND METHODS: We summarize the oral-gut-brain axis mechanistic pathways, key evidence from human clinical and animal studies, and how the oral microbiome modulates human health and disease.

RESULTS: Periodontal disease (PD) is associated with increased oral pathogen presence in diseased tissues throughout the human body. Preclinical models recapitulate these findings. Experimental periodontal infection induces dysbiosis that is linked to activation of inflammatory pathways that promote diseased phenotypes. Novel therapeutic approaches, including the probiotic fbacteriocin nisin, are increasingly recognized for targeted microbiome therapy at multiple inflection points across the axis. Nisin restores microbial balance, reduces inflammation, inhibits end-organ pathology, prevents periodontal bone loss, and reduces brain amyloid/tau accumulation and cytokine expression.

CONCLUSIONS: These findings highlight the complexity of the oral-gut-brain axis and the ability to modulate the axis using bacteriocin-based approaches.

CLINICAL RELEVANCE: Future probiotic or antimicrobial strategies aimed at ameliorating neuroinflammatory and metabolic diseases via microbiome-targeted therapy hold clinical promise.},
}

@article {pmid42394367,
year = {2026},
author = {Kreiselmaier, S and Keller, M and Nardi, L and Mueller, C and von Wiegen, N and Bickenbach, K and Gröbner, L and Abukhalaf, M and Tholey, A and Mueller, MM and Körschgen, H and Schmeisser, MJ and Becker-Pauly, C and Pietrzik, CU},
title = {The Role of Meprins on the Brain Extracellular Matrix and Perineuronal Nets.},
journal = {FASEB journal : official publication of the Federation of American Societies for Experimental Biology},
volume = {40},
number = {13},
pages = {e72097},
doi = {10.1096/fj.202601333R},
pmid = {42394367},
issn = {1530-6860},
support = {CRC 1080 A15//Deutsche Forschungsgemeinschaft (DFG)/ ; CRC 1080 Z2//Deutsche Forschungsgemeinschaft (DFG)/ ; },
mesh = {Animals ; *Perineuronal Nets/metabolism ; *Extracellular Matrix/metabolism ; Mice ; Brevican/metabolism ; *Metalloendopeptidases/metabolism/genetics ; *Brain/metabolism ; Mice, Transgenic ; Synapses/metabolism ; Long-Term Potentiation/physiology ; Male ; Neurocan/metabolism ; Alzheimer Disease/metabolism ; Humans ; },
abstract = {Meprin α and meprin β are zinc metalloproteases that are strongly expressed in intestinal and renal tissues and are expressed as homo- and heterodimers. In the kidney and intestine, they are involved in extracellular matrix assembly and modulation of inflammatory responses. However, meprin β has recently attracted attention because it generates Alzheimer's Disease (AD)-specific Aβ peptides and cleaves brevican, a major component of the perineuronal nets (PNNs) in the brain. PNNs stabilize synapses, thereby regulating plasticity and memory formation. Brevican cleavage correlated with impaired spatial memory formation and impaired CA1 long-term potentiation (LTP) in meprin β transgenic mice. Furthermore, numerous studies have shown the dysregulation of PNN components in AD. Still, the physiological and pathological functions of proteolytic PNN remodeling remain elusive. This study identified an essential role of meprin α in brevican cleavage. It enhanced meprin β's catalytic activity on brevican in co-expression. Moreover, an N-terminomics analysis identified novel meprin β substrates, neurocan, and receptor-type tyrosine-protein phosphatase zeta (RPTPζ) in the brain. Both are key components of PNNs. RPTPζ cleavage by meprin α and meprin β was confirmed in vitro. To assess the functional impact of meprin-mediated proteolysis on the brain extracellular matrix, PNNs and synaptic organization were investigated in vivo using immunofluorescence and electron microscopy. Meprin-mediated proteolysis disrupted PNN structure and decreased synapse density in the hippocampal CA1 region of meprin β transgenic mice. This identifies meprin-dependent PNN remodeling as a novel mechanism contributing to synaptic dysfunction.},
}

Animals
*Perineuronal Nets/metabolism
*Extracellular Matrix/metabolism
Mice
Brevican/metabolism
*Metalloendopeptidases/metabolism/genetics
*Brain/metabolism
Mice, Transgenic
Synapses/metabolism
Long-Term Potentiation/physiology
Male
Neurocan/metabolism
Alzheimer Disease/metabolism
Humans

@article {pmid42394391,
year = {2026},
author = {Rabichow, BE and Nixon, L and Tallant, LE and Gibson, KA and Nascari, DG and Barnett, JH and Massa, N and Fryer, JD},
title = {Amyloid exacerbates tau and alpha-synuclein pathologies, behavioral impairments, and neuroinflammation in a mixed dementia model.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {22},
number = {7},
pages = {e71639},
doi = {10.1002/alz.71639},
pmid = {42394391},
issn = {1552-5279},
support = {NS110435//NINDS Lewy Body Dementia Center Without Walls/ ; //Translational Genomics Research Institute (TGen) Foundation/ ; NS084974/GF/NIH HHS/United States ; AG062556/GF/NIH HHS/United States ; AG062110/GF/NIH HHS/United States ; NS094137/GF/NIH HHS/United States ; AG057997/GF/NIH HHS/United States ; AG062077/GF/NIH HHS/United States ; AG047327/GF/NIH HHS/United States ; AG049992/GF/NIH HHS/United States ; NS110435/GF/NIH HHS/United States ; },
mesh = {Animals ; *alpha-Synuclein/metabolism/genetics ; *tau Proteins/metabolism/genetics ; Disease Models, Animal ; Mice ; *Neuroinflammatory Diseases/pathology/metabolism ; *Mixed Dementias/pathology ; *Amyloid beta-Peptides/metabolism ; Brain/pathology/metabolism ; Mice, Transgenic ; Plaque, Amyloid/pathology ; Phosphorylation ; },
abstract = {INTRODUCTION: Neurodegenerative diseases often involve overlapping alpha-synuclein (asyn), amyloid beta, and tau proteinopathies, yet the mechanisms, impact, and directionality of their interactions remain unclear.

METHODS: We induced brain-wide neuronal asyn/tau pathologies via viral expression of wild-type asyn, mutant asyn[E46K], mutant tau[A152T], or both asyn[E46K]/tau[A152T] in adult amyloidosis knock-in mice and controls, either post-plaque deposition (6 months old) or pre-plaque (3 months old). Open-field behavior was assessed baseline and 3 and 6 months post-transduction, followed by neuropathology and neuroinflammation analyses.

RESULTS: Post-plaque induction in amyloid mice increased asyn/tau total and phosphorylated levels and exacerbated amyloid-related hyperlocomotion/anxiety. Pre-plaque induction produced robust phosphorylated pathologies irrespective of amyloid, while causing similar amyloid-dependent behavioral synergy. Tau pathology drove LGALS3[+] inflammatory glial responses in white-matter fibers.

DISCUSSION: Amyloid context gates vulnerability, with certain synergies manifesting across stages. White-matter gliosis is a novel mechanism of tau[A152T] risk. Together, our data argue for the development of stage-aware, multitarget interventions and biomarkers.},
}

Animals
*alpha-Synuclein/metabolism/genetics
*tau Proteins/metabolism/genetics
Disease Models, Animal
Mice
*Neuroinflammatory Diseases/pathology/metabolism
*Mixed Dementias/pathology
*Amyloid beta-Peptides/metabolism
Brain/pathology/metabolism
Mice, Transgenic
Plaque, Amyloid/pathology
Phosphorylation

@article {pmid42394394,
year = {2026},
author = {Prados, M and Acosta, C and Mattke, S},
title = {Estimated labor market outcomes of people progressing from preclinical to early-stage Alzheimer's disease in the United States.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {22},
number = {7},
pages = {e71628},
doi = {10.1002/alz.71628},
pmid = {42394394},
issn = {1552-5279},
support = {//Research contract from Biogen to USC/ ; },
mesh = {Humans ; *Alzheimer Disease/economics/epidemiology ; United States/epidemiology ; Female ; Male ; *Employment/statistics & numerical data ; Aged ; Middle Aged ; Disease Progression ; *Cognitive Dysfunction/epidemiology/economics ; *Income/statistics & numerical data ; },
abstract = {INTRODUCTION: Secondary prevention treatments for Alzheimer's disease (AD) that are currently in late-stage clinical trials may preserve productivity and workforce participation.

METHODS: Using the nationally representative Health and Retirement Study waves from 1996 to 2020, we estimated changes in labor force participation, annual earnings, and social assistance payments between incident cases of cognitively impaired and statistically matched cognitively normal individuals.

RESULTS: Among 20,717 respondents (aged 50 to 79), 5232 developed mild cognitive impairment or mild dementia. Disease onset was associated with a five-percentage-point (p.p.) reduction in workforce participation, annual earnings losses of US$8233 (23%) and US$5616 (18%) for men and women who remained in the labor force, respectively, and an increase of 3.5. p.p. male and 5.6 p.p. female social assistance beneficiaries.

DISCUSSION: Onset of cognitive impairment was associated with statistically significant and meaningful reduction in workforce participation and earnings and increased participation in social assistance programs.},
}

Humans
*Alzheimer Disease/economics/epidemiology
United States/epidemiology
Female
Male
*Employment/statistics & numerical data
Aged
Middle Aged
Disease Progression
*Cognitive Dysfunction/epidemiology/economics
*Income/statistics & numerical data

@article {pmid42394416,
year = {2026},
author = {Ceron, C and Casquero-Veiga, M and Lamanna-Rama, N and Fernández-Nueda, I and Fernández-Pena, A and Olazagoitia, N and Sobrino, G and Herraiz, A and González, MI and Muñoz-Hernando, M and Ruperti-Repilado, A and Romero-Sanz, E and Morcillo, MÁ and Pérez-Medina, C and Moro, MA and Villaverde, G and Rubio, J and Fernandez-Ferro, J and Desco, M and Herranz, F and Salinas, B and Fuster, V and Cortes-Canteli, M},
title = {Unveiling the procoagulant state in Alzheimer's disease: A novel PET imaging strategy.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {22},
number = {7},
pages = {e71652},
doi = {10.1002/alz.71652},
pmid = {42394416},
issn = {1552-5279},
support = {CPII21/00007//Instituto de Salud Carlos III/ ; AC20/00091//Instituto de Salud Carlos III/ ; AC20/00077//Instituto de Salud Carlos III/ ; A2023012F//BrightFocus Foundation/ ; JDC2022-048922-I//Ministerio de Ciencia e Innovación (MCIN/AEI/10.13039/501100011033)/ ; RED2022-134299-T//Ministerio de Ciencia e Innovación (MCIN/AEI/10.13039/501100011033)/ ; JDC2022-048922-I//European Union NextGenerationEU/PRTR/ ; ICT2021-006950//European Union NextGenerationEU/PRTR/ ; PID2024-157521OB-I00//European Union NextGenerationEU/PRTR/ ; CNS2023-144316//European Union NextGenerationEU/PRTR/ ; PID2022-140616OB-I00//European Union NextGenerationEU/PRTR/ ; PDC2022-133493-100//European Union NextGenerationEU/PRTR/ ; ref.202180E048//Nanomedicine CSIC Hub/ ; S2022/BMD-7403//Comunidad de Madrid/ ; //PTI-NEUROAGING CSIC/ ; JPND2020-568-025//EU Joint Programme - Neurodegenerative Disease Research/ ; RYC2023-043741-I//Ministerio de Ciencia, Innovación y Universidades (ES, MICIU/AEI/10.13039/501100011033)/ ; ICT2021-006950//Ministerio de Ciencia, Innovación y Universidades (ES, MICIU/AEI/10.13039/501100011033)/ ; PID2024-157521OB-I00//Ministerio de Ciencia, Innovación y Universidades (ES, MICIU/AEI/10.13039/501100011033)/ ; CNS2023-144316//Ministerio de Ciencia, Innovación y Universidades (ES, MICIU/AEI/10.13039/501100011033)/ ; PID2022-140616OB-I00//Ministerio de Ciencia, Innovación y Universidades (ES, MICIU/AEI/10.13039/501100011033)/ ; PDC2022-133493-100//Ministerio de Ciencia, Innovación y Universidades (ES, MICIU/AEI/10.13039/501100011033)/ ; CEX2020-001041-S//Ministerio de Ciencia, Innovación y Universidades (ES, MICIU/AEI/10.13039/501100011033)/ ; },
mesh = {Animals ; *Alzheimer Disease/diagnostic imaging ; *Positron-Emission Tomography/methods ; Humans ; Mice ; Mice, Transgenic ; *Brain/diagnostic imaging/pathology/metabolism ; Fibrin/metabolism ; Female ; Male ; Aged, 80 and over ; Gallium Radioisotopes ; Zirconium ; Disease Models, Animal ; Blood Platelets ; },
abstract = {INTRODUCTION: A subset of Alzheimer's disease (AD) patients exhibits a procoagulant state that remains undiagnosed despite available treatments. We developed positron emission tomography (PET) strategies to in vivo detect cerebral microthrombi in TgCRND8 mice.

METHODS: PET was performed with a fibrin-binding probe (FBP) in TgCRND8 and wild-type mice using a zirconium-89-radiolabeled and a click-chemistry pre-targeted gallium-68 radiotracer. Platelet content was assessed in post mortem brain tissue from AD patients and TgCRND8 mice, and evaluated by PET using a CD41 pre-targeted gallium-68 nanoradiotracer.

RESULTS: Cerebral FBP uptake differentiated TgCRND8 from wild-type mice, particularly ex vivo and with advancing age. Cerebral fibrin burden correlated with platelet content in AD patients, and elevated cerebral platelet burden in TgCRND8 mice was confirmed in post mortem tissue and in vivo by PET.

DISCUSSION: Our findings support PET-based detection of AD-associated cerebral microthrombi and the development of imaging biomarkers to stratify AD patients by procoagulant status and inform personalized therapies.},
}

Animals
*Alzheimer Disease/diagnostic imaging
*Positron-Emission Tomography/methods
Humans
Mice
Mice, Transgenic
*Brain/diagnostic imaging/pathology/metabolism
Fibrin/metabolism
Female
Male
Aged, 80 and over
Gallium Radioisotopes
Zirconium
Disease Models, Animal
Blood Platelets

@article {pmid42394922,
year = {2026},
author = {Zhang, D and Zhang, J and Liu, B and Liu, M and Chen, W and Du, G},
title = {HDFT-MViT: a progressive core-enhanced mix framework for Alzheimer's disease classification using MRI images.},
journal = {Frontiers in neurology},
volume = {17},
number = {},
pages = {1860368},
pmid = {42394922},
issn = {1664-2295},
abstract = {BACKGROUND: Early and accurate diagnosis of Alzheimer's disease (AD) is critical. In MRI-based computer-aided diagnosis, convolutional neural networks (CNNs) excel at extracting local features but struggle to model long-range dependencies, while Vision Transformers (ViTs) offer strong global modeling capabilities but suffer from high computational complexity, limiting their deployment in resource-constrained settings.

NEW METHODS: This paper proposes HDFT-MViT, a lightweight hybrid architecture based on MobileViT that integrates a hierarchical dynamic filter with a lightweight Transformer. The model adopts a progressive Core-Enhanced Mix design: Shallow layers employ MobileNetV2 inverted residual blocks for efficient local feature extraction; intermediate and deep layers incorporate a dual-branch module that integrates a dynamic filter for frequency-domain global modulation and a lightweight Transformer for spatial long-range dependency modeling, followed by hierarchical fusion via learnable weights. A channel attention mechanism is further introduced to enhance feature discriminability.

RESULTS: Evaluations on the public ADNI-1 (3-class) and ADNI-2 (4-class) MRI datasets show that HDFT-MViT achieves state-of-the-art classification accuracies of 98.85 ± 0.27% and 98.07 ± 0.54%, respectively, while maintaining a lightweight profile with only 3.46 M parameters, confirming its effectiveness and efficiency.

CONCLUSION: HDFT-MViT achieves an optimal balance between local detail perception and global semantic understanding within a computationally efficient framework, offering a promising tool for clinical AD diagnosis. Code will be released upon acceptance.},
}